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1. Drug Product Development
Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance). May be produced by
chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc.
New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties. According to the FDA,
NCE is an unapproved API.
Drug product: finished dosage form containing API and excipients.
Generic drug products: after patent expiration of brand drug. Therapeutically equivalent to the brand and has the same drug amount
in the same dosage form. Must be bioequivalent (same rate and extent of absorption) same clinical results. May differ from brand in
excipients (tablets only unless safety studies are done) or physical appearance.
Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs. Preclinical safety and efficacy
studies are not required. Human bioequivalence is needed (on healthy human volunteers). Chemistry, manufacturing and controls for
generics are similar to the brand.
Specialty drug products: existing products developed for new delivery system or new therapeutic indication. Safety and efficacy
studies are not required. Example nitroglycerin transdermal patch after sublignual tablets.
New drug approval
Preclinical (animal safety / pharma) IND Phase I (healthy human safety) Phase II (↓# patients) Phase III (↑# patients)
NDA FDA green light for marketing Phase IV (scale up) Phase V (continuous improvements).
Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy. Formulation is not final.
Phase I: Submit an Investigational New Drug (IND) clinical studies on healthy volunteers to determine toxicity and tolerance. For
oral drugs simple hard gelatin capsule.
Phase II: small number of patients under close supervision. Dose-response studies to determine optimum dosage for treatment.
Determine the therapeutic index (toxic dose/effective dose). Develop final drug formulation (bioequivalent to that used in i nitial clinical
studies). Start chronic toxicity studies for 2 years in 2 species.
Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients.
Watch for new, rare, toxic or side effects.
NDA submission: FDA satisfaction with safety and efficacy for marketing.
Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed.
Phase V: continuous drug product improvements after marketing.
New chemical entities
Physical and chemical characterization of the drug and dosage form during preclinical phase. Includes general properties (particle size
/ shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility (dissolution, pH-solubility profile, various
solvents), chemical properties (surface energy, pH stability profile, pKa, temperature stability, excipient interactions), stability analytical
Formulation development: continuing process.
Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no bioavailability for
Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation and systemic
absorption are the issues.
Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III.
Oral drugs: final formulation in phase II.
Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production equipment / site.
Product line extensions:
Dosage forms with change in physical form or strength but not use or indication. Usually occurs during Phases III, IV, V.
Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials
Different strength in a tablet or capsule form only bioequivalence required (simplest case). Easier if in vitro dissolution / in vivo
bioavailability correlation exists.
Modified release: clinical trials required.
If new indication new NDA and new efficacy studies.
If an extension of a liquid same as above for solids
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If an extension of a solid if big difference in extent / rate of absorption new clinical trials.
Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA.
Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation, consults the
chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.
Scale-up and post-approval changes (SUPAC)
Guidelines to # of manufacutring changes that require preapproval by the FDA.
Examples: minor formulation changes, change site of manufacture, batch size or , change manufacturing process / equipment.
1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with guidance, label
description, deletion of colorant, expiration date extension, ∆ container / closure type (not size), analytical method
2. Changes being effected supplement: minor changes but require some validation, documentation. A supplement but no pre-
approval is required. Examples: new specs, label changes on clinical info, different cGMP manufacturing facility but same process.
3. Preapproval supplement: major changes require specific preapproval. Examples: adding or deleting an ingredient, relaxing specs,
deleting a spec or method, method of manufacture, in-process controls.
Therapeutic and Bio-equivalence: must be shown for any change. Minor change comparable dissolution profiles. Major change
in vivo bioequivalence study.
Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel, facilities, processes to
ensure final product has the correct identity, strength, quality, purity.
Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test the product and
verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging components, water, drug products,
Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written procedures are
2. Pharmaceutical Calculations and Statistics
Fundamentals of measurement and calculation
Inverse proportion: the inverse of the ‘scissors’ method is used in case of dilutions. Example: 100 ml of 10% solution is diluted to 200
ml, what is the final concentration? Inverse ‘scissors’ 200/10 = 100/x 5%.
Aliquot: used when the sensitivity of the measurement device is not great enough for the required measurement.
Example: balance sensitivity is 6 mg, accuracy is +/-5% minimum weighable quantity is: 5/100=6/x = 120 mg. If you need to weigh
10 mg drug add a diluent to get a final concentration of 120 mg drug in the diluted mixture (120x120 = 1440 mg) then weigh 120
mg of the diluted mixture.
Systems of measure: Apothecaries’ system of fluid measure, Apothecaries’ system for measuring weight, Avoirdupois system for
measuring weight (pound, ounce, grain=65 mg), metric system.
First choice: body weight or mass and mg/kg dosing.
Fried’s rule for infants: (age in month / 150) x adult dose
Clark’s rule: (weight in lb / 150) x adult dose
Child’s dosage based on body surface area: (BSA in m2 / 1.73) x adult dose
Percentage, ratio strength, concentrations
Percentage w/v, Percentage v/v, Percentage w/w, Ratio strength
Be careful 3 g drug in 27 g water is 10% solution (3/30) BUT 3 g drug in 30 g water is 9% (3/33).
Molarity: number of moles of solute dissolved in 1 liter of solution
Molality: number of moles of solute dissolved in 1 kg of solution. Advantage over molarity: using weight avoids problems with volume
expansion or contraction upon the addition of solutes.
Normality: is the number of equivalent weights of solute per liter of solution. Equivalent weight = atomic weight or molecular weight /
valence. Preferred way of expressing concentration of acids, bases and electrolytes. One equivalent is the quantity that supplies or
donates one mole of H+ or OH-. One equivalent of acid reacts with one equivalent of base.
Mole fraction: ratio of number of moles of one component to the total moles of a mixture or solution.
Dilution and concentration
Constant amount of drug volume is inversely proportional to concentration.
Quantity1 x concentration1 = quantity2 x concentration2.
Allegation medial: method for calculating average concentration of a mixture of two or more substances.
Allegation alternate: method for calculating number of parts (relative amounts) of two or more components of known concentration to
be mixed when final concentration is known. IMPORTANT. See example is page 16.
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Dilution of alcohols: alcohol + water volume contraction. Use w/w instead of v/v for accuracy.
Percentage strength: of concentrated acids is expressed in w/w. For diluted acid w/v. To determine the volume of concentrated
acid for dilution, use specific gravity.
Divalent: calcium, ferrous, magnesium, sulfate. Trivalent: aluminum, ferric, citrate. All others are monovalent.
Definition: amount in mg equivalent to a solute equal to 0.001 of its gram equivalent weight.
Unit used to express concentration of electrolytes
Osmotic pressure is directly proportional to the total number of particles in solution. Unit for measuring osmotic concentration: mOsmol.
For non-electrolytes: 1 millimole = 1 mOsmol (1 molecule = 1 particle)
For electrolytes: number of particles depends on degree of dissociation.
Example: completely dissociated KCl 1 millimole = 2 mOsmol (2 particles, K and Cl for each molecule).
Example: completely dissociated CaCl2 1 millimole = 3 mOsmol
↑ solute concentration ↑ interaction between dissolved particles ↓ actual osmolar concentration compared to ideal osmolar
Isosmotic: solution with the same osmotic pressure.
Isotonic: solution with the same osmotic pressure as body fluids.
Hypotonic: solution with ↓ osmotic pressure than body fluid (opposite is hypertonic)
Preparation of isotonic solutions
Colligative properties (e.g. freezing point depression) are representative of the number of particles in solution.
Dissolve 1 g MWt of non-electrolyte in 1 L of water depression of freezing point by -1.86 C.
For electrolytes: freezing point depression = -1.86 x number of species produces upon dissociation.
Freezing point depression of body fluids = -0.52 C.
Take dissociation of weak electrolytes into account.
In weak solutions, every 2 ions produce 1.8 ions, every 3 ions produce 2.6 ions (about 10% loss).
Definition: the amount of NaCl that is equivalent to the amount of particular drug in question.
Isotonic fluid: 0.9% NaCl.
Example: NaCl equivalent for KCl to 0.78 1 gram KCl = 0.78 g of NaCl.
Calculating amount of NaCl required to adjust isotonicity: calculate the total amount of NaCl required (volume x 0.9%) calculate the
NaCl equivalent of all substances in the solution calculate and add the difference as NaCl or another material (as NaCl equivalent).
Frequency distribution: classify individual observations into categories corresponding to fixed numeric intervals (interval frequencies)
plot number of observations in each category versus category descriptor.
Normal distribution: bell-shaped (Gaussian) curve.
Estimates of population mean: the population mean is the best estimate of the true value. Sample mean: arithmetic average.
Accuracy: degree to which measured value agrees with true value. Error (bias): difference between measured value and true value.
Median: midmost value of a data distribution (average of two midmost values if even number of observations). Normal distribution
median = mean. Median is less affected by outliers or skewed distribution. Mode: most frequently occurring value in a distribution, it is
useful for non-normal distributions especially bimodal distributions.
Estimates of variability: infinite # of observations population variance. Finite # of observations sample variance. Range: useful
to describe variability only in very small number of observations. Standard deviation: square root of variance. Precision
(reproducibility): degree to which replicate measurements made exactly the same way agree with each other (expressed as relative
Standard deviation of the mean (standard error): estimate of variability or error in the mean obtained from N observations. SE =
SD/(sq. root of N). Used to establish confidence intervals.
3. Pharmaceutical Principles and Drug Dosage Forms
I. Intermolecular forces of attraction
Atoms vary in electronegativity, so, electron sharing between atoms will be unequal. So, the molecule behaves like a dipole over a
Dipole moment (mu) = distance of charge separation X charge
Nonpolar molecules: perfect symmetry and dipole moment = zero. Example: carbon tetrachloride.
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When the negative pole of a dipole approach the positive pole of another molecular attraction called “dipole-dipole interaction”.
If similar poles approach molecular repulsion (intermolecular repulsive forces)
Types of intermolecular forces of attraction
Van der Waals forces (liquids)
Induced dipole induced dipole (London dispersion force): when a transient dipole in a nonpolar molecule induces another transient
dipole in another molecule. Force = 0.5-1 Kcal/mole
Dipole-induced dipole (Debye induction force): A transient dipole is induced by a permanent dipole. Force = 2 Kcal/mole
Permanent dipole (Keesom orientation force): 4 Kcal/mole
Hydrogen ions are small and have a large electrostatic field, so it approaches highly electronegative atoms (O, F, Cl, N, S) and interact
electrostatically to form a hydrogen bond. Force = 5 Kcal/mole.
Ion-ion, ion-dipole, ion-induced dipole
Force of positive-negative ion interaction in the solid state = 150 Kcal/mole. Covalent and ionic forces are much stronger than van der
States of matter
Molecules move in straight path at high speed until they randomly collide with another molecule, creating pressure. Intermol ecular
forces ~ zero.
Ideal gas law:
Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R) X Temperature (T)
Gases in pharmacy: anesthetics (nitrous oxide, halothane), compressed oxygen, liquefiable aerosol propellants (nitrogen, CO2,
hydrocarbons, halohydrocarbons), ethylene oxide for sterilization of heat labile objects.
Volatile liquids (ether, halothane, methoxyfurane) are used as anesthetics. Amyl nitrite (volatile liquid) is inhaled as a vasodilator in
Sublimation: a solid is heated directly to the gaseous or vapor state (or vice versa, also called deposition) without passing through the
liquid state. Examples: camphor, iodine.
Van der Waals intermolecular forces are sufficient to impose some ordering. Hydrogen bonding cohesion in liquids.
Surface and interfacial tension
Molecules at the surface of the liquid experience a net inward pull from the interior and they tend to contract. This makes liquids
assume a spherical shape as it is the volume with minimum surface and least free energy.
Surface free energy / surface tension: the work required to the surface area A of the liquid by 1 unit area. Example: SFE for water
= 72 mN/m.
Interfacial tension: at the surface of two immiscible liquids.
Viscosity = shear stress / shear rate
Non-Newtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosity.
Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of small deflocculated particles with high solid content.
Shear thinning (pseudoplastic): as in polymer solutions. Plastic (Bingham body): as in flocculated particles in concentrated
suspensions that have yield value.
Time dependent viscosity: yield value of plastic systems may be time dependent. Thixotropic systems are shear thinning but they
do not recover viscosity after shear is removed, i.e., structural recovery is slow compared to structural breakdown. It occurs in
heterogenous systems with three dimensional structural network (gel-sol transformation). Negative (anti)thixotropy: viscosity with
shear up to an equilibrium (sol-gel transformation).
High intermolecular forces.
Crystalline solids: fixed molecular order, distinct melting point, anisotropic (properties are nto the same in all directions).
Amorphous solids: randomly arranged molecules, nondistinct melting point, isotropic (properties are the same in all direction).
Polymorphs: substance has more than one crystalline form. Different molecular arrangments / crystalline lattice structure, melting
point, solubility, dissolution rate, density, stability. Polymorphs are common in steroids, theobroma oil, cocoa butter.
Latent heat of fusion: heat absorbed when 1 g of solid melts.
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III. Physicochemical behavior
Solution: homogenous system in which a solute is molecularly dispersed or dissolved in a solvent.
Nonelectrolytes: substances that do not form ions in solution, e.g., estradiol, glycerin, urea, sucrose. Solution doesn’t conduct
Electrolytes: form ions in solutions. Solution conducts electricity. Can be strong (completely ionized in water; HCl, NaCl) or weak
(partially ionized; aspirin, atropine).
Depend on the total number of ionic and nonionic solute molecules in solution. They are dependent on ionization but independent of
other chemical properties of the solute.
Vapor pressure depression: (Raoult’s law): partial vapor pressure is equal to the product of the mole fraction of the component in
solution and the vapor pressure of the pure component.
Boiling point elevation and freezing / melting point depression
Osmotic pressure: Osmosis is the process by which solvent molecules pass through semipermeable membrane from dilute solution
to concentrated solution. That is because solvent molecules have lower chemical potential in concentrated solution. Osmotic
pressure is the pressure that must be applied to solution to prevent the flow of pure solvent. It is defined by the van’t Hoff equation.
Electrolyte solutions and ionic equilibria
Arrhenius dissociation theory: an acid is a substance that liberates H
(donates protons) in water, a base liberates OH
protons). Lowry Bronsted theory: applies to both aqueous and nonaqueous systems. In water, a free proton combines with water
forming hydronium ion (H3O
). A strong acid in water can behave as a weak acid in a different solvent.
Lewis theory: defines acid as a molecule or ion that accepts an electron pair from another atom. A base donates an electron pair to
be shared with another atom.
pH is the negative logarithm of molar H+ concentration.
As pH , H+ concentration exponentially.
Ionization: is the complete separation fo the ions in a crystal lattice when the salt is dissolved. Dissociation: is the separation of ions
in solution when the ions are associated by interionic interactions. For weak electrolytes, dissociation is reversible. According to the
law of mass action, concentration of dissociation products results in dissociation. pKa is the dissociation constant of a weak acid.
pKb is used for weak bases.
Acids and bases that can accept or donate more than one proton will have more than one dissociation constant.
Henderson-Hasselbalch equation: describes the relationship between ionized and nonionized species of a weak electrolyte (base is
UP). pH = pKa when [dissociated species] = [nondissociated species], i.e., 50% ionization.
Solubility of a weak electrolyte varies as a function of pH. Solubility of a weak acid with pH. Opposite is true for weak bases.
Buffer: a mixture of salt with acid or base that resists changes in pH when small quantities of acid or salt are added. Buffer is a
combination of weak acid and its conjugate base (salt) (more common), or a weak base and its conjugate acid (salt).
Buffer capacity: is the number of gram equivalents in an acid or base that changes the pH of 1 liter buffer by 1 unit. Maximum buffer
capacity occurs when pH = pKa. Higher concentration of buffer constituents buffer capacity due to the acid or base reserve.
Heterogenous (disperse) systems:
Suspension: two phas system that is composed of solid material dispersed in a liquid. Particle size is > 0.5 mm.
Emulsion: heterogeneous system that consists of one immiscible liquid dispersed in another as droplets. Droplets diameter > 0.1
micron. Emulsions are inherently unstable because the droplet tend to coalesce. An emulsifying agent is used to prevent coalescence.
In ideal (not real) dispersion, the dispersed particles are uniform in size and do not interact.
Stokes’s law defines Sedimentation rate. The rate with particle size and the difference in density between particles and medium.
The rate with medium viscosity.
High particulate (dispersed phase) concentration leads to particle collision and aggregation, coalsecnce, instability.
Avoidance of particle-particle interactions: if particles have similar electrical charge (e.g. from the surfactant). Zeta potential
(magnitude of the charge) is the difference in electrical potential between the particle charged surface and dispesion medium. When
zeta potential is high (<25 mV), interparticulate repulsive forces > attractive forces, which results in deflocculation and stability.
Coalescence of droplets in O/W emulsions is by electrostatic repulsion of similarly charged particles.
Creaming: is the reversible separation of a layer of emulsified particles. Mixing or shaking may be sufficient to reconstitute the
Phase inversion: from o/w to w/o emulsion or vice versa.
IV. Chemical kinetics and drug stability
Degradation rate depends on concentration, temperature, pH, solvents, additives, light, radiation, catalysts (polyvalent cati ons),
surfactants, buffers, complexing agents.
Order of reaction: the way in which the concentration affects rate.
Zero order: rate is independent of concentration, e.g., 5 mg/hr, i.e., straight line concentration vs. time.
First order: rate depends on the first power of concentration, e.g., 5% / hr. Concentration exponentially with time. Straight line log
concentration vs. time. t1/2 = 0.693/k, t90% = 0.104/k. Half life is concentration independent.
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Temperature: T reaction rate (Arrenius equation).
Solvent: may change pKa, surface tension, viscosity, reaction rate, etc. Additional reaction pathways may be created (e.g. aspirin in
pH: H+ catalysis occurs at pH, OH- catalysis occurs to pH. Rate constant at intermediate pH range is usually lower than at or
pH. pH of optimum stability (point of inflection) is measured.
Aromatic esters (benzocaine, procaine, tetracaine) t1/2 is presence of caffeine due to complex formation.
Modes of pharmaceutical degradation:
Hydrolysis: most common. Occurs for esters, amides, lactams. H+ and OH- are the most common catalysts. Esters easily hydrolize
and should be avoided in liquids.
Oxidation: by oxygen in the air or in solvent. Oxidizable compounds should be packed in an inert atmosphere (nitrogen or CO2).
Oxidation involves free radical mechanism and chain reaction. Free radicals take electrons from other compounds. Antioxidants react
with free radicals by providing electrons. Antioxidants include: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate.
Photolysis: degradation in sunlight or room light. Molecules may absorb the proper wavelenght of light (usually <400 nm) and acquire
sufficient energy to undergo reaction. Prevent by using opaque container or amber glass bottle. Examle: sodium nitroprusside in water.
Determination of shelf life. It’s affected by storage temperature. Preparation is considered fit if it varies from nominal concentration
by no more than 65% provided the decomposition products are not more toxic. Stability testing at 4 C and room temperature (22C).
Rate of decomposition is determined. Temperature-ccelerated stability is also conducted. Arrhenius equation can be used. T90% can
also be calculated.
Drug dosage forms
May contains polyols (e.g. sorbitol, glycerin) to ↓ crystallization, modify solubility, taste, mouth feel.
Advantages (over solid forms): more homogenous, easier to swallow, ↑ bioavailability and ↓ onset of action for slow dissolution drugs.
Disadvantage: bulkier, degrade faster, ↑ interactions with constituents
Types of water:
Purified water USP: obtained from distillation, reverse osmosis, ion exchange. Solids < 10 ppm. pH = 57. It can not be used for
ophthalmics or parenterals.
Water for injection USP: purified water that is pyrogen free
Sterile water for injection USP: water for injection that is sterilized and packaged in single dose containers < 1 liter for type I or II
Bacteriostatic water for injection USP: sterile water for injection containing bacteriostatic agent(s) in one or multiple dose containers
< 30 ml in type I or II glass.
Sterile water for inhalation USP: purified by distillation or reverse osmosis and rendered sterile. It contains no antimicrobials.
Sterile water for irrigation USP: water for injection that is sterilized and contains no antimicrobials.
Oral drug solutions
Syrups: contains ↑ sugar concentration. Sweet and viscous. Syrup NF (simple syrup): 85% w/v sugar. Sugars have low solvent
capacity for water soluble drugs because hydrogen bonding between sugar and water is very strong. Dilute sucrose solutions are
excellent media for microbial growth. As sugar concentration approaches saturation, the solution becomes self-preserved, however
temperature fluctuations may cause sugar crystallization. Syrup USP is self-preserved with ↓ crystallization potential.
Elixirs: contain alcohol as a solvent (5-40%). Elixirs become turbid when diluted by aqueous liquids. Alcohol ↑ salt taste. Salts also
have limited solubility in alcohol. Aromatic elixir NF: mixture of two alcohol concentrations resulting in 22% alcohol.
Aromatic waters: are saturated aqueous solutions of volatile oils. Used for flavoring. Stored in tight, light resistant containers.
Adding large amount of water soluble drug may cause insoluble layer to form (salting out) due to better attraction with the water solvent
than the oils.
Spirits (essences): volatile substances in 50-90% alcohol. It water is added, oils separate. Used medicinally or as flavors. Store in
Tinctures: stable alcohol solutions of chemicals or soluble constituents or vegetable drugs. Prepared using extraction using
maceration or percolation. Alcohol content varies widely.
Fluidextracts: liquid extracts of vegetable drugs that contain alcohol as a solvent, preservative, or both. Prepared by percolation.
Ten times as concentrated and potent as tinctures (100% vs. 10%).
Mouthwashes: use alcohol or glycerin to dissolve volatile ingredients.
Astringents: locally applied solutions that ppt protein. Astringents ↓ cell permeability without causing injury. They cause constriction,
wrinkling and blanching of skin. They ↓ secretions and are used as antiperspirants. Examples: alulminum acetate, aluminum
subacetate, calcium hydroxide.
Antibacterial topical solutions: e.g. benzalkonium chloride, strong iodine, providone-iodine. .
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Magmas: suspensions of finely divided material in a small amount of water.
Drugs may be packed dry to avoid instability in aqueous dispersions.
Sustained effect: requires dissolution or diffusion step. Stability: drug degradation is slower than in a solution. Taste: for insoluble
drugs used in suspension. Solubility: when solvent is not available. Example: only water can be used in ophthalmics, but suspension
offer an alternative.
Preparation: first solids are wetted by levigation (addition of nonsolvent levigating agent to solid material to form a paste). A surfactant
can be used. Then suspending agent is added as aqueous dispersion by geometric dilution.
A. Hydrophilic colloids
↑ viscosity by binding with water. Support microbial growth and require preservation. Mostly anionic, except methyl cellulose (neutral)
and chitosan (cationic), therefore incompatible with quaternary antimicrobials. Insoluble in alcohol.
Acacia: used as 35% water dispersion (mucilage). Neutral pH.
Tragacanth: 6% mucilage (less needed).
Methyl cellulose: heat and light stable polymer. Soluble in cold but not hot water. Prepared using boiling water.
Carboxy methyl cellulose: anionic and water soluble.
Anionic silicates. Strongly hydrated and exhibit thixotropy. Examples: bentonite (5% magma), veegum.
↑ Solubility: e.g. oil soluble drug in aqueous formulation. ↑ Stability: usually better than in aqueous solution. ↑ Drug action: as in IM
injections. ↑ Taste: oil soluble drug hidden in aqueous outer phase. ↑ Appearance: as in oily material for topical application.
Phases of emulsions: most are 2-phases. Internal phase (dispersed or discontinuous phase) in an external phase (dispersion
medium or continuous phase).
Type of emulsion is determined by relative phase volumes and emulsifying agent used (more important). Maximum volume of internal
phase is 74%.
Emulsifying agents: lower interfacial tension and form a film at the interface.
Natural emulsifying agents: see hydrophilic colloids under suspending agents (acacia, tragacanth, celluloses). Also pectin, gelatin
and agar. Agar: ↑ viscosity. Gelatin: 1%, can be anionic or cationic.
1. Wet gum (English) method: emulsion of fixed oil, water, acacia. Make mucilage of water and acacia, then add oil gradually.
2. Dry gum (Continental) method: emulsion of fixed oil, water, acacia. Fixed oil added to acacia and then water is all added at once
followed by rapid titration.
Electrolyte in high concentration can break the emulsion. Add last.
Alcohol can dehydrate and ppt hyrocolloids. Use in ↓ concentration.
3. Bottle method: similar to dry method. Used for volatile oils.
4. Nascent soap method: by mixing equal portions of oil and alkali solution to form soap, which acts as an emulsifying agent.
Example: olive oil (contains oleic acid, free fatty acid) and lime water calcium oleate for calamine lotion.
The drug can be added after emulsion formation if it is soluble in the external phase. If drug is soluble in internal phase, it should be
dissolved first during emulsion formation.
Synthetic emulsifying agents:
1. Anionic: Soaps form w/o except alkali soap. Examples: SLS
2. Cationic: e.g. benzalkonium chloride. Incompatible with soap.
3. Nonionic: Spans (sorbitan esters, ↑ HLB) for w/o, Tweens (polysorbates, ↓ HLB) for o/w
Used as emollients (make skin more pliable), protective barriers, or vehicles for drugs.
1. Oleaginous bases: not washable. Petrolatum: occlusive, does not rancid, use wax to ↑ viscosity. Synthetic esters: e.g. glyceryl
monostearate, isopropyl myristate, butyl palmitate, PEG, long chain alcohols. Lanolins: e.g. lanolin oil and hydrogenated lanolin.
2. Absorption bases: anhydrous, water-insoluble, not washable, but can absorb water. Example: anhydrous lanolin (wool fat),
hydrophilic petrolatum (petrolatum, bees wax, stearyl alcohol, cholesterol), e.g. Aquaphor.
3. Emulsion bases: Hydrous wool fat (lanolin): w/o with 25% water, emollient and occlusive. Cold cream: w/o with almond oil, white
wax, sodium borate. Vanishing cream: o/w with ↑ water and humectants (PEG, glycerin). Hydrophilic ointment: o/w with SLS.
4. Water soluble bases: washable and absorb water. PEG ointment: PEG 400 and 4000 by fusion method. PG and PG-alcohol:
forms clear gel with 2% hydroxypropyl cellulose.
Preparation: metal spatula may interact with iodine or mercuric salts. Use levigation or fusion method.
Fusion method: used for solids with ↑ melting point. Oil phase melted with highest melting point materials first. Heat water soluble
ingredient separately to above the highest melting point. Mixed the two phases in the appropriate order for o/w or w/o.
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Used for local (hemorrhoids, infection) or systemic effect.
Systemic effect bypasses the first pass metabolism
Used when oral route is not possible, e.g., infants, nausea, vomiting, GI distress, coma, debilitation.
Types of suppositories:
1. Rectal: cylindrical, tapered bullet like. Adult: 2 g.
2. Vaginal: oval, 5 g, for antiseptics, contraceptives, anti-infective.
3. Urethral: long (6 cm), tapered, local anti-infective.
Minimum 30 C narrow, sharp melting point. Oil soluble drug has ↑ mucous absorption from an oil base, and vice versa.
Bases that melt: cocoa butter (theobroma oil), witepsol (saturated fatty acid mixture), wecobee (from coconut oil); or Bases that
Preparation: the suppository is molded with the fingers after a plastic mass is formed.
1. Hand-rolling: Correct the amount of base needed based on the quantity of the drug and density of the base.
2. Compression: Mixture is placed into compression device. Pressure is applied and mixture is forced into lubricated mold cavities.
Used with cocoa butter.
3. Fusion (molds): most common. Use mineral oil to lubricate mold. Pour melt continuously to avoid layering. Avoid for thermolabile
drugs and insoluble powders (settle).
Advantages: compounding flexibility, chemical stability, rapid ingredients dispersion. Disadvantages: time consuming preparation,
inaccurate dosing, unsuitable for bad taste / hygroscopic drugs.
Milling: mechanical process of reducing particle size (comminution). Micrometrics: is the study of particles.
Advantages of milling: ↑ surface area ↑ dissolution rate and bioavailability (e.g. griseofulvin), ↑ drying of wet masses. ↑
ointment texture / stability / appearance. ↑ uniform distribution of colorants. Particles of same size ↑ mixing, ↓ segregation.
Disadvantages of milling: may change polymorphic form ↓ activity. ↑ heat / adsorption degradation. Flow problems and
segregation. ↑ static charge particle aggregation / ↓ dissolution. ↑ surface area ↑ air adsorption / ↓ wettability.
Comminution techniques: Trituration reducing particle size or mixing with a mortar and pestle. Pulverization by intervention
a solvent is added to help pulverization and then evaporated (e.g. alcohol to camphor). Used with gummy substances that
reagglomerate or resist grinding. Levigation add a nonsolvent (levigating agent, e.g., mineral oil) to form a past and help
pulverization in mortar and pestle or ointment slab and spatula. Avoid gritty feel of solids.
Spatulation: using spatula to mix small amounts of powder on paper or pill tile. Not possible for potent drugs or large quantities.
Useful to eutectic mixtures (mixture melting point is lower than each ingredient), such as phenol, camphor, menthol, thymol, aspirin,
phenyl salicylate, phenacetin. Inert diluent can be used to minimize contact (MgO, MgCO3, kaolin, starch).
Trituration: used both to comminute and mix. For comminution, use porcelain or ceramic mortar with rough surface. For mixing,
colorants and easy cleaning, use glass mortar.
Geometric dilution: used for mixing potent drugs with large amount of diluent. First mix equal amounts of drug and diluent in a mortar
by trituration, repeat until diluent is used up.
Sifting: powders are passed through sifters similar to flour sifters, resulting in a light fluffy product. Not suitable for potent drugs.
Tumbling: mix powders in a large container rotated by motor.
Use and packaging of powders:
As bulk powders or divided powders. For bulk powders, a perforated sifter can is used for external dusting or an aerosol container is
used for spraying onto skin.
Powders dispensed in bulk: antacids and laxatives (e.g. PEG is mixed with a drink). Douches are mixed with water and applied
vaginally. Dentifrices and dental cleansing powders. Powders for ear, nose, throat, tooth sockets, vagina. Non potent substances.
Divided powders: dispensed usually in folded paper (chartulae). If drug is not potent, approximate portions by block and divide
method (do not weight).
Special problems: volatile substances (camphor, menthol, essential oils) use sealed containers. Liquids added to divided
powders in small amounts. Hygroscopic substances become moist divide, add diluent, double wrap. Eutectic mixtures.
Hard gelatin capsules
Storage: contain 15% water, so when ↓ humidity capsules become brittle, when ↑ humidity capsules become shapeless.
Size: empty capsules are numbered (000 largest / 600 mg, 5 smallest / 30 mg). Large capsules are for veterinary use. May add
lubricant to ↑ flow or wetting agent to ↑ dissolution.
Filling: by the punch method. Powder is placed on paper and the capsule is pressed into powder until filled.
Soft gelatin capsules
Preparation: from gelatin shells. Glycerin or polyhydric alcohol (sorbitol) is added to make shells more elastic. Contain preservatives
(sorbic acid, parabens).
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Uniformity and disintegration
Uniformity is demonstrated by weight variation or content uniformity. Disintegration are usually not requires unless they are enteric
Contents may be designed for sprinkling on food (e.g. Theo-Dur Sprinkle).
Advantages of solid dosage forms: accurate dose, easy shipping / handling, less shelf space, no preservative, no taste masking
problems, more stable / longer expiration.
Advantages of liquid dosage forms: more effective (antacids, adsorbents), easier to swallow.
Advantages of tablets; precise dose, ↓ content variability, ↓ manufacturing cost, easy packaging and shipping, easy to identify, easy to
swallow, specific release forms, stable, tamperproof.
Disadvantages of tablets: difficult compression, difficult formulation / ↓ bioavailability (poor wetting, ↓ dissolution, ↑ dose).
Ideal tablet: free of defects, strong / durable, stable, predictable drug release.
Tablet design and formulation (excipients)
Diluents: fillers to make up the tablet bulk of ↓ dose drugs. May ↑ cohesion, flow, or direct compression. Examples: kaolin, lactose,
mannitol, sugar, starch, microcrystalline cellulose, calcium phosphate. Do not use calcium salts with tetracycline (↓ absorption).
Binders / adhesives: added dry or liquid to ↑ granulation or direct compression. Examples: cornstarch, glucose, molasses, natural
gum (acacia, may be contaminated), celluloses (methylcellulose, CMC, microcrystalline cellulose), gelatins, provide (PVP). Liquid
binders are more effective.
↑↑ too hard, ↓ dissolution. ↓↓ soft crumbling tablets.
Disintegrants: ↑ disintegration on gastric fluid contact (critical for dissolution and bioavailability). They draw water to tablet, swell and
burst. Examples: cornstarch, potato starch, sodium starch glycolate, celluloses (sodium CMC), clays (veegum, bentonite), cation
A portion can be added with the diluent and another with the lubricant after granulation double disintegration.
Lubricants / antiadherents / glidants: lubricants ↓ friction between tablet and die upon ejection (talc, magnesium stearate,
calcium stearate). Anti-adherents ↓ sticking, adhesion of granules to the punches or die. Glidants ↓ particle friction ↑ powder
/ granule flow.
Colors / dyes: disguise off-color drugs, product ID. FDC dyes are applied in solution. Lakes are dyes absorbed on a hydrous oxide
Flavoring agents: only for chewable or mouth dissolving tablets. Flavor oils or powders are ↑ stable, water soluble flavor are ↓ stable.
Artificial sweeteners: only for chewable or mouth dissolving tablets. May come with diluent (mannitol, lactose). Other agents;
Adsorbents: hold fluid in apparently dry state. Example: magnesium oxide, magnesium carbonate, bentonite.
For oral ingestion:
May be mask taste, color, odor, control release, enteric coating, incorporate another drug, avoid incompatibility, ↑ appearance.
Compressed: from powders, crystals or granules with or without excipients. No coating.
Multiple compressed: layered compress tablet granules around previously compressed granules, then repeat. Compression
coated / dry coated made by feeding previously compressed tablet to a machine that compresses an shell around it separate
incompatible drugs, provide repeat action / prolonged action.
Repeat-action: multiple compressed tablet where the outer shell rapidly disintegrates in the stomach. Example: Repetabs, Extentabs.
The components of the inner layer are insoluble in the stomach but soluble in the intestine.
Delayed action / enteric coated: delays drug release to prevent stomach destruction, prevent stomach irritation, or better stomach
absorption. Enteric: intact in stomach, release in intestine (e.g. Ecotrin).
Sugar / chocolate-coated: to protect drug from air / humidity, mask taste / odor. Process includes seal coating (waterproofing),
subcoating, syrup coating (for smoothing, coloring), polishing. Disadvantage: time consuming, require expertise, bulky coats.
Film coated: compressed tablets coated with water soluble or insoluble polymer (HPMC, povidone, PEG). Film is colored, ↑ durable, ↓
chipping, ↓ bulky (3% wt ↑), ↓ time consuming than sugar coating. May contain film former, plasticizer, surfactant, opacifier, sweetner,
color, flavor, glossant, volatile solvent.
Air-suspension coated: fed into vertical cylinder and supported by air column (Wurster process) where the coating solution is applied.
Chewable: disintegrate rapidly when showed or dissolved. Contains flavored and colored mannitol. Used for chi ldren, multivitamins,
Used in oral cavity
Buccal / sublingual: allow absorption through oral mucosa after dissolution. Avoid gastric destruction or intestinal ↓ absorption.
Examples: sublingual nitroglycerin, buccal progesterone.
Troches / lozenges / dental cones: dissolves slowly in the mouth and provide local effect.
Used to prepare solutions:
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Effervescent: made by compressing granular effervescent salts (citric acid, tartaric acid, sodium bicarbonate) that release CO2 when
contacting water. Example: alkalinizing analgesics (Alka-Seltzer, ↑ dissolution, absorption).
Other tablets to prepare solution: dispensing tabs, hypodermic tabs, tab triturates.
Capping: separation of the top or bottom crown from main body of tab. Lamination: separation of tab into two or ↑ layers. Usually
due to air entrapment.
Picking: removal of the surface material by a punch. Sticking: adhesion of material to the die wall. Due to excess moisture or melting
Mottling: unequal color distribution. Due to different color drug vs. excipient or drug degradation.
Tablet evaluation and control
General appearance: size, shape, color, odor, taste, surface, texture, physical flaws, consistency, marking legibility.
Hardness / friability resistance: Hardness affects dissolution / disintegration. Slow dissolved tabs are harder, vice versa. Hardness
tester measure force required to break tab. Friabilators measure weight loss when tabs roll and fall (<1%). Chewable / effervescent
tabs are highly friable, require special packaging.
Weight variation: USP standards apply to tabs containing >50 mg drug where drug is > 50% of total weight.
Content uniformity: USP standards apply if drug <50 mg.
Disintegration: USP test is conducted in vitro. Disintegration time: nitroglycerin (2 min), aspirin (5 min), most other drugs (<30 min),
buccal tabs (4hr), enteric coated (none in 1 hr is simulated gastric fluid, within 2 hr in simulated intestinal fluid).
Dissolution: standards in USP. Increased emphasis on dissolution replaced disintegration for many drugs.
Pressurized dosage forms that deliver drugs topically or systemically with the aid of liquefied or propelled gas (propellant).
Valve allows pressurized product to be expelled continuously or intermittently when the actuator is pressed. Dip tube conveys the
formulation for the container’s bottom to the valve.
Metered dose inhalers (MDIs): aerosol systems for systemic or pulmonary delivery. They contain fine drug mist solution or dispersion.
1 Actuation = 1 dose.
Propellants: compressed gases (CO2, N2, NO), ↓ pressure with time due to ↑ head space. Liquefiable gases: saturated
hydrocarbons, hydrofluorocarbons, dimethyl ether, chlorofluorocarbons (CFC). CFC are banned now.
Advantages: push-button dispensing convenience, stability of closed container (protects from light, moisture, air, microbes), ↓
tampering, wide product range. Disadvantage: propellants are environmental hazard.
Controlled release dosage forms
They release drug slowly. Also known as delayed-release, sustained-action, prolonged-action, sustained-release, prolonged-release,
timed-release, slow-release, extended-action, extended-release.
Advantages: ↑ compliance, ↓ total drug used, ↓ local or systemic SE, ↓ drug accumulation / potentiation / loss of activity with prolonged
use, ↑ treatment efficiency, rapid condition control, ↑ bioavailability, ↓ level fluctuation, ↓ cost.
Coated beads or granules:
Examples: Theo-Dur Sprinke, Spansules, Sequels,.
Produce drug level similar to multiple dosing.
Non-aqueous (e.g. alcohol) drug solution is coated onto small inert beads or granules (starch/sugar). Beads may be made of drug if
dose is ↑. Some granules take no further coating to give immediate release. Otherwise, coats of a lipid (e.g. beeswax) or cellulosic
(e.g. ethylcellulose) material are applied. Thickness is varied by varying # of coats to provide SR.
Example: Bayer time-release aspirin.
Solids, liquids or gases are encased in microscopic capsules.
Coacervation: most common method of encapsulation. A hydrophilic substance is added to a colloidal drug dispersion and causes
layering and formation of microcapsules.
Film forming substances for coating (natural or synthetic) include shellacs, waxes, gelatin, starches, cellulose acetate phthalate,
ethylcellulose. After the coating dissolves, the drug is immediately available.
Examples: Gradumet, Lontabs, Dospan, Slow-K
Use hydrophilic polymers (methyl cellulose, HPMC), insoluble plastics (polyethylene, polyvinyl acetate, polymethacrylate), fatty
compounds (waxes, glyceryl tristearate).
The drug is mixed with matrix material then compressed.
The immediate dose is coated as a top layer.
Example: Oros system (Alza)
Oral osmotic pump composed of a core tablet and semipermeable coating that has a small hole (0.4 mm) produced by laser beam for
drug exit. The system requires only osmotic pressure to be effective and is independent of pH.
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Drug release rate is controlled by changing surface area, membrane nature, or hole diameter.
Example: biphenamine (amphetamine and dextroamphetamine), lonamin (phentermine), Pennkinetic system.
Ion exchange resins are complexed with drugs by passage of a cationic drug solution through a column that contains the resin. The
drug is complexed to the resin by replacement of hydrogen atoms. Then the resin-drug complex is washed and tableted.
Release is dependent on ionic environment in GI and resin properties (↓ pH ↑ release).
Example: hydroxypropyl-beta-cyclodextrin forms a chemical complex slowly dissolves depending on pH.
Example: Valrelease (SR diazepam) includes hydrodynamically balanced system (HBS). HBS contains a matrix that is ↓ dense
than gastric acid, so it remains buoyant. Multiple hydrocolloid layers swell when contacting gastric acid and slowly erode releasing the
4. Biopharmaceutics and Drug Delivery Systems
Drug transport and absorption
Transport across cell membranes
Cell membrane: is a semipermeable structure composed of lipids and proteins. Proteins, protein bound drugs and macromolecules do
not cross cell membranes easily. Nonpolar lipid soluble and smaller molecular weight drugs diffuse through cell membranes faster.
Passive diffusion / partitioning: passive diffusion is dominant within the cytoplasm or in interstitial fluid (Fick’s law). Passive transport
across cell membranes involves successive partitioning of solute between aqueous and lipid phase as well as diffusion within phases.
Nonionized drugs are more lipid soluble and partition better across cell membranes.
Carrier-mediated transport: Active transport: drug moves against concentration gradient, requires energy, carrier may be selective
for drugs that resemble natural substrates, system may saturate at concentrations, process may be competitive. Facilitated
diffusion: carrier mediated transport that occurs with a concentration gradient and does not require energy.
Paracellular transport: drug transport across tight junction between cells or channels. It involves diffusion and convective (bulk) flow
of water and dissolved molecules
Vesicular transport: the process of engulfing particles by a cell. Only mechanism that does not require water solubility for absorption.
Pinocytosis: engulfment of small solute or fluid volumes. Phagocytosis: engulfment of large particles or macromolecules by
Endo/Exo-cytosis: movement of macromolecules in and out of the cell.
Transport proteins: (e.g. P-glycoprotein) are embedded in the lipid bilayer of cell membranes. These are ATP energy dependent
pumps. Work closely with cytochrome P450 3A4 to intracellullar drug concentration. Substrates: cyclosporin, nifedipine, digoxin.
Routes of drug administration
Parenteral: IV Bolus is directly injected to the blood stream, very quick action / SE. IV infusion: constant input rate maintains
constant plasma concentration. Intra-arterial: to achieve concentration in specific tissue before systemic drug absorption, mostly
diagnostic and chemotherapy. IM: rate of absorption depends on muscle vascularity, drug lipid solubility / matrix. SC: vasculature
slow absorption. Intra-articular: into the joint. Intrathecal: into the spinal cord. Intradermal: into the dermis.
Enteral: Buccal / sublingual: allows nonpolar lipid soluble drug absorption, bypassing first pass metabolism. Peroral: most common,
convenient, safe. Disadvantages: inconsistent / incomplete absorption (gastric emptying, intestinal motility), GI enzyme digestion, acid
pH decomposition, GI irritation, first pass metabolism. Absorption is usually by passive diffusion. Duodenum is the main absorption
site (villi / microvilli surface area). Residence time (period of contact) is needed for absorption. Double peak: cimetidine or
acetaminophen as immediate release on empty stomach produce two peak plasma level. Rectal: drug in solution (enama) or
suppository is placed in the rectum. Drugs absorbed in the lower 2/3 bypass the liver first pass metabolism.
Respiratory: Intranasal: as spray or drops for local (decongestant, steroid) or systemic effect. Pulmonary: inhaled perorally
(nebulizer, MDE) into pulmonary tree. Particles > 60 um deposit on trachea. Particles > 20 um do not reach bronchioles.
Particles 2-6 um reach alveolar ducts. Particles 1-2 um retained in the alveoli. Particles < 0.6 um exhaled, not deposited.
Transdermal (percutaneous): suitable for small lipid soluble molecules (clonidine, nitroglycerin, fentanyl, scopolamine, testosterone,
Local activity: topical antibiotics, anti-infectives, antifungals, loacal anesthetics. Minimum systemic absorption.
Drug dissolution: bioavailability rate limiting step for drugs with limited solubility. Diffusion is described by Noyes Whitney equation
(similar to Fick’s law).
Drug solubility in a saturated solution is a static equilibrium property. Dissolution rate is a dynamic property with a rate.
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Particle size / surface area: inversely related. surface area dissolution rate. For some hydrophobic drugs, particle size
aggregation to surface free energy. To prevent aggregate formation, small particles are molecularly dispersed in PEG, PVP
(povidone), dextrose. Examples: Griseofluvin molecular dissolution in water soluble carrier (PEG 400) bioavailability.
Partition coefficient: ratio of solubility at equilibrium in nonaqueous solvent (n-octanol) to that in aqueous solvent (water). Hydrophilic
drugs ( water solubility) dissolution.
Ionization: ionized form is more polar and more water soluble. Based on Henerson-Hasselbalch equation.
Salt formation: type of salt affects dissolution, bioavailability, duration of action, stability, irritation, toxicity. Soluble salt may be
stable than nonionized form (e.g. sodium aspirin vs. aspirin).
Effervescent forms: contains acid drug and sodium bicarobnate, tartaric acid, citric acid. Water is added prior to use. Excess sodium
bicarbonate forms an alkaline solution in which the drug dissolves. CO2 is formed by the decomposition of carbonic acid. For weak
acids, potassium and sodium salts are more soluble than polyvalent cation salts. For weak bases, common water soluble salts include
hydrochloride, sulfate, citrate, gluconate.
Polymorphism: ability to exist in > 1 crystalline form. Polymorphs have different physical properties. Amorphous non-crystalline forms
Chirality: drug exists as optically active stereoisomers or enantiomers different PK / PD. Most chiral drugs are used as racemic
mixtures. Example: ibuprofen has R and S enantiomers, only S is active.
Hydrates: drug may exist in hydrated, solvated form and anhydrous form. Anhydrous ampicillin dissolves faster than hydrated
Complex formation: Chelates are complexes involving a ring-like structure and a metal. Natural chelates: hemoglobin,
cyanocobalamin, insulin). Tetracycline forms a chelate with polyvalent metal ions water solubility absorption. Many drugs
adsorb strongly on charcoal or clay (kaolin, bentonite) by forming complexes. Theophylline + ethylene diamine water soluble
complex (aminophylline). Many drugs are complexed with cyclodextrins to solubility. Large drug complexes (drug-protein) do not
cross cell membranes easily free drug must first dissociate for absorption or glomerular filtration.
Delivery system formulation
Complex formulation bioavailability issues. For oral solid dosage forms, dissolution is the rate limiting step. For CR or SR, release
from the delivery system is the rate limiting step.
Solutions: are homogeneous mixtures of solutes dispersed molecularly in a dissolving medium. Aqueous solution is the most
bioavailable and consistent form (no dissolution). Oral solutions are used as reference preparations for solid oral forms. Elixir (drug
dissolved in hydroalcoholic solution) has bioavailability. Alcohol solubility. However, drug may ppt when elixir is diluted in the GI
with food, but absorption is still rapid because of surface area. A viscous drug solution (syrup) may mixing, dilution and GI gastric
Suspensions: bioavailability from suspension is similar to solutions due to surface area. Suspending agents: hydrophilic colloids
(celluloses, acacia, xantham gum). viscosity may have issues as syrups above.
Capsules: Hard gelatin caps are simple (contain powders) and preferred new drugs early clinical trials. Soft gelatin caps contain
nonaqueous solution, suspension or powder. It may have bioavailability if water miscible vehicle is used (e.g. lanoxicaps), and vice
versa. Aging and storage may affect gelatin shell moisture content and bioavailability.
Compressed tablets: ratio of excipients : drug possiblity of excipients affecting bioavailability. Lubricants are usually
hydrophobic, water-insoluble drug surface wetting dissolution and bioavailability. Surfactants dissolution and bioavailability.
Modified release dosage forms: products that alter the rate or timing of drug release. More stringent quality control is used. Dose
dumping, abrupt drug release, is a problem. Allows in dosing frequency. They provide more flat consistent plasma concentration that
avoids toxicity and lack of efficacy. A loading dose may be used. Delayed release control the timing of release, e.g. enteric coating.
Transdermals: have occlusive backing film to prevent TEWL to hydration and permeation. Concentration gradient is maintained by a
Targeted drug delivery: place the drug at or near the receptor (e.g. specific cell such as tumor, organ, tissue). Systems include
macromolecular drug carriers (proteins), liposomes, nanoparticles, monoclonal antibodies.
Inserts and implants: drug is impregnated into a biodegradable material and released slowly. Inserted into vaginal, buccal cavity, skin.
Example: l-norgestrol implant is inserted in the upper arm for 5-year contraception.
6. Basic Pharmacokinetics
Rates and orders of reactions
Reaction rate: velocity of the reaction
Reaction order: way in which the drug (reactant) affects the rate
Zero order reaction: drug concentration changes with time at a constant rate. Rate constant = Ko (concentration / time; mg/ml/hr).
Linear correlation of concentration vs. time with slope=Ko and intercept = Co.
First order reaction: change of concentration with time is the product of the rate constant and concentration of the remaining drug.
Drug concentration decreases by a fixed percent in each time unit. Linear correlation of log concentration with time. Rate constant )K)
= 1/hour. Half life t1/2=0.693/k.
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Models and compartments
Model: mathematical description to express quantitative relations in a biological system.
Compartment: group of tissues with similar blood flow and drug affinity.
Drugs distribute quickly to tissues with ↑ blood flow
Drug cross capillaries by passive diffusion and hydrostatic pressure.
Drugs easily cross the capillaries of the kidney glomerulus.
Brain capillaries are surrounded by glial cells forming a thick lipid membrane (BBB) ↓ diffusion of polar and ionic hydrophilic drugs.
Tissue accumulation due to drug/tissue physicochemical or affinity.
Lipid soluble drug accumulate in adipose (fat) tissue
Tetracycline accumulate in bone (calcium Complexation).
Plasma protein binding: results in a big complex can’t cross membranes. Albumin: major plasma protein for drug binding.
Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the plasma. ↑ bound drugs (e.g. phenytoin) can be displaced by other ↑
bound drug ↑ free unbound drug in effect / toxicity.
Intravenous bolus injection
Very rapid drug entry. Rate of absorption is negligible.
Entire body is one compartment all tissue equilibrate rapidly.
Drug elimination: first order kinetics. Elimination rate constant = renal excretion rate constant + metabolism (biotransformation) rate
Some controlled release oral drugs have zero absorption rate constant.
Apparent volume of distribution (Vd): hypothetical volume of body fluid in which drug is dissolved. Vd is needed to estimate amount
of drug in the body (Db) relative to concentration in plasma (Cp).
Cp = Db / Vd
More drug distribution into tissues ↓ Cp ↑ Vd
Single oral dose
Rapid absorption then elimination, both with first order kinetics.
Time to reach max concentration (tmax) depends only on absorption and elimination rate constants but not on Vd or Db.
AUC: calculated using trapezoidal rule by integrating the plasma drug concentration over time. AUC depends on Do, Vd, elimination K
but not absorption K.
Lag time: at the beginning of systemic drug absorption, e.g. due to delay in gastric emptying.
Absorption: zero order. Elimination: first order (when infusion stops)
Steady state concentration (Css): target plateau drug concentration where fraction of drug absorbed = fraction of drug eliminated.
Loading dose (DL): initial IV bolus dose to produce Css as rapidly as possible. Start IV infusion at the same time.
DL: amount of drug that, when dissolved in the apparent Vd, produces the desired Dss. Reaching 07% of Css without DL takes ~ t1/2.
Time to reach Css depends on the drug elimination half life.
IV infusion: ideal for drugs with narrow therapeutic window (controls Cp).
Intermittent intravenous infusion
Drug is infused for short periods to prevent accumulation and toxicity.
Used for aminoglycosides (e.g. gentamicin).
Drug is given intermittently in multiple-dose regimen for continuous or prolonged therapeutic activity to treat chronic disease.
Give new dose before previous dose completely eliminated Cp accumulation ↑ to Css.
At steady state: Cp fluctuations between a max and a min (C
Superposition principle: assumes that previous drug doses have no effect on subsequent doses total Cp = cumulative residual Cp
from each previous dose.
Dosing rate = dose size (Do) / dose interval (e.g. X mg/hr).
Same dosing rate same average Css but may be different (C
Some AB multiple rapid IV bolus injections.
Oral immediate release drug products (multiple doses) rapid absorption, slow elimination.
Maintenance dose (DM): after loading dose to maintain Cp at Css. If DM dosing interaval = elimination t1/2 DL = 2 x DM
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Drug distributes into different tissue groups at different rates. Tissues with ↑ blood flow equilibrate rapidly with the drug.
Two-compartment model (IV bolus): First, rapid distribution into highly perfused tissue (central compartment) rapid decline in Cp
(distribution phase). Both are first-order processes. Then, slow distribution into peripheral tissues (tissue compartment) slow
decline in Cp after equilibration (elimination phase). Vd = Vd at steady state + central + tissue compartment volumes.
Two-compartment model (oral): two-compartment ONLY if absorption is rapid but distribution is slow.
Models with additional compartments: example of a third compartment: deep tissue space. If frequent interval dosing third
Elimination rate constant: two constants; one for elimination from central compartment, the other for elimination after complete
Also known as capacity-limited, dose-dependent, or saturation PK.
Result from the saturation of an enzyme of carrier-mediated system.
Do not follow first-order kinetics as the dose ↑.
AUC or drug excreted in urine are not proportional to dose
Elimination t1/2 may ↑ at ↑ doses.
Michaelis-Menten equation: describe velocity of enzyme reactions in nonlinear PK. It described rate of change of Cp after IV bolus. If
Cp is ↑ the equation is a zero-order rate of elimination. If Cp is ↓↓ first-order.
Note that first-order PK = linear PK
Total body clearance (ClT)
ClT = drug elimination rate / Cp = K x Vd
ClT and Vd are independent variables. T1/2 is a dependent variable.
A constant volume of the Vd is cleared from the body per unit time.
First order PK: ClT = renal clearance + non-renal (hepatic) clearance
↓ ClT ↑ t1/2. ↑ Vd ↑ t1/2
Renal drug excretion
Major route of elimination for: polar drugs, water-soluble drugs, drugs with ↓ MWt (<500), drugs that are biotransformed slowly.
Glomerular filtration: passive process that filters small molecules. Drugs that are bound to plasma proteins are too big to be filtered.
Creatinine and inulin undergo only glomerular filtration (not tubular secretion or reabsorption) used to measure glomercular filtration
Tubular reabsorption: passive process that follow Fick’s first law of diffusion to reabsorb lipid-soluble and non-ionized weak
electrolytes drugs back to the systemic circulation. If ionized or water-soluble excreted in the urine. Diuretic ↑ urine flow ↓
time for reabsorption ↑ drug excretion.
Active tubular secretion: carrier-mediated active transport system that requires energy. Two systems: for weak acids and weak
bases. Competitive nature: e.g. probenecid (weak acid) compete for the same system as penicillin ↓ penicillin excretion. Another
example: p-aminohippurate. Measure using effective renal blood flow (ERBF).
Renal clearance (ClR)
It is the volume of drug in the plasma remove by the kidney per unit time.
ClR = rate of drug excretion / Cp = ml/minute.
Clearance ratio: relates drug clearance to inulin clearance (GFR). If = 1 filtration only. If < 1 filtration + reabsorption. If > 1
filtration + active tubular secretion.
Volume of drug-containing plasma cleared by the liver per unit time.
Measurement of hepatic clearance (ClH)
Main mechanism for non-renal clearance. Measured indirectly (difference between total and renal clearance).
ClH = hepatic blood flow x extraction ratio.
Extraction ratio: drug fraction irreversibly removed by an organ or tissue as the drug-containing plasma perfuses the tissue.
Blood flow, intrinsic clearance, protein binding
All these factors affect hepatic clearance.
Blood flow: to the liver is ~ 1.5 L/min. After oral GI absorption to mesenteric vessels to hepatic portal vein through the liver
to hepatic vein to systemic circulation.
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Intrinsic clearance: ability of the liver to remove the drug independent of blood flow due to inherent ability of the bi otransformation
enzymes (oxidases) to metabolize the drug as it enters the liver. This is affected by enzyme inducers (Phenobarbital, tobacco) and
inhibitors (cimetidine, lead).
Protein binding: bound drugs are not easily cleared by the liver or kidney. Only free drug crosses the membrane into the tissue and is
available to metabolizing enzymes.
Biliary drug excretion
Active transport (secretion) process. Separate systems for weak acids and weak bases.
Excretes ↑ MWt drugs (>500) or polar drugs (digoxin, reserpine, glucuronide conjugates).
Drugs may be recycled by enterohepatic circulation. GI absorption mesenteric vessels hepatic portal veins liver secrete to
the bile store in gallbladder empty into the GI through the bile duct (recirculation).
First pass effect (pre-systemic elimination)
Portion of oral drugs may be eliminated before systemic absorption due to rapid drug biotransformation by liver enzymes.
Measure absolute bioavailability (F). If F < 1 some drug was eliminated before systemic absorption.
Common for drug with high liver extraction ratio.
If ↑ first-pass effect ↑ dose (e.g. propranolol, penicillin), different route (e.g. nitroglycerin, insulin), or modified dosage form (e.g.
Some PK parameters can be estimated with non-compartment methods using comparison of the AUCs.
Mean residence time (MRT): average time for the drug molecules to reside in the body. Called Mean Transit Time or Sojourn Time. It
depends on the route of administration. Assumes elimination from the central compartment. MRT = total residence time of all drug
molecules in the body / total number of drug molecules.
Mean absorption time (MAT): difference between MRT and MRTIV and an extravascular route.
Clearance: volume of plasma cleared of the drug per unit time.
Steady-state volume of distribution (Vss): amount of drug in the body at steady sate and the average steady-state drug
The application of PK principles to the rational design of an individualized dosage regimen.
Objectives: maintenance of an optimum drug concentration at the receptor site to produce effect for the desired period, and
minimization of SE.
Application of PK principles to the design, conduct, and interpretation of drug sate evaluation studies.
Used to validate dose-related exposures in animals in preclinical drug development to predict human toxicity.
Clinical toxicology: study of SE of drugs and poisons. PK in intoxicated patient (↑↑ dose) may be very different from a patient taking
Study of sources and correlation of variability in drug concentration in the target patient population. Includes PK and non-PK
parameters such as age, gender, weight, creatinine clearance, concomitant disease.
7. Bioavailability and bioequivalence
Bioavailability: measurement of the rate and extent to which the active moiety becomes available at the site of action. It is also the
rate and extent of active drug that is systemically absorbed.
Bioequivalent drug products: a generic drug product is considered bioequivalent to the reference brand drug product if both products
are pharmaceutical equivalents and have statistically the same bioavailability for the same dose, in the same chemical form, similar
dosage form, by same route of administration, under same experimental conditions.
Generics: requires abbreviated NDA for FDA approval after patent expiration. Must be a therapeutic equivalent but may differ in shape,
scoring, packaging, excipients, expiration dates, labeling.
Pharmaceutical equivalents: drug product that contain the same active drug, same salt, ester or chemical form, same dosage form,
identical in strength and route of administration. May differ in release mechanism, shape, scoring, packaging, excipients.
Reference drug product: usually the currently marketed brand name with full NDA and patent protection.
Therapeutic equivalent drug products: are pharmaceutical equivalents that can be expected to have the same clinical effect and
safety profile under same conditions.
Pharmaceutical alternatives: are drug products that contain the same therapeutic moiety but are different salts, ester or complexes or
are different strength or dosage forms (tablet vs cap, instant release vs SR).
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Bioavailability and bioequivalence
Acute pharmacologic effect
Examples: change in heart rate, blood pressure, ECG, clotting time, Forced Expiratory Volume (FEV1). Alternative to plasma
concentration when that is not possible or inappropriate. Measure effect vs. time. Onset time: time from drug administration till
achieving the minimum effective concentration (MEC) at the receptor site as evidenced by pharmacological response. Intensity:
proportional to the # of receptors occupied by the drug up to a maximum pharmacological effect, which may occur before, at or after
peak drug absorption. Duration of action: time for which the drug concentration remains above MEC. Therapeutic window:
concentration between the MEC and minimum toxic concentration (MTC). As concentration ↑ other receptor interactions lead to SE.
In vitro test (e.g. dissolution) can be used instead if statistical correlation to in vivo data has been established. Example: dermato-PK
for topical drugs for local effect.
Plasma drug concentration
Most common method for measuring systemic bioavailability.
Time for peak plasma concentration (Tmax): relates the rate constant for drug absorption and elimination. Absorption depends on
the dosage form and formula, while elimination is only drug dependent.
Peak plasma concentration (Cmax): Cmax at Tmax relates to the intensity of pharmacological response. Ideally Cmax should be
within the therapeutic window.
AUC vs time: relates the amount or extent of systemic drug absorption. AUC is calculated using the trapezoidal rule, expressed as
Urinary drug excretion
Accurate method if the active moiety is excreted unchanged in ↑ quantities in urine. Cumulative amount of active drug excreted in
urine is related to extent of systemic drug absorption. Rate of drug excretion is related to rate of systemic absorption. Time for
complete excretion relates to the total time for complete systemic absorption and excretion.
Relative and absolute bioavailability
Relative bioavailability: systemic availability of the drug from a dosage form as compared to reference standard given by the same
route. It is a ratio of the AUCs (maximum is 1 or 100%). Very important for generic bioequivalence studies.
Absolute bioavailability (F): fraction of drug that is systemically absorbed. It’s the ratio of AUC for oral dosage form / AUC for IV. A
parenteral IV drug solution has F = 1.
Bioequivalence for solid dosage forms
Design of bioequivalence studies
Guidance provided by Division of Bioequivalence, Office of Generic Drugs, FDA. All studies are done with healthy subjects.
Fasting study: blood samples are taken at zero time, and appropriate intervals to obtain adequate description of concentration vs. time
Food intervention study: required if bioavailability is known to be affected by food. Give products immediately after a standard high
fat content breakfast.
Multiple dose steady-state study: required for extended release products in addition to single-dose fasting and food intervention
study. Measure three consecutive days of trough concentrations (Cmin) to ascertain steady state. Last morning dose is given after
overnight fast, continue fasting for 2 hours. Take blood samples.
In vitro bioequivalence waiver: a comparative in vitro dissolution may be used instead for some immediate release oral dosage forms.
No bioequivalence study is required for certain solution products (oral, parenteral, ophthalmic).
PK data evaluation
Single dose studies: calculate AUC to last quantifiable concentration, AUC to infinity, Tmax, Cmax, elimination rate constant (K),
elimination half life (t1/2).
Multiple dos studies: steady state AUC, AUC to last quantifiable concentration, Tmax, Cmax, Cmin, % fluctuation (Cmax-Cmin /
Statistical data evaluation
Drug considered bioequivalent if difference from reference is < -20% or +25%. ANOVA is done on log transformed AUC and Cmax
data. The 90% confidence interavals of the means of AUC and Cmax should be 80-125% of the reference product.
Drug production selection
Generic drug substitution
It’s dispensing generic drug in place the prescribed product. The substituted drug has to be a therapeutic equivalent.
Prescribability: current basis for FDA approval of therapeutic equivalent generic product. It’s measurement of average bioequivalence
where test and reference population means are statistically the same.
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Switchability: assures that the substituted product produces the same response in the individual patient. It’s the measurement of the
individual bioequivalence including intra-subject variability and subject-by-formulation effects.
The process of dispensing a therapeutic alternative. For example: dispensing amoxicillin for ampicillin. The substituted drug is usually
in the same therapeutic class (e.g. calcium channel blockers) and is expected to have a similar clinical profile.
A formulary is a list of drugs. Positive formulary: lists all drugs that may be substituted. Negative formulary: lists drugs which can’t
be substituted. Restrictive formulary: lists only drugs that may be reimbursed without justification by the prescriber. States provide
guidance for drug product selection through formulary.
FDA annually publishes Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”). It is also published in
the USP/DI Volume III.
Orange Book Codes: A Rated: drug products that are considered therapeutically equivalent. B Rated: drug products that are not
considered therapeutically equivalent. AB Rated: products meeting bioequivalence requirements.
8. Organic Chemistry and Biochemistry
Functional groups affect hydrophilicity, lipophilicity, reactivity, shelf life, stability, biotransformation, metabolism.
Also called paraffins, saturated hydrocarbons.
General formula: R-CH2-CH3. Lipid soluble.
Common reactions: halogenation, combustion.
Chemically inert to air, heat, light, acids, bases. Stable in vivo.
Also called olefins, unsaturated hydrocarbons.
General formula: R-CH=CH2. Lipid soluble.
Common reactions: addition of hydrogen or halogen, hydration (to form glycols), oxidation (to form peroxides).
Volatile alkenes and peroxides may explode in presence of O2 and spark
Stable in vivo. Hydration, peroxidation, reduction may occur.
Based on benzene. Exhibit multicenter bonding. Lipid soluble.
Common reactions: halogenation, alkylation, nitration, sulfonation.
In vivo: hydroxylation, diol formation.
Halogenated hydrocarbons. General formula: R-CH2-X.
Lipid soluble. ↑ degree of halogenation ↑ Solubility.
Common reactions: dehyro-halogenation, nucleophilic substitution.
Stable on the shelf. Not readily metabolized in vivo.
Contains OH group. May be primary (R-CH2-OH), secondary (R1/R2-CH-OH), or tertiary (R1/R2/R3-C-OH).
Alcohols are lipid soluble.
Low molecular weight alcohols are water soluble. ↑ hydrocarbon chain length ↓ water solubility.
Common reactions: oxidation, esterification.
Oxidation: primary alcohol aldehyde acid. Secondary alcohol ketone. Tertiary alcohol not oxidized.
Stable on shelf. In vivo: oxidation, sulfation, glucuronidation.
Aromatic compounds containing OH groups directly connected to aromatic ring. Monophenols one OH. Catechols two OH.
Phenol (carbolic acid): water soluble. ↑ ring substitution ↓ water solubility. Most phenols are lipid soluble.
Common reactions: with strong bases to form phenoxide ion, esterification with acids, oxidation to form colored quinones.
On the shelf: oxidation with air or ferric ions.
In vivo: sulfation, glucuronidation, aromatic hydroxylation, o-methylation.
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General formula: R-O-R.
Lipid soluble. Partially water soluble. ↑ hydrocarbon chain ↓ water solubility.
Common reaction: oxidation to form peroxides (may explode).
In vivo: o-dealkylation. Stability ↑ with size of alkyl group.
General formula: R-CHO (contains a carbonyl group C=O).
Lipid soluble. Low molecular weight aldehytes are also water soluble.
Common reactions: oxidation (to acids, in vivo and in vitro) and acetal formation.
General formula: R-CO-R (contains a carbonyl group C=O).
Lipid soluble. Low molecular weight ketones are also water soluble.
Nonreactive and very stable on the shelf.
In vivo: some oxidation or reduction.
Contain an amino group (-NH2). Primary (R-NH2), secondary (R1/R2-NH), tertiary (R1/R2/R3-N), quaternary (R1/R2/R3/R4-N+ X-).
Lipid soluble. Low molecular weight amines water solubility. ↑ branching ↓ water solubility (primary amines and most soluble).
Quaternary amines (ionic) and amine salts are water soluble.
Common reactions: oxidation (air oxidation on shelf), salt formation with acids. Aromatic amines are ↓ basic ↓ reactive with acids.
In vivo: glucuronidatin, sulfation, methylation. 1ry oxidative deaminatin. 12y/2ry acetylation. 2ry/3ry dealkylation.
General formula: R-COOH (Carboxyl group –COOH).
Lipid soluble. Low molecular weight acid and Na/K salts water soluble.
Common reactions: salt formation with bases, esterification, decarboxylation.
Very stable on shelf. In vivo: conjugation (with glucuronic acid, glycine, glutamine), beta oxidation.
General formula (R-COOR).
Lipid soluble. Low molecular weight esters are slightly water soluble.
Common reaction: hydrolysis to form carboxylic acid and alcohol (in vivo by esterases / in vitro).
General formula: R-CONH2 or R-CONR1/R2 (lactam form).
Lipid soluble. Low molecular weight amides are slightly water soluble.
No common reactions. Very stable on shelf.
In vivo: enzymatic hydrolysis by amidases in the liver.
Amino acid and proteins
Monomeric units of protein (peptide bonds). Formula: NH2-CH-R/-COOH. Proteins are made of 20 AA, differ in R side chain (alpha
Protein hydrolysis to AAs by acids, bases, enzymes.
AA ionize (depending on pH) to zwitterions structure (NH3
/R) ↓ water solubility, ↑ melting point.
Levels of protein structure: primary, secondary (alpha/beta), 3ry, 4ry.
Polyhydroxy aldehydes or ketones
Monosaccharides: simple single unit sugars, e.g., glucose, fructose.
Oligosaccharides: short chains of monosaccharides joined covalently, e.g. sucrose (has to convert into glucose, fructose before GI
absorption), maltose (hydrolyzed by maltase into 2x glucose), lactose (milk sugar, has to convert into galactose, glucose bef ore GI
Polysaccharides: long chains of monosaccharides, e.g., cellulose, glycogen.
Pyrimidines and purines
Bases bond with ribose nucleosides bond with phosphoric acid nucleotides building blocks of nucleic acid.
Exhibit tautomerism (isomerism): can be keto or enol.
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Pyrimidines bases: cytosine, uracil, thymine.
Purine bases: adenine, guanine
DNA bases: thymine, cytosine, adenine, guanine
RNA bases: uracil, cytosine, adenine, guanine.
Linked amino acid chains (proteins) catalysts for biological reactions. They reactions’ ↓ activation energy but do not change reaction
equilibrium point, are used up or changed in the reaction. May require cofactors or coenzymes.
Cofactor: inorganic (metal ion) or nonprotein organic molecule. Prosthetic group: cofactor firmly bound to apoenzyme (protein
portion of a complex enzyme). Coenzymes: organic cofactor that is not firmly bound but actively involved in catalysis. Holoenzyme:
complete catalytically active enzyme system.
Lyases: removes functional group (deaminase, decarboxylase).
Ligases: bind two molecules (e.g. DNA ligase 2 nucleotides).
Isomerases: change DL, cistrans, vice versa.
Also called glycans. Long chain polymers of carbohydrates.
Homopolysaccharides: Contains one type of monomeric units. Starch plant’s reserve food, two glucose polymers (linear water
soluble amylose, and branched water insoluble amylopectin), enzymatic hydrolysis maltose (glucose disaccharide). Glycogen
branched D-glucose chain, polysaccharide storage in animal cells (liver, muscles). Cellulose water soluble, in plant cell wall, linear
D-glucose chain, can’t be digested (hydrolyzed) by humans.
Heteropolysaccharides: contains two or more monomeric units. Heparin acid mucopolysaccharide with sulfate derivatives,
contains glucosamine, in lung tissue, used to prevent clotting. Hyaluronic acid in bacterial cell wall, virteous humor, synovial fluid,
Linear polymers of nucleotides pyrimidine and purine bases linked to ribose or deoxyribose sugars (nucleosides) and bound to
Phosphodiester bonds: join successive DNA / RNA nucleotides.
DNA: compared to RNA it lacks an OH group and contains T rather than U. (DT, RU).
DNA: two complementary alpha helical strands coiled to form double helix. Hydrogen bonding between specific base pairs hold the
strands together. Hydrophobic bases are on the inside of the helix. Hydrophilic deoxyribose phosphate on the outside.
Backbone: alternating phosphate and pentose units with a purine or pyrimidine attached to each.
Strong acids associated with cellular cations and basic proteins (histones, protamines).
rRNA (ribosomal): in ribosomes.
mRNA (messenger): the template for protein synthesis specifies the polypeptide amino acid sequence.
tRNA (transfer): carries activated amino acids to ribosomes for incorporation to the growing polypeptide chain.
Factors affecting metabolism: substrate concentration, enzymes, allosteric (regulatory) enzymes, hormones, compartmentation.
Catabolism: degradation reactions that release energy for useful work (e.g. mechanical, osmotic, biosynthetic).
Anabolism: biosynthetic (build-up) reactions that consumer energy to form new biochemical compounds (metabolites).
Amphibolic pathways: may be used for anabolic or catabolic purposes. Example: Krebs cycle, it breaks down metabolites to release
90% of the organism’s energy, but it also uses metabolites for form compounds such as AA.
Substrate level phosphorylation: forms one unit of ATP per unit of metabolite, no oxygen required.
Oxidative phosphorylation: forms 2 or more ATP per unit of metabolite. Uses oxidoreductase enzymes (e.g. dehydrogenases) using
cofactors NAD (nicotinamide A dinucleotide) or FAD (flavin). Energy released from the reaction is used to form ATP in the mitochondria.
Catabolism: releases energy from carbohydrates.
Glycogenolysis: breakdown of glycogen into glucose phosphate in the liver, skeletal muscles controlled by glucagon and
Glycolysis: breakdown of sugar phosphates (e.g. glucose, fructose, glycerol) into pyruvate (aerobically) or lactate (anaerobically) to
produce energy (ATP)
Anabolism: consumes energy to build complex from simple molecules
Glycogenesis: formation of glycogen in the liver and muscles from glucose in diet controlled by insulin.
Gluconeogenesis: formation of glucose from noncarbohydrate sources (e.g. lactate, pyruvate).
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Location: in the mitochondria. Absent in RBCs (no mitochondria)
Catabolism: converts pyruvate (glycolysis), acetyl CoA (fatty acid degradation) and amino acids into CO2 and water with release of
energy. Oxygen dependent (aerobic).
Anabolism: forms amino acids (aspartate, glutamate) and heme ring from metabolites.
Electron transport: accept electrons and hydrogen from oxidation of Krebs cycle metabolites and couples the energy released to
Triglycerides stores in fat cells (adipocytes) are hydrolyzed by hormone-sensitive lipases into three fatty acids and glycerol
Fatty acids: broken down by beta oxidation to acetyl CoA to Krebs cycle breaks down to CO2, water and energy release.
Ketogenesis: very rapid break down of fatty acids leading to formation of ketone bodies (as in DM).
Glycerol: enters glycolysis oxidized to pyruvate to Krebs cycle CO2 and water.
Steroids: may be converted to bile acids, vitamin D, hormones.
Fatty acids: formed in the cytoplasm. Unsaturation occurs I the mitochondria or endoplasmic reticulum. Essential fatty acids: linoleic
acid (can not be synthesized, diet is only sources).
Terpenes: derived from acetyl CoA. Include: cholesterol, steroids, fat soluble vitamins (ADEK), bile acids.
Sphingolipids: forms a ceramide backbone with fatty acids. Joins with other compounds to form cerebrosides, sphingomyelin
Phosphatidyl compounds: i.e. phosphatidyl choline (lecithin), ethanolamine.
Amino acids: amino group is removed by transaminase. Carbon skeleton is broken down to acetyl CoA or citric acid derivatives
oxidized to CO2 and water for energy. Glycogenic amino acids form glucose as needed by guconeogenesis.
Purines: 90% is salvaged, 10% degrade to uric acid using xanthine oxidase.
Pyrimidines: breaks down to B-alanine, ammonia, CO2
Amino acids: from citric acid cycle intermediates. Essential AA: TIM (threonine, isoleucine, methionine), HALL (histidine, arginine,
lysine, leucine), PVT (phenylalanine, valine, tryptophan) PVT TIM HALL
Purines / Pyrimidines: from aspartate, carbamoyl phosphate, CO2, other AA.
Excess nitrogen is toxic must be eliminated, mainly as urea.
Urea synthesis: in the liver using the Krebs-Henseleit pathway. Amino acid AA transferases (transaminases) + pyridoxine
(vitamin B6) as coenzyme Ammonia + glutamate glutamine + CO2 carbamoyl phosphate urea cycle urea.
Uric acid synthesis: most purines are salvages. Remaining purines are excreted as uric acid.
Taxonomy and nomenclature
Classification or ordering into groups based on degree of relatedness.
Bacteria are named using the Linnaean or binomial system (genus species = homo sapiens = human)
Based on size, shape and texture or colonies grown inj axenic (pure) cultures
Each colony originates from a Colony Forming Unit (CFU) consisting of a single cell or group of adherent cells
Based on size, shape and arrangement of bacterial cells
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Bacteria are small and transparent must be stained to be examined by light microscopy
Single dye colors the cells (e.g. gentian violet, safranin)
Gram-positive = purple
Gram-negative = pink
Stains only cells that have an outer layer of a waxy lipid (acid-fast) not those lacking that layer (non acid-fast)
Heat is used to facilitate the dye entering the spore
Two dyes stain the cell and backgrounds allowing the visualization of the unstained capsular material
Bacterial cell shape and arrangement
-Chains (streptococci) -Pairs / diplococci (streptococcus pneumoniae)
-Clusters (staphylocci) -Packets
Bacilli Cylindrical rod-shaped (pseudomonads, Escherichia)
Coccobacilli (combination of small rods or flattened cocci)
Spirochetes (helical like a corkscrew)
Fusobacteria (tapered ends and slightly curved)
Filamentous (organisms are branching)
Vibrios (comma shaped)
Pleomorphic (exist in varied forms)
Presence or spores, capsules or slime layers
Mobility or type of flagella
Monotrichous = single flagella at either pole
Amphitrichous = flagellum at both poles
Lophotrichous = flagella at either or both poles
Peritrichous = flagella distributed evenly all around
Structure of the prokaryotic cell
Small and simple in design
Less complex inside, more complex outside
Lack a true nucleus, nuclear membrane or intracytoplasmic membraneous organelles (e.g., endoplasmic reticulum)
Cytoplasm is immobile (no endo or exocytosis)
Multiply asexually by binary fission (no mitosis)
Protein synthesis mediated by 70s not 80s ribosomes
Genetic materialsingle supercoiled circular strand of DNA (nucleoid)
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Capsule and slime layer
Cell wall periplasmic space and cytoplasmic membrane
Metabolism and energy production
12. Principles of PD / Med Chemistry
Effects of drugs
Drug action is the results of interaction between drug molecules and cellular components (receptors) modulate ongoing cellular
processes alteration of function.
Drug receptor: any macromolecular component
Physiological receptors: receptors for endogenous ligands. Example: adrenergic receptors for catecholamines.
Agonist: drugs that resemble the effects of endogenous molecules. Example: bethanechol stimulates cholinergic receptors.
Pharmacologic antagonists: drugs that lack intrinsic activity and produce effects by ↓ action of endogenous molecules at receptors.
Competitive: propranolol competes with catecholamines at beta receptors. Noncompetitive: MAO irreversible inhibitor
Partial antagonist: inhibits endogenous ligand from binding to the receptor but has some intrinsic activity. Example: nalorphine on
Physiological antagonism: drug acts independently at different receptor to produce opposing action. Example: epinephrine and
Neutralizing antagonism: two drugs bind to each other to form inactive compound. Example: digoxin-binding antibody sequesters
Mechanisms of drug action
Cell surface receptors: can be proteins, glycoproteins or nucleic acids. Can be located at the cell surface, cytoplasm, or inside the
nucleus. Receptor binding is very specific. Interactions: van der Waals, ionic, hydrogen, covalent influence duration and reversibility
of drug action. Interaction depends on chemical structure of drug and receptor.
Signal transduction by cell-surface receptors: drug receptor binding triggers signal through second messenger or effector in the
cycoplasm. Example: isoproterenol binds beta receptor (coupled to adenylate cyclase via stimulatory G protein) ↑ cAMP. Second
messengers may cause change in protein synthesis.
Signaling mediated by intracellular receptors: drugs bind to soluble DNA-binding protein cytoplasmic receptors regulate gene
transcription. Examples: thyroid hormone, steroid hormones, vitamin D, retinoids.
Target cell desensitization / hypersensitization: cellular protective mechanisms exist to maintain homeostasis and prevent
overstimulation / understimulation of target cells. Down regulation: occur due to continuous prolonged drug exposure ↓ receptor #.
Desensitization: is the result of down regulation. Effect of subsequent drug exposure is ↓. Example: chronic albuterol use down
regulation of beta receptors tolerance. Heterogenous desensitization: nonspecific desensitization by altering components of the
signaling pathway. Hyperactivity/hypersensitivity: due to long term exposure to antagonists followed by abrupt cessation new
receptor synthesis upregulation.
Pharmacologic effects not mediated by receptors: Colligative drug effects lack requirement for specific structures. Examples:
volatile general anesthetics are lipophilic interact with cell membrane lipid bilayer ↓ excitability. Cathartics (mg sulfate, sorbitol)
↑ osmolarity of intestinal fluids. Antimetabolites: structural analogs of endogenous compounds incorporated into cellular
components, examples: methotrexate, 5-fluorouracil, cytarabine. Antacids: such as Al hydroxide, Ca carbonate, Mg hydroxide act by
ionic interaction to ↓ gastric acidity
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↑ dose ↑ concentration at site of action ↑ effect up to a ceiling.
Quantal dose-response curve: # of patients exhibiting a defined response by specific drug dose. Bell shaped.
Graded dose-response curve: magnitude of drug effect vs. drug dose. Efficacy is measured by the maximum effect. Potency
compared different molar doses of different drugs needed to produce the same effect.
Log dose-response curve: drug effect vs. log dose. Used to compare efficacy and potency of different drugs with same mechanism
of action (same slope). Efficacy; determined by the height of the curve (Emax). Potency: compared using ED50 (dose producing
50% of Emax). Competitive antagonist: parallel shift to the right, same Emax is achieve but at ↑ dose. Noncompetitive antagonist:
nonparallel shift to the right, lower Emax (action cannot overcome if more agonist is present).
Enhancement of drug effect
Addition: two different drugs with same effect cumulative effect. Example: trimethoprim and sulfamethoxazole inhibit two different
steps in folic acid synthesis ↓↓ bacterial growth.
Synergism: two different drug with same effect effect is ↑ than cumulative sum. Example: penicillin and gentamicin against
Potentiation: one drug with no effect alone will ↑ effect of another active drug. Example: carbidopa (inactive dopa analog) ↓
degradation of levodopa.
Selectivity of drug action
Therapeutic index: TD50/ED50 (median toxic dose / median effective dose).
Margin of safety: minimum toxic dose for 0.1% of population (TD0.1) / minimum effective dose for 99.9% of population (ED99.9).
Drug sources and major classes
Alkaloids (x-ine): plant-derived nitrogen containing compounds. Alkaline. Examples: morphine (opium poppy), atropine (belladonna),
colchicine (autumn crocus, neutral).
Peptides / polypeptides: polymers of amino acids. From humans or animals. Smaller than proteins. No oral activity, short half life.
Example: somatostatin, glucagon.
Steroids: from humans or animal. Estradiol, testosterone, hydrocortisone.
Hormones: chemicals formed in one organ and carried in the blood to another. Mostly steroids or proteins. Made synthetically, by
recombinant DNA (insulin) or from animals (thyroid, conjugated estrogens).
Glycosides: sugar moiety bound to non-sugar (aglycone) moiety by glycosidic bond. From plant (digitoxin) or microbial (streptomycin,
Vitamins: Water soluble: B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cyanocobalamin), C (ascorbic acid), folic
acid, pantothenic acid, H (biotic). Lipid soluble: A (retinol), D (ergocalciferol), E (alpha-tocopherol), K (phytonadione).
Polysaccharides: polymers of sugar from animals or humans (heparin).
Antibiotics: penicillin, tetracycline, doxorubicin.
Drugs synthesized from organic compounds. May have chemical structure resembling active natural products (hydroxymorphone
morphine, ampicillin penicillin).
Peptidomimetics: molecules with no peptide bonds, molecular weight < 700, activity similar to original peptide (e.g. losartan).
Drug action and physiochemical properties
Drugs must enter and be transported by body fluids. Drugs must pass membrane barriers, escape ↑ distribution to site of loss,
penetrate to active site, be removed from active site, metabolized to a form easily excreted.
Drug polarity: relative measure of lipid and water solubility. Measured in Partition Coefficient: ratio of solubility in organic solvent to
solubility in aqueous solvent (log value).
Water solubility: depends on ionic character and hydrogen ion bonding. Nitrogen and oxygen containing functional groups ↑ water
solubility. Required for GI dissolution, parenteral solutions, ophthalmic solutions, good urine concentration.
Lipid solubility: ↑ by nonionizable hydrocarbon chains and ring systems. Required for penetrating GI lipid barrier, penetrating BBB, IM
Ionization constant (Ka): indicates the relative strength of acids and bases. Expressed in negative log (pKa).
Strong acids: HCl, H2SO4, HNO3 (nitric), HClO4 (perchloric), HBr, HIO3 (iodic).
Strong bases: NaOH, KOH, MgOH2, CaOH2, BaOH2, quaternary ammonium hydroxides.
Weak acids: organic acids containing carboxylic (-COOH), phenolic (Ar-OH), sulfonic (-SO2H), sulfonamide (-SO2NH-R), imide (-CO-
NH-CO-), beta carbonyl (-CO-CHR-CO-) groups.
Weak bases: organic bases containing amino groups (1ry –NH2, 2ry -NHR, 3ry –NR2) and saturated heterocyclic nitrogen. Aromatic
or unsaturated heterocyclic nitrogen are very weak bases do not form salts.
Le Chatelier’s priniciple governs ionization (weak acid at ↓ pH ↓ ionization cross lipid membranes).
Rule of nines: |pH-pKa|=1 90:10 (1 nine), |pH-pKa|=2 99:1 (2 nines).
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Salts: virtually all salts are strong electrolytes. Inorganic salts: made by combining drugs with inorganic acids or bases (HCl, NaOH).
Salt form has ↑ water solubility ↑ dissolution. Organic salts: made by combining acidic and basic organic molecules ↑ lipid
solubility depot injections (e.g. penicillin procaine). Amphoteric salts: contain acidic and basic functional groups form internal
salts or zwitterions solubility problems.
Neutralization reaction: e.g., occur when an acidic solution of an organic salt is mixed with a basic solution. The nonionized organic
acid or base will ppt IV drug incompatibility.
Drugs whose cation ends with –onium or –inium and anoic is Cl, Br, I, nitrate, sulfate (e.g. benzalkonium chloride, cetylpyridinium
chloride) are quaternary ammonium salts neural solution in water.
Structure and pharmacologic activity
Drug structure specificity
Structurally non-specific drugs: drug interaction with cell membrane depends more on the drug’s physical properties than on its
chemical structure. Interaction usually depends on cell membrane’s lipid nature and drug’s lipid attraction. Examples: general
anesthetics, some hypnotics, some bactericidal agents.
Structurally specific drugs: pharmacologic activity depends on drug binding to specific endogenous receptors.
Drug receptor binding
Receptor site theories: Lock-key theory: over-simplification that assumes a complete complementary relationship between drug and
receptor. Induced fit theory: also assumes a complete complementary relationship between drug and receptor but provides for mutual
conformational changes between drug and receptor, it can explain phenomenon of allosteric inhibition. Occupational theory of
response: further postulates that intensity of pharmacologic response is proportional to number of occupied receptors.
Receptor site binding: ability of a drug to bind to specific receptor is mostly determined by its chemical structure not physical
properties. Chemical reactivity influences its bonding ability and exactness of fit to the receptor. Drug interaction is similar to fitting a
jigsaw puzzle pieces, only drugs of similar shape and chemical structure can bind and producer response. Usually only a portion of the
drug molecule is involved in receptor binding. Pharmacophore: functional group that is critical for receptor interaction. Drugs with
similar pharmacophores may have similar qualitative but not quantitative activity. Agonist: good receptor fit ↑ affinity ↑ response.
Antagonist: drug with some binding but no pharmacophore no response but it blocks other drugs from binding.
Types of stereoisomers: optical, geometric, conformational.
Optical isomers: contains at least one chiral (asymmetric) carbon (four different substitutes).
Enantiomers: optical isomers that are mirror image of each other, identical physical and chemical properties, potentially different
potency, receptor fit, activity, metabolism, etc. One enantiomer rotate the plane of polarized light clockwise (dextro, D, +), the other
counter clockwise (Leve, L, -). Example: dextrorphanol narcotic analgesic and antitussive, levorphanl only antitussive. Racemic
mixture: equal mixgture of D and L enantiomers, optically inactive.
Diastereomers: stereoisomers which are neither mirror image, nor superimposable. Drug must have a minimum of 2 chiral centers.
Different physicochemical properties (solubility, volatility, melting point).
Epimers: special type of diastereomers, compounds are identical in all aspects except stereochemistry around one chiral center.
Epimerization is important for drug degradation and inactivation.
Geometric (cis-trans) isomers: occurs due to restricted rotation around a chemical bond (double bond, rigid ring system). Cis-trans
are not mirror images, have different physicochemical and pharmacologic properties, because functional groups can be separated by
different distances not equal fit to receptors. If functional groups are pharmacophores different biologic activity. Example: cis-
diethylstilbestrol has 7% estrogenic activity of trans-diethylstilbestrol.
Conformational isomers (rotamers, conformers): non-superimposable molecule orientations due to atoms rotation around single
bonds. Common for most drugs, allows drugs to bind to multiple receptors. Example: Ach 2-forms: transmuscarinic, gauche
Bioisosteres: molecules containing groups that are spatially and electronically equivalent, same physicochemical properties. Isosteric
replacement of functional groups alter metabolism ∆ potency, SE, activity, duration of action (e.g. procainamide, an amide, has
longer duration of action than procaine, an ester). Isosteric analogs: may act as antagonists (e.g. alloxanthine is a xanthine oxidase
inhibitor, compared to its isostere, xanthine, the enzyme substrate).
Mechanisms of drug action
Interaction with receptors
Agonists: have both affinity and intrinsic activity with the receptor.
Partial agonists: interact with same receptors but with similar affinity but lower intrinsic activity ↓ response.
Pharmacologic antagonists: bind to the same receptor as the agonist but with no intrinsic activity. Can be reversible, irreversible,
competitive, noncompetitive (like enzyme inhibitors).
Chemical antagonists: two compounds react inactivation of both. Example: heparin (acidic polysaccharide) with protamine (basic
protein), chelating agents as metal poisoning antidotes (EDTA for calcium / lead, penicillamine for copper, dimercaprol for mercury /
gold / arsenic).
Functional / physical antagonists: produce antagonistic physiologic actions by binding at separate receptors. Example: acetylcholine,
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Interaction with enzymes
Due to ↑ enzyme protein synthesis.
Examples: barbiturates, antiepileptics (phenytoin), rifampin, antihistamines, griseofulvin, oral contraceptives.
Mechanism: by allosteric binding or coezymes such as vitamins (esp vitamin B complex), cofactors (Na, , Mg, Ca, Zn, Fe).
Due to interaction with the apoenzyme, coenzyme or enzyme.
Reversible inhibition: results from non-covalent interaction. Equilibrium exists between bound and free drug.
Irreversible inhibition: results from covalent stable interaction.
Competitive inhibition: occurs when there is a mutually exclusive binding of the substrate and inhibitor.
Noncompetitive inhibition: occurs when the drug binds to an allosteric site on the enzyme.
Interaction with DNA/RNA
Inhibition of nucleotide biosynthesis: caused by folate, purine, pyrimidine antimetabolites. Folic acid analogs: e.g. methotrexate,
trimetrexate, ↓ dihydrofolate reductase ↓ purine, thymidylate. Purine analogs: e.g. 6-mercaptopurine, thioguanine, act as
antagonists in the purine bases synthesis. Pyrimidine analog: e.g. 5-fluorouracil, ↓ thymidine synthase.
Inhibition of RNA/DNA biosynthesis: due to interference with nucleic acid synthesis. Use mainly as antineoplastic agents (Cancer
Inhibition of protein synthesis
Tetracyclines: ↓ tRNA binding to ribosomes and block release of completed peptides from ribosomes.
Erythromycin, chloramphenicol: bind to ribosomes, ↓ peptidyl transferase, ↓ formation of peptide bond, ↓ peptide chain formation
Aminoglycosides: binding to ribosomes formation of abnormal protein, ↓ addition of AAs to peptide chain, misreading of mRNA
tempelate incorporation of incorrect AAs in peptide chain.
Interaction with cell membranes
Digitalis glycosides: ↓ cell membrane Na-K pump ↓ K influx, ↓ Na outflow.
Quinidine: prolong polarized and depolarized states of membrane potential in myocardial membranes.
Local anesthetics: interfere with membrane permeability to Na-K block impulse conduction in nerve cell membranes.
Polyene antifungals: e.g. nystatin, amphotericin B, alter membrane permeability.
Antibiotics: e.g. polymyxin B, colistin, alter membrane permeability
Acetylcholine: ↑ membrane permeability to cations.
Proton pump inhibitors: ↓ H+/K+ pump in parietal cell membranes ↓ efflux of protons to the stomach.
Form monomolecular layer over entire areas of cells. Large dose is given. Examples: volatile general anesthetic gases (ether, nitrous
oxide), some depressants (ethanol, chloral hydrate), antiseptics (phenol, rubbing alcohol).
13. Autonomic and Central Nervous Systems
Receptor summary tables
Inhibitory receptors Excitatory receptors
Types: M2, Alpha-2, D2, GABA, Opioid
(mu, delta, kappa)
Action: ↓ cAMP, ↑ K conductance, ↓ Ca
conductance, ↑ Cl conductance (GABA)
Types: M1, Nicotinic, Alpha1, Beta-1, D1, Glutamate, H1-2.
Action: ↑ cAMP, ↓ K conductance, ↑ Ca (cation)
conductance, ↑ IP3/DAG
Mechanism Adrenergic Cholinergic
Ganglion blocker Hexamethonium, mecamylamine
Bretylium, guanethidine Botulinum toxin
Cocaine, desipramine Not a major mechanism
Pargyline (MAOAI), selegiline
(MAOBI), tolcapone (COMTI)
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Heart B1 ↑ conduction velocity, ↑ contraction rate /force
M ↓ conduction velocity, ↓ contraction rate /force
Arterioles Alpha-1 Constricts cerebra, cutaneous, visceral arterioles
Beta-2 Dilates skeletal muscle arterioles
Eye Alpha-1 Iris contracts mydriasis
M Sphincter / ciliary contraction miosis
Lung Beta-2 Relaxes bronchial / tracheal muscles
M Contraction, ↑ secretions
Alpha-1 Contracts sphincter muscles
M Relax sphincters, contracts smooth muscles.
Apha-1 Contracts sphincter
M ↑ motility (perisalsis), relax sphincters, ↑ secretions
Uterus Alpha-1 Contraction
Beta-3 Adipolysis, mobilize fatty acids
Glands M ↑ secretions (eye, sweat, saliva, nasal)
Direct-acting agonists: Examples: Ep, NEp, terbutaline, dobutamine, naphazoline. Alpha agonist: phenhylephrine. Beta agonist:
Catecholamine (Ep, NEp) synthesis: Tyrosinse tyrosine hydroxylase DOPA dopa decaroxylase dopamine dopamine
hydroxylase NEp Ep.
Catecholamine deactivation: methylation by catechol O-methyltransferase (COMT) and oxidative deamination by monoamine oxidase
Indirect acting agonists (sympathomimetics): Chemically related to catecholamines. Act by ↑ neurotransmitter release. Examples:
amphetamine, tyramine, ephedrine.
Post-junctional alpha-1: Location: iris, arteries, veins, hair follicle muscles, heart, GI sphincters. Agonist effect: vasoconstriction,
smooth muscle contraction. Examples: phenylephrine.
Pre-junctional alpha-2: Effect: ↓ neurotransmitter release, lipolysis, platelet aggregation. Examples: clonidine, methylnorepinephrine.
Beta-1: Location: heart. Effect: ↑ force / rate of contraction. Examples: dobutamine.
Beta-2: Location: bronchial / vascular smooth muscles. Effect: smooth muscle dilatation / relaxation. Examples: albuterol, terbutaline.
Beta-3: Location: fat cells. Effect: lipolysis (for obesity).
Epinephrine: medullary hormone, stimulate all receptors (alpha1-2, beta1-2). Use: treat bronchospasm, hypersensitivity / anaphylactic
reactions, ↑ duration effect of local anesthetics (SC), restore cardiac activity in cardiac arrest, glaucoma (topically, vasoconstriction ↓
aqueous humor production).
Norepinephrine: adrenergic neurotransmitter, stimulate alpha1-2, beta-1 (weak beta-2).
Phenylephrine: alpha-1 agonist. Use: pressor in hypotensive emergency, ↑ duration effect of local anesthetics, nasal decongestion
Alpha-1 agonists for nasal decongestion: phenylephrine, oxymetazoline, xylometazoline, phenylpropanolamine
Alpha-2 agonists (clonidine, methyldopa, guanfacine, guanabenz): for ↑ BP. Clonidine is used to ↓ intraocular pressure during surgery.
Isoproterenol: beta1-2 agonist, bronchodilator, cardiac stimulant in cardiac shock / arrest.
Dobutamine: beta-1 agonist, improve heart function in CHF emergency.
Beta-2 agonists (albuterol, terbutaline, metaproterenol): systemic or local bronchodilators for asthma.
General SE: arrhythmias, pulmonary hypertension, edema, cerebral hemorrhage, rebound nasal congestion, anxiety.
Alpha blockers: include ergotamine, prazosin (alpha-1), phenoxybenzamine (nonselecive, irreversible), tolazoline.
Beta blockers: similar structure to beta agonists. Examples: metoprolol (beta-1), propranolol (nonselective).
Prazosin (x-azosin): vasodilation for hypertension and BPH symptoms. SE: first dose syncope, de BP, dizziness, drowsiness,
palpitation, fluid retention, priapism (continuous penis erection).
Phenoxybenzamine / phentolamine: nonselective alpha blockers, treat vasospasm, acute hypertensive emergency (e.g.
pheochromocytoma, MAOI, sympathomimetics). SE: ↓ BP, tachycardia, ↓ ejaculation, miosis, nasal congesion. Tolazoline: for
neonatal pulmonary hypertension.
Labetolol: alpha-1 and beta1-2 blocker, for hypertension.
Propranolol: nonselective beta blocker, for prophylaxis of angina pectoris, ventricular arrhythmias, migraine, for hypertension, ↓ heart
rate in anxiety and hyperthyroidism. SE: bradycardia, CHF, bronchoconstriction, ↑ triglycerides, ↓ HDL, depression. Sudden d/c is
B1 blockers (acetbutolol, metoprolol, atenolol): for hypetension, arrhythmia, angina.
For glaucoma: eye drops of timolol (B1-2 blocker) and betaxolol (B1 blocker).
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Nicotinic receptors: Location: at postganglionic neuroeffector sites.
Muscarinic receptors: Location: at all autonomic ganglia and at the neuromuscular junction of somatic nervous system.
Acetylcholine: endogenous neurotransmitter, very short half life (v. rapid hydrolysis by AChE), ester of acetic acid and choline, very
Direct acting agonists: structurally similar to acetylcholine but more resistant to AChE longer duration. Examples: methacholine,
bethanecol. Use: non-obstructive urinary retention (bethanechol), glaucoma (pilocarpine, miosis).
Indirect acting agonists: most are AChE inhibitors. Reversible inhibitors: most are carbamates (carbamic acid esters), e.g.
physostigmine, neostigmine, pyridostigmine. Irreversible inhibitors: organophosphate esters, insecticides, nerve gas, e.g.
isoflurophate, echothiophate. Use: glaucoma (miosis), myasthenia gravis, hypercholinergic crisis (neuromuscular junction
depolarization blockade), anticholinergic toxicity.
General SE: bronchospasm, abdominal cramps, ↓ BP, syncope, ↓ heart rate, salivation, sweating, lacrimation, miosis, flushing, tremors,
Quaternary nitrogen: doesn’t pass BBB, e.g. ipratropium, glycopyrrolate, propantheline.
Tertiary nitrogen: pass BBB, e.g. benztropine, dicyclomine, pirenzepine, tropicamide.
Uses: ↓ gland / bronchial secretion before anesthesia (atropine, glycopyrrolate), induce sedation / ↓ motion sickness (scopolamine), ↓
vagal stimulation of the heart (atropine), produce mydriasis / cycloplegia (homatropine), ↓ GI spasms (propantheline), asthma
(ipratropium), Parkinson’s / extrapyramidal disorders (benztropine, trihexyphenidyl), cholinergic toxicity (atropine).
Ganglionic blockers: e.g. mecamylamine, trimethaphan, for hypertensive crisis.
SE: mydriasis, ↑ intraocular pressure, blurred vision, dry mouth, constipation, urinary retention, fever, nervousness, drowsiness,
Nondepolarizing (competitive) drugs
Examples (x-curine, x-curonium, x-curium): curare alkaloids (tubocurarine, metocurine, contain a tertiary amine), and synthetic
analogs (atracurium, doxacurium, mivacurium, pancuronium, vecuronium, pipercuronium).
Mechanism: compete with ACh for nicotinic receptors at the NMJ ↓ end-palate potential depolarization potential not reached.
Action is overcome by ↑ dose cholinesterase inhibitor.
SE: respiratory paralysis, histamine release, bronchospasm, tachycardia
Depolarizing (noncompetitive) drugs
Examples: succinyl choline (pseudo-cholinesterase metabolism short action), galantamine. Contain quaternary nitrogen.
Mechanism: desensitize nicotinic receptors at NMJ. React with nicotinic receptors long (2 min) depolarization of excitable
membrane ↓ receptor sensitivity unresponsive. Similar effect to excess ACh.
SE: respiratory paralysis, painful muscle fasciculation, Muscarinic response (bradycardia, ↑ secretion, cardiac arrest).
Effect: depress CNS and induce reversible state of analgesia, amnesia, unconsciousness, ↓ sensory / autonomic reflexes, skeletal
muscle relaxation, loss of all sensation.
Ideal drug: rapid smooth induction and rapid recovery.
General SE: respiratory / CNS / CV depression. Halothane ↑ sensitivity to catecholamines.
Volatile (inhalation) anesthetics:
Examples: simple lipophilic molecules, nitrous oxide (N2O, inorganic), halothane (halogenated HC), ethers (x-flurane, methoxyflurane,
isoflurane, desflurane, sevoflurane).
Mechanism: absorbed and excreted through the lungs. May be supplemented with analgesics (↓ anesthetic dose), skeletal muscle
relaxants, antimuscarinics (↓ bronichial secretions during surgery).
Halothane ↑ heart sensitivity to catecholamines, arrhythmia.
Nonvolatile (IV) anesthetics
Water soluble: Ultra-short acting barbiturates (thiopental), ketamine, BZD (diazepam, midazolam), morphine, fentanyl, droperidol.
Imidazole: propylene glycol solution. Propofol: emulsion.
Use: induce drowsiness and relaxation before inhalational general anesthesia.
Most are structurally similar to cocaine.
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Ester drugs: rapid hydrolysis by plasma esterases short action. Examples: cocaine, procaine, chloroprocaine, benzocaine,
Amide drugs: longer acting, liver metabolism. Examples: lidocaine, dibucaine, mepivacaine, bupivacaine, etidoacione, prilocaine.
Mechanism: block Na channels in nerve membrane reversible block of nerve impulse conduction, reversible loss of sensation, no
loss of consciousness. At tissue pH lipophilic, uncharged, 2ry or 3ry amine form diffuse through connective tissue and cell
membrane enter nerve cells convert to ionized charged ammonium cation active form block generation of action potential
remain trapped in cell (ionized can’t cross cell membrane).
Epinephrine: mix with local anesthetic vasoconstriction ↓ blood flow ↓ systemic absorption longer local effect, no systemic
Use: regional nerve block for pain relief, anesthesia for minor operations, topical anesthesia (dyclonine and pramoxine as throat
lozenges and hemorrhoids cream), anesthesia for lower limb / pelvic / obstetric surgery when injected in the epidural.
SE: systemic absorption seizures, CNS / respiratory / myocardial depression.
Typical (classical) drugs: phenothiazines, thioxanthines (x-othixene, thiothixene, chlorprothixene), butyrophenones (haloperidol).
Atypical (newer) drugs: clozapine, risperidone, pimozide, loxapine, molindone, quetapione, sertindole, remoxipride. Advantages:
more effective for negative symptoms, ↓ extrapyramidal SE.
Phenothiazines (x-omazine, x-perazine): chlorpromazine, triflupromazine, prochlorperazine, trifluoperazine, fluphenazine, thioridazine.
Fluphenazine esters (decanoate, enanthate) very lipophilic very long acting.
Mechanism: block dopamine receptors in the brain (extrapyramidal SE). Other possible effects: H1, alpha1, muscarinic. Atypical
drugs: also serotonin antagonism.
SE: Central: drowsiness, extrapyramidal (akathesia, dystonia, akinesia, tardive dyskinesia), poikilothermy, ↑ appetite, weight gain, ↑
release of hormones. Peripheral: postural hypotension, reflex tachycardia, impaired ejaculation, dry mouth, blurred vision, liver toxicity.
Antidepresseants / antimanics
MAO-I: phenelzine, isocarboxazid (↓ potent), tanylcypromine (↑ potent). Mechanism: block oxidative deamination of brain biogenic
amines (NEp, serotonin). Effect takes 3 weeks. Use: depression, phobic anxiety, narcolepsy, ↑ SE ↓ use. SE: CNS (stimulation,
tremor, agitation, mania, insomnia), ↓ BP, anticholinergic SE (constipation, dry mouth, urinary retention). DI: tyramine foods,
sympathomimetic drugs (hypertensive crises),
TCA: secondary or tertiary amines, x-ipramine, x-triptyline, x-pin (doxepin, amoxapine, dibenzoxazepine). Mechanism: ↓ CNS re-
reuptake of biogenic amines (Nep, serotonin). Also block beta, serotonin receptors, ↓ reuptake. Use: depression, enuresis
(bedwetting), obsessive-compulsion, anxiety. SE: CNS (drowsiness, confusion), ↓ BP, tachycardia, anticholinergic SE, bone marrow
Atypical antidepressants: bupropion, trazadone, mefazadone, SSRI, venlafaxine. Mechanism: ↓ CNS re-reuptake of biogenic amines.
SE: similar to TCA + blurred vision, tinnitus, sex dysfunction.
Antimanics (mood stabilizers): lithium carbonate, valproic acid, carbamazepine. Mechanism: lithium ∆ transmembrane Na exchange,
∆ neurotransmitter release, ↓ inositol metabolism. Use: manic depression / bipolar disease. SE: lithium causes ↑ urination, fine hand
tremor (↓ with time).
Anxiolytics / sedative-hypnotics
Examples: BZD (diazepam, alprozlam, flurazepam, halazepam, oxazepam, prazepam, lorazepam, chlordiazepoxide, clorazepate),
Old drugs: barbiturates, hydroxyzine no longer used due to ↑ risk of tolerance, dependence, withdrawal reactions, and ↑ SE (↑ CNS
Diazepam: not basic enough to form water soluble salt with acid dissolve in propylene glycol for IV, may ppt if mixed with water.
Barbiturates: derivatives of barbituric acid. Long / branched / unsaturated side chain ↑ lipid solubility ↑ metabolism, ↓ onset, ↓
duration of action, ↑ potency. Phenobarbital (barbiturates) strong enzyme inducer. Weak acids, in overdose alkalinize the urine
BZD: Mechanism: GABA-ergic, ↑ chloride channel opening ↑ chloride conduction ↑ membrane hyperpolarization. Also CNS
depression (hypnotic, anesthetic, anticonvulsant, muscle relaxant, ↑ alcohol depression). Use: anxiety, insomnia, pre-anesthesia,
during acute alcohol withdrawal. SE: CNS depression, ataxia, confusion, abuse / dependence.
Buspirone (x-pirone): Mechanism: bind to central dopamine, serotonin receptors. No CNS depression (hypnosis, anti-convulsion,
alcohol interaction, no abuse, no rebound anxiety). Use: anxiolytic (effect takes a week). SE: headache, dizziness.
Zolpidem (Ambien): Mechanism: strong sedation but ↓ anxiolytic effect (for insomnia). Use: insomnia. No abuse, rebound insomnia,
or respiratory depression.
Barbiturate: Mechanism: similar to BZD. Use: Ultra-short acting barbiturates (thiopental): induce anesthesia. Long acting barbiturates
(phenobarb): antiepileptics. SE: hypnosis, drowsiness, nystagmus, bradycardia, ↓ BP, anemia, liver toxicity, respiratory depression. DI:
Chloral hydrate: aldehyde prodrug. Use: induce sleep, pre-anesthesia. SE: toxic active cumulative metabolite, CNS depression, ↑
alcohol effect, leukopenia. DI: enzyme induction
Older agents: long-acting barbiturates (phenobarb, mephobarb, metharbital, primidone), phenytoin (hydantoin), succinimides
(ethosuximide, phensuximide), valproic acid, trimethadione, dimethadione.
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Newer agents: carbamazepine, BZD (diazepam, clonazepam, clorazepate), gabapentin (GABA analog), lamotrigine, felbamate.
Pharmacology: ↓ or prevent excessive discharge and ↓ spread of excitation from CNS seizure center.
Phenytoin: ↑ Na efflux
Barbiturates, BZD, valproic acid: ↑ GABA-ergic inhibitory neuronal function.
Tonic-clonic (grand mal) carbamazepine, pheytoin, phenobarb.
Status epilepticus diazepam, phenytoin, phenobarb
Absence (petit mal) clonazepam, phenobarb, valpric acid
Partial gabapentin, lamotrigine, flebamate
Pscyhomotor carbamazepine, phenytoin, phenobarb
General SE: CNS (drowsiness, confusion, diplobia, nystagmus), blood toxicity, allergy, Stevens-Johnson, birth defects (no safe drugs
Phenytoin: gingival hyperplasia, arrhythmias.
IV barbiturates / BZD SE: CV collapse, respiratory depression
Autacoids are local autopharmacological agents or local hormones. May also function as neurotransmitters (e.g. histamine, serotonin).
Also include leukotrienes (discussed later).
Chemistry: bioamine derived from dietary histidine. H1-antagonists: diphenhydramine, dimenhydrinate, doxylamine, clemastine,
meclizine, cyclizine, hydroxyzine, cyproheptadine, promethazine, chlorpheniramine, brompheniramine, tripelennamine, pyrilamine.
New H1 antagonists (loratadine, desloratadine, fexofenadine, cetirizine, astemazole, acrivastine) are less sedating due to their inability
to cross BBB. H2-antagonists: ranitidine, cimetidine, famotidine, nizatidine.
Pharmacology: H1-receptors: allergic and anaphylactic responses (bronchoconstriction, vasodilation, spasmodic GI smooth muscle
contraction, ↑ capillary permeability, itching, pain). H2-receptors: ↑ secretion of gastric acid, pepsin, intrinsic factor.
Indications: exogenous histamine may be used for diagnosing gastric acid function (not very safe). H1-blockers: ↓ allergy
symptoms (seasonal rhinitis, conjunctivitis), common cold (rhinovirus) infection, urticaria. Agents with ↑ anticholinergic effect (meclizine,
cyclizine, dimenhydrinate, diphenhydramine): motion sickness and vertigo nausea and vomiting. Promethazine: antiemetic.
Hydoxyzine: mild anxiolytic. H2-blockers: gastric hypersecrtion (ulcers, Zollinger-Ellison, GERD).
SE: H1-blockers: CNS (sedation, depression, fatigue, except in new agents), GI upset, anticholinergic (dry mouth, constipation). Non-
sedating H1-blockers: arrhythmia, especially with hepatic enzyme inhibitors, grapefruit. H2-blockers: CNS (dizziness, confusion),
liver / kidney damage, liver enzyme inhibition (cimetidine), androgenic effects (cimetidine).
Chemistry: serotonin is 5-HT (5-hydroxytryptamine). Bioamine synthesized from tryptophan. Serotonin agonists (triptans): idole
derivatives of serotonin. Also cisapride, benzamide, ergot alkaloids (ergonovine, dihydroergotamine, bromocriptine, methylsergide,
partial agonists / antagonists). Serotonin antagonists: ondasetron, granisetron.
Pharmacology: Serotonin: vasoconstriction, platelet aggregation, nausea / vomiting, anxiety, depression, appetite, ↑ acetylcholine
release. Serotonin agonists: Cisapride: releases Ach (treat GERD, off market). Serotonin antagonists: prevents nausea / vomiting.
Indications: Agonists: drugs use the serotonin system to affect the CNS and modulate behavior (dexfenfluramine as anorexiant,
buspirone as anxiolytic, SSRI for depression). Triptans and ergots are used for migraines. Ergots are used to postpartum hemorrhage
(vasoconstriction uterine contraction). Bromocriptine is used to prevent post partum breast enlargement. Antagonists: prevents
nausea and vomiting due to cancer chemotherapy.
SE: Agonists: dizziness, tight chest, coronary vasoconstriction (CI in angina, ↑BP). Cisapride: arrhythmia, diarrhea. Ergots: cold /
ischemic extremities, GI upset. Antagonists: headache, dizziness, constipation.
Chemistry: derivatives of prostanoic acid (ringed structure). Membrance phospholipids phospholipase A2 arachidonic acid
COX enzyme PG. COX I: protects gastric mucosa (PG), homeostasis (thromboxane synthesis). COX II: expressed only in
response to inflammation or injury. PG classification subscripts relates to the number and position of double bonds in the aliphatic
Pharmacology: Endogenous: release in response to insults (chemical, bacterial, mechanical). Cause pain and edema. Physiologic
responses: PGI: vasodilation, ↓ platelet aggregation, ↑ gastric release of bicarbonate and mucus (protect epithelium). PGE: ↓
platelet aggregation, ↓ gastric acid secretion, broncho-relaxation. PGD/PGF: bronchoconstriction.
Indications: PGE1 analogs: misoprostol to prevent NSAID induced GI ulcers, alprostadil for impotence due to erectile dysfunction.
PGE2 analogs: dinoprostone is abortifacient, for cervical ripening in pregnancy. PGF2alpha analogs: latanoprost topically to ↓
intraocular pressure in glaucoma, carboprost is abortifacient (not available in US). PGI analog: epoprostenol treats pulmonary
SE for PGE: CNS (irritability, fever, seizures, headache), cardiovascular (hypotention, arrhythmia, flushing), respiratory depression,
hematologic (anemia, thrombocytopenia), diarrhea, abortion.
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Posterior pituitary hormones
Oxytocin: octapeptide. Action: stimulate uterine contraction, induce labor. Use: promote delivery, control postpartum bleeding. SE:
uterine spasm / rupture, fetal effects (bradycardia, jaundice), water intoxication / coma.
Vasopressin: octapeptide. Action: vasopressor and anti-diuretic. hormone (ADH) activity. It ↑ reabsorption of water at distal renal
tubules. Use: neurogenic diabetes insipidus, postoperative abdominal distention. SE: GI cramps, vomiting, tremor, sweating,
Anterior pituitary hormones
Protein molecules: available therapeutically, include: corticotropin, thyrotropin, thyrotropin-releasing hormone, growth hormone
Corticotropin: also known as Adrenocorticotropic hormone (ACTH). Single chain 39-AA polypeptide. Action: stimulate adrenal cortex
to secrete adrenocorticosteroids. Use: diagnosis of adrenal insufficiency.
Growth Hormone: also known as Somatotropin, 191-AA chain. Action: stimulate protein, carbohydrate and lipid metabolism to ↑ cell,
tissue, organ growth. Use: for children with growth failure due to ↓ endogenous growth hormone secretion. SE: antibody formation.
Thyrotropin: also known as Thyroid Stimulating Hormone (TSH). It’s a glycoprotein.
Thyrotropin-Releasing Hormone: tripeptide.
Pituitary gonadotropins: not available therapeutically, include: Follicle-Stimulating Hormone (FSH), Luetinizing Hormone (LH),
Prolactin (Luteotropic Hormone, LH), menotropin (human Menopausal gonadotropin, hMG).
Menotropin: produce ovarian follicular growth and induce ovulation by FSH and LH-like actions. Use: induce ovulation and pregnancy
in anovulatory infertile women, ↑ spermatogenesis in men. SE: gynecomastia in men, hypersensitivity, thromboembolism, ovary
Estrogen receptors: in the nucleus in the vagina, uterus, mammary glands, anterior pituitary, hypothalamus alter mRNA.
Uses: oral contraceptives (with progestins), menopause symptoms, acne, osteoporosis, prostate cancer.
SE: edema / fluid retention, weight gain, ↑ triglycerides, hypertension, thromboembolism, MI, stroke, GI upset, endometrial cancer.
Estradiol: principal estrogenic hormone, in equilibrium with estrone. Estradiol esters are used as IM injections in oil for depot action
(valerate, cypionate). The esters hydrolyze slowly in muscle tissue before absorption (prodrugs).
Synthetic estrogens: resist first pass metabolism ↑ oral efficacy. Examples: ethinyl estradiol, 3-methyl ether mestranol
(contraceptives), quinestrol (ERT).
Non-steroidal synthetic estrogens: e.g. diethylstilbestrol.
Estrogen antagonists: e.g. clomiphene, tamoxifen citrate, toremifene citrate. Uses: clomiphene induce ovulation, tamoxifen
Aromatase inhibitors: anastrozole, letrozole (non-steroidal) ↓ conversion of androgens to estrogens. Use: advanced breast
Selective estrogen receptor modulators (SERM): raloxifene ↓ bone resorption, ↓ bone turnover. Estrogen effect on bone and
lipids but estrogen antagonist effect on uterus and breast. Use: prevention of osteoporosis.
Progesterone: C-21 natural steroidal progestin.
Synthetic progestins: 17alpha-hydroxyprogesterones, 17alpha-ethinylandrogens. ↑ lipid solubility, ↓ first pass metabolism, ↑ oral
Mechanism: similar to estrogens (intracellular receptors ∆ mRNA).
Uses: oral contraceptives (alone or with estrogens), uterine bleeding, dysmenorrhea, endometriosis.
SE: irregular period, breakthrough bleading, amenorrhea, weight gain, edema.
17alpha-hydroxyprogesterones: e.g. medroxyprogesterone acetate, megestrol acetate
17alpha-ethinylandrogens: e.g. norethindrone, norgestrel, androgens with progesterone activity. Used as oral contraceptives.
Androgens / anabolic steroids
Testosterone: C-19 steroid natural androgen / anabolic agent.
Androgens: testosterone 17-enanthate (ester with long IM action), fluoxymesterone (oral).
Anabolics: oxandrolone, dromostanolone.
Mechanism: testosterone 5alpha-reductase (in cytoplasm) dihydrotestosterone bind to androgen receptor in nucleus ∆
Uses: androgen replacement, breast cancer, endometriosis, female hypopituitarism (with estrogens), treating –ve nitrogen balance,
SE: fluid retention, ↑ LDL, ↓ HDL, female masculinity, ↓ female fertility.
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Anti-androgens: flutamide, bicalutamide, nilutamide (all non-steroids) competitive androgen inhibition by receptor binding. Use:
prostate cancer (with luteinizing hormone releasing hormone).
5alpha-reducatse inhibitors: finasteride ↓ conversion of testosterone to dihydrotestosterone. Use: BPH, androgenic alopecia.
Synthesis: in the adrenal cortex.
All steroids have fused reduced 17-carbon-atom ring.
Most natural steroids have some mineralo- and gluco- effect.
All require cytoplasmic receptors to transfer to the nuclei of target tissue cells.
Uses: replacement therapy (adrenal insufficiency), last resort for severe disabling arthritis, severe allergic reactions, ulcerative colitis,
kidney disease, cerebral edema, topical anti-inflammatory.
SE: peptic ulcer, GI bleeding, ↑ intraocular / intracranial pressure, headache, muscle weakness, skin atrophy, edema, weight gain,
excitation, irritability, hypertension, hyperglycemia, osteoporosis, flushing, hirsutism, cushingoid moon face / buffalo hump, ↓ immunity,
Mineralocorticoids: ↑ Na retention, ↑ K excretion.
Glucocorticoids: anti-inflammatory, protein-catabolic, immunosuppressant.
Cortisone / hydrocortisone: natural glucocorticoids. Synthetic and semi-synthetic glucocorticoids try to ↓ mineralocorticoid activity.
Examples: prednisone, prednisolone, triamcinolone, betamethasone, dexamethasone.
Aldosterone: natural mineralocoritoid. Synthetics: fludrocortisone acetate, desoxycoriticosterone acetate.
Iron preparations: ferrous salts are better absorbed from GI than ferric salts. Examples: ferrous sulfate, ferrous gluconate, ferrous
fumarate. Iron dextran (IV) = colloidal complex of ferric hydroxide and low molecular weight dextrans.
Iron (ferrous salts): easy GI absorption stored in bone marrow, liver, spleen as ferritin and hemosiderin incorporate into
hemoglobin iron reversibly binds molecular oxygen.
Iron (ferrous salts): iron deficiency anemia (hypochromic, microcytic RBCs poor oxygen transport).
Cyanbocobalamin (Vit B12): nucleotide-like macro-molecule. Includes cyanide and cobalt.
Iron (ferrous salts): GI distress, constipation, diarrhea, heartburn
Vitamin B12 (cyanocobalamin)
Vit B12: easy GI absorption in the presence of intrinsic (Castle’s) factor (glycoprotein produced by gastric parietal cells). Deficiency
causes megaloblastic anemia and demyelination of nerve cells irreversible CNS damage. Important for cell growth.
Vit B12: megaloblastic anemia due to vit B12 deficiency (hyperchromic, macrocytic, immature RBCs).
Vit B12: no common SE
Folic acid: structure includes PABA, glutamic acid.
Folic acid: easy GI absorption, stored intracellularly. Precursor for several coenzymes (derivatives of tetrahydrofolic acid). Deficiency
causes megaloblastic anemia but not neurologic damage.
Folic acid: megaloblastic anemia due to folic acid deficiency.
Folic acid: rare allergy if taken parenterally.
Thyroid hormones / inhibitors
Synthesis of thyroid hormones
Concentration of iodide in thyroid gland iodination of tyrosine residues on thyrogobulin (glycoprotein) proteolysis of thyroglobulin
into T4 (thyroxine, levothyroxine), and T3 (triiodothyronine, liothyronine).
T4 is less potent but has longer duration than T3.
T4 converts to T3 by peripheral deiodination.
Control: involves hypothalamic-pituitary-thyroid feedback. TRH is secreted by hypothalamus ↑ release of TSH (thyrotropin) by the
anterior pituitary ↑ production of T4/T3 in thyroid.
Action: mimic the activity of endogenous thyroid hormones regulate growth and development, calorigenic and metabolic activity,
positive inotropic / chronotropic effects (sensitize beta receptors).
Use: hypothyroidism (e.g. Myxedema), Myxedema coma, cretinism, simple goiter, endemic goiter.
SE: rare, palpitations, nervousness, insomnia, weight loss.
Sodium salts of T4/T3. T4 can be given alone (converts to T3).
Liotrix: 4:1 mixture of levothyroxine sodium to liothyronine sodium, no advantages over levothyroxine only.
Thyroid USP: from dried defatted thyroid gland of domestic animals. Standardized based on iodine content.
Thyroglobulin: purified extract of frozen porcine or bovine thyroid gland, contains T4 and T3.
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Thyrotropin (TSH): purified and lyophilized hormone from bovine anterior pituitary. Use: detection and treatment of thyroid cancer. SE:
anaphylaxis, urticaria, gland swelling, tachycardia, arrhythmia, GI upset.
Use: treat hyperthyroidism (e.g. Grave’s disease, toxic adenoma).
Ionic inhibitors: such as thiocyanate (SCN-) and perchlorate (ClO4-), inorganic monovalent anions ↓ concentration of iodide by the
thyroid. Use: rarely use as drugs, but metabolism of foods (e.g. cabbage) and drugs (e.g. nitroprusside) can produce excess SCN-.
↑ concentration iodides: such as Lugol’s solution, iodides ↓ their own transport, ↓ synthesis of mediators, ↓ hormone release. Use:
before thyroid surgery to make gland firmed and ↓ its size. SE: Iodism (↑ salivation, skin rashes, eyelid swelling, sore
Radioactive iodine (
I) sodium: trapped by thyroid gland incorporated into tyrosine / thyroid hormone. Radioactive beta particles
local destruction of thyroid cells. SE: delayed hypothyroidism.
Thiourylenes: ↓ thyroid synthesis. Examples: propylthiouracil, methimazole. Use: with
I to control mild hyperthyroidism. SE:
urticaria, dermatitis, blood toxicity, joint pain / stiffness.
17. Drug Metabolism and Interactions
Definition: drug metabolism (or biotransformation) is the biochemical changes drugs an foreign chemicals (xenobiotics) undergo in the
body leading to formation of metabolites.
Inactive metabolites: examples: hydrolysis of procaine to p-aminobenzoic acid, oxidation of 6-mercaptopurine to 6-mercapturic acid.
Metabolites with similar activity: examples: codeine is demethylated to morphine (↑ activity), acetohexamide is reduced to l-
hydroxyhexamide (↑ activity), imipramine demethylated to desipramine (same activity).
Metabolites with altered activity: retinoic acid (vitamin A) is isomerized to anti-cancer agent isoretinoic acid, antidepressant iproniazid
is dealkylated to anti-TB isoniazid.
Bioactivated metabolites (prodrugs): enalapril hydrolyzed to enalaprilat, suldinac is reduce to the active sulfide, levodopa is
decarboxylated to dopamine.
Phase I reactions
Polar functional groups are introduced to the molecule, or unmasked by oxidation, reduction, hydrolysis.
Most common reaction. Mostly in the liver. Catalyzed by cytochrome P450.
Cytochrome P450: oxidases, bound to smooth endoplasmic reticulum, require NADH, exist in multiple isoforms (CYP11Ax, CYP17By,
etc) large # of substrates. Involved in metabolism or bile acids, steroids, xenobiotics / drugs.
Oxidized drug ↑ polarity / water solubility ↓ tubular reabsorption ↑ urine excretion.
Same goal as oxidation (↑ polarity by reductases).
GI bacterial flora azo and nitro reduction reactions.
Addition of water across a bond ↑ polar metabolites.
Esterase: present in the plasma and tissues, nonspecific, hydrolyzes esters to alcohol and acid, responsible for activation of many
prodrugs. Example: procaine.
Amidase: hydrolyze amides into amines and acid (deamidation) in the liver. Example: procainamide.
Phase II reactions
Functional groups of the original drug or a phase I metabolite are masked by a conjugation reaction ↑↑ polar metabolites ↑
excretion, no crossing of cell membranes (pharmacologically inactive, no toxicity).
Conjugation reactions: combine parent drug (or metabolite) with certain natural endogenous constituents (glucuronic acid, glutamine,
glycine, sulfate, glutathione). Requires high energy molecule and an enzyme.
High energy molecule: consist of coenzyme bound to endogenous substrate, parent drug, or metabolite.
Enzyme: called transferases, found in the liver and catalyze the reaction.
Glucuronidation: most common conjugation pathway due to large supply of glucuronic acid (high energy form reacts using glucuronyl
transferase). Common with OH group (form ethers) and COOh group (form esters). Reaction adds 3-OH groups and 1-COOH group
↑↑ hydrophilicity. Glucuronides with ↑ MWt bile excretion to intestines intestinal beta-glucuronidase hydrolyze the conjugate
Sulfate conjugation: using sulfo-transferase.
Amino acid conjugation: reaction of glycine or glutamine with aliphatic or aromatic acids to form amides using N-acyltransferase.
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Glutathione conjugation: very critical for preventing toxicity from harmful electrophilic agents (halides, epoxides). Glutathione
(tripeptide) + electrophile + glutathione S-transferase mercapturic acid.
Methylation: of oxygen- nitrogen- or sulfer-containing drugs less polar but inactive metabolites. Example: COMT methylates
catecholamines such as epinephrine.
Acetylation: less polar metabolites with N-acetyl-transferase. Metabolites (e.g. of sulfonamides) may accumulate in the kidney
crystalluria / tissue damage.
Factors influencing metabolism
Qualitative differences: occur mainly in Phase II reactions. Determines the actual metabolic pathway. It can result from a genetic
deficiency of a particular enzyme or difference in a particular endogenous substrate.
Quantitative differences: occur mainly in phase I reactions. Due to difference in the enzyme level, presence of species specific
isozymes, amount of endogenous inhibitor or inducer, extent of competing reactions.
Physiologic / disease state
Due to pathologic factors that alter liver function.
Congestive heart failure: ↓ output ↓ hepatic blood flow ↓ metabolism
∆ albumin production fraction of bound drug.
Acetylation rate: depends on the amount of N-acetyl-transferase, which depends on genetic factors. Fast acetylators ↑
hepatotoxicity from isoniazid. Slow acetylators ↑ other isoniazid SE.
PM Phenotype: ↓ metabolism of B-blockers, antiarrhythmics, opioids, antidepressants.
↑ dose may saturated metabolic enzymes. As the saturation approaches 100% change from first to zero-order metabolism.
When metabolic pathway is saturated > possible alternative pathways. Example: therapeutic APAP doses glucuronic / sulfate
conjugation, toxic doses conjugation is saturated N-hydroxylation liver toxicity
Conjugation agent levels (sulfate, glutathione) is dependent on nutrition
↓ protein diet ↓ glycine, ↓ oxidative drug metabolism capacity.
Diet ↓ in essential fatty acids (linoleic acid) ↓ synthesis of certain enzymes ↓ metabolism of hexobarbital.
Diet ↓ in minerals (Ca, Mg, Zn) ↓ metabolism. ↓ Fe ↑ metabolism.
Diet ↓ in vitamins (A, B, C, E): ↓ C ↓ oxidation. ↓ E ↓ dealkylation, hydroxylation.
Metabolic enzyme systems are not fully developed at birth ↓ doses in infants / children to avoid SE, especially for glucuronide
Older children liver develops faster than ↑ in body weight ↓ efficacy.
Elderly ↓ metabolizing enzymes ↓ elimination ↑ Cp ↑ SE
Due to ∆ androgen, estrogen, adrenocorticoid activity ∆ CYP450 isozymes. Example: oxidative metabolism is faster in men.
Oral: first-pass effect ↑ oral dose
IV: by pass first-pass effect ↓↓ dose compared to oral dose.
Sublingual / rectal: also bypass first-pass effect. Variable absorption from rectal administration.
Presence of certain functional groups influences drug’s metabolic pathway (route, extent, degree of metabolism).
Nocturnal Cp of theophylline, diazepam are ↓ than diurnal Cp.
Plasma: contains esterases (hydrolyze esters). Simple esters (procaine, succinyl choline) are rapidly hydrolyzed in the blood.
Esterases can also activate prodrugs.
Intestinal mucosa: microsomal oxidation, conjugation (glucuronide, sulfate) first pass effect of lipid soluble drugs during absorption.
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Intestinal bacterial flora: secrete metabolizing enzymes. Ulcerative colitis ↑ flora. Diarrhea, antibiotics ↓ flora. Flora secrete
beta glucuronidase hydrolyze polar glururonide conjugates of bile reabsorption of free nonpolar bile acids eneterohepatic
circulation. Flora convert vitamin K to active form, and cyclamate (sweetener) to cyclohexylamine (carcinogen). Flora produce
azoreductase converts sulfasalazine to 5-aminosalicylic acid (anti-inflammatory) and sulfapyridine (antibacterial).
Stomach acidity: degradation of penicillin G, carbenicillin, erythromycin, tetracycline, peptides / proteins (insulin).
Nasal mucosa: ↑ CYP450 activity and metabolism on nasal decongestants, anesthetics, nicotine, cocaine.
Lung: first pass metabolism of IV, IM, transdermal, SC drugs but to ↓ degree than the liver. Also, second pass metabolism for drugs
leaving the liver.
Placenta: if drug is lipid soluble enough to get to circulation pass through the placenta too. Placenta is not a physical or metabolic
barrier to xenobiotics. Very little metabolism occurs. Smoking induce certain enzymes in pregnant women ↑ carcinogens from
Fetus: depends on fetal age, ↓↓ glucuronic acid conjugation. Chloramphenical ↓ glucuronidation gray baby syndrome. ↓
bilirubin glucuronide neonatal hyperbilirubinemia.
Strategies to manage metabolism
Sublingual tablets: deliver drugs directly to systemic circulation, bypassing hepatic first pass metabolism. Example: nitroglycerin.
Transdermal products: continuous drug supply for long period of time. Example: nitroglycerin.
IM depots: continuous drug supply for long period of time. Example: highly lipid soluble esters of esradiol (benzoate) and testosterone
(enanthate) slow absorption and activation by hydrolysis.
Enteric coated tablets: protect acid sensitive drugs. Examples: omeprazole, erythromycin, methenamine.
Nasal administration: for lung delivery of peptides (e.g. calcitonin salmon) which has no oral bioavailability. Lung contains protease
inhibitors peptide stability.
Levodopa (L-dopa): amino acid precursor of dopamine (for Parkinson’s). Unlike dopamine, it can penetrate BBB and reach CNS to be
decarboxylated to dopamine. Carbidopa: DOPA decarboxylase inhibitor that does not cross BBB ↓ peripheral activation and SE.
Beta-lactam AB: use clavulanic acid (a beta-lactamase inhibitor).
Ifosfamide: alkylating agent in vivo metabolic activation nitrogen mustard. Acrolein is a byproduct of metabolic activation react
with nucleophiles on renal proteins hemorrhagic cystitis. Combine ifosfamide. with mesna (neutralizes acrolein in the kidney).
Testosterone: not orally active due to rapid oxidation of 17-OH group. Methyl-testosterone: 17alpha-methyl group ↓ potent but no
rapid first pass metabolic deactivation used orally. Same for estradiol analogs.
Tolbutamide: oxidation of para-methyl group rapid deactivation. Chlorpropamide: non-metabolizable para-chloro group long
Isoproterenol: potent beta agonist for asthma. Rapid metabolism by COMT (catechol) poor oral activity. Metaproterenol: not
metabolized by COMT orally active, long t1/2.
Octreotide: synthetic octa-peptide ↓ severe diarrhea in tumors, SC. It mimics action of somatostatin (14-AA peptide, short t1/2, only
IV infusion) but resistant to hydrolysis, proteolysis.
Require in vivo biotransformation (phase I) to produce activity
The following are potential advantages for prodrugs:
↑ water solubility
Useful for ophthalmic and parenteral formulations
Example: sodium succinate esters, sodium phosphate esters to make water-soluble steroid prodrugs
↑ lipid solubility
↑ duration of action: estradiol lipid-soluble esters (benzoate, valerate, cypionate) prolonged activity (IM of esters in oil).
↑ oral absorption: by converting carboxylic acid groups to esters converted back to active acids by plasma esterases. Example:
lipophilic orally absorbed enalapril very potent orally inactive enalaprilat.
↑ topical absorption: of steroids by masking hydroxyl groups as esters or acetonides ↓ polar ↑ dermal permeability. Examples:
triamcinolone acetonide, betamethosone valerate, diflorasone diacetete.
↑ palatability: sulfisoxazole acetyl (ester, ↓ water solubility, ok taste for children) sulfisoxazole (bitter)
↓ GI irritation
NSAIDs ulceration by direct irritant effect of acidic molecules and ↓ of gastro-protective PG. Sulindac, nabumetone prodrugs with
↓ GI effect
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Methyldopa: structurally similar to L-dopa transported to CNS metabolized to active alpha-methyldopamine central alpha-2
Omeprazole: activated at acidic pH < 1 inhibition of H+/K+ATPase.
Formaldehyde: effective urinary tract antiseptic. Orally ↑ toxicity. Methenamine non-toxic prodrug hydrolyzes to
formaldehyde and ammonium ions in acidic urine (pH<5.5). Use enteric coating to prevent activation in the stomach.
Olsalazine: polar dimer of 5-aminosalisalyic acid poor oral absorption. In large intestine colonic bacteria cleave azo bond free
Diethylstilbestrol: synthetic estrogen for prostate cancer feminizing SE. Diethylstilbestrol diphosphate (ester prodrug) activated
by acid phosphatase in prostate tumor cells ↑ local action, ↓ systemic SE.
generation cephalosporin, unstable in solid dosage forms. Cefamandole nafate: stable formic acid ester
hydrolyzed by plasma esterases.
Cyclophosphamide: stable prodrug in vivo oxidation + nonenzymatic decomposition active phosphoramide mustard.
Types of interactions: drug-drug, drug-food, drug-chemical, drug-laboratory.
Precipitant: drug, food or chemical causing the interaction.
Object: drug affected by the interaction.
Epinephrine, erythromycin decompose in IV alkaline pH do not mix with aminophylline (alkaline).
Due to ∆ in absorption, distribution (protein / tissue binding), elimination (excretion / metabolism).
Epinephrine (vasoconstrictor) ↓ percutaneous absorption of lidocaine (local anesthetic).
CHF ↓ GI blood flow ↓ drug absorption
MAO inhibitors + foods w/ tyramine ↓ metabolism hypertensive crisis
Antibiotics (erythromycin) ↓ intestinal flora ↓ digoxin microbial deactivation ↑ bioavailability.
Antacids / H2 antagonists ↑ GI pH ↓ ketoconazole dissolution
∆ intestinal motility (anticholinergics ↓, laxatives ↑) ∆ absorption
Cholestyramine / kaolin digoxin adsorption ↓ bioavailability
Complexation by divalent cations ↓ tetracycline bioavailability
Due to ∆ in plasma protein binding / displacement or tissue / cellular interactions. Valproic acid displaces phenytoin and ↓ its liver
metabolism ↑↑ phenytoin. Quinidine displaces digoxin and ↓ digoxin clearance ↑↑ digoxin.
Elimination / clearance
Due to ∆ in kidney or liver clearance (enzyme induction / inhibition, enzyme substrate competition, ∆ blood flow) .
Grapefruit juice is a powerful inhibitor of CYP3A4.
Enzyme inducers: tobacco (polycyclic aromatic HC), barbiturates, rifampin, carbamazepine, phenytoin, omeprazole, troglitazone.
Enzyme inhibitors: cimetidine, ketoconazole, ciprofloxacin, erythromycin, ritonavir / nelfinavir, clopidrogel.
∆ drug absorption. Example: Complexation of tetracycline + calcium
Delayed/ ↓ absorption: NSAIDs, APAP, antibiotics, ethanol.
↑ absorption: griseoflulvin, metoprolol, phenytoin, propoxyphene
Smoking (enzyme induction) ↑ clearance of theophylline, BZD, TCA
Alcohol: acute use ↓ metabolism, chronic use ↑ metabolism.
Antagonistic, additive or synergistic effect.
Similar action excessive or toxic response. Example: alcohol + antihistamine both CNS depressants, promethazine +
antihistamine both anticholinergic.
Thiazide diuretic deplete potassium ↑ sensitivity to digoxin, deplete sodium ↑ lithium toxicity, anticoagulant + aspirin ↑ risk of
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Significance and management of interactions
Potential drug interactions
Multiple-drug therapy: including Rx and OTC. ↑ ↑ potential.
Multiple prescribers: different prescribers are not aware of history
Patient compliance: example: tetracycline not on empty stomach.
Patient risk factors: elderly at ↑ risk (∆ body composition, GI transit, drug absorption, distribution, ↓ protein binding, ↓ drug clearance).
Patients with diseases (DB, AIDS, etc) and atopic (hyper-responsive) patients are at ↑ risk.
Not all interactions are dangerous. Interacting drugs can be prescribed under supervision with monitoring. Example: cimetidine with
antacids do not take both at the same time
Some interactions are good ↑ efficacy, ↓ SE. Examples: trimethoprim + sulfamethoxazole (↑ efficacy in UTI), amoxicillin +
clavulanate potassium (beta lactamase inhibitor ↑ spectrum), hydrochlorothiazide + enalapril (balance potassium), penicillin +
probenicid (↓ tubular secretion, ↑ t1/2), saquinavir + food (↑ absorption).
Likelihood: established, probable, suspected, possible, unlikely
Consider dose side and duration, interaction onset / severity.
Management of drug interactions
Review patient profile: drug history and risk factors
Avoid complex therapeutic regimens
Determine probability of a significant interaction
Suggest alternatives: APAP not aspirin for headache with warfarin
Monitor SE. Monitor prothrombin time if warfarin is given with sulfonamides (may be prolonged).
Re-evaluate profile when changing therapy. Example: if d/c a thiazide diuretic d/c potassium supplement also.
20. Drug information resources
Drug information resources
Benefits: most current source, learn from case studies, new developments, ↑ communications with professionals / consumers, CE
credits, prepare for board certification exams.
Limitations: information is not always 100% accurate.
Secondary (abstracts / indexes)
Benefits: enable quick and selective screening of primary literature for specific information. May have enough info to answer the
Limitations: only finite number of journal reviewed, lag time between article publication and citation in the index, usually good only to
locate the original article (no full answers), contain only interpretations / description of the study which may be misleading (not whole
Benefits: easy and convenient access to large number of topics, include background information on drugs / diseases, validity and
accuracy of information can be verified by using references.
Limitations: may take years to publish information may be outdated, chapter author may not have done a thorough literature search,
author may have misrepresented the original article.
Considerations: author, publisher, edition, year of publication, scope, presence of bibliography.
Benefits: expanded searching capabilities, most useful for company specific information, issues currently in the news, alterative
medicine, government information.
Limitations: may not be peer reviewed or edited, not always reliable (evaluate source).
Strategies for evaluating information requests
Talk with the inquirer
Determine reason for inquiry: news-related question, medical condition
Clarify drug ID / availability: correct name spelling, generic vs. brand, manufacturer, country, Rx vs. OTC, under investigation drug,
dosage form, purpose for use.
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Identify / assess product / resource availability
US drugs: American Drug Index, Drug Facts and Comparisons, Drug Topics Red Book, PDR, Martindale the Extra Pharmacopoeia,
American Hospital Formulary Service
Foreign drugs: Martindale the Extra Pharmacopoeia, Index Nominum, US Adopted Names, USP Dictionary of Drug Names.
Investigational drugs: Martindale the Extra Pharmacopoeia, Drug Facts and Comparisons, Unlisted Drugs, NDA Pipeline.
Orphan drugs: for rare disease affected < 200,000 people cost of development is unlikely to be offset by sales FDA offers
assistance and financial incentives to encourage development. Drug Facts and Comparisons, National Information Center for Orphan
Drugs and Rare Diseases (NICODARD).
Unknown drugs: are drugs on hand but are not identified identify by physical characteristics or chemical analysis. Sources: PDR,
Facts and Comparisons, Drug Topics Red Book, Ident-A-Drug Handbook, Lexi-Comp, manufacturer, lab.
Unapproved (off-label) uses: Drug Facts and Comparisons, Martindale the Extra Pharmacopoeia, Index Medicus, Drugdex, USP DI,
Drug interactions: Drug Interactions Facts, Evaluations of Drug Interactions, Hansten’s Drug Interactions Analysis and Management.
Drug stability / compatibility: Trissel’s Handbook of Injectable Drugs, Trissel’s Stability of Compounded Formulations, King’s Guide to
Manufacturer: good source for any missing information.
Comparisons X X X X X X
pharmacopiea X X X X
PDR X X
Nominum X X
Red book X X
Drug Index X
USP DI X
Is it a clinical or research-related question? Define as specifically as possible.
Identify appropriate index search terms (keywords, descriptors).
Determine quantity and quality of needed information.
Ascertain as much as possible about the drug and the inquirer.
What is the drug indication? Is the drug approved or not? Patient information (age, sex, weight, medical conditions, other drugs, signs
of SE, allergies, etc).
Guidelines for responding to information requests
Do NOT guess
Intended use of information (abuse, misuse).
Organize information and response first.
Tailor to the inquirer’s background (e.g. public vs. professional).
Evaluating a clinical study
Study objective: was the objective clearly stated? One or more objectives?
Study subjects: profile of study population. Healthy subjects or patients? Degree of disease severity if patients? Volunteers? Number
/ ID of subjects (sex, age, race, etc)? Co-morbidities? Inclusion / exclusion criteria? Stratification can be used in case of ↑ inter-patient
Administration of drug treatment: dose, frequency, time of day, route, drug source, dosage form, timing vs. factors affecting
absorption (e.g. food), duration.
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Study setting: environment, dates, type of professionals making observations, inpatient vs. outpatient, length of study.
Study methods / design: are methods and design clearly described?
Retrospective vs. prospective: Retrospective examination of past events to find links between variables, relies on patient memory
and accurate records, used for rare disease, may lead to a decision to conduct prospective study. Prospective looks forward in time,
can be observational or experimental (clinical trials).
Treatment allocation: Parallel different patient groups are studied concurrently, identical treatment for all groups except for one
variable. Crossover good control of inter- / intra-patient variability, each group undergoes each treatment, with the sequence
reversed for one group vs. the other, includes a washout period.
Control measures: own control (crossover design), concurrent controls, stratification, matched subgroups, run-in period.
Controls: blind assessment / blind patients (double blind vs. open label (non-blind)), randomization, matching dummies (placebos),
comparison (to placebo or standard drug).
Analysis: appropriate statistical methods should be used
22. Clinical Toxicology
Clinical toxicology: studies the effects of substances on patients caused by accidental poisoning or intentional overdose of
medications, abuse drugs, household products or other chemicals.
Intoxication: toxicity associated with any chemical substance
Poisoning: clinical toxicity secondary to accidental exposure
Overdose: intentional exposure to cause self-injury or death
Computerized databases: Poisindex: CD database updated quarterly and used by poison control centers. TOMES: Toxicologic,
Occupational Medicine and Environmental Series info on industrial chemicals.
Printed publications: textbooks and manuals are useful but suffer a lag time of information published in primary literature.
Internet: Center for Disease Control and Prevention, FDA, and National Library of Medicine websites.
Poison control centers: accredited by the AAPCC. Provides info for the public and health care providers. Most reliable and up to date
sources of information.
Evaluate and support vital functions as a first step until patient is stabilized. Airway, Breathing, Circulation (ABC).
Patients with depressed mental status
Hypoglycemia: to rule out or treat 50 ml of 50% dextrose IV
Glucose can ppt Wernicke-Korsakoff syndrome in thiamine-deficient patients give IV thiamine push.
Opiate: give naloxone IV push.
History of exposure
Identity: of ingested substance, route of exposure, quantity ingested, time since ingestion, symptoms of overdose, associated illness /
Neurologic examination: seizures, altered consciousness, confusion, ataxia, slurred speech, tremor, headache, syncope.
Cardiopulmonary examination: syncope, palpitations, cough, chest pain, shortness of breath, upper airway burning / irritation.
GI examination: abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing.
Past medical history: Rx/OTC drugs, herbal medicines, alcohol / drug abuse, psychiatric history, allergies, occupational / hobby
exposures, travel, domestic violence / neglect.
Routine lab assessment: Complete blood count (CBC), serum electrolytes, BUN, serum creatinine, BG, urinalysis, ECG
Toxicology lab tests
Advantages: confirm or determine substance identity, predict severity of toxic effects, may help guide therapy
Disadvantages: diagnosis is not always specific, not available for all poisons, supportive care is the first priority.
Generally, only qualitative determination is need. However, quantitative determination is required for some substances (e.g metals,
lithium, methanol, APAP, salicylate, theophylline, ethylene glycol)
Required when skin absorption may cause systemic toxicity or when contamination substance may produce toxic effects (e.g. acid
Remove clothes, irrigate area with plenty of water. DO NOT neutralized (exothermic reaction).
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Contraindications: children < 6 months, CNS depression, seizures, strong acids / alkali, sharp object, compromised airway, coma,
convulsions, HC or petroleum distillates, patients already vomiting, substance that are very fast acting.
Syrup of ipecac: consider only if within 60 (even 30) minutes since ingestion, otherwise, no benefit. Onset of emesis: within 30
minutes, 3 vomiting episodes in 1 hour. SE: diarrhea, drowsiness, lethargy
Use: if patient is not alert or has ↓ gag reflex, if ↑↑ quantity was ingestion short while ago or if not responding to ipecac
Procedure: aspire gastric contents instill 250 ml tap water or saline aspire repeat until content is clear for 2 liters.
Adsorbs the majority of substances. Always give ASAP.
Exceptions: iron, lead, mercury, cyanide, lithium, ethanol, methanol, organic solvents, strong acids / alkali.
Form: colloidal dispersion with water or sorbitol.
Avoid multiple doses of cathartics may cause electrolyte imbalance, dehydration.
SE: charcoal aspiration avoid if vomiting, bowel obstruction with multiple doses.
Whole bowel irrigation
Effective when charcoal is not available / effective.
Use osmotic cathartic solution (e.g. PEG (Golytely, Colyte). Continue until rectal effluent is clear.
Forced diuresis / urine pH manipulation
Use: for substance with kidney elimination, ↓ Vd, ↓ protein binding
Alkaline diuresis: ↑ ionization of weak acids (aspirin, long-acting barbiturates (phenobarbital)) ↓ kidney reabsorption ↑ elimination.
Use IV sodium bicarbonate urine pH at 8.0, maintain adequate urine output. SE: metabolic alkalosis, hypernatremia, hyperosmolarity,
Acid diuresis: ↑ ionization of weak alkali (amphetamines, phencyclidine, quinidine) ↓ kidney reabsorption ↑ elimination. Use
ascorbic acid (vitamin C) or ammonium chloride urine pH at 5.0.
Last resort for decontamination. Hemodialysis or peritoneal dialysis.
Hemodialysis: used for water soluble substances with ↓ Vd, ↓ MWt, ↓ protein binding. Use for life threatening ingestions of ethylene
glycol, methanol. Can correct fluid and electrolyte abnormalities.
Anticoagulated blood is passed through (perfused) a column containing activated charcoal or resin particles. Quicker than hemodialysis.
Can NOT correct electrolyte / fluid abnormalities. Less effective for methanol / ethanol. SE: thrombocytopenia, leukopenia,
Management of specific ingestions
Toxicokinetics: mostly metabolized in the liver (Cytochrome P450) toxic metabolite liver toxicity, especially in alcoholics / elderly.
Symptoms: phase I (1 day): nausea, vomiting, phase II (2 days): no symptoms, phase III (3 days): abdominal pain, coma, death.
Treatment: ipecac or gastric lavage (within 2 hr), N-acetylcystein (specific antidote, oral / IV). Metoclopramide: ↓ emesis during / ↑
absorption of N-acetylcysteine therapy.
Forms: antifreeze, windshield deicing. Colorless, sweet taste.
Toxicokinetics: live metabolism by alcohol dehydrogenase glycoaldehydge by aldehyde dehydrogenase glycolic acid
glyoxylic acid oxalic acid (most toxic).
Symptoms: phase I (12 hr): ↓ tendon reflex, ataxia, nystagmus, metabolic acidosis, hypocalcemia, phase II (1 day): tachypnea,
cyanosis, tachycardia, pulmonary edema, phase III (2 days): flank pain, oligouric renal failure.
Treatment: gastric lavage (within 30 min), IV ethanol, fomepizole (alcohol dehyrogenase inhibitor), pyridoxine / thiamine (convert
glyoxylic acid to non-oxalate metabolites), sodium bicarbonate (correct acidosis), hemodialysis.
Forms: gas-line antifreeze, windshield washe.
Toxicokinetics: alcohol dehyrogenase formaldehyde formic acid.
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Symptoms: phase I: euphoria, muscle weakness, phase II: vomiting, diarrhea, dizziness, headache, dyspnea, blurred vision,
photophobia, blindness, cardiac / respiratory depression, metabolic acidosis, hyperglycemia, coma, seizures, death.
Treatment: gastric lavage (NOT charcoal), IV ethanol, fomepizole (alcohol dehydrogenase inhibitor), folic acid (↑ metabolism of
format), sodium bicarbonate (correct acidosis), hemodialysis.
Toxicokinetics: t1/2 = 24 hr, liver metabolism, enterohepatic circulation, ↑↑ plasma protein binding.
Symptoms: atropine-like SE (mydriasis, urinary retention, fever), tachycardia, ↓ BP, pulmonary edema, agitation, confusion,
Lab data: ECG
Treatment: GI decontamination (activated charcoal), alkalinzation (sodium bicarbonate to ↑ arterial blood pH), phenytoin / BZD (to
control seizures, fosphenytoin cause less hypotension than phenytoin), physostigmine (for anticholinergic symptoms, may cause
asystole (no heart beat)).
Selective serotonin reuptake inhibitors (SSRI)
Toxicokinetics: t1/2 = 24 hr, liver metabolism
Symptoms: agitation, drowsiness, confusion, seizures
Lab data: ECG
Treatment: gastric lavage, supportive treatment
Dosage forms: IV, SC
Toxicokinetics: t1/2 = 1 hr, liver metabolism
Symptoms: bleeding, bruising
Lab data: PTT, bleeding time, platelet count
Treatment: Protamine IV (combines with and neutralized heparin), 1 mg protamine neutralized 100 heparin units.
Dosage forms: oral, parenteral
Toxicokinetics: absorbed orally, t1/2 = 36 hr, 99% protein bound, 5-day activity duration.
Symptoms: bleeding, bruising, hematuria, conjunctiva hemorrhage, GI / intracranial bleeding.
Lab data: PT, INR, bleeding time.
Treatment: Phytonadione (vitamin K), blood products with clotting factors.
Toxicokinetics: liver metabolism
Symptoms: drowsiness, confusion, ataxia
Treatment: supportive (gastric emptying, activated charcoal, cathartic), Flumazenil (IV, short t1/2, careful observation for re-sedation
in case of long acting BZD).
Symptoms: hypotension, bradycardia, atrioventricular block, bronchospasm, hypoglycemia.
Treatment: gastric lavage, activated charcoal, Glucagon, Epinephrine (.
Calcium channel blockers
Symptoms: hypotension, bradycardia, atrioventricular block. Nifedipine does not affect the heart. Verapamil pulmonary edema,
Treatment: GI decontamination (gastric lavage, activated charcoal, whole bowel irrigation). Clacium chlrodie (IV) for hypotension,
bradycardia, heart block. Glucagon.
Forms: alkaloid from Erythroxylon coca
Toxicokinetics: good absorption from oral, inhalation, intranasal, IV route. Metabolized in the liver, excreted in the urine.
Symptoms: CNS / sympathetic stimulation (↑BP, tachycardia, seizures, tachypnea). Death due to respiratory failure, cardiac arrest, MI.
Treatment: Symptomatic. BZD for seizures. Labetolol for hypertension. Neuroleptics for psychosis.
Symptoms: strong acids and alkali cause skin burns.
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Treatment: decontamination. Irrigate exposed skin with water. AVOID neutralization (exothermic reactions more burns and tissue
Forms: industrial chemicals, nail polish removers.
Toxicokinetics: quick absorbed orally or by inhalation.
Symptoms: headache, dyspnea, ataxia, coma, seizures, death
Treatment: amyl or sodium nitrite converts hemoglobin to methemoglobin binds to cyanide ion (cyano-methemoglobin)
sodium thiosulfate to regenerate hemoglobin. Oxygen for dyspnea. Sodium bicarbonate for acidosis.
Symptoms: confusion, anorexia, GI upset, dysrhythmia.
Lab data: digoxin Cp, serum potassium, ECG.
Treatment: ipecac or activated charcoal, correct blood potassium, heart support, Digoxin specific fab antibodies.
Forms: cathartics (mg citrate) ↑ mg with charcoal.
Toxicokinetics: Mg is found intracellularly kidney elimination
Symptoms: Mild weakness, ↓ tendon reflexes. Severe respiratory paralysis, heart block, ECG abnormalities.
Treatment: 10% calcium chloride to temporarily antagonize cardiac effects of Mg. Use hemodialysis in severe cases.
Toxicokinetics: main intracellular cation. ∆ acid-base balance ∆ potassium. ↑ pH ↓ potassium.
Symptoms: cardiac irritability, peripheral weakness, bradycardia, dysrhythmia, ECG abnormalities.
Treatment: Calcium: antagonize cardiac effects of potassium, sodium bicarbonate: ↑ serum pH move potassium from
extracellular to intracellular space, Glucose + insulin: move potassium from extracellular to intracellular space, cation exchange
resins (sodium polystyrene sulfonate): bind potassium in exchange for sodium, hemodialysis: last resort for life-threatening
Elemental iron: 33% in fumarate, 20% in sulfate, 12% in gluconate.
Symptoms: phase I (nausea, vomiting, diarrhea, GI bleeding), phase II (improvement within 24 hr), phase III (metabolic acidosis, renal
/ hepatic failure, pulmonary edema, death).
Lab data: serum iron, hemoglobin, hematocrit, radiopaque pills in radiography.
Treatment: Deferoxime chelates iron (red urine). Ipecac emesis if within minutes of small quantity ingestion. Whole bowel irrigation
for ↑ quantities. Also, supportive treatment.
Symptoms: nausea, vomiting, slow speech, ataxia, seizures, coma
Lab data: lactic acidosis, hypoglycemia, hyperkalemia, leukocytosis
Treatment: AVOID emesis (due to ↑ risk of seizures), ↑ quantity activated charcoal gastric lavage. Pyridoxine reverses isoniazid
induced seizures (infusion in D5W). Sodium bicarbonate for acidosis.
Forms: paint or gasoline fume inhalation.
Toxicokinetics: slow distribution (t1/2; 2 months).
Symptoms: nausea, vomiting, GI pain, peripheral neuropathy, convulsions, coma.
Lab data: anemia, ↑ lead level in blood.
Treatment: Calcium EDTA (IM/IV), dimercaprol (IM).
Toxicokinetics: absorbed orally, not plasma protein bound, small Vd, kidney eliminatin.
Symptoms: Mild polyuria, blurred vision, tremor, weakness. Severe seizures, coma, delirium, fever.
Lab data: determine the degree of toxicity form lithium Cp.
Treatment: sodium polystyrene sulfonate, ipecac (within minutes), whole bowel irrigation (if ↑ quantity), hemodialysis (if acute exposure
+ severe symptoms).
Toxicokinetics: methadone / heroin ↑ t1/2
Symptoms: respiratory depression, miosis, ↓ consiousness, hypotension, bradycardia. opiates are downers.
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Treatment: Naloxone (short t1/2, repeated dosing), Nalmefene (longer t1/2).
Forms: pesticides, chemical warfare agents
Toxicokinetics: absorbed through lungs, skin, GI, conjunctiva
Symptoms: DUMBELSS: diarrhea, urination, miosis, bronchoconstriction, excitation, lacrimation, salivation, sweating.
Lab data: RBC acetylcholinesterase activity.
Treatment: atropine, pralidoxime (both IV).
Toxicokinetics: longer t1/2 at toxic doses
Symptoms: Mild nausea, vomiting, tinnitus, malaise. Severe metabolic acidosis, convulsions, coma. Other SE: BI bleeding, ↑ PT.
Treatment: ipecac emesis (if within minutes), ↓ doses repeated activated charcoal + a cathartic dose, moderate doses whole
bowel irrigation, ↑ doses hemodialysis. Alkaline diuresis: with sodium bicarbonate to ↑ excretion. Fluid / electrolyte replacement.
Vitamin K to correct ↓ coagulation.
Toxicokinetics: liver metabolism highly variable (depends on age, other drugs, disease).
Symptoms: nausea, vomiting, seizures, dysrhythmias. Acute toxicity hyperglycemia, hypokalemia. SE are due to ↑ cAMP.
Treatment: supportive (maintain airways, treat seizures, beta blocker (esmolol) treats tachycardia, disrhythmia), ipecac (if within
minutes), repeated activated charcoal, whole bowel irrigation (if ↑ quantitiy), charcoal hemoperfusion or hemodialysis.
Dosage forms: oral (tabs, caps, elixir), IV solution
Lab data: blood sample at time of dose and after 12 hours, range is 5 to 15 mcg/mL
23. Federal Pharmacy Law
Federal Controlled Substances Act
Schedules of controlled substances
Drugs that have potential for abuse leading to physical or psychological dependence. Lists are published annually. US attorney general
has the authority to modify lists.
Schedules II-V have accpeted medical uses but schedule I does not. Schedule II has the highest potential for abuse / severe
dependence and Schedule V has the least.
Schedule I: drugs can not be kept in the pharmacy or dispensed except for authorized research or investigative reasons. Drugs with
abuse potential but no accepted medical use or esablished safety record. Examples: heroin, marijuana, LSD, ecstacy,
Schedule II: Highly restricted. Examples: morphine, oxycodone, methyphenidate, amphetamine, methamphetamine, cocaine, opium,
fentanyl, short acting barbiturates.
Schedule III: Less potential for abuse / dependence than CI or CII. Examples: anabolic steroids (testosterone, androgens),
hydrocodone / codeine with APAP / aspirin, intermediate acting barbiturates (talbutal).
Schedule IV: Examples: BZD (diazepam, chlordiazepoxide, alprazolam, long acting barbiturates (phenobarbital), propoxyphene,
Schedule V: May be available w/o Rx but sales are documented. Examples: small amounts of opium or codeine.
All handlers of controlled drugs have to register with the DEA.
DEA issues an Order To Show Cause to allow the registrant to appeal.
Entities that must register: wholesalers (annual renewals), dispensers (pharmacies, practitioners) (renew every 3 years). Pharmacists
/ pharmacy employees do not have to register.
Registration for separate activities: certain activies require separate registartion. Examples: manufacturing, distributing, dispensing,
conducting research, narcotic treatment programs, chemical analysis, importing / exporting, maintenance, disposal, detoxification,
Registration for separate locations: separate registration for each pharmacy, pharmacy chain, clinic, hospital. Wholesalers do not
have to register if distributing to a registered location.
Registration procedure: submit application to DEA by individual, partners, corporate officer, or person with power of attorney.
Registration action by the DEA: certificate of registration is granted by DEA if appropriate, otherwise it may be denied.
Modification of registration: e.g. for change of name, address, extension of authorized activities, etc.
Transfer of registration: not allowed except in case of pharmacy ownership transfer.
Suspension / revocation of registration: May be due to imminent danger to public health or safety. If revoced / suspended deliver
certificate or registration, any DEA 222 order forms, all controlled substances or place them under seal.
Exemptions from registration: Military officials: can prescribe, administer or dispense but not purchase. Law-enforcement
officials: federal and state. Civil defense officials: and disaster relief organizations during prolaimed emergencies or disasters.
Agents and employees of registrants: such as pharmacists or delivery personnel.
Termination of registration: death, cease of legal existence (company), d/c business or pratice. DEA must be notified and drugs
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All registered entities have to conduct biennial inventory.
Initial inventory: must be taken on the day of start or end of business or change of ownership. If no controlled substances in
possession must be documented.
Biennial inventory: any date within 2 years of the previous inventory.
Inventory procedures: conducted at either the open or close of business. Separate inventory record required for CII keep drugs
Inventory content: inventory must contain: date of inventory, dosage form, strength, number of units or volume in each container.
Exact count is required for open bottle of only CII (estimate is OK for other Cs, unless containers contains > 1000 tablets).
Inventory record maintenance: keep inventory separate at the registered location for 2 years. Keep CII inventory separate. Must be
readily retrievable. Submission to DEA is not required.
Perpetual inventories: not required.
New or changes in schedules: inventory required for that drug only.
Obtaining controlled substances
CII: DEA Order Form 222 is required. Forms are issued by DEA, serially numbered with the certificate of registration inforamtion.
Triplicate copies each. List info for drugs and supplier (one supplier per form). Form is invalid for purchasing 60 days of signature. Only
used by previously authorized and deisgnated individuals. Send copy 1 and 2 to supplier, retain copy 3. Maintain for 2 years. A
purchaser / supplier may cancel part or all of the order by notifying the other party in writing.
CIII-V: no form is required but records need to be maintained (2 years).
Storage of controlled substances
One of two ways: in a securely locked well constructed cabinet OR dispersed throughout the stock of other drugs to prevent theft.
Report theft or significant loss immediately to DEA using Form 106.
Disposal of controlled substances
DEA Form 41 must be submitted and pre-authorized. Always keep records. Options for disposal: transfer to a registered person or
entity (use Form 222 for CII), delivery to or destroy in the presence of DEA agent or office. Regular disposal of controlled
substances: DEA may authorize disposal without pior approval. Always keep records.
Disposal (dispensing) pursuant to a valid Rx
Only by a practioner who is licensed by the state (not federally). Usually: physicians, dentists, vets, podiatrists (DEA starts with A or B).
Other professionals may be licensed but with restrictions (DEA starts with M).
Authentication of DEA number (7 digits): (1 + 3 + 5) + 2x(2 + 4+ 6) double digit the right digit has to match digit 7.
Purpose for prescribing
Must be in good faith only for legitimate medical reasons during the normal course of pratice (medical history and physical exam
performed). A vet can not prescribe for humans. It does not have to be within specialty if physician is a specialist. Can not prescibe
controlled drugs for the sole purpose of detoxification of maintenance of addiction (only if within a treatment program).
CII must be written unless it is an emergency oral drugs only, no alternative, written Rx is not possible, only necessary quantity,
prescriber must be known to the pharmacist written Rx must be provided within 7 days of oral Rx (mail or in person), otherwise notify
DEA. CIII-V can be oral or fax.
Faxed Rx: ok for CIII-V. For CII ok to prepare the Rx but no released to the patient without written Rx exceptions include
injectable home health, hospice, and LTC Rx (no written Rx required) .
Dispensing a Rx
Time validity: 6 months for CIII-IV and no time limit for CII and CV (although questionable after 6 months). No limitation on quantity
either. Apply good faith principles.
All information on the Rx must be complete (including S/N).
Label: must have pharmacy name / address, S/N, date of original filling, patient name, prescriber name, drug info, directions,
Cautionary Auxilliary Sticker.
Separate record files: CII, CIII-V, other Rx all separate, OR Combine all C with CIII-V or combine CIII-V with non control as long as C is
stamped in red on CIII-V.
Refills: no refills for CII. For CIII-IV up to 5 refills in 6 months. No limit for C-V (use good faith).
Maintain either physical or computerized records (certain characteristics).
Partial dispensing: allowed for CIII-IV within 6 months. For CII: allowed only if not enough stock(within 72 hr), or terminally ill patient /
LTC (within 60 days).
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Transfer of refills (CIII-V): allowed only once. Write ‘Void’ or ‘Transfer’ on Rx.
Dispensing without a prescription
Only if not a prescription drug. Only pharmacist can dispense only limited quantities (wihtin 48 hr period) with records kept (2 years), in
good faith. Purchaser must be 18 years and present an ID (if not familiar).
Seals / seals: seals required for all packages and containers. Labels must clearly designate the schedule (II-V).
Felony convictions: no registrant may employ felons conviced with a narcotic offense.
Inspected are conducted only in a reasonable manner and during business hours, only after registrant notification or court warrant.
Specifics of the inspection scope must be provided.
Violation under the act
Penalties depend on type of schedule, nature of violation, and knowledge and intent of the violator, first or recurrent offense.
Pharmacist must be proven to be negligent not only an inadvertent mistake. May include civil penalty or imprisonment.
Federal Food, Drug and Cosmetic Act
Passed following the sale of sulfanilamide elixir with deadly diethylene glycol (car antifreeze) in 1937. Act requires the use of NDA to
prove to the FDA that the drug is safe and effective.
Drug: articles intended for use in diagnosis, cure, mitigation, treatment or prevention of disease in man or animals. Also, articles other
than food intended to affect the structure or function of the body. Also, articles in the USP.
Legend (Rx) drugs
Includes the following types of drugs: Habit-forming drugs: such as narcotics or hypnotics. Safety: drugs that are not safe except
under supervision of a licensed practioner.
IND: files on a NCE. Allows the conduct of research to prove safety and efficacy (exemption from the Act). Include phases 1-3.
Phase 1: use on healthy humans to determien metabolism, pharmacology, mechanism, SE.
Phase 2: well-controlled closely monitored studies on small # of patients to evaluate efficacy for a certain indication and also SE and
Phase 3: expanded clinical trials on patients to confirm safety and efficacy and risk/benefit relationship
NDA: acceptable proof of safety and efficacy to the FDA approved for use in certain indications.
Treatment INDs (treatment protocols): allows a practioner to use an investigational drug as treatmetn in serious and life-threatening
disease when no alternatives are available.
FDA determined drug is safe for self-administration. Usually, drugs are not habit forming, toxicity / SE. Must have adequate clear
directions and must comply with FDA monograph (to avoid misbranding). A legend (Rx) drug may be converted by the FDA to OTC.
Generic / Proprietary drugs
Generic name is the chemical name, common name or official name in the compendium.
ANDA: submitted for drugs that have already been proven safe and effective. The brand / generic must have the same active, dosage
form, strength, route, indications, conditions of use. Only bioavailability and bioequivalence have to be shown. Approved bioequivalent
drugs are listed in the orange book.
Established names for drugs
Established name: Commissioner of the FDA has the authority to designate names. Name has to be simple and useful. The FDA
recongizes the US Adopted Names Council (USAN) in deriving names for NCE. Otherwise, use the name in the official compendium
title. Otherwise, common or usual name is used.
Voluntary manufacturer recall: may be completely voluntary or after several attempts by the FDA to receive court ordered recalls.
Drug recall classification: assigned by the FDA. Class I: potential for serious SE and death. Class II: potential for temporary or
reversible SE or when serious SE are unlikely. Class III: not likely to cause serious SE
Recall procedure: strategy should consider the depth of the recall, need for public warning. First layer of notification (to wholesalers)
is done by the company. Public notification is made by the FDA in the weekly FDA Enforcement Report.
Misbranding and adulteration
Adulteration: change or variation from official formulary or manufacturer’s standards. Drug contains filthy, putrid, decomposed
substance. Drug was prepared, packed, held under unsanitary conditions where it might have been contaminated. Container has
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poisonous substance. Drug contains unsafe color. Drug strength, quality or purity is different from claimed compendium standard. Drug
contains another substance that its quality or strength. OTC that is not properly packaged (tamper-proof) or labeled. Ophthalmic
product that is not sterile. cGMP: a drug is adultrated if not manufactured in conformity with cGMP.
Misbranding: a drug is sold or dispensed with a violative label. False or misleading label. Imitation or name used of another drug.
Insulin or antibiotic that is not batch certified. Drug dispensed in non-child proof container. Label without proper info (drug info,
precautions, pharmacy info, Rx#, date, names of patient / prescriber, directions, etc), oral contraceptive / estrogen / progesterone / IUD
without patient insert, package, Rx drug without Rx, ophthalmic preparation that is not sterile.
Violations under the Act: exemption in certain cases of good faith (violative product receive by the pharmacy in good faith), receipt of
drug with a signed written guaranty from the wholesaler.
Seizures: of adultrated / misbranded product after a court hearing or without a hearing if there is propable cause of danger to public
Investigations and inspections: done by the US Secretary of Health and Human Services. Investigations must be authorized, within
reasonable limits, time, manner and scope.
Manufacturer’s insert: full disclosure is required by the manufacturer. Enclosed with every commercial container. Contains essential
informative and accurate scientific information for safe and effective drug use. It can’t be promotional in tone, false or misleading.
Patient package insert: due to certain SE with certain products, patient inserts must be dispensed, including refills. That includes the
following: Oral contraceptives, IUDs, Estrogen products, Porgestational products, Isoproterenol inhalation products, Miscellaneous (e.g.
Isotretinoin serious fetal harm if pregnant). For isoproterenol, label with “Do not exceed prescribed dose. Contact physician if
Prescription drug samples
Currently, sample distribution is very restricted. All sale, purchase, trade of samples are banned. Sample records are maintained by the
manufacturer for 3 years. Pharmacies can not accept samples. Importation after exporting is illegal.
Safety and effectiveness are required.
Class I: reasonable assurance of safety and quality
Class II: no reasonable assurance of safety and quality, but has sufficient info to establish controls to ensure safety and quality
Class III: no reasonable assurance of safety and quality (generally, they can not be marketed).
Medical device tracking: required if failure may lead to serious SE. Tracking allows recalls.
Manufacturer’s reports: manufacturer, hospitals, pharmacies, etc are required to report to the FDA potential link to death or adverse
Misbranding and adulteration: same as drugs
Poison Prevention Packaging Act
The Act (1970) require child-resistant containers for all drugs (difficult for children under age of 5 to open easily within short period of
time). Enforced by the Consumer Product Safety Comission.
Requests for non-child resistant container: request can be made by the prescriber in a specific prescription, but a blanket request
can’t be made. Patient can request that for one or all Rx (does not have to be in writing).
Reuse of child-resistant containers: generally prohibited. Allowed for glass containers when a new child resistant cap is used.
Manufacturer’s packaging: no child-resistant container if the product will be repackaged by the pharmacist, but is required if product
will be dispensed directly to the patient.
Exemptions for easy access: OTC non-child-resistant packaged can be sold as long as child-resistant alternative is offered. Label
“For Households Withouth Children” or “Package Not Child Resistant”.
Hospitals and institutions: the Act applies to houshold substances (“any substance produced or distributed for sale for consumption
or use by individuals in the household”). Act does not apply if drug is given by hosptial personnel and not directly dispensed to the
Miscellaneous special packaging: such as furniture polish containing petroleum distillates, drain pipe cleaners, turpentine, pain
solvents, lighter fluid.
Sublingual nitroglycerin and sublingual / chewable isosorbide dinitrate at low doses.
Erythromycin ethylsuccinate granules for oral suspension ( doses).
Oral contracpetives / conjugated estrogen / norethindrone acetate in memory-aid (mnemonic) packages ( dose).
Medroxyprogesterone acetate tablets.
Anhydrous cholestyramine powder.
Colestipol powder ( dose)
Potassium supplements (effervescent tablets, liquid, powder) ( dose).
Sodium fluoride (tablet / liquid, dose).
Betamethasone tablets in dispenser packages ( dose).
Prednisone or methylprednisolone tablets ( dose)
Pancrelipase tablet, capsule, powder ( dose)
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Mebendazole tablets ( dose)
Act passed in 1984 due to death from OTC capsules containing cyanide. Applies to consumer products (food, drug, device, cosmetic,
OTC tamper-resistant packaging: required from some products (contact lens, ophthalmic solutions). Contain a visible indicator of
breach or tampering. Product / tamper-resistant technology design must be distinct to avoid easy duplication by commonly available
OTC tamper-resistant labeling: clearly alert consumers to specific tamper-resistant feature on the package.
Medical devices and cosmetics: required for certain products
Violations: include tampering, false communication or conspiracy for either.
Mailing Prescription Medications
All drugs, including narcotics, can be mailed by the physician or pharmacist. Place drugs in a plain outer container or securely wrap in
plain paper. Make no outside markings that indicate nature of content. Exception: do not mail flammable liquids or alcoholic beverages.
Omnibus Budget Reconciliation Act (OBRA)
The US Constitution states that the federal government has no authority to regulate the practice of pharmacy (done by the states).
Federal government can indirectly affect practice by attaching conditions of participation and reimbursement for federally funded
Medicaid: Rx are paid jointly by federal and state governments. Federal reimbursement require the pharmacist to get a patient and
medication history, conduct DUR, offer counseling to the patient.
Manufacturer’s best price: for manufacturer’s to participate in Medicaid, they must offer “best price” (lowest price for the purchaser).
Narcotic Treatment Programs
Methadone can be used as part of a total narcotic addition treatment program. Regulations were established by the FDA and DEA. It is
used for maintenance or detoxification. Facility has to be approved by the FDA, DEA and state authority.
Detoxification treatment: dispensing a narcotic drug in doses to withdrawal physiologic or psychologic symptoms. Maximum
period: 6 months.
Maintenance treatment: dispensing a narcotic drug at stable dosage levels to treat heroin or morphine-like dependence.
Requirments for patient admittance: has been physiologically dependent on a narcotic for one year and still is. Patient participation
must be voluntary. Patient has to sign “Conset to Methadone Treatment” after being infomred properly.
Take home methadone: only to patients, judged by the physician, are responsible in handling narcotic drugs. Patient must come to the
clinic for observation at least 6 days a week, then gradually observations to once a week. Dispense methadone as any CII drug.
24. Reviewing and dispensing prescriptions
Prescriptions: orders for medications, non-drug products, and services. Practitioners may prescribe medications only in their field of
Information in the Rx: patient name and address, date, name and dosage form of the product, product strength, quantity (directly or
indirectly), directions to the pharmacist (preparation, labeling), directions for the patient (quantity, schedule, duration, avoid “as
directed”), refill information (“as needed” means one year), prescriber information (signature, DEA if controlled).
Medical orders: orders for medications intended for use by patients in an institutional setting.
Information in medication order: patient information, date and time, name and dosage form, product strength, route of administration,
signature, directions to the pharmacist, instructions for administration.
Understanding the Rx
Understanding the order: all info must be understood and consistent, including disease condition, reason for treatment, type of units
Evaluating appropriateness: follow up if incomplete info was provided. Evaluate allergies, route of administration, drug-drug / food /
disease interactions, safety for intended use, proper quantity and dosage, incompatibilities, legitimate prescriber.
Discovering inappropriate Rx: Drug Utilization Review: review medication profiles to ensure appropriateness. Therapeutic
intervention: calling the prescriber to discuss concerns regarding the Rx. Following the intervention, the Rx may be dispensed as
written, with changes or not at all.
Processing the Rx
Involves use of technicians and automation, save pharmacist’s time for patient counseling and education. Record Rx number, original
date of filling, product and quantity dispensed, pharmacist’s initials.
Product selection: involves generic substitution, formulary / therapeutic substitution policies.
Product preparation steps: obtain proper medication amount, reconstitute if necessary, extemporaneous compounding, assembly of
delivery unit, selection of proper package or container.
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Labeling: contains name and address of pharmacy, patient’s name, original date of filling, Rx number, directions for use, product name
and manufacturer, product strength, quantity dispensed, prescriber name, expiration date, pharmacist initials. Unit-dose packages:
contain one dose or unit of medication, label identifies drug name, strength, lot#, expiration date. Auxiliary labels: to ensure proper
medication use, storage, federal transfer of narcotics, etc.
Record-keeping: include patient profile system that includes demographic information (allergies, DOB, disease, weight, occupation,
OTC use) and record of all medications.
Dispensing medication and counseling
Counseling patients: evaluate patient’s understanding, supply additional information, proper use, storage, appearance, name, route of
administration, duration of use, reason for the Rx, SE (frequency, severity, actions to manage and minimize), OTC or food interactions.
Counseling health professionals: especially in institutional setting where the professional administers the drug. Other information:
cost, drug-drug or nutrition interactions, physical incompatibilities, interference with lab tests,
Pharmaceutical care plan: to ↑ frequency and benefits of desired outcomes. Includes: assessment (review medical conditions and
symptoms), plan (decision on appropriate therapy), monitoring (review outcome goals and endpoints).
Drug-related problems: unnecessary therapy, wrong drug, wrong dose, SE, poor compliance, need for additional therapy.
25. Sterile Products and Parenterals
Sterile products: parenterals, irrigating solutions, ophthalmics
Aseptic technique: preparation procedures to maintain sterility
Pyrogens: metabolic byproducts of live and dead microorganisms that cause fever upon injection.
Tonicity: related to osmotic pressure. Hypotonic solution: ↓ osmotic pressure than blood or 0.9% NaCl. Cause cells to expand
hemolysis, pain. Isotonic: exert same osmotic pressure as blood or 0.9% NaCl. Hypertonic: must be administered through a large
vein to avoid phlebitis and ensure rapid dilution.
Clean rooms: areas constructed and maintained to ↓ probability of environmental contamination of sterile products. They have the
High-efficiency particulate air (HEPA) filters: used to clean the air entering the room. Remove all particulates < 0.3 mm with
efficiency ~ 100%. HEPA filtered rooms are Federal Class 10,000, i.e., they contain <10,000 particles 0.5 mm or larger per cubic foot
Positive-air pressure flow: used to prevent contaminated air from entering a clean room.
Counters: in the clean room are made of easily cleaned nonporous material, e.g., stainless steel.
Wall / floors: free from cracks / crevices, rounded corners, made of nonporous material, easily disinfected.
Air flow: air moved with uniform velocity (90 fpm) along parallel lines.
Laminar flow hoods: clean air work benches in clean rooms designed as aseptic environment for making sterile products (Class 100).
Horizontal: air flow moves across the surface of the work area (disadvantage: no protection for the operator). Vertical: advantages:
air flows down on the work space, which protects the operator, portion of the air is circulated a second time.
Inspection / certification: for clean rooms and laminar flow hoods is done annually or when moved. The dioctyl phthalate (DOP)
smoke test ensures that no particle > 0.3 mm passes through HEPA filter. Anemometer is used to measure air flow velocity and a
particle counter is used to count particles.
Sterilization methods and equipment
Thermal: using either moist or dry heat. Moist heat (autoclave): most reliable and widely used. Microorganisms are destroyed by
cellular protein coagulation. Minimum 121 C for 15 minutes. Dry heat: minimum 160 C for 120 minutes. More potential damage to
product due to ↑ temperature.
Chemical (gas): used for surfaces and porous materials (e.g. surgical dressings). Ethylene oxide is used with gas and moisture.
Residual gas must be dissipated before product use.
Radioactive: for industrial sterilization of products in sealed packages that can not be heated (e.g. surgical equipment, ophthalmic
ointments). Use either electromagnetic or particulate radiation. May accelerate drug decomposition.
Mechanical (filtration): removes but does not destroy and clarifies solutions by eliminating particulates. Depth filter: consists of fritted
glass or unglazed porcelain. Membrane (screen) filter: with thickness of 1-200 mm. A mesh of millions of microcapillary pores filter
the solution by physical sieving. Pores make up 75% of surface ↑ flow rate than depth filters. Particulate filters (0.5-5 mm):
remove particles or glass, rubber, plastic, etc. Used to ↓ risk of phlebitis by removing undissolved particles of reconstituted powders,
cannot be used for blood, emulsions, suspensions, colloids. Microbial filters (<0.22 mm): ensures microbe removal (cold sterilization).
Either filter can be used as part of the tubing in drug administration (in-line filter).
Ampules: made entirely of glass. Single use. Disadvantages: glass fragments may contaminate the product during opening must
be filtered, not multiple use. Not commonly used now.
Vials: glass or plastic closed with a rubber stopper and sealed with aluminum crimp. Advantages: can be multiple use (if bacteriostatic
agent is added), easier to remove product, no glass fragment risk, no need for filtration. Disadvantages: coring of rubber stopping can
get into product, multiple use can cause microbial contamination. Drugs that are unstable in solution are packaged in solid form and
must be reconstituted with a diluent (sterile water or NaCl) before use. Lyophilization (freeze drying) can be used to ↑ dissolution rate
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and permit rapid reconstitution. Double chamber system: one chamber with sterile water for injection is separated from
unreconstituted drug chamber by rubber closure no need to enter vial twice ↓ contamination risk.
Add-vantage system: drug is in a vial attacked to an IV bag for reconstitution. Add-vantage vial is screwed into the top of Add-vantage
IV bag and rubber diaphragm is dislodged to allow the mixing.
Prefilled syringed: for immediate drug administration in an emergency (epinephrine, atropine). Prefilled cartridges: ready to use
parenteral packages with ↑ accuracy and sterility. Used for narcotics.
Infusion solutions: Small Volume Parenterals (SVP): volume < 100ml. Large VP (LVP): volume > 100ml.
Packaging materials: Glass: clarity for easy inspection, ↓ interaction with content. Plastic polymers: durability, easy storage /
disposal, ↓ weight, ↑ safety, e.g., PVC and polyolefin.
Routes of administration
Subcutaneous: usually in the arm or thigh. Example: insulin.
Intramuscular: e.g. mid-deltoid, gluteus medicus, < 5ml. Used for prolonged or delayed absorption (e.g. methylprednisolone).
Intravenous: most important and common, immediate therapeutic response, no recall of inadvertent overdose, e.g., antibiotics, cardiac
Intradermal: only very limited volume, e.g., skin tests and vaccines.
Intra-arterial: deliver ↑ drug concentration into target side with little dilution by circulation, e.g., diagnostic radiopaque materials and
Hypodermoclysis: injection of large volumes of solution into SC tissue to provide continuous abundant drug supply, e.g., antibiotics for
Intraspinal: e.g. local anesthetics during surgery (lidocaine, bupivacaine).
Intra-articular: injection into joint space, e.g., corticosteroids (hydrocortisone, methylprednisone) for arthritis.
Intrathecal: injection into the spinal fluid, e.g., antibiotics, cancer chemotherapy.
IV admixtures: one or more sterile drug product added to an IV fluid.
Used in preparation of parenteral products (vehicles for IV admixtures).
Dextrose (d-glucose): 5% dextrose in water (D5W). Used for reconstitution, as hydrating solution. Higher concentration dextrose (e.g.
D10W) provide source of carbohydrates in parenteral nutrition. pH of D5W is 3.5-6.5 instability of acid-labile drugs. Concentration >
15% give through central vein. Use cautiously in DM.
Sodium chloride: usually as 0.9% solution isotonic (normal saline). NaCl 0.45% is half-normal saline. Used for admixtures, fluid
and electrolyte replacement. Bacteriostatic NaCl for injection (0.9%): for multiple reconstitutions (bacteriostatic benzyl alcohol,
Water: for reconstitution and dilution of NaCl, dextrose. Use Sterile or Bacteriostatic Water for Injection.
Ringer’s solution: used post-surgically for fluid and electrolyte replacement. Lactated Ringer’s (Hartmann’s solution): contains
sodium lactate, NaCl, KCl, CaCl2, may be combined with D5W. Ringer’s injection: does not contain sodium lactate, may be
combined with D5W.
Sodium: main extracellular cation, important for interstitial osmotic pressure, tissue hydration, acid-base balance, nerve-impulse
transmission, muscle contraction. Examples: Na chloride, acetate, phosphate.
Potassium: main intracellular cation, important for muscle (esp cardiac) contraction, neuromuscular excitability, protein synthesis,
carbohydrate metabolism. Examples: potassium chloride, phosphate, acetate.
Calcium: important for nerve impulse transmission, muscle contraction, cardiac function, bone formation, cell membrane permeability.
Examples: calcium chloride, gluconate, gluceptate.
Magnesium: important for enzyme activities, muscle excitability, neuromuscular transmission. Example: magnesium sulfate.
Chloride: main extracellular anion. With sodium, it controls interstitial osmotic pressure, blood pH. Examples: sodium, potassium,
Phosphate: main intracellular anion. Important for enzyme activities, controlling calcium levels, buffer to prevent changes in acid-base
balance. Examples: sodium, potassium phosphate.
Acetate: bicarbonate precursor used as alkali to preserve plasma pH. Examples: sodium, potassium acetate.
Route: direct IV, short term IV infusion, IM, intrathecal.
Use: serious infections requiring ↑ concentration, GI is inaccessible.
May be toxic and hazardous during prep, administration.
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Safe handling: use vertical laminar flow hood, syringes and IV tubing with Luer-Lok fittings, closed-front cuffed surgical gowns, double
layered gloves, negative pressure technique, final dosage adjustment with care, special care priming IV sets, prime before adding the
drug, special disposal, wash hands, monitor health of personnel.
Patient problems: Infusion phlebitis: vein inflammation, pain, swelling, heat sensation, site redness, avoid by drug dilution and
filtration. Extravasation: infiltration of the drug into SC tissues surround the vein. Response: local hydrocortisone or anti-inflammatory,
antidote with cold compress, warm compress to ↑ blood flow and wash vesicant away from damage tissue.
Parenteral biotechnology products
Examples: monoclonal antibodies, vaccines, colony-stimulating factors.
Uses: cancer chemotherapy, HIV, hepatitis B, infections, transplant rejection, rheumatoid arthritis, inflammatory bowel, respiratory
Characteristics: protein and peptide biotechnology drugs: short t1/2, special storage (freezing, refrigeration), avoid vigorous shaking
not to destroy protein molecules.
Route: direct IV, IV infusion, IM, SC. Require reconstitution.
Manufactured by the same standards for IV products but not intended for injection. Labeling differenced specified in USP, i. e., different
acceptable particulate matter levels, volume, container design.
Topical administration: packaged in pour bottles into desired. For irrigating wounds, moistening dressings, cleaning surgical
Infusion: e.g., perfuse tissues to maintain integrity of surgical field, remove blood, clear field of view as in urologic surgeries. Add
Neosporin G.U. irrigant, an antibiotic, to ↓ risk of infection.
Dialysis (dialysates): e.g., in renal failure, poisoning, electrolyte disturbances. They remove waste matter, serum electrolytes, toxic
products. Peritoneal dialysis: hypertonic dialysate (dextrose, electrolytes) is infused in the peritoneal cavity via surgically implanted
catheter remove toxins by osmosis and diffusion finally drain. Antibiotics, heparin may be added. Hemodialysis: patient’s blood
is transfused through a dialyzing membrane that removes toxins.
Needles and syringes
Stainless steel or aluminum.
Gauge: the outside diameter of the shaft. Large number (27) small diameter (13). SC: 24-25. IM: 19-22. Compounding: 18-20.
Bevels: slanting edges cut into needle tips to facilitate insertion. Regular bevel: most common, for SC, IM. Short bevel: used onlyfor
shallow penetration (IV). Intradermal bevel: most beveled.
Lenghts: from ¼ to 6 inches, depending on desired penetration. IV: 1¼ - 2½ inch. Compounding parenterals: 1½. Intradermal / SC:
¼. Intra-cardiac: 3½.
Glass or plastic barrel and tight-fitting plunger, small opening to accommodate needle.
Luer syringe: oldest, universal attachment for all needle sizes.
Syringe volumes: 0.3 – 60 ml. Insulin syringes have unit graduations (100 units/ml) rather than volume graduations.
Calibrations: may be metric or English, vary depending on size.
Syringe tips: Luer-Lok: threaded to ensure needle fit tightly, for antineoplastic drugs. Luer-Slip: unthreaded so needle does not lock
into place, may be dislodged. Eccentric: set off center to allow needle to remain to injection site and minimize venous irritation.
Catheter: used for wound irrigation and enteral feedings and not for injections.
Intravenous drug delivery
Peripheral vein injection: preferred for non-irritating drugs, isotonic solutions, short term IV therapy. Use dorsal forearm for
Central vein injection: preferred for hypertonic solutions, long-term IV therapy. Use thoracic cavity vein, e.g., subcalvian.
Continuous drip infusion: slow infusion to maintain therapeutic level ro provide fluid and electrolyte replacement. Rate: ml/hr or
drops/min. Use for drugs with narrow therapeutic index, e.g., heparin, aminophylline.
Intermittent infusion: infusion at specific intervals (4hr), for antibiotics. Direct bolus injection: rapidly deliver small volume of
undiluted drug. Use for immediate effect as in emergency. Additive set infusion: using volume control device, for intermittent
delivery of small amounts. Piggyback method: used when drug cannot be mixed with primary solution, a supplemental secondary
solution is infused through the primary system, avoids a second puncture or further dilution. Admixtures: also called manufacturer’s
piggyback, a vehicle is added to the drug, example: Add-Vantage system.
Intermittent infusion injection devices: also called scalp-vein, heparin-lock, butterfly infusion set. Permit intermittent delivery without
multiple punctures or prolonged venous access. Use dilute heparin or normal saline to prevent clotting in the cannula.
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Pumps and controllers
Piston-cylinder mechanism: a syringe like apparatus
Linear peristaltic mechanism: external pressure to expel fluid out of the pumping chamber.
Volumetric pump: for intermittent infusion (e.g. antibiotics), continuous infusion, parenteral nutrition, etc.
Syringe pump: used for intermittent or continuous infusion of drug in concentrated form (e.g. antibiotics, opiates).
Mobile infusion pump: small infusion devices for ambulatory and home patients. For chemotherapy and opiates.
Implantable pump: surgically planted under skin to provide continuous drug release, usually an opiate. The pump reservoir is refilled
by injecting drug into pump diaphragm.
Patient-controlled analgesia (PCA) pump: used for intermittent or on demand delivery of narcotics.
Benefits: ↑ cost, ↑ training, ↑ accurate flow rate, detect infiltration, occlusion and air, save nurse time.
Use no pumping pressure. Use gravity and control infusion rate by electronic counting of drops. Compared to pumps: ↓ complex, ↓
expensive, reasonable accuracy, used for uncomplicated infusion but not arterial or small vein infusion.
Types of incompatibilities
Physical: mixing causes visible change in appearance. Example: evolution of CO2 when sodium bicarbonate and HCl are mixed. It
can be a visible color change or pptn (e.g. phosphate and calcium).
Chemical: chemical degradation causing toxicity or loss of activity. Complexation: such as calcium and tetracycline inactive
tetracycline complex. Oxidation: when a drug loses electrons color change, inactivity. Reduction: when a drug gains electrons.
Photolysis: chemical decomposition by light hydrolysis or oxidation color change.
Therapeutic: e.g. bacteriostatic (tetracycline) then bactericidal (penicillin G) ↓ activity of penicillin G.
Factors affecting compatibility
pH: ∆ in pH ↑ incompatibility. Acid + base = salt may ppt.
Temperature: ↑ temp ↑ degradation. Use fridge or freezer.
Degree of dilution: ↑ dilution ↓ ion interaction ↓ incompatibility.
Length of time in solution: ↑ time ↑ chance of incompatibility
Order or mixing: do not add incompatible drugs in sequence (e.g. calcium, phosphate), mix well.
Administer solutions quickly after mixing, mix each drug well after addition, ↓ number of mixed drugs, consult references.
Hazards of parenteral drug therapy
Phlebitis: usually a minor problem, minimize by proper IV insertion technique, dilution of irritating drugs, ↓ infusion rate.
Extravasation: caused by vesicant drugs
Irritation: ↓ by varying injection site and applying moisturizer
Pain: common with peripheral infusion of concentration drugs, ↓ by diluting the drug or switching to central vein.
Air embolism: can be fatal
Infection: critical in central IV lines, can be local or systemic (septicemia).
Allergic reaction: due to hypersensitivity to IV solution, additive
Central catheter misplacement: may cause air embolism or pneumothorax, verify proper placement radiologically
Hypothermia: due to shock or cardiac arrest, may be due to cold IV solution, injection solution at room temp only.
Neurotoxicity: serious problem in intrathecal / intraspinal injection of drugs containing preservatives (avoid preservatives)
Pump/controller failure: may cause fluid overload, incorrect dose, or runaway infusion.
IV tubing: can become kinked, split, cracked, produce particles
Glass containers: may break injury
Rubber vial closures: may interact with drug solution
Drug instability: may lead to therapeutic ineffectiveness
Incompatibility: may cause toxicity or ↓ effectiveness
Labeling errors: may cause using incorrect drug or dosage
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Drug overdose: may be caused by runaway IV infusion, pump / controller failure, nursing / pharmacy errors.
Preservative toxicity: can be serious, esp in children. Example: benzyl alcohol in premature infants gasping syndrome (fatal
acidotic toxic state).
Quality Control / Quality Assurance
Quality control: day-to-day assessment of all operations including analytical testing of raw materials and finished product.
Quality assurance: oversight function, involves the auditing of QC procedures and systems.
Sterility testing: USP standard calls for 10-test samples from large batches, minimum of 2 samples from small batches. Test
conducting using membrane sterilization method membrane is cultured for microbial growth.
Pyrogen testing: qualitative fever response in rabbits or in vitro limulus lysate testing.
Clarity testing: to check for particulate matter. Swirl and look it against light source and dark background.
QA programs: include training, monitoring the manufacturing process, QC check, documentation.
Process validation: a mechanism for ensuring processes consistently result in sterile products of acceptable quality. Includes written
procedures, evaluation of aseptic technique by process simulation.
Process stimulation testing: duplicate sterile product production except that a growth media is used instead of drug product.
Incubate final product: no growth successful aseptic technique.
Documentation: of training procedures, QC results, laminar flow hood certification, production records, etc.
35. Drug use in special patient populations
PK parameters change as children mature from birth to adolescence.
Gastric pH: neonates are achlohydric (pH >4) but pH ↑ quickly in the first few weeks of life ↑ absorption of basic drugs and ↓
absorption of acidic drugs, ↑ absorption of drugs destroyed by acidic pH (penicillins).
Gastric emptying: long and highly variable in neonates and preemies, normal by age 6 months (t1/2 65 min). Drugs absorbed in the
intestine: ↓ emptying rate ↓ absorption, ↓ peak concentration. Formula has ↑ caloric density 2x as fast gastric emptying in breast
Underlying disease state: may ∆ gastric emptying rate, total surface area, absorption of lipids
Bile acid production: ↓ in preemies (1/2) than adults ↓ fat and drug absorption (e.g. Vitamin D).
Pancreatic enzyme function: affects absorption of lipid soluble drugs. Neonates have ↓ lipases ↓ absorption of chloramphenicol
Skin hydration ↑ in neonates and preemies. SC thickness normal in newborns, ↓ in preemies. TEWL ↑ in neonates.
Affected by absorption surface area, blood flow, injection site, muscle activity. Preemies ↓ muscle mass, ↓ muscle contractility
erratic IM absorption. IM absorption is normal in infants and children but is discouraged due to pain.
Protein binding: acidic drugs bind to albumin. Basic drugs bind to alpha1-acid glycoprotein. Both proteins are ↓ in neonates ↑ free
drug. Normal levels at 1 year old of age.
Size of body compartments: Extracellular fluid volume is 40% in neonates, 20% at age one. Polar compounds (e.g. aminoglycosides)
distribute into extracullar fluids loading dose is requires in neonates to rapidly achieve therapeutic concentrations. Body fat is ↓↓ in
preemies, higher in newborns and reaches a peak at one year. A ↓ body fat ↓ Vd for lipophilic drugs (diazepam).
Endogenous substances: neonates may have ↑ free fatty acid and unconjugated bilirubin bind to plasma proteins and ↓ degree of
drug protein binding (↑ unbound drug).
Bilirubin competes with certain drugs for albumin binding sites. If displaced potential drug induced kernicterus.
Mostly occur in the liver. Some occur in the intestine, lung, skin. Liver metabolism is affected by enzyme inducers (Phenobarbital,
phenytoin, carbamazepine, rafampin) and enzyme inhibitors (cimetidine, erythromycin).
Phase I reactions: non-synthetic reactions (oxidation, reduction, hydrolysis, hydroxylation) that usually result in inactive or ↓ activity
metabolites. Most important enzymes are cytochrome P-450 monoxygenase system (50% of adult level at birth).
Phase II reactions: synthetic conjugation reactions (with glycine, glucuronide, sulfate) that result in polar water soluble inactive
compounds for renal and bile elimination. Enzymes systems are ↓ at birth and ↑ with age. Glucuronide conjugation chloramphenical,
sulfate conjugation acetaminophen, sulfonamides acetylation,
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Kidney is the major route of elimination for water soluble drugs and metabolites. Processes involved: glomerular filtration, tubular
secretion, tubular reabsorption. Filtration and secretion ↑ eilimination, reabsorption ↓ elimination. All processes are ↓ in neonates.
Renal blood flow (important for glomerular filtration) is ↓ in neonates. Only unbound drugs undergo glomerular filtration.
Problems in drug monitoring
Therapeutic monitoring depends on correlation between serum concentration and therapeutic effect. The relationships are
established for adults and may not work for infants.
Side effects: Most common with antibiotics (vancomycin, penicillins, cephalosporins), anticonvulsants, narcotics, antiemetics, contrast
agents. Examples: red-man syndrome with vancoymcin, syndrome of inappropriate antidiuretic hormone (SIADH) with carbamazepine.
Dosing consideration: Body surface area = square root of (height x weight / 3600). Dose intervals: may be longer for neonates and
shorter for older children.
Withdraw all unnecessary medications 3-6 months before plans for conception.
Blastogenesis: first 2-3 weeks after fertilization. Germ formation occurs. Embryonic cells are undifferentiated.
Organogenesis: 2-8 weeks. Most critical period of development as organs start to develop. Drug exposure may cause major
Fetal period: 9 weeks to birth. At 9 weeks, the embryo is called a fetus. Maturation and growth occurs. Low risk of major congenital
Placental transfer of drugs
Functions of placenta: nutrition, respiration, metabolism, excretion, endocrine activity to maintain fetal and maternal well being. In
order for a drug to cause teratogenic or pharmacological effect, it has to pass from the maternal circulation to the fetal circulation
through the placenta.
Placenta is not a protective barrier: most substances pass the placenta by passive diffusion due to concentration gradient. Placenta
acts similar to any other lipid membrane.
Factors affecting drug transfer: Molecular weight: ↓ (< 500 dalton) cross easily, large (heparin) does not cross. pH: weakly
acidic and weakly basic drugs cross easily. Lipid solubility: ↑ cross easily. Most oral drugs are designed for optimal lipid
membrane transfer. Drug absorption: during pregnancy ↓ gastric tone and motility delayed gastric emptying ↓ absorption.
Drug distribution: during pregnancy ↑ Vd with gestational age, ↑ fat content, ↑ total body fluid. Plasma protein binding: only free
unbound drugs cross placenta. Albumin and alpha1-acid glycroprotein are ↓ during pregnancy ↓ free drugs. Placenta membrane
becomes thinner with gestational age. Blood flow ∆ with meals, exercise, drugs and may ∆ placental crossing.
Embyotoxic drugs: may terminate or shortens pregnancy, especially in early pregnancy. Examples: ACE inhibitors, hormones,
Teratogenic drugs: risk of teratogenesis is highest during the 1
trimester physical malformations, mental abnormalities.
Teratogenic effect depend on the time during gestation when the drug is taken, and organs developing at this point. FDA
Classification: Category A (safety documented in humans), Category B (safety documented in animals, or safe in humans but
damaging in animals), Category C (human safety unknown, may be damaging in animals), Category D (damaging in humans, only use
in life-threatening situations), Category X (highly damaging in humans and may be animals, absolute contraindication). Examples:
vitamin A derivatives (isotretinoin), ACE inhibitors, warfarin (use heparin instead), estrogens, androgens, thyroids (methimazole,
carbimazole, propylthiouracil), cortisone, ethanol (Fetal Alcohol Syndrome, FAS), antibiotics (tetracycline (teeth), metronidazole,
quinolone), anticonvulsants (phenytoin, valproic acid, sodium valproate, trimethadione), lithium (Ebstein’s anomaly), antineoplastics
(methotrexate, cyclophosphamide, chlorambucil, busulfan), finasteride (avoid handling of tablets and semen of male users).
Fetotoxic drugs: more likely during fetal period (9 weeks to birth). CNS depression (barbiturates, tranquilizers, antidepressants,
narcotics), Neonatal bleeding (NSAIDs, anticoagulants, use Tylenol instead), Drug withdrawal (habitual maternal use of barbiturates,
narcotics, benzodiazepines, alcohol), Reduced birth weight (cigarette smokers, alcoholics, drug abusers), constriction of ductus
arteriosus (NSAIDs in 3
trimester may cause pulmonary hypertension).
Drug excretion in breast milk
Transfer from plasma to breast milk: affected by factors influencing human membrane transfer. This is, like other membranes, a
semipermeable lipid barrier. Unionized drugs may pass by passive diffusion. Low molecular weight molecules pass through small
pores. Larger molecules must dissolve first in the lipid membrane.
Drug’s physicochemical properties: human milk is more acidic than plasma. Acidic drugs are unionized diffuse into milk and back.
Basic drugs become ionized in milk trapped in milk. Plasma protein bound drugs can’t pass into milk. ↑ lipid solubility ↑ passage
Drugs affecting hormonal influence: primary hormone is prolactin. Bromocriptine ↓ prolactin suppress lactation if desired.
Other drugs to ↓ prolactin: L-dopa, ergot alkaloids. Drugs to ↑ prolactin: metoclopramide, sulpiride.
Minimizing infant’s drug exposure: choose drugs with no active metabolites, short t1/2, no milk accumulation. Adjust route of
administration, dosing schedule to ↓ infant’s exposure.
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Drugs that enter breast milk: narcotics, barbiturates, BZD, alcohol, antidepressants, antipsychotics, metoclopramide, anticholinergics
People >65 years use 33-50% of all prescriptions. 75% of elderly are Rx users.
20% of elderly experience SE. Incidence of SE is 2-3x higher in elderly.
SE may be overlooked in elderly because they are similar to disease symptoms.
Causes of ↑ SE in elderly: polypharmacy, multiple diseases, more severe diseases, ↓ drug elimination, ↑ sensitivity to drug effects.
One third of elderly use => 6 drugs.
Polypharmacy ↑ drug interactions, ↑ drug-disease interactions.
↑ noncompliance in elderly especially with females, ↓ socioeconomic status, living alone, polypharmacy, multiple disease, complicated
Disease ↑ noncompliance. Example: macular degeneration, cataract, hearing loss, arthritis, Alzheimer.
Clinical trials during drug development may not test drugs on the elderly (↑ SE).
↑ osteoporosis ↑ fractures due to falls because of drugs causing dizziness, drowsiness, syncope, hypotension, blurred vision.
Avoid long acting BZD, use lorazepam, oxazepam (no active metabolites, phase I metabolism).
↓ liver metabolism (phase I) ↑ drug accumulation
Absorption: can be affected by delayed gastric emptying, ↑ gastric pH, ↓ GI motility. Usually, the rate but not the extent of absorption
Distribution: ↑ body fat / lean muscle mass ratio ↑ Vd of fat soluble drugs (diazepam, propranolol). ↓ total body water ↓ Vd of
water soluble drugs (acetaminophen). ↓ serum albumin ↓ protein binding ↑ free drug (warfarin, phenytoin).
Kidney excretion: very important. ↓ glomerular filtration, ↓ tubular secretion rate. 50% ↓ in renal function by age 70 in normal patients.
Serum creatinine is not a good measure of renal function as creatinine also ↓ with age. ↓ dose of renally eliminated drugs to avoid SE
and toxicity. Examples: digoxin, procainamide, H2 antagonists, lithium, aminoglycosides.
Liver metabolism: ↓ phase I (but not phase II) metabolism and ↓ blood flow ↑ t1/2, ↑ SE of BZD, some analgesics.
Altered response to certain drugs. ↓ response to beta blockers, ↑ response to analgesics, BZD, warfarin. Generally, start low and
↑ sensitivity to anticholinergic SE avoid if possible.
36. Clinical laboratory tests
Monitor therapeutic / SE: e.g. serum uric acid after allopurinol, or liver function after isoniazid.
Estimate proper dose: serum creatinine or creatinine clearance before giving renally excreted drug
Decide on alternative / additional therapy: WBC count after AB
Drug-caused test misinterpretation: false positive urine glucose test after cephalosporin.
Normal test values: usually mean +/- 2 SD.
Standardization: using international system of units (SI). Basic SI unit is the mole (more physiologically meaningful as reaction occurs
at molecular level).
Lab error: due to specimens (spoiled, incomplete, wrong sampling time), bad reagents, inaccurate procedure, technical errors.
Basic battery of tests: with routine physical and hospital admission include ECG, chest x-ray, electrolytes, urinalysis, hemogram.
Types of test: quantitative (normal range), qualitative (-ve / +ve), semi-quantitiatve (1+, 2+, e.g. urine glucose).
RBC count: number of RBCs per cubic mm of blood, an estimate of the blood Hb content. Normal: 4.5 million/mm3 (higher in men).
Hematocrit or packed cell volume (PCV): measures percentage (fraction) by volume of packed RBCs in whole blood after
centrifugation. Hct is usually 3x the Hb value. Normal: 45% (higher in men). Low Hct anemia, over hydration, blood loss. High
Hct polycythemia, dehydration.
Hemoglobin test: measures grams of Hb in 100 ml (1dl) of whole blood, an estimate of the oxygen carrying capacity of RBCs. It
depends on the number of RBCs and amount of Hb in each RBC. Normal: 15 g/dl (higher in men). Low Hb anemia.
RBC (Wintrobe) indices: info on the size, Hb concent, Hb weight of RBCs. Used to categorize anemias. Poikilocytosis: ∆ in RBC
shape as in sickle-cell anemia. Anisocytosis: ∆ in RBC size as in folic acid and iron deficiency anemia.
Mean corpuscular volume (MCV): ratio of Hct to RBC count. Measures average RBC size (anisocytosis). Normal: 90. Low MCV
microcytic anemia (iron deficiency). High MCV macrocytic anemia (folic acid or vitamin B12 deficiency).
Mean cell Hb (MCH): measures amount of Hb in average RBC. Normal: 30.
Mean cell Hb concentration (MCHC): measures average Hb concentration in average RBC. Normal: 35. Low MCHC
hypochroma (pale RBCs) as in iron deficiency.
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RBC distribution width (RDW): normal RBCs are equal in size bell-shape normal histogram distribution high RDW in anemia
(iron, folic acid, vitamin B12 deficiency). RDW is never below normal.
Reticulocyte count: measures immature RBCs (reticulocytes), which contain nuclear material (reticulum), Normal: 1% of all RBCs. It
measures bone marrow production of mature RBCs. High reticulocyte count hemolytic anemia, acute blood loss, response to
treatment of factor deficiency anemia. Low reticulocyte count drug-induced aplastic anemia.
Erythrocyte sedimentation rate (ESR): measures rate of RBC sedimentation of whole uncoagulated blood. It reflects plasma
composition. Normal: 10 mm/hr (higher in females). High ESR acute or chronic infection, tissue necrosis, infarction, malignancy.
Use to follow disease course, differentiate diagnosis (angina normal ESR, MI ↑ ESR).
WBC count: number of WBCs in whole blood. Normal: 7000 / mm3. High WBC count (leukocytosis) due to infection (esp.
bacterial), leukemia, tissue necrosis. Low WBC count (leukocytopenia) due to bone marrow depression due to cancer, lymphoma
or antineoplastic drugs.
WBC differential: evaluates the distribution and morphology of WBC cell types including granulocytes (neutrophils, basophils,
eosinophils), and non-granulocytes (lymphocytes, monocytes).
Neutrophils: may be mature or immature. Chemotaxis: congregation of neutrophils at site of tissue damage of foreign body invasion
first line defense phagocytosis and degradation of invaders. Neutrophilic leukocytosis (↑#, ↑ fraction of immature cells)
systemic bacterial infection (e.g. pneumonia), viral infection, fungi, stress (physical, emotional, blood loss), inflammatory disease
(rheumatism), drug hypersensitivity, tissue necrosis, leukemia, certain drugs (Ep, lithium). Neutropenia (↓#, < 1000/mm3)
overwhelming infection as bone marrow is unable to keep up with demand, viral infections, chemotherapy drug reactions.
Basophils: called mast cells in the tissues. Basophilia (↑#) leukemia.
Eosinophils: associated with immune reactions. Eosinophilia (↑#) acute allergic reaction (asthma, hay fever, allergy), parasitic
Lymphocytes: critical for immunologic activity, produce antibodies. Types: T and B. Lymphocytosis (↑#) viral infection.
Lymphocytopenia (↓#) severe debilitating disease, immunodeficiency, AIDS. Atypical lymphocytes in infectious
Monocytes: phagocytic cells. Monocytosis (↑#) TB, bacterial endocarditis, during recovery of acute infections.
Smallest in size. Involved in clotting. Normal: 225,000 / mm3.
Thrombocytopenia: ↓ platelets due to disease or drugs. Moderate: < 100,000. Severe: < 50,000.
Serum enzyme tests
Creatinine kinase (CK)
Location: heart, skeletal muscle, brain tissue
Use: aid diagnosis of acute MI (necrosis) or skeletal muscle damage.
Isoenzymes of CK: CK-MM in skeletal muscle (major), CK-MB in heart, CK-BB in brain used to identify source of damage.
↑ CK-MB heart necrosis
Interference: exercise, fall, IM injection.
Lactate dehydrogenase (LDH)
LDH converts lactate to pyruvate and vice versa. Found in all cells.
Isoenzymes: 1 and 2 (heart), 3 (lungs), 4 and 5 (liver, skeletal muscles).
Use: aid diagnosis of MI, liver / lung disease.
Alkaline pohsphatase (ALP)
Location: produced mainly in the liver and bones
Use: serum ALP is sensitive (↑) to biliary obstruction as in bile duct stone. Serum ALP ↑ due to ↑ osteoblastic activity (e.g. Paget’s
disease, hyperparathyroidism, osteomalacia).
Asparatate aminotransferase (AST)
Formerly known as serum glutamic-oxaloacetic transaminase (SGOT)
Location: mainly in the heart and liver.
Use: ↑ AST in acute hepatitis, cirrhosis, fatty liver, passive liver congestion (as in CHF).
Alanine aminotransferase (ALT)
Formerly known as serum glutamic-pyruvic transaminase (SGPT)
Location: mainly in the liver
Use: more specific but less sensitive than AST for liver damage. ALT ↑ only in severe liver damage.
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Use: identify MI injury, prognosis of unstable angina. More specific than CK-MB. Troponin T in cardiac and skeletal muscles.
Tropnonin I only in cardiac muscle.
Normal: Troponin T < 0.1 ng/ml, Toponin I < 1.5 ng/ml.
Liver function tests
Certain enzymes (LDH, ALP, AST, ALT) ↑ with liver dysfunction.
They indicate only liver damage but not ability to function
Bilirubin is a breakdown product of hemoglobin, main bile pigment.
Indirect bilirubin (unconjugated): bilirubin released from Hb breakdown, bound to albumin, water insoluble, not filtered by glomerulus.
Direct bilirubin (conjugated): Unconjugated bilirubin travel to the liver separate from albumin conjugate actively secret to the
bile filtered by the glomerulus.
Normal values: Total bilirubin 0.5 mg/dl. Direct bilirubin 0.1 mg/dl.
↑ bilirubin tissue deposition jaundice. Causes: hemolysis, biliary obstruction, liver cell necrosis.
Hemolysis: ↑ total but not direct bilirubin. Normal urine.
Biliary obstruction: may be intra-hepatic (e.g. due to chlorpromazine), or extra-hepatic (biliary stone) ↑ total and direct bilirubin.
Bilirubin present in urine dark color.
Liver cell necrosis: due to viral hepatitis ↑ total and direct bilirubin. Bilirubin present in urine dark color.
Normal total serum protein level: 7 g/dL. Transport agents.
Albumin: made in the liver (liver disease ↓albumin )
Globulin: ↓ albumin compensatory ↑ in globulin.
Normal urine: clear, pale yellow to deep gold color.
Red urine: presence of blood or phenolphthalein (laxative)
Brownish-yellow urine: presence of conjugated bilirubin.
Normal urine: slightly acidic (pH = 6)
Alkaline pH: due to acetazolamide use (bicaronaturia), or due to leaving urine sample at room temperature.
Normal urine: 1.015
↑ specific gravity: DM, glucose in urine, nephrosis (protein in urin)
↓ specific gravity: due to diabetes insipidus (↓ urine concentration).
Normal: 65 mg/24 hr.
Glomerular membrane prevents most blood protein from entering urine
Albuminurea: abnormal glomerular permeability.
Proteinuria: due to kidney disease, bladder infection, fever
Normal renal threshold for glucose: blood glucose of 180 mg/dl.
Glycosuria: due to DM.
Usually absent in urine. Excreted when body has used available glucose stores and began to metabolize fat due to uncontrolled DM, or
due to ↓↓ carbohydrate diet Ketonuria.
Ketone bodies: betahydroxybutyric acid (major), acetoacetic acid, acetone.
Hematuria: presence of RBCs may indicate trauma, tumor, systemic bleeding. Squamous cells indicated vaginal contamination due to
menstruation in women.
Casts: protein conglomerations may be due to renal disease.
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Crystals: pH-dependent, uric acid crystals in acidic urine, phosphate crystals in alkaline urine.
Bacteria: usually absent in urine (sterile), if present may be due to UTI or urethral contamination.
Renal function tests
Renal function ↓ with age. Use results to adjust drug dosage if needed.
↓ renal function ↓ urea / creatinine excretion ↑ their blood levels.
Azotemia/uremia: ↑ retention of nitrogenous waste (BUN / creatinine) in blood.
Renal azotemia: due to renal disease, e.g. glomerculonephritis.
Prerenal azotemia: due to dehydration, ↑ protein intake, hemorrhagic shock.
Postrenal azotemia: tumors or stones in the uterers, urethra, prostate.
Clearance: volume of plasma from which a measured amount of substance is eliminated (cleared) into urine per unit time. Use to
measure glomerular function
BUN (blood urea nitrogen)
Urea: end product of protein metabolism, produced in the liver.
Urea is filtered at the glomerulus, then 40% is reabsorbed at the tubules urea clearance is 60% of true GFR
Normal BUN: 13 mg/dl.
↓ BUN: due to liver disease
↑ BUN: due to renal disease, ↑ renal blood flow, ↑ protein intake.
Creatinine: metabolic breakdown product of muscle creatine phosphate
Normal level: 1 mg/dl, but varies based on the muscle mass
Creatinine excretion: by glomerular filtration and tubular secretion.
↑ serum creatinine renal insufficiency.
50% ↓ in GFR doubling of serum creatinine.
Rate at which creatinine is removed from blood by the kidney.
Normal value: 100 ml/min (100 ml of blood cleared of creatinine / min).
Creatinine clearance parallels GFR, more sensitive than BUN.
Creatinine clearance = (urine creatinine concentration x urine rate) / serum creatinine.
Cockroft and Gault equation: used to estimate Clcr based on body weight, age, gender, and serum Cr when urine information is N/A.
Major extracellular cation. Cellular osmosis and water balance: controlled by sodium, potassium, chloride and water.
Normal level: 140 mEq/L. Concentration is a ratio of Na to water.
∆ Na ∆ water balance not electrolyte balance.
Na control: by antidiuretic hormone (ADH) and aldosterone.
Hypothalamus release ADH from pituitary gland ↑ renal reabsorption of sodium.
↓ blood Na,↑ blood K, angiontesin II aldosterone (mineralocorticoid) release from adrenal cortex ↑ Na reabsorption in exchange for
K urine secretion.
Hyponatremia: due to ↑ Na loss (kidney disease), ↓ Na intake, overhydration (non-saline fluid replacement, ↑ water intake), ↓
mineralocorticoid (↓ Na reabsorption), SIADH.
Hypernatremia: due to ↓ Na excretion, ↑ Na intake (hypertonic IV), dehydration (loss of free water as in diabetes insipidus), ↑
mineralocorticoid, ↑ Na drug (Na bicarbonate, ticarcillin).
Most common intracellular cation. Normal level: 140 mEq/L intracellular, 4.5 mEq/L in blood (10% extracellular can not use that
Role: electrical conduction in heart and skeletal muscles, water balance, acid-base balance.
K regulation: by kidneys, aldosterone, blood pH, insulin, K intake.
↑ blood pH ↓ blood potassium / ↓ blood sodium
Hypokalemia: most K is lost through kidneys, due to vomiting, diarrhea, laxative abuse, diuretics (mannitol, thiazides, loop), ↑
mineralocorticoids, glucosuria, ↓ K intake, metabolic alkalosis / insulin / glucose (all move K intacellularly). Signs: fatigue, dizziness,
ECG, pain, confusion
Hyperkalemia: due to ↓ kidney elimination, ↑ K intake, cellular breakdown (tissue damage, hemolysis, burns, infections), metabolic
acidosis, potassium sparing diuretics, ACE inhibitors.
Major extracellular anion critical for acid-base balance.
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Not important clinically. Only confirms Na levels. Normal: 100 mEq/L
Cl retention usually happens with Na and water retention.
Anion gap = sodium – (chloride + bicarbonate)
Hypochloremia: due to fasting, diarrhea, vomiting, diuretics.
Hyperchloremia: usually due to metabolic acidosis, or dehydration, ↑ Cl intake, renal failure.
Bicarbonate / CO2
HCO3-/CO2 is the most important buffering system to maintain pH (acid base balance). Normal level: 25 mEq/L.
Bicarbonate binds to hydrogen to form carbonic acid which can convert to CO2 and water.
Hypobicarbonatemia: due to metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhydrase inhibitors, drug toxicity
(salicylate, methanol, ethylene glycol).
Hyperbicarbonatemia: due to metabolic alkalosis, hypoventilation, ↑ bicarbonate intake, diuretics.
Role: bone integrity, nerve impulse transmission, muscle contraction, pancreatic insulin release, gastric hydrogen ion release, blood
Normal level: 10 mg/dl. Ca reservoir in bones (44% calcium) maintains plasma level. 40% of calcium is bound to plasma proteins
Only free unbound ionic calcium is important physiologically depends on amount of serum protein (albumin)
Hypocalcemia: due to ↓ parathyroid hormone or ↓ vitamin D. Can be caused by loop diuretics.
Hypercalcemia: due to malignancy or metastasis, hyperparathyroidism, Paget’s disease, thiazide diuretics, ↑ Ca intake, ↑ vitamin D.
PO4 is a major intracellular anion source of phosphate for ATP and phospholipids synthesis. Normal level: 4 mg/dl.
Ca and PO4 are affected by same factors consider together
Hypophosphatemia: due to ↓ vitamin D, hyperparathyroidism, malnutrition / anabolism, aluminum antacids, Ca acetate, alcoholism
Hyperphosphatemia: renal insufficiency, ↑ vitamin D, ↑↓ parathyroid
Second most abundant intracellular and extracellular cation.
Role: activates enzymes for carbohydrate / fat / electrolyte metabolism, protein synthesis, nerve conduction, muscle contraction.
Normal level: 2 mEq/L.
Hypomagnesemia: more common, due to ↓ GI absorption, ↑ GI fluid loss, ↑ renal loss. Signs: weakness, tremor, ↑ reflexes,
Hypermagnesemia: due to ↑ Mg intake with renal insufficiency, Addison’s disease. Signs: bradycardia, flushing, sweating, ↓ Ca.
Indicator Normal High Low
RBC Count 4.5 million/mm3 ↑ in men, ↑ erythropoiesis as
45% (~3xHb) ↑ in men, polycythemia,
anemia, blood loss, over-hydration
Hemoglobin 15 g/dl ↑ in men anemia
Poikilocytosis ∆ RBC shape sickle-cell anemia
Anisocytosis ∆ RBC size folic acid, iron deficiency
90: average RBC
size, (Hct / RBC
folic acid or vitamin B12
iron deficiency anemia
Mean cell Hb
35: average Hb /
hypochroma (pale RBCs), ↓ iron
anemia (iron, folic acid,
vitamin B12 deficiency)
hemolytic anemia, acute
drug-induced aplastic anemia
10 mm/hr ↑ in females, acute or
chronic infection, rheumatoid
arthritis, tissue necrosis, MI,
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WBC Count 7000 / mm3 Leukocytosis infection
(esp. bacterial), leukemia,
Leukocytopenia bone marrow
depression due to cancer, lymphoma,
Neutrophils Neutrophilic leukocytosis
bacteria (pneumonia), viral,
fungi, stress, rheumatism,
drug hypersensitivity, tissue
overwhelming infection, chemothrepay
Lymphocytes Lymphocytosis viral
debilitating disease, ↓ immunity, AIDS
Basophils Basophilia leukemia
Monocytes Monocytosis TB, bacterial
Eosinophils Eosinophilia acute
allergy, parasite infection
Platelet Count 225,000 / mm3 Thrombocytopenia (disease or drugs)
acute MI (necrosis), skeletal
Toponin I < 1.5
MI injury, prognosis of
MI, liver / lung disease
biliary obstruction (bile duct
stone), Paget’s disease,
(AST) (also celld
Acute hepatitis, cirrhosis,
fatty liver, liver congestion
(as in CHF).
severe liver damage, less
sensitive / more specific
Liver enzymes LDH/ALP/AST/
liver dysfunction / damage
/ unconjugated +
0.5 mg/dl Jaundice (hemolysis, biliary
obstruction, liver cell
(↑ bilirubin may also show in urine
0.1 mg/dl biliary obstruction, liver cell
(not bound to albumin, secreted to bile,
Serum proteins 7 g/dL Liver disease, nephritic syndrome,
Urine color Clear yellow to
Red blood or
pH Slightly acidic (6) Alkaline: acetazolamide,
Acidic: vitamin C, ammonium chloride
Specific gravity 1.015 DM, glucose or protein
(nephrosis) in urine
diabetes insipidus (↓ urine
Protein 65 mg/24 hr. ∆glomerular permeability,
Glucose 180 mg/dl Glycosuria: due to DM
Ketones None Ketonuria: uncontrolled DM
RBCs None trauma, tumor, systemic
Squamous cells None vaginal contamination due to
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Casts None protein conglomerations due
to renal disease
Crystals None Acidic uric acid crystals
Bacteria None UTI, urethral contamination
(60% of GRF)
renal disease, ↑ renal bl.
flow, ↑protein intake
liver disease (protein is broken to urea
Serum creatinine 1 mg/dl renal insufficiency
100 ml/min renal insufficiency
Sodium 140 mEq/L ↑ Na intake, hypertonic IV,
insipidus, ↑ Na drug (Na
bicarb), ↑ mineralocorticoid).
kidney disease, ↓ dietary intake, ↑
water intake, overhydration, ↓
Potassium 140 mEq/L (only
↑ intake, cellular breakdown
acidosis, K sparing diuretics,
↓ K intake, vomiting, diarrhea, laxative
abuse, diuretics, glucosuria, metabolic
alkalosis, insulin / glucose, ↑
Chloride 100 mEq/L metabolic acidosis, ↑intake,
dehydration, renal failure
fasting, diarrhea, vomiting, diuretics
Bicarbonate 25 mEq/L metabolic alkalosis,
bicarbonate intake, diuretics.
metabolic acidosis, renal failure,
hyperventilation, diarrhea, carbonic
anhydrase inhibitors, salicylate,
Calcium 10 mg/dl ↑ parathyroid, ↑ vitamin D,
thiazides, Paget’s disease, ↑
↓ parathyroid, ↓ vitamin D, loop
Phosphate 4 mg/dl ↑ vitamin D, ↓ parathyroid,
↓ vitamin D, ↑ parathyroid, malnutrition
/ anabolism, aluminum antacids, Ca
Magnesium 2 mEq/L ↑ intake, renal insufficiency,
↓ GI absorption, ↑ GI fluid loss, ↑ renal
38. Cardiac Arrhythmias
Definition: deviations from the normal heartbeat pattern cardiac output, BP, vital organ perfusion. Causes include the
Abnormal impulse formation: heart rate (∆ autmaticity, brady- tachy-cardia), rhythm, site of impulse origin
Abnormal impulse conduction: abnormal sequence of atrial / ventricular activation, conduction block / delay, re-entry (impulse re-
routed through areas where it has already traveled double-depolarization extra impulse).
Supraventricular arrhythmia: atuomaticity (from SA node) or re-enntry conduction.
Ventricular arrhythmia: due abnormal (ectopic) pacemaker triggering ventricular contraction before SA node fires. Common in MI.
Causes: heart disease (coronary artery / valvular / rheumatic / ischemic disease, infections), MI, drug toxicity (digitalis), sympathetic
tone, parasympathetic tone, vagal stimulation (stool straining), oxygen demand (stress, exercise, fever), metabolic disturbances,
hypertension, hyperkalemia, hypocalcemia, COPD, thryoid .
Two electrical sequences: 1. Impulse formation: occurs first as a result of automatic electrical impulse. 2. Impulse transmission:
occurs second to signaling the heart to contract.
SA node AV node Bundle of His Purkinje fibers
Conduction system structures (see figure): tissues that can generate or conduct electrical impulses. Sinoatrial (SA) node: main
heart pacemaker, in the wall of the right atrium, spontaneously start action potential triggering atrium contraction. Atrioventricular (AV)
node: in the lower interatrial septum, delays impulse briefly to allow complete atrium contraction and ventricle filling before ventricle
contraction. Bundle of His: muscle fibers from the AV junction, impulses travel along bundle branches. Purkinje fibers: network that
ends in the ventricular surface ventricle contraction.
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Latent pacemakers: AV node, bundle of His and Purkinje fibers contain cells that can generate impulses but at slower firing rate
(called Overdrive Suppression in case of SA node damage or depression).
Myocardial action potential
Depolarization and repolarization: caused due to Na / K exchange in electrical potential across cell membrane. Has to occur
before cardiac contraction.
Phase 0 (rapid depolarization): rapid sodium influx to cell, cell membrane electrical charge changes from –ve to +ve.
Phase 1 (early rapid repolarization): Na channels close, potassium leaves the cell return to resting potential.
Phase 2 (plateau, absolute refractory period): more potassium out, also calcium enters the cell, cell cannot respond to any stimulus
Phase 3 (final rapid ventricular repolarization): more potassium ions out complete repolarization membrane electrical charge
back to –ve. Called relative refractory period: phase 3, responds only to strong stimuli.
Phase 4 (slow depolarization): back to resting state with potassium in and sodium and calcium out.
Fast channels (sodium): in heart muscle cells rapid depolarization.
Slow channels (calcium): electrical cells of SA node and AV junction slow depolarization.
Electrocardiography (ECG) (PQRST)
P wave: atrium depolarization (activation).
PR inverval: impulse spreads from atria to Purkinje fibers. Delay by AV node to allow ventricle filling. ↑ by digitalis.
QRS complex: ventricular depolarization. ↑ by mexiletine, quinidine, class IC
ST segment: beginning of ventricular repolarization, phase 2 (absolute refractory period), ↓ in angina
T wave: ventricular repolarization (phase 3), inverted in angina
QT: ventricular depolarization and repolarization. ↑ by quinidine, procainamide, sotalol,
Chest pain, brain perfusion anxiety / confusion, dyspnea, cyanosis, abnormal pulse rate / rhythm, palpitations, BP, syncope,
weakness, convulsions, urine output.
Diagnostic test results
ECG: a 12-lead ECG provides definitive diagnosis.
Electrophysiologic testing: intracardiac procedure that determines the location of ectopic center and the need for packemaker /
surgery. Probes are hooked through veins and arteries each heart segment is stimulated until arrhythmia occurs.
His bundle study: locates origin of heart block / re-entry pattern
Laboratory findings: test for hyperkalemia or hypocalcemia.
Class Action Drugs
IA Sodium channel blockers, conduction
Also prolong repolaziation (K blocker)
quinidine, procainamide, disopyramide
IB Sodium channel blockers, condcution lidocaine, phenytoin, tocainide, mexiletine
IC Sodium channel blockers, condcution flecainide, propafenone, moricizine
II Beta blockers propranolol, acebutolol, esmolol
III Potassium channel blocker prolong
Bretylium, sotalol, amiodarone
IV Calcium (slow) channel blockers verapamil, diltiazem
Other adeonsine, magnesium, atropine, digoxin
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Class I (sodium / fast channel blockers)
Mechanism: slow sodium flow into cells during phase 0 (rapid depolarization) slow impulse conduction through AV node. IA prolong
repolarization (refractory period). IB shorten repolarization.
CI: cardiogenic shock, AV block (w/o pacemaker).
If AV conduction: slow conduction using verapamil / digoxin.
If toxic arrhythmia occurs: give catecholamines, glucagon, or sodium lactate.
Cinchona alkaloids: quinidine is an optical isomer of quinine. Quinine oral sulfate or gluconate salt (not preferred IM/IV).
and also K
SE: GI upset, diarrhea (use Al hydroxide), Narrow therapeutic index (target 3 ug/ml). Toxicity: conduction SA block. Cinchonism:
tinnitus, hearing loss, blurred vision, photophobia, diplobia, psychosis.
CI: AV block, prolonged QT interval (may cause torsades, quinidine syncope and sudden death). dose in liver dysfunction and elderly.
DI: cause digitalis toxicity, severe BP with vasodilators, alkalinizers cause toxicity.
IV/IM (acute) and as SR orally (long term therapy).
N-acetylprocainamide: active metabolite.
SE: SLE (arthlagia, myalgia, fatigue), anticholinergic, GI upset than quinidine. Narrow therapeutic index (target 7 ug/ml). Toxicity:
ventricular arrhythmia, conduction SA block.
CI: procaine hypersensitivity, myasthenia gravis, prolonged QT interval, torsades, AV block, SLE. dose in CHF (due to Vd), in
kidney or liver damage.
SE: ventricular dysfucntion, anticholinergic (dry mouth, constipation, etc). Targel level: 3 ug/ml. Used orally
CI: AV block, cardiogenic shock, CHF, myasthenia gravis.
IV/IM. For arrhythmia due to MI and heart surgery
SE: hemodynamic compromise, CNS (dizziness, resltessness, tremors, convulsions), tinnitus, blurred vision. Target: 4 ug/ml. Toxi c
DI: toxicity with phenytoin and beta blockers.
Orally or IV. To treat digitalis-induced arrhythmia (mostly), acute MI, heart surgery.
SE: SLE, gingival hyperplasia, nystagmus, CNS (drowsiness, ataxia, vertigo), cardiac SE. Target: 14 ug/ml. Chronic use can cause
toxicity. Multiple drug intractions toxicity.
Hypersensitivity reactions: blood, skin, Stevens-Johnson, and liver.
Similar structure to lidocaine except taken orally (avoid in lidocaine hypersensitivity).
SE: CNS (dizziness, restlessness, tremors, confusion), GI upset, diarrhea, blurred vision, blood. Target: 6 ug/ml.
Similar structure to lidocaine but first-pass metabolism taken orally.
SE: dizziness, ataxia, BP, QRS complex, blood, liver. Toxicity: tremor. Target: 1 ug/ml.
Prolong QRS complex, slow of phase 0 (rapid depolarization) and slow conduction, no effect on repolarization. May mortality due to
pro-arrhythmic effect use is questionable. Orally.
Flecainide: Use only in refractory life-threatening ventricular arrhythmia. SE: -ve inotropic effect (CI in CHF), CNS (dizziness,
headache, tremor), GI upset, blurred vision. Target: 1 ug/ml.
Propafenone: SE: dizziness, headache, GI upset, bitter taste. Target: 0.5 ug/ml.
Moricizine: SE: dizziness, headache, GI upset.
IC: CV (arrhythmia esp in MI), eye toxicity (blurring, diplobia)
Class II (beta blockers)
Approved drugs for arrhythmia: propranolol, esmolol, acebutolol
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Mechanism: ↓ heart stimulation, ↓ AV impulse conduction, ↑ refractory period ↓ heart rate, ↓ heart oxygen demand.
Propranolol: IV or oral for tachy-arrhythmia due to catecholamine stimulation, digitalis-induced ventricular arrhythmias. SE: ↓ BP,
cardiac arrest (↓ AV conduction), fatigue, bronchospasm. Sudden d/c acute MI, arrhythmia, angina ↓ dose gradually. CI: AV
block, cardiogenic shock, CHF, asthma, DB (masks hypoglycemia).
Esmolol: very short t1/2 (minutes), give IV. SE: ↓ BP, dizziness, headache, fatigue, GI upset, bronchospasm. CI: CHF.
Class III (potassium channel blockers)
Mechanism: potassium channel blockers, prolong refractory period and action potential / repolarization. No effect on conduction or
Amiodarone: oral or IV, prophylactically to control refractory ventricular arrhythmia. Oral effect may take days / weeks, very long t1/2
(2 months). Mechanism: sodium, beta, potassium and calcium blocker properties. SE: pulmonary toxicity, eye damage,
photosensitivity, liver toxicity, thyroid toxicity (hypo / hyper), CNS toxicity, ↓ BP, ↓ heart rate. DI: ↑ level / effect of many drugs (calcium
channel blockers, beta blockers, IA antiarrhythmics, digitalis, warfarin).
Bretylium: quaternary ammonium, short term IV or IM only for life-threatening ventricular arrhythmias. SE: ↓ BP. CI: digitalis-induced
Sotalol: orally, also a beta blocker. SE: beta blocker (↓ BP, prolonged repolarization (QT), bronchospasm, bradycardia).
Class IV (calcium / slow channel blockers)
Use: supraventricular arrhythmias. Verpamil and diltiazem but not nifedipine are used for arrhythmias (IV and oral).
Mechanism: ↓ calcium influx in phase 2 (action potential plateau, sustained depolarization), ↑ effective refractory period, depress
phase 4 depolarization, ↓ SA and AV conduction (dominant calcium channels)
SE: verapamil may cause constipation.
CI: AV block, BP, beta blockers, CHF / digitals use, MI
DI: affected by and affect other drugs that are liver metabolized.
Class IV: verapamil, diltiazem, block slow inward.
Mechanism: naturally occurring nucleoside in all body cells. Acts on G-protein coupled adenosine receptors ↑ AV node
refractoriness AV conduction, re-entry through AV node.
Given IV (very short t1/2, 10 seconds).
SE: short-lived flushing, BP, sweating, palpitations, short breath, chest pressure (bronchospasm, X theophylline).
DI: antagonize methylxanthines (caffeine, theophylline) effect.
Other uses: exercise tolerance during exercise testing.
Use: IV for sympathetic sinus bradycardia.
Mechanism: blocks vagal effects on SA node AV conduction heart rate.
Initial doses may cause reflex bradycardia.
Also Digoxin: vagotonic response of impulse generation ↑ AV node refractoriness.
37. Coronary Artery Disease
Ischemic heart disease: insufficient supply of oxygen to the heart (oxygen demand > supply).
Risk factors: hyperlipidemia (cholesterol > 200 mg/dl, LDL > 130 mg/dl, HDL < 35 mg/dl), hypertension, smoking, diabetes, obesity,
family history, sedentary life style, chronic stress type A personality, ↑ age, male gender, oral contraceptives, gout.
Factors that ↑ O2 demand: exercise, smoking, cold temp.
1. ↓ blood flow: atherosclerosis with or without coronary thrombosis is the most common cause. Coronary arteries are progressively
narrowed by smooth muscle cell proliferation and accumulation of lipid deposits (plaque). Coronary artery spasm is a sustained
contraction that can occur spontaneously or induced by irritation (catheter, hemorrhage), cold exposure, ergot drugs. The spasm can
cause Prinzmetal angina or MI. Traumatic injury such as impact of steering wheel on the chest. Embolic events can also occur
2. ↓ blood oxygenation: blood oxygen carrying capacity ↓ in anemia.
3. ↑ oxygen demand: can occur with exertion or emotional stress (sympathetic stimulation). Systole: two phases (contraction and
ejection). Contractile (inotropic) state affects oxygen requirement. ↑ ejection time ↑ oxygen demand.
Episodic reversible oxygen insufficiency. May be caused oxygen imbalance (tachycardia, anemia, hyperthyroidism, hypotension,
arterial hypoxemia). .
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Patient complaints: squeezing pressure, sharp pain, burning, aching, bursting, indigestion-like discomfort, radiating pain to the arms /
legs / neck / shoulders / back.
Physical examination: usually not revealing, especially between attacks. Note history, risk factors, description of attacks, precipitation
patterns, intensity, duration, relieving factors.
Treat risk factors: Hypertension should be controlled. Obesity should be ↓ through diet and exercise. Smoking should be stopped,
but watch for anxiety. Quitting results in 50% ↓ in morality. Transdermal nicotine patches helps quitting over 10 weeks usi ng
decreasing doses of nicotine. Nicotine gum and bupropion can also be used. Also, clonidine.
Stable (classic / exertion) angina: most common form, usually due to a fixed obstruction in a coronary artery. Triggered by exertion,
emotional stress or heavy meal and relieved by rest or nitroglycerin. The pain builds a peak radiating to the jaw, neck, shoulder, arms
and then subsides.
Prinzmetal’s angina (vasospastic or variant angina): due to coronary artery spasm (↓ blood flow). Initially occurs at rest, pain may
disrupt sleep. Calcium channel blockers are preferred over beta blockers. Nitroglycerin may not help.
Unstable angina: due to significant coronary artery vasospasm and platelet aggregation. Characteristics: may occur at rest, ↓
response to nitroglycerin, pattern change / ↑ severity. Progressive unstable angina may signal imminent MI. Immediate hospi talization
Nocturnal angina (angina decubitus): occurs in the recumbent position and is not related to rest or exertion. Occurs due to ↑
ventricular volume (↑ demand). Relieved by diuretics (↓ left ventricular volume). Nitrates may improve nocturnal dyspnea.
ECG: normal in 60% of patients. May show ↑ Q-wave, T-wave inversion, ↓ ST segment.
Stress / exercise ECG: helps diagnose patients with normal ECG. ↓ ST-segment.
Stress perfusion imaging: with
technetium sestamibi. Expensive.
Pharmacologic stress test: when coronary artery disease is suspected but patient can’t exercise. Use IV dipyridamole, adenosine (↓
AV conduction), dobumatime to induce cardiac ischemia in ECG.
Coronary arteriography / cardiac catheterization: very specific, sensitive, invasive, expensive, risky (2% mortality rate).
Bile acid sequestrants: Cholestyramine chloride is a basic anion-exchange resin. Colestipol HCl is a copolymer. Mechanism:
insoluble, nonabsorbable, hydrophilic, anion-exchange resins bind bile acids in the intestine ↑ bile acid synthesis from cholesterol
cholesterol depletion. SE: bad taste (before meals), GI upset, constipation, bloating, dyspepsia, ↓ other drugs’ absorption (e.g. digoxin,
may use in toxicity), fat soluble vitamine (ADEK) deficiency.
Statins: lovastatin, atrovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin. Preferred in the evening. Mechanism: ↓ HMG-CoA
reductase (converts HMG-CoA to mevalonate; precursor for cholesterol) ↓ cholesterol synthesis. SE: liver toxicity, monitor creatine
kinase (CK) in case of skeletal muscle complaints (myopathy, rhabdomyolysis), headache, rash. CI: fibrates / cyclosporins ↑ risk of
Fibric acid derivatives: gemfibrozil, clofibrate, fenofibrate (micronized prodrug). Mechanism: ↓ synthesis / ↑ catabolism of
triglycerides / cholesterol. SE: GI upset, ↑ liver function (monitor combined use for statins).
Niacin (nicotinic acid): SE: flushing / itching (tolerance in 2 weeks, may be ↓ with aspirin), ↑ liver function, GI upset.
Other drugs: probucol, eicosapentaenoic acid (EPA), docashexanoic acid (DHA). Probucol SE: arrhythmia, syncope.
Chemistry: Nitrites (amyl nitrite) organic esters of nitrous acid, Amyl nitrite: very volatile, flammable liquid, by inhalation for CN
poisoning. Nitrates (nitroglycerin, isosorbide) organic esters of nitric acid. Nitroglycerin: very volatile, flammable, special storage,
dispense in original glass container, protect from body heat, special IV plastic tubes to avoid absorption and loss of effect, extensive
first pass effect (use transdermal or sublingual).
Dosage form: Nitroglycerin: sublingual / buccal tabs, topical ointment, transdermal, IV. Isosorbide mono / dinitrate: tablets.
Mechanism: fast acting, form free radical nitric oxide (NO, endothelium-derived relaxing factor, EDRF) activates guanylyl cyclase
↑ cGMP dephosphorylation of myosin light chain muscle relaxation, venous dilation (↓ vascular resistance) peripheral blood
pooling ↓ venous return ↓ preload (left ventricular volume) ↓ respiratory symptoms (shortness of breath, nocturnal dyspnea).
Also ↓ arterial pressure ↓ afterload ↓ oxygen demand. Also some ↓ in afterload.
Use: use sublinigual (up to 3 tabs in 15 minutes), transmucosal (buccal tabs / spary) or IV nitroglycerin for acute attacks of angina
pectoris. Sublingual tabs / oral tablets / transdermals can be used prophylactically before known stress (eating, sex). IV nitroglycerin is
used for emergency unstable angina.
SE: may ↓ BP reflex tachycardia / postural hypotension, headache (transient, temporary, prevented by Tylenol 15-30 beforehand),
Nitrate tolerance: loss of efficacy, avoid by requiring 12hr nitrate free periods. Otherwise, higher doses may be required.
Mechanism: ↓ sympathetic heart stimulation (B1) ↓ heart rate and contractility (-ve inotropic / chronotropic) ↓ oxygen demand at
rest / exertion, ↓ arterial blood pressure.
Use: with nitrates to ↓ frequency and severity of exertional angina. May narrow coronary artery combine with calcium blocker, avoid
in Prinzmetal’s angina. Use propranolol.
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SE: bronchoconstriction, mask hypoglycemia (tachycardia), cardiac compensation (fatigue, shortness of breath, edema, dyspnea).
Withdrawal syndrome and angina / MI if suddenly d/c.
Calcium channel blockers
Mechanism: prevent / reverse coronary spasm by ↓ calcium influx into smooth / cardiac muscle ↑ blood flow / oxygen supply. Also ↓
dilate arterioles and ↓ heart contractility ↓ total peripheral resistance ↓ oxygen demand / afterload.
choice to nitrates and beta blockers in stable angina (may combine). Critical in Prinzmetal’s angina / angina at rest.
Diltiazem / verapamil / bepridil: watch for heart block / cardiac compensation due to –ve inotropic effect. Careful with other –ve
inotropic drugs (beta blockers, anti-arrhythmics). Verapamil constipation straining and ↑ oxygen demand.
Nifedipine: peripheral vasodilation, limited –ve inotropic effect. SE: hypotension, tachycardia (combine with beta blocker), dizziness,
Maximal therapy: nitrate, CCB, beta blocker combination.
Morphine: in unstable angina when nitroglycerin fails.
Aspirin: use indefinitely in stable and unstable angina.
Heparin/enoxaparin/dalteparin: with aspirin in unstable angina.
Severe prolonged deprivation of oxygen to part of the heart irreversible necrosis. Usually due to occlusive thrombus near a ruptured
atherosclerotic plaque. May lead to ventricular fibrillation (most disorganized arrhythmia) cardiac arrest and death (sudden death
syndrome). Mortality rate: 30%.
Signs and symptoms:
Persistent severe chest pain or pressure (crushing, squeezing, elephant heavy). Pains beings in the chest and may radiate to the left
arm, neck, leg, etc. Onset of pain is not associated with exertion. Unlike in angina, pain persists > 30 minutes and is not relieved by
nitroglycerin. MI may be silent (no pain). Other symptoms: anxiety, impending doom, sweating, GI upset.
Lethal (ventricular) arrhythmia: arrhythmias resistant to lidocaine may respond to procainamide and bretylium.
CHF: left ventricular failure pulmonary congestion diuretics. Digoxin ↑ contractility, compensate for heart damage.
Cardiogenic shock: due to ↓ cardiac output. Occurs when area of infarction > 40% and compensatory mechanisms are ineffective.
Vasopressors (alpha stimulants to ↑ BP) and inotropes may be used. Use vasodilators (nitropursside) to ↓ preload and afterload.
Intra-aortic balloon pump may be used.
Because MI is life threatening emergency, diagnosis is presumed and treatment is initiated based on complaints and immediate 12-lead
Serial 12-lead ECG: abnormalities may be absent in the first few hours. ST elevation. Ventricular premature beats and ventricular
arrhythmia are the most common arrhythmia.
Cardiac enzymes: creatine kinase (MB-CK) is elevated within hours, peaks at 24 h and back to normal at 72 h. Cardiac troponin I
and T (cTnI, cTnT) patterns are similar to MB-CK but more sensitive. Lactase dehydrogenase (LDH) use is not longer common.
Cardiac imaging include
tc pyrophosphate scintigraphy, myocardial perfusion, radionucleotide ventriculography, coronary
Nitrates: may ↓ chest pain ↓ anxiety and ↓ catecholamine release (↓ coronary spasm less ↑ in oxygen demand).
Morphine: causes venous pooling and ↓ preload, cardiac workload, oxygen consumption (IV). Drug of choice to ↓ MI pain and anxiety.
SE: orthostatic hypotension, respiratory depression, constipation (use docusate). Vagomimetic effect bradyarrhythmia (if excessive
reverse using atropine).
Oxygen: Three liters/min via nasal cannula for chest pain, hypoxia and ischemia
Warfarin: for treatment of acute MI to ↓ mortality, prevent recurrence, ↓ complications (stroke). Target INR: 2.5-3.5.
Antiplatelet agents: abciximab, eptifibatide, tirofiban ↓ platelet glycoprotein receptors.
Beta blockers: propranolol, metoprolol, atenolol. Given in early acute MI to ↓ oxygen demand, cardiac workload, ischemia, infarction
↓ post MI mortality.
ACE inhibitors: after MI to ↑ exercise capacity, ↓ mortality in case of CHF, ↓ ventricular remodeling.
Antihyperlipidemics: ↓ cholesterol ↓ MI mortality.
Calcium channel blockers: avoid in acute MI or in left ventricular malfunction. ↓ incidence of reinfarction.
Dipyridamole: relax smooth muscles, ↓ coronary vascular resistance (↑blood flow). Also, anti-platelet action. Used for angina pectoris
prophylaxis. SE: ↓ BP, headache, dizziness.
Others: intra-aortic balloon, coronary angiography, PTCA.
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Atherosclerotic plaques are made of lipids and fibrous proteins. Lesion rupture triggers release of serotonins, thromboxane A2 and
adenosine diphosphate alteplase platelet aggregation clot. The resulting fibrin traps RBCs, platelets, plasma proteins to form
thrombus. Clot dissolution is caused by conversion of plasminogen to plasmin mediated by plasmingoen activators. Use as early as
possible (<12 h after pain starts).
Absolute CI: internal / eye hemorrhage, intracranial / intraspinal injury, pregnancy, aneurysm, ↑↑hypertension.
Recombinant tissue plasminogen activator (t-PA): front-loaded regimen (IV bolus then infusion).
Streptokinase (SK): SE: systemic antibody formation ↑ chances of refractory response and allergy if repeated within 6 months
(avoid if unknown). Monitor for bleeding, reperfusion arrhythmia (within 30 min), hypotension, anaphylaxis.
Other thrombolytic agents: reteplase, tenecteplase, anisoylated plasminogen streptokinase activator complex (APSAC).
Post thrombolysis adjunctive therapy: antiplatelet and anticoagulant therapy after reperfusion to prevent reoccolusion, ischemia and
Aspirin: during thrombolyic therapy ↓ post-infarct mortality. Also: clopidrogel, ticlopidine, dipyridamole.
Heparin: with thrombolytics to prevent reocclusion after reperfusion, ↓ mortality in MI. Give bolus then infusion. Goal: maintain APTT
(activated partial thromboplastin time) at 1.5 – 20 times control. Avoid combining with streptokinase (↑ bleeding). Give SC, but not IM.
Alternatives: ↓ MWt heparins (enoxaparin, dalteparin).
Arterial pressure = cardiac output X Peripheral Resistance
Cardiac output = heart rate X stroke volume
Conditions that increase stroke volume: fever, aortic regurgitation, thyrotoxicosis
Starling's Law: ↑ ventricular stretch ↑ myocardial contractility
↑ blood volume returning ↑ ventricular dilation
Initiators of baroreceptor reflexes: stretch receptors located in the wall of large chest and neck arteries
Causes of hypertension: Cushing's disease, oral contraceptives, acromegaly, polycystic kidney disease
Hypertension of unknown etiology: essential hypertension, toxemia of pregnancy, acute intermittent porphyria
Essential hypertension: unknown cause (90% of cases). Chronic vasoconstriction (↑ tone).
Endocrine hypertension: pheochromocytoma (tumor causing ↑ in catecholamine release)
Renal hypertension: chronic pyelonephritis.
Neurogenic hypertension: familial dysautonomia
Other causes: aortic coarctation
Factors causing systolic hypertension with wide pulse pressure: ↑ stroke volume. ↓ aortic compliance
Anesthetized patients receiving antihypertensives ↑↑ responses to body position changes and acute blood loss, altered responses
to sympathomimetic drugs
Perioperatively: antihypertensive drug treatment should be maintained
Rapid increases in BP vagal center excitation negative iontropic effect (↓ contractility), negative chronotropic effect (↓ heart rate).
Africans: use Ca channel blockers and diuretic (CaD) (ACE inhibitors/beta blockersless effective)
Generally, avoid prescribing two drugs from the same therapeutic class.
Effectiveness of antihypertensive drugs is highly unpredictable, requires dose/drug adjustments.
Withdrawal antihypertensives gradually to reduce SE (e.g. MI with b-blocker)
Elderly: esp. vulnerable to CNS SE, orthostatic hypotension. Lower doses may be needed.
Use: recommended (with beta blockers) as initial therapy for BP. Diuretics are also used for CHF, edema, fluid retention.
Precaution: take during the day to avoid interruption of sleep due to frequent urination. May raise lithium level (CI)
Examples: Chlorthiazide, hydrochlorthiazide, cyclothiazide, polythiazide, trichlormethiazide, methyclothiazide, hydroflumethiazide,
benzthizide, bendroflumethiazide, chlorthalidone, metolazone, indapamide. Structure: most are related to sulfonamides.
Mechanism: Act on Na
co-transporter at the distal convoluted tubule. Other actions: directly dilate arterioles, ↓ total fluid
(extravascular) volume, ↓ cardiac output.
1. ↑ urinary excretion of Na
/ water due to ↓ Na / Cl reabsorption
2. ↑ urinary excretion of K
and bicarbonate hypokalemia ↑ potassium dietary intake, use supplements / potassium
3. ↑ blood glucose (hyperglycermia, care with diabetics), ↑ uric acid retention (hyperuricemia, care with gout), ↑ serum lipids
(hyperlipidemia), ↑ calcium levels (hypercalcemia)
4. ↑ effect on other antihypertensives by ↓ re-expansion of extracellular / plasma volumes.
SE: electrolyte imbalance (↓K, ↓Mg, ↑Cadehydration, postural hypotension, dizziness, headache, fatigue, hypovolemic shock,
arrhythmia, palpitation), metabolic alkalosis, ↓ K muscle cramps, light sensitivity / rash (use sunscreen), ↑ uric acid / gout, ↑
lipoproteins, ↑ BG, sulfonamide hypersensitivity.
Interactions: NSAIDs (e.g. ibuprofen) ↓ renal perfusion ↓ effect of thiazides. Sulfasenstivity. Hyperlipidemia ↑ risk of coronary
artery disease. Digitoxin (↑ toxicity due to hypokalemia)
↓ urinary Ca excretion use for kidney stones (calcium nephrolithiasis).
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Metolazone: most effective thiazide diuretic.
Chronic use↑ water reabsoprtion↓ polyuria and polydipsia in diabetes insipidus (instead of ADH) (??)
Loop (high-ceiling) diuretics
Examples: furosemide, torsemide, bumetanide (all are sulfonamide derivatives), ethacrynic acid. Most intense, shortest duration action.
Use: patients intolerant / irresponsive to thiazides, or with renal impairment (↓↓ golmerular filtration rate). Very strong diureticsnot
routinely used for hypertension. Used in edema in CHF / liver cirrhosis / kidney disease / lungs, hypercalcemia
Mechanism: Blocks Na
co-transporter in the thick ascending limb of Loop of Henle (luminal side) excretion of water, Na
metabolic alkalosis. ↑ BG, ↑ blood lipids, ↑ uric acid.
SE: dehydration, ↓ BP, hypovolemia, ↓ K, ↓ Ca, metabolic alkalosis, ↑ uric acid, ↑ BG, ↑ lipids, tinnitus, transient hearing loss (CI
aminoglycosides), sulfonamide hypersensitivity, blurred vision, blood toxicity, distal tubular hypertrophy (with chronic use).
Interactions: like thiazedsNSAIDs (e.g. ibuprofen) ↓ effect, aminoglycosides ototoxicity, digoxin ↑ toxicity (↓ K).
Potassium sparing diuretics
Examples: spironolactone, amiloride, triametrene.
Use: when if ↑ K
loss and not corrected by supplements. May combine with thiazides / loops to balance potassium. Least potent
Uses: prevent hypokalemia from thiazide / loop diuretics, edema from CHF, liver cirrhosis, hyperaldosteronism (Spironolactone).
Triamterene, amiloride mechanism: block Na
channels at collecting duct ↓ Na
exchange with K
and H ↓ K
excretion alkaline urine.
Triamterene SE: hyperkalemia, headache, dizziness, ↑ uric acid, ↓ dihyrofolate reductase methemoglobinemia in case of alcoholic
cirrhosis. CI: history of kidney stones
Spironolactone: synthetic steroidal competitive inhibitor of aldosterone at mineralocorticoid receptors at the collecting duct ↓
sodium-potassium exchange ↓ potassium excretion alkaline urine use in hyperaldosteronism. SE: gynecomastia, hirsutism,
menstrual disruption, lethargy, hyperkalemia.
Interactions: ACE inhibitors and potassium supplements ↑ risk of hyperkalemia. Renal impairment.
Examples: mannitol, glycerin, urea
Mechanism: highly polar, water soluble inert chemicals, freely filtered at the glomerulus but poorly reabsorbed from renal tubules ↑
osmolarity of glomerular filtrate ↓ tubular reabsorption of water ↑ diuresis ↑ water, Na
, bicarbonate excretion alkaline
Use: prevent oliguria, anuria, ↓ cerebral edema, ↓ intracranial pressure, ↓ intraocular pressure (glaucoma).
SE: headache, blurred vision. Not absorbed well by the gut (causes osmotic diarrhea) only given IV.
Carbonic anhydrase inhibitors
Examples: acetazolamide, related to sulfonamides
Mechanism: ↓ carbonic anhydrase at the proximal tubules ↓ sodium bicarbonate / Na reabsorption ↑ water, Na
excretion alkaline urine. ↓ affect due to Na reabsorption in distal sites
Use: glaucoma (aqueous humor has ↑ bicarbonate), acute mountain sickness, alkaline urine and ↑ excretion of acidic drugs (aspirin,
SE: hyperchloremic metabolic acidosis (due to bicarbonate loss), sulfonamide hypersensitivity, CNS depression, drowsiness, fatigue,
constipation, blood SE (bone marrow depression, thrombocytopenia, hemolytic anemia, leukopenia, agranulocytosis)
Use: recommended (with diuretics) as initial therapy, especially for patients with rapid resting heart rate (atrial fibrillation, tachycardia),
ischemic heart disease (angina pectoris, MI)
Mechanism: ↓ cAMP ↓ heart contraction and rate. Other: ↓ rennin secretion ↓ cardiac output, central ↓ in sympathetic output.
Block autonomic reflex response (e.g tachycardia).
Examples (x-olol): atenolol, , propranolol, timolol, acebutolol, betaxolol, bisoprolol, carteolol, metoprolol, nadolol, penbutolol, pindolol,
esmolol, labetalol, carvedilol
Nonselective B1 (heart) - B2 (lung) blockers: propranolol, nadolol, timolol.
Selective B1 (heart) blockers: atenolol, metoprolol, acebutolol (A.M.A.), betaxolol, bisoprolol. Less likely to mask hypoglycemiause
Intrinsic sympathomimetics (partial agonists, P.A.): pindolol, acebutolol, carteolol, penbutolol
Labetalol: beta (1/2) and alpha-1 blocker (racemic mixture), for hypertensive crisis due to pheochromocytoma (tumor with ↑
catecholamines). SE: bronchospam, orthostatic hypotension, urinary retention.
Carvedilol: beta (1/2) + alpha blocker and vasodilator.
Timolol: mainly for ocular hypertension (B1/B2).
Esmolol: ultrashort duration of action, IV.
Carteolol: ↓ lipid solubility↓ CNS penetration.
Propranolol: -ve inotrophic/chronotropic ↓ oxygen demand angina
Side effects, interactions, and precautions:
Withdrawal syndrome if suddenly d/c ↑ anginal attacks, MI, rebound in BP above normal
↑ lipids, hypertriglyceridemia
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Impotence and ↓ libido ↓ compliance
NSAID’s may ↓ effect of beta blockers
↑ SE with neurologic disorders if drug enters CNS ↑ poor memory, depression, fatigue, lethargy
↓ kidney blood flow ↓ glomerular filtration.
Ca channel blockers
CHF cardiac decompensation due to ↓ contractibility and ↓ electrical conduction
DM may mask tachycardia (hypoglycemia), ↓ BG
COPD, asthma, bronchospams (selectivity is dose dependent)
Peripheral vascular disease / Raynaud’s phenomenon vasoconstriction
Peripherial alpha-1 blockers
Examples (x-osin): prazosin, terazosin, doxazosin
Mechanism: block peripheral postsynaptic alpha-1 adrenergic receptors vasodilation (arterioles and veins).
First dose syncope: within 60 min of first dose postural hypotension, dizziness, headache, palpitation, tachycardia, sweating.
Minimize by starting with low dose at bedtime.
Other SE: diarrhea, weight gain, edema, dry mouth, sexual dysfunction.
Uses: refractory ↑ BP, CHF,
Central alpha-2 agonists
Mechanism: act on central presynaptic alpha-2 inhibitory receptors to ↓ sympathetic flow to cardiovascular system ↓ peripheral
Examples: methyldopa, clonidine, guanabenz, guanfacine.
General SE: rebound hypertension (if abruptly d/c), sedation, dry mouth
Methyldopa: SE: hemolytic anemia (+ve Coomb’s test) with prolonged use, SLE, orthostatic hypotension, fluid accumulation, fever/flu-
symptoms (due to liver damage). CI: MAOI (↓ methyldopa activity), hepatic disease. Safest in pregnancy.
Clonidine: safer with renal impairment. ↓ BP, heart rate. SE: depression (CI: alcohol), initial ↑ then ↓ in BP (with IV). No orthostatic
hypotension (cardiovascular reflex blocked). Available as weekly patch. Also analgesic (alpha-2 agonist in spinal cord) and used pre-
anesthetically to ↓ BP. Rapid onset, long duration.
Guanabenz/guanfacine: SE: dizziness, ↓ heart rate. CI: other sedatives, coronary insufficiency, MI, hepatic/renal disease.
Postganglionic adrenergic neuron transmitter blockers
Use: ↑↑ SE avoid if possible, obsolete. Possibly for severe refractory hypertension (other drugs ineffective).
Guanethidine / Guanadrel: very powerful not first choice for ↑BP. Mechanism: ↓ release norepinephrine from adrenergic nerve
endings (depletes NEp). Does not enter CNS not sedation. ↑↑ SE: sodium / water retention, orthostatic hypotension, impotence,
diarrhea. CI: cocaine/TCA ↓ effect
Reserpine: Low dose with other antihypertensives (e.g. diuretics). Mechanism: depletes catecholamines centrally and peripherally.
SE: drowsiness, dizziness. CI: depression (cause nightmares, suicide), peptic ulcer.
Use: last line of treatment. Do not use alone (cause ↑ heart rate, heart output, plasma rennin). Directly relax peripheral vascular
smooth muscles. Commonly used in hypertensive crisis (IV).
General SE: tachycardia, headache, dizziness, fluid retention, nasal congestion.
CI: coronary vascular disease the reflex cardiac stimulation (tachycardia) will ↑ myocardial oxygen demand.
Diazoxide, Minoxidil potassium channel activators membrane hyperpolarization arteriolar vasodilation. Hydralazine ↑ NO
(EDRF) arteriolar vasodilation.
Hydralazine: dilates arteries (renal, cerebral). Triggers sympathetic compensatory reactions. SE: reflex (barorecceptor) ↑ heart
rate/output (may cause angina), ↑ stroke volume, reversible systemic lupus erythematosus (SLE) fatigue, fever regular blood
Minoxidil: dilates arteries. SE: Hypertrichosis (used to treat male pattern baldness; alopecia), tachycardia reflex (give beta blocker),
Diazoxide: dilates arteries. Quick and prolonged action. For hypertensive crisis.
Nitroprusside: dilates arteries and veins. 44% cyanide. Mechanism: reacts with oxyhemoglobin (forms methemoglobin), forms nitric
oxide which activates guanylyl cyclase. First choice for hypertensive crisis (IV, short duration). Use for controlled hypotension during
surgical anesthesia (bloodless surgery, good cerebral perfusion). Also for heart failure (acute/chronic). Avoid in infants. Solution in
water is susceptible to photolysis.
Calcium channel blockers
Use: initial treatment for patients with angina, bronchospam, Raynaud’s disease. For ↑BP in elderly / Africans with low renin.
Mechanism: block voltage-gated slow calcium channels ↓ Ca influx vascular smooth muscle relaxation (more for arteries) ↓
BP. Different agents: systemic / coronary vasodilation, SA/AV nodal depression, ↓ myocardial contractility.
SE: ↓ BP, dizziness, headache, flushing, edema, ↑ beta blocker effect (AV block). Amlodipine: pruritus
Diltiazem / Verapamil ↓ cardiac contractility, ↓ AV conduction. Diltiazem: for arrhythmia and angina. Verapamil: similar action to
diltiazem (more ↓ electrical conduction). Verapamil SE: constipation, bradycardia. CI: beta blockers CHF / bradychardia, ↓
electrical conduction to AV node. Avoid diltiazem and verapamil in patients with AV / SA node problems.
Dihydropyridines (nifedipine / nicardipine / nitredipine) vasodilation but no cardiac effects (no effect on SA / AV node) reflex
sympathethetic response tachycardia. ↓ SE with SR form.
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Second generation dihydropyridine derivatives (related to nifedipine): amlodipine, isradipine, felodipine, nicardipine, nisoldipine.
Chemically related to nifedipine. Selective effect on target tissues. Less reflex tachycardia.
Nimodipine: ↑ lipid solubilityenters brainfor cerebral spasm
Angiotensin Converting Enzyme (ACE) inhibitors
Examples (x-pril): benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, perindopril.
Use: ↑ BP, diabetes with renal problems (delays diabetic neuropathy and glomerculosclerosis), renal disease, left ventricular
dysfunction, good for CHF.
Mechanism: renin-angiotensin-aldosterone system long term BP control. ↓ Renin (aspartyl protease) ↑ hydrolysis of
angiotensiongen to angiotensin I. ↓ ACE (peptidyl dipeptidase) conversion of angiotensin I (weak peptide vasoconstrictor) to
angiotensin II (potent rapid peptide vasoconstrictor, i.e. pressor) ↑ release of aldosterone Na/water retention ↑ fluid volume.
ACE blocks the breakdown of bradykinin ( cough).
SE: initial dry cough, angioedema (skin swelling), hyperkalemia (↓ aldosterone ↓ K excretion), syncope, neutropenia, proteinuria,
rhinorrhea, renal damage.
CI: effect ↓ by NSAID (e.g. ibuprofen), renal problems, K
sparing diuretics / K
supplements ( ↑↑ hyperkalemia). Pregnancy X. ↑
Enalapril: prodrug, converts to the active metabolite enalaprilat (w/ can be used for hypertensive crisis).
Lisinopril: long-acting enalapril analog. .
Longer duration ACE inhibitors (once daily): benazepril, fosinopril, moexipril, trandolapril, perindopril, ramipril, quinapril.
Zankiren: renin inhibitor
Angiotensin II (type I) receptor antagonists
Examples (x-sartan): candesartan cilexetil, eprosartan, irbesartan, losartan, telmisartan, valsartan.
Mechanism: nonpeptide antagonists of angiotensin II receptor (AT1 subtype) in vasculature, heart, kidney, brain vasodilation, ↓
aldosterone release from adrenal gland ↑ Na/water excretion ↓ blood volume. Less effective than ACE inhibitors. No effect on
SE: hyperkalemia (monitor renal function), NO cough or angioedema (unlike ACE inhibitors).
sparing diuretics, diabetics with nephropathy, CHF.
Definition: systolic > 200 or diastolic > 140 ↑↑ quick organ damage.
Reduction of BP must be gradual (15 mmHg over first hour) to avoid compromising organ perfusion (esp. cerebral)
Drugs: vasodilatos (nitroprusside, hydralazine, diazoxide, nicardipine, nitroglycerin), enalaprilat, adrenergic inhibitors (labetolol,
esmolol, phentolamine (alpha blocker)), fenoldopam (dopamine D1 agonist, vasodilator), trimethaphan (ganglionic blocker)
40. Congestive Heart Failure
Definition: condition due the inability of the ventricle to deliver adequate quantities of blood to the metabolizing tissues during normal
activity or at rest. It’s called ‘Congestive’ because of the edema caused by fluid backup due to poor pump function.
Etiology: common in the elderly. CHF is not an independent diagnosis as it is superimposed on an underlying cause (usually coronary
Low-output failure: metabolic demands are normal but heart is unable to deliver be enough blood output. This is the most common
High-output failure: due to ↑ metabolic demands (hyperthyroidism, anemia).
Treatment goals: remove underlying cause (drugs, anemia, hyperthyroid); relieve symptoms / ↑ pump function (↓ metabolic demand, ↓
fluid volume excess, digitalis, inotropes, cardiac transplant).
CHF compensatory mechanisms to normalize cardiac output (stroke volume x heart rate) ∆ left ventricle geometry ventricular
dilation, hypertrophy, ↑ cardiac wall thickness (cardiac remodeling).
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Sympathetic response: ↓ cardiac output sympathetic activation ↑ Ep, NEp ↑ heart rate, ↑ blood flow to vital organs (brain,
Hormonal stimulation: sympathetic blood flow redistribution ↓ renal perfusion ↓ glomerular filtration rate sodium / water
retention, activation of renin-angioensin-aldosterone system more sodium retention, volume expansion.
Concentric cardiac hypertrophy: ventricular remodeling.
Frank-Starling mechanism: ↑ blood volume ↑ cardiac chamber stretch to accommodate excess fluid (distention) ↑ contractile
force to expel fluid to the arteries.
Over time, compensatory mechanisms become exhausted and ineffective viscous cycle of compensation compensation become
self-defeating. Afterload: tension in ventricular muscles during contraction, amount of force needed for the ventricle to overcome
pressure in the artery, also called ‘intravascular systolic pressure’. Preload: force exerted on the ventricular muscle at the end of
diastole that determines degree of muscle stretch, also called ‘ventricular end diastolic pressure’. As fluid volume ↑ ↑ demand on
exhausted pump fluid backup symptoms of CHF.
Symptoms are due to blood backing up behind the failing ventricle. Symptoms are first related to the failing side, then to both sides.
Blood can’t be pumped from the left ventricle to the peripheral circulation left ventricle can’t accept blood from left atrium and lung
blood back up in pulmonary alveoli pulmonary edema.
Symptoms: dyspnea, less effort to trigger exertional dyspnea, wheezing cough, exertional fatigue, nocturia. Paroxysmal (sudden)
nocturnal dyspnea and orthopnea result from volume pooling in the recumbent position relieved by propping with pillow or sitting
Physical findings: Crackles indicate air movement through fluid-filled passages, tachycardia (early compensatory mechanism).
Diagnostic tests: cardiomegaly (heart enlargement), left ventricular hypertrophy, pulmonary congestion.
Blood can’t be pumped from the right ventricle to the lung right ventricle can’t accept blood from right atrium and circulation blood
back up in whole body systemic edema.
Symptoms: tightness and swelling (fingers, skin), nausea, vomiting, abdominal pain on exertion due to liver enlargement.
Physical findings: vein distention due to ↑ venous pressure, tender enlarged liver, bilateral leg edema.
Diagnostic tests: ↑ liver enzymes (ALT) due to liver congestion.
Advantages: ↓ metabolic needs, ↓ heart workload, ↓ heart rate and dyspnea, ↑ diuresis ↓ fluid volume.
Disadvantages: venous stasis thromboembolism, ↓ risk by using anti-embolism stockings, leg exercises.
Small frequent meals with ↓ calories ↓ metabolic demand
↓ sodium (3g/d) to ↓ volume. Education patient about sodium containing products (antacids, NSAIDs, sodium bicarbonate, baking soda,
↑ ejection fraction can be achieved by:
1. Directly ↑ heart contractility using inotropic agents: dopamine, dobutamine, milrinone, amrinone.
2. ↓ resistance to ejection by relaxing peripheral blood vessels: vasodilators such as hydralazine, nitroprusside, nitrates
3. Affecting cardiac remodeling: ACE inhibitors, beta blockers, vasodilators (nitrates).
Addressing the underlying problem is more important than symptoms.
Digitalis glycosides (Digoxin)
Source: Plant steroidal glycosides. Digoxin: from Digitalis lanata; Digitoxin: from Digitalis pupurea; Ouabain: from Strophanthus
Chemistry: Sugar (glycone portion) + steroidal nucleus (aglycone/genin portion) bonded with glycoside (ether) linkage. ↑ hydroxyl
groups ↑ polarity ↓ protein binding / liver biotransformation / renal reabsorption ↓ duration of action. Ouabin v. short duration
Mechanism: Inhibit Na
ATPase ↑ intracellular Na
, ↓ intracellular K
, ↑ calcium entry +ve inotropic effect, ↑ CO, ↑ renal
blood flow (perfusion) deactivate RAAS ↑ diuresis, ↓ edema, prolongs PR interval in EKG. Also: ↑ vagal tone in SA node -ve
chronotropic effect, ↓ CNS sympathetic flow, systemic vasoconstriction.
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Use: CHF, left ventricular systolic dysfunction, rapid atrial fibrillations / flutter, paroxysmal atrial tachycardia. (CI in ventricular fibrillation
Dosage forms: tablet, capsule, injection, elixir.
Dosing: Rapid digitalization: IV in acute need, steady state in 1 day. Slow digitalization: orally, steady state in 1 week. Serum
levels: first ↑ sharply and then ↓ sharply as drug enters the heart. Measure after 5 hr of dosing (steady state). Target: 1 ng/ml.
Potassium: antagonize digitalis effect. ↓ potassium ↑ digitalis toxicity. DI with potassium altering drugs (diuretics, ACE inhibitors).
Magnesium: inversely related to digitalis effect (↓ Mg ↑ toxicity) (similar to potassium).
Calcium: ↑ digitalis inotropic effect. ↑ calcium arrhythmia.
Metabolism: in the kidneys. Serum creatinine affects elimination.
Toxicity: common due to narrow therapeutic index. Can be fatal. ↑ toxicity with quinidine, verapamil, amiodarone. Early: GI
(anorexia, diarrhea, nausea, vomiting), CNS (headache, confusion, delirium, muscle weakness, fatigue, visual disturbance). Later:
ventricular fibrillation / flutter, AV block, atrial tachycardia, premature ventricular contraction. Treatment of toxicity: d/c digitalis and
any potassium depleting drug, give potassium IV if hypokalemic, treat arrhythmia with lidocaine IV, cholestyramine to prevent
absorption (binds digitalis), purified digoxin-specific Fab fragment antibodies.
Inotropic drugs (IV emergency use)
Dopamine: ↓ dose: ↑ kidney blood flow, ↑ urine output. Moderate dose: ↑ cardiac output. ↑ dose: ↑ peripheral resistance, ↑
pulmonary pressure, tachycardia. Very short t1/2.
Dobutamine: similar chemical/pharmacological alternative to dopamine.
Amrinone / milrinone bipyridine derivatives. Mechanism: inhibit phosphodiesterate (PDE) isozyme in heart cells ↑ cAMP
vasodilation, ↑ cardiac contractility. SE: thrombocytopenia, hypotension, headache.
Amrinone: nonglycoside, non-sympathomimetic inotrope. Unstable in dextrose use saline for IV (sodium may also be a problem in
Milrinone: renally excreted.
Used for all CHF patients with fluid retention / edema.
Monitor fluid loss and ↓ in edema by following body weight
Thiazides: effective, commonly used. Disadv: weak, hypokalemia.
Loop: v. effective, orally / IV for acute pulmonary edema. Hypokalemia.
Potassium sparing: weak, balance the hypokalemia.
Aldosterone antagonists: e.g. spironolactone.
For long term, not acute, management of CHF. First line agents.
Mechanism: ↓ enzyme for converting angiotensin I to angiotensin II (potent vasoconstrictor) ↓ total peripheral resistance ↓
afterload. ↓ angiotensin II also ↓ aldosterone release ↓ sodium / water retension ↓ venous return and ↓ preload.
Mechanism: ↓ afterload (artery dilation) / ↓ preload (venous dilation) ↓ pulmonary congestion, ↑ cardiac output.
Nitroprusside: IV, dilates both veins and arteries.
Prazosin: alpha-1 blocker, dilates both veins and arteries.
Hydralazine: dilates arteries.
Nitrates: dilates veins. Higher dose for CHF than for angina.
For long term, not acute, management of CHF.
Only carvedilol (Beta-1-2-Alpha-1 blocker) is approved for CHF.
Actions of norepinephrine: peripheral vasoconstriction, sodium retention by the kidney, cardiac hypertrophy, arrhythmia, hypokalemia,
cell death (apoptosis) due to ↑ stress.
Calcium channel blockers
No evidence of benefit in CHF symptoms. Do not use. Verapamil is particularly contraindicated because of the significant –ve inotropic
effect. Nifidipines are less dangerous (no heart effect)
41. Thromboembolic Disease
Defintion: venous thromboembolic disease (VTED) occurs when elements of the Virchow’s triad (vascular injury, venous stasis,
hypercoaglate state ( protein C / S, antirhombin III)) are present resulting in deep venous thrombosis (DVT) and pulmonary embolism
(PE). Incidence: total is 500K, symptomatic is 250K.
Risk factors: patient specific (age>40, obesity, varicose veins, immobility, pregnancy, dose estrogen, hypercoagulate state, lupus
anticoagulant), illness / surgery (pelvic / hip / lower limb trauma or surgery or cancer, MI, heart failure, inflammatory bowel, sepsis,
kidney disease, polycythemia).
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Prevention: nonpharmacologic ( venous stasis with external pneumatic compression or graduate compression stockings),
pharmacologic (anticoagulant drugs or heparins).
Oral anticoagulants – warfarin
Prevention of: VTED (1ry, 2ry), systemic arterial embolism in prosthetic heart valve or atrial fibrillation, acute MI in peripheral arterial
disease, stroke and death in acute MI, venous thrombosis, pulmonary embolism, coronary occlusion in acute MI.
Chemistry: Coumarin derivatives (warfarin, dicumarol) are water insoluble weak acids. Chemically related to vitamin K. ↑ protein
bound. ↑ liver metabolism. ↓ therapeutic index. Therefore, ↑↑ drug interactions.
Mechanism: antagonists of vitamin K. ↓ reductase responsible for interconversion of vitamin K and its epoxide liver production of
defective () vitamin K-dependent coagulant proteins or clotting factors (2 (prothrombin), 7, 9, 10). Does not work in vivo.
Warfarin is a racemic mixtuer of equal R/S forms
Rapid absorption Cmax in 90 minutes.
inter-individual variability in dose response.
Used mostly orally, but also IV. Pregnancy X.
Effect and depletion of clotting factors occurs after 3 day. Meanwhile, use UFH or LMWH if needed (5 day overlap). Effect also take
time to wear off after d/c. Dose: 2.5-10 mg. Duration: 3-12 months.
Initial daily monitoring of prothrombin time (PT) and international normalized ratio (INR). Then frequency of monitoring gradually to
every 4 weeks. PT results are highly dependent of type of reagent.
INR = patient PT / mean lab control PT. Target: 2-3 (risk 2.5-3.5).
ISI: International Sensitivity Index, a measure of thromboplastin responsiveness to in clotting factors. ISI responsive reagent
PT ~ INR
Warfarin is sensitive to metabolic enhancers / inhibitors, vitamin K.
Antibiotics ↓ GI bacterial flora ↓ vitramin K ↑ warfarin toxicity.
SE: hemorrhage / bleeding (treat with vitamin K, i.e. phytonadione IM/SC), skin necrosis (due to ↓ protein C), urticaria, purpura,
Chemistry: large very acidic muco-polysaccharide molecule
Indications: IV/SC with warfarin for proven VTED. Prevents / treats DVT, PE. Works in vivo to prevent clotting of blood samples.
Avoid IM ( hematoma).
Mechanism: inhibition / inactivation of thrombin (factor IIa, converts fibrinogen to fibrin clot), activated factor Xa (converts prothrombin
II to thrombin IIa), by antithrombin (AT) III.
PK: plasma proteins other than AT III compete for heparin binding. Short t1/2. Large molecule can’t cross placenta safer in
Clearance: combination of saturable and non-saturable first-order kinetic models. Involve rapid followed by gradual elimination.
inter- and intra- individual variability (due to ∆ plasma proteins and clearance).
Administration: start with a 70 units/kg loading dose for fast response, then continuous dose (1000 unit/hr or weight-based)
SE: hemorrhage, thrombocytopenia (common), urticaria. Antidote: protamine sulfate (ver basic protein).
Monitoring: measure activated partial thromboplastin time (aPTT) (patient aPTT / mean lab control aPTT) target: 1.5-2.5, but is
dependent on the reagent. Heparin assay may also be used for monitoring.
Low molecular weight heparin
Examples (x-parin): enoxaparin (Lovenox), dalteparin, ardeparin
Chemistry: fragments of standard heparin produced by controlled chemical or enzymatic depolymerization of heparin. Minimum 18
saccharide units. Very acidic anions at physiologic pH ↓ absorption from GI. Given only parenterally as sodium salts. Heparin:
mean MWt 15K. LMWH: mean MWt 5K.
Indications: prevention and treatment of venous thromboembolism (venous thrombosis, VTED, unstable angina pectoris, MI, surgery).
Mechanism: very similar to heparin with more effect on Xa than on IIa.
PK: binding to heparin-binding proteins than heparin bioavailability at doses and more predictable effect / uniform absorption.
binding to endothelial cells plasma t1/2 and dose-independent renal clearance. ↓ SE than heparin.
aPTTT can NOT be used to monitor effect. No approbriate assay available.
Danaparoid: low MWt heparinoid. It’s a glycosaminoglycan from porcine mucosa. Similar mechanism / uses. CI: bleeding and pork
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Chemistry: recombinant DNA (almost identical to hirudin).
Mechanism: ↓ thrombin (factor IIa) thrombogenic activity (antithrombin).
Use: anticoagulant in case of heparin-induced thrombocytopenia.
SE: cerebral bleeding, allergic/ skin reactions.
Aspirin: Mechanism: ↓ dose permanent inhibition of COX ↓ thromboxane A2. Use: ↓ mortality post-MI, prevent MI reinfarction.
Ticlopidine / clopidrogel: Mechanism: interfere with ADP-induced platelet-fibrinogen binding ↓ glycoprotein GPIIb/IIIa receptor.
Use: ↓ MI, stroke risk. SE: ↑↑, diarrhea, rash, GI upset, neutropenia.
Fab fragments (Abciximab): Mechanism: monoclonal antibodies against GPIIb/IIIa receptor ↓ platelet interaction. Use: coronary
angioplasty, atheroctomy. SE: bleeding, thrombocytopenia, antibody formation, arrhythmia.
Eptifibatide / Tirofiban: Mechanism: same as Abciximab. Use: acute coronary syndrome, coronary angioplasty. Glycoprotein IIb/IIIa
receptor antagonists ↓ fibrinogen, adhesion ligands. SE: bleeding, fever, headache.
Dipyridamole: Mechanism: ↓ RBC adenosine, ↓ phosphodiesterase ( ↑ cAMP), ↓ thromboxane A2. Use: for thromboembolism
prophylaxis after valve replacement. SE: nausea, GI upset, headache, rash, dizziness. Also relax smooth muscles, ↓ coronary vascular
resistance (↑blood flow).
Anagrelide: Mechanism: ↓ platelet production. Use: ↓ platelet count in thrombocythemia. SE: CHF, MI, heart block, arrhythmia.
Cilostazol: Mechanism: PDE III inhibitors ↑ cAMP vasodilation. SE: CHF.
General Mechanism: ↑ conversion of plasminogen to plasmin (serine protease), which hydrolyzes fibrin and dissolves clots.
General SE: bleeding (GI / GU / intracranial / catheter site), and allergic reactions (skin rash, bronchospasm, edema, urticaria).
Alteplase / reteplase (t-PA): recombinant DNA-derived tissue plasminogen activators (t-PA) consisting of amino acids. Called ‘Clot
Selective’ because it acts on fibrin-bound plasminogen. SE: acute MI, acute pulmonary embolism. No allergy issues (human-derived)
Streptokinase: protein derived from cultures of Group C beta-hemolytic streptococci ( hypersensitivity). ↓ fibrinogen and factors 5
& 8. Acts on bound & free plasminogen (not selective). Use: acute MI, DVT, arterial thrombosis.
Anistreplase: also called ‘Anisolyated Plasminogen Streptokinase Activator Complex, APSAC’. Prodrug, activated in vivo by
deacylation. Use: acute MI, coronary arterial thromobi. SE: arrhythmia, ↓ BP
Urokinase: two-chain serine protease from cultured human kidney cells. Mechanism: enzymatically active (plasminogen plasmin).
Use: coronary arterial thrombi, pulmonary embolism.
42. Infectious Diseases
Principle: Infectious disease therapy is based on the principle of selective toxicity: estroy the infecting organism without damage to the
host by exploiting basic biochemical and physical differences between the two organisms.
Drug choice is related to the mechanism of drug action in one of the following general categories:
a. Inhibits bacterial cell wall biosynthesis
b. Inhibits bacterial protein synthesis
c. Inhibits bacterial metabolism
d. Inhibits bacterial nucleic acid synthesis
Gram stain, microbiological culturing, and susceptibility tests should be performed before antiinfective therapy is initiated. Test materials
must be obtained by a method that avoids contamination of the specimen by the patient’s own flora.
a. Gram-positive microorganisms stain blue or purple.
b. Gram-negative microorganisms stain red or rose-pink.
c. Fungi may also be identified by gram stain.
Microbiological cultures: To identify the specifi c causative agent, specimens of body fluids or infected tissue are collected for
Susceptibility tests: Different strains of the same pathogenic species may have widely varying susceptibility to a particular anti-
infective agent. Susceptibility tests determine microbial susceptibility to a given drug and thus can be used to predict whether the drug
will combat the infection effectively.
Microbiological cultures: To identify the specifi c causative agent, specimens of body fluids or infected tissue are collected for
Susceptibility tests: Diff erent strains of the same pathogenic species may have widely varying susceptibility to a particular anti-
infective agent. Susceptibility tests determine microbial susceptibility to a given drug and thus can be used to predict whether the drug
will combat the infection effectively.
The lowest drug concentration that prevents microbial growth aft er 18 to 24 hrs of incubation is called the minimum inhibitory
Th e lowest drug concentration that reduces bacterial density by 99.9% is called the minimum bactericidal concentration (MBC).
Breakpoint concentrations of antibiotics are used to characterize antibiotic activity.
Kirby–Bauer disk diff usion technique: Th is test is less expensive but less reliable than the
microdilution method; however, it provides qualitative susceptibility information.
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Definition and Classification: Used to treat infections caused by bacteria, antibacterial agents fall into several major categories:
aminoglycosides, carbapenems, cephalosporins, erythromycins, penicillins (including various subgroups), sulfonamides, tetracyclines, fl
uoroquinolones, metronidazole, urinary tract antiseptics, and miscellaneous anti-infectives.
Inhibitors of Bacterial Cell Wall Biosynthesis
Structure and mechanism of action: Have a beta lactam ring, the integrity of which is required for antibacterial activity.
Modifications of the R-group side-chain (attached to the β-lactam ring) alter the pharmacologic properties and resistance to β –
A. Penicillins are bactericidal, inactivate bacterial transpeptidases and prevent the cross-linking of peptidoglycan polymers that
is essential for bacterial cell wall integrity. This results in loss of rigidity and a susceptibility to rupture.
Penicillins also bind to, and inactivate, penicillin-binding proteins (PBPs) involved in cell wall synthesis. The action of autolysin in the
presence of penicillin further weakens the cell wall. Gram-positive bacteria with thick external cell walls are particularly susceptible.
The major cause of resistance is the production of a -lactamases (penicillinases). Organisms capable of producing penicillinase include
Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Bacillus, Proteus, and
Absorption: best absorbed on empty stomach and well distributed throughout body and penetrate CSF. Penicillin V has poor
Penicillin G is mainly used to treat infections with the following organisms (resistant strains of bacteria are being isolated more
(a) Gram-positive cocci (aerobic): Pneumococci, streptococci (except S. faecalis), and non-penicillinase-producing staphylococci.
(b) Gram-positive rods (aerobic): Bacillus species, also Clostridium perfringens,C. diphtheriae, and Listeria spp., although the
use of these agents is declining due to the availability of better drugs.
(c) Gram-negative aerobes: Gonococci (non-penicillinase-producing) and meningococci
(d) Gram-negative rods (aerobic): None
(e) Anaerobes: Most, except Bacteroides fragilis. This agent is used against oral anaerobes.
(f) Other: Treponema pallidum (syphilis) and Leptospira spp. These are common pathogens for which first-generation penicillins are
Penicillin G benzathine and Penicillin G procaine are suspensions of penicillin G
Penicillinase-resistant penicillins (oxacillin, dicloxacillin, methicillin, andnafcillin) are used predominantly for penicillinase-producing
Extended spectrum Penicillins: are inactivated by beta lactamases. These agents have a broadened gram-negative coverage.
Ampicillin: Ampicillin is useful for infections caused by Haemophilus influenzae, Streptococcus pneumonia, Streptococcus
pyrogenes, Neisseria meningitidis, Proteus mirabilis, and Enterococcus faecalis
Amoxicillin (Amoxil) is similar to ampicillin, but has better oral absorption. Amoxicillin is commonly used for endocarditis prophylaxis
before major procedures.
Piperacillin has good activity against Pseudomonas spp. and Enterobacter spp
Clavulanic Acid: Clavulanic acid is structurally related to penicillin, but has no antimicrobial properties of its own. Irreversibly inhibit
Clavulanic acid is used in combination products amoxicillin/clavulanic acid (Augmentin) and ticarcillin/clavulanic acid (Timentin) for oral
and parenteral administration, respectively.
Sulbactam/tazobactam: These agents are lactamase inhibitors structurally related to penicillin. Sulbactam is marketed in the
combination product ampicillin/sulbactam (Unasyn).
Tazobactam is used in combination with piperacillin.
Ampicillin/sulbactam is used parenterally and provides coverage similar to that provided by amoxicillin/clavulanic acid. It is most
commonly used for gram-negative bacteria as well as most anaerobes. Piperacillin/tazobactam is effective against most gram-
negative organisms, including Pseudomonas spp.
Adverse Effects: Penicillins cause hypersensitivity reactions in nearly 10% of the patients. All types of reactions, from a simple rash
to anaphylaxis, can be observed within 2 minutes or up to 3 days following administration.
Amoxicillin/Penicillin is DOC for endocartitis prophylaxis.
B. Cephalosporins: Cephalosporins also have a β -lactam ring. Substitutions at R1 determine antibacterial activity. Substitutions at R2
determine pharmacokinetics.Cephalosporins have the same mechanisms of action as penicillins.
Absorption: Cephalosporins are widely distributed in body fluids; selected agents (cefuroxime [Ceftin, Zinacef ], cefotaxime [Claforan],
and ceftizoxime [Cefizox]) penetrate CSF.
Each newer generation of cephalosporins is increasingly resistant to penicillinases.
Third-generation cephalosporins are sensitive to another class of β -lactamase, the cephalosporinases (genes are generally located on
chromosomes as opposed to plasmids)
First Generation Cephalosporins:
First-generation cephalosporins include cephalexin (Keflex), cefazolin (Ancef, Kefzol), and Cefadroxil (Duricef ) and do not penetrate
These agents have good activity against some gram-positive organisms (streptococci) and some gram-negative organisms. First
generation cephalosporins are used mainly for E. coil, Klebsiella infections, and penicillin- and sulfonamide-resistant urinary tract
infections. They are also used prophylactically in various surgical procedures.
Second Generation Cephalosporins:
Second-generation cephalosporins include cefoxitin (Mefoxin), cefaclor (Ceclor), cefuroxime (Zinacef, Ceftin), cefotetan (Cefotan), and
cefprozil (Cefzil) and have broader coverage. Only cefuroxime penetrates CSF.
They are used in the treatment of streptococcal infections as well as infections caused by E. coli, Klebsiella, and Proteus spp.
Most anaerobes (with exception of Clostridium difficile ) are covered as well.
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These are used primarily in the management of urinary and respiratory tract, bone, and soft-tissue infections and prophylactically in
various surgical procedures.
Third Generation Cephalosporins:
Third-generation cephalosporins include cefdinir (Omnicef), cefixime (Suprax), cefotaxime (Clarofan), ceftizoxime (Cefizox), ceftazidime
(Fortaz,Tazicef ), and ceftriaxone (Rocephin).
These agents have enhanced activity against gram-negative organisms. They demonstrate high potency against H. influenzae,
N. gonorrhoeae, N. meningitides, Enterobacter, Salmonella, indole-positive Proteus, and Serratia spp., and E. coli; and moderate
activity against anaerobes. Cefoperazone and ceftazidime have excellent activity against P. aeruginosa. Ceftriaxone is used for
sexually transmitted infections caused by gonorrhea, as well as in empiric therapy for community-acquired meningitis.
All third generation cephalosporins penetrate CSF except cefoperazone.
These agents are excreted by the kidney, except cefoperazone and ceftriaxone, which are excreted through the biliary tract, thus
enabling the use of these agents for infections of the biliary tree.
Third-generation cephalosporins are used to treat gonorrhea, Lyme disease, meningitis, and serious hospital-acquired gram-
negative infections, alone or in combination with an aminoglycoside.
Fourth Generation Cephalosporins:
Cefepime (Maxipime) has a powerful coverage against Pseudomonas spp., as well as other gram-negative bacteria.
Ceftaroline fosamil (Teflaro) is a prodrug that is active against methicillin resistant staphylococci used to treat skin infections and
Adverse effects: Hypersensitivity (2 to 5%) and 5%–10% of penicillin-sensitive persons are also hypersensitive to cephalosporins.
Alcohol intolerance (disulfiram-like) is seen with cefamandole and ceftriaxone.
Cephalosporins may cause bleeding disorders; these disorders can be prevented by vitamin K administration.
Cephalosporins may be nephrotoxic when administered with diuretics.
These agents may cause superinfection with gram-positive organisms or fungi. Cephalosporins are the number one cause of
hospital-acquired C. difficile colitis, a potentially life-threatening infection.
Other beta lactam drugs:
Aztreonam (IV) is a naturally occurring monobactam lacking the thiazolidine ring that is highly resistant to a lactamases. Has good
activity against gram-negative organisms, but it lacks activity against anaerobes and gram-positive organisms. Demonstrates no
cross-reactivity with penicillins or cephalosporins.
Aztreonam is useful for various types of infections caused by E. coli, Klebsiella pneumoniae, H. influenzae, P. aeruginosa, Enterobacter
spp., Citrobacter spp., and P. mirabilis.
43. Seizure Disorders
44. Parkinson’s disease
Disease state and pathology
Slowly progressive degenerative neurologic disease.
Incidence: over 50 years of age (mostly 60’s)= 0.1%.
Pathogenesis: Depigmentation of substantia nigra. Loss of dopaminergic input to the basal ganglia (extrapyramidal system) which is
responsible for initiating, modulating, sequencing motor activity motor disability. Parkinson’s is due to imbalance between dopamine
(inhibitory neurotransmitter, ) and acetylcholine (excitatory neurotransmitter, ).
Diagnosis: depends on clinical findings, tests to rule out secondary cause, PET scan to visualize dopamine uptake in substantia nigra
and basal ganglia.
Primary (idiopathic): called classic Parkinson’s or paralysis agitans. Most common. Incurable disease. Can be due to absorption of
highly potent neurotoxins (CO, manganese solvent, MPTP) or exposure to cell toxic hydrogen peroxide and free radicals; both products
of dopamine catabolism.
Secondary: small percentage, usually curable. Drugs: dopamine antagonists / antipsychotics (phenothiazines (chlorpromazine,
perphenazine), haloperidol, reserpine). Toxins: CO, heavy metals (manganese, mercury, MPTP). Infections: syphilis, encephalitis.
Others: Wilson’s disease, arteriosclerosis.
Pseudo-Parkinson’s: due ↑ dose of older (traditional) antipsychotic agents, more in the elderly
Signs and symptoms
Tremor: initial complaint. Most evident at rest (resting tremor) and with frequency movement. Pill-rolling tremor: involve thumb and
forefinger. Action tremor: with activity.
Limb rigidity: ratchet-like movement when limb is moved passively
Akinesia (difficult) / bradykinesia (slow): including masked-face (fixed expression) with spontaneous emotional responses.
Postural difficulty: walking with stooped, flexed posture, arm swing in rhythm with the legs.
Mental status: depression (50%), dementia (25%), psychosis.
2ry disease effects: cardiovascular (orthostatic hypotension, arrhythmia), GI (constipation, salivation), urinary frequency,
Unified Parkinson’s Disease Rating Scale (UPDRS): used to monitor disease progress and evaluate drug efficacy. Includes: mental
status, behavior, mood, daily activities (speech, swallowing, walking, etc), clinicians motor evaluation (speech, mobility, tremor, etc).
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Non-drug: Exercise / physical therapy: very beneficial for mobility and mood. Nutrition: to risk of poor nutrition, weight loss,
muscle mass. fiber and fluid intake to prevent constipation. calcium to preserve bone structure. antioxidants (e.g. vitamin E) to
oxidative stress. Psychological rehabilitation: support for patient, family. May need to treat depression, dementia.
Drugs: TCA (anticholinergic, dopaminergic, for depression). Beta blocker (propranolol, lipid solubility), BZD, primidone for action
tremor. Diphenhydramine: antihistamine with anticholinergic effect for mild tremor (CNS SE, avoid in elderly).
Principles of therapy: if drug fails use another class, except bromocriptine and pergolide (try both in sequence). Build dose
gradually up. Never d/c drug suddenly.
Late disease disabilities: Levodopa motor fluctuation, dyskinesia, response control by changing dose and timing. Non-
levodopa: urinary urgency oxybutynin, constipation fiber / PEG, salivation antihistamines / anticholinergics, sweating
beta blocker / anticholinergic, orthostatic hypotension desmopressin, pain amitriptyline, depression / dysphagia liquid
levodopa, daytime sleepiness selegiline.
Definitions: Dyskinesias: reversible jerky movements. On-off effect: oscillations in response and sudden changes in mobility from
no symptoms to full symptoms within minutes. End-dose (wearing-off) effect: may improve by shortening the dosing interval. Drug
holiday: temporary d/c of levodopa to reverse down-regulation of dopamine receptors and regain efficacy.
Examples: benztropine, trihexyphenidyl (both structurally related to atropine), biperidene, procyclidine, orphenadrine.
Use: mild symptoms, esp. tremors (not bradykinesia / pos. imbalance).
Mechanism: block action of acetylcholine in basal ganglia.
SE: dry mouth, sweating ( heat tolerance), urinary retention, constipation (use stool softener), delayed gastric emptying,
intraocular tension, GI upset, dizziness, agitation, hallucinations, hypotension.
CI: obstructed GI or GU, glaucoma, cardiac disease. Avoid drugs with anticholinergic activity (antihistamines, antidepressants,
phenothiazines), digoxin level. Avoid combo with haloperidol ( tardive dyskinesia severeity, schizophrenia, haloperidol level).
Dopamine precursor (Levodopa/carbidopa)
Most effective. effect / SE in 4 years. Dopamine can’t cross BBB (not used).
Mechanism: Levodopa: converted by dopa decarboxylase to dopamine dopamine in CNS (crosses BBB). Carbidopa: levodopa
analog that does not cross BBB peripheral decarboxylation of levodopa peripheral SE, CNS bioavailability, dose needed
SE: due to peripheral conversion to dopamine (GI upset, arrhythmia, postural hypotension). Others: hallucinations, psychosis, blood
dyscriasis, GI upset, insomnia
CI: glaucoma, may activate malignant melanoma. Pyridoxine (vit B6) ↑ peripheral decaroxylation ↓ effect. MAOI
hypertension. TCA / Food absorption. Metoclopramide: levodopa level.
General dopamine agonist SE: ↓ BP, syncope, arrhythmia, insomnia, hallucinations, psychosis.
Direct acting dopamine agonists
Ergot alkaloids (ergolines): bromocriptine, pergolide. Others: pramipexole, ropinirole. All mimic dopamine effect (direct agonist).
SE: first-dose cardiovascular collapse (postrual hypotension, fainting, tachycardia, dysrhythmias, dizziness), hallucinations, pulmonary
toxicity, GI upset. V. long t1/2. response variability.
Mechanism: semisynthetic ergosine derivative. 1000x more potent than bromocriptine. prolactin, LH, growth hormone.
SE: dysrhythmias, ↓ BP, hallucinations, insomnia, GI upset
CI: 90% protein bound (cautious with other protein bound drugs), antipscychotics contradictory effects.
Non-ergot dopamine agonists
Examples: pramipexole, ropinirole
Mechanism: bind to dopamine D2/D3 receptors. Also, antioxidant/O2 free radical scavenger, moderate antidepressant.
Start dose and gradually to titrate best balance of efficacy / SE. Also d/c gradually. levodopa dose if used together.
SE: compared to non-selective agonists (motor fluctuations, dyskinesia). Orthostatic hypotension, syncope, bradycardia,
hallucinations, GI upset,
CI: liver metabolism. pramipexole: cimetidine clearance. Ropinirole: smoking metabolism, ciprofloxacin metabolism.
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Indirect acting dopamine agonists
Mechanism: MAO-B selective inhibitor catecholamine (dopamine) breakdown in the brain (MAO-A is in the GI, MAO-B is in the
brain). Used when levodopa wears off. Only MAO-A metabolizes tyramine (exogenous amine in beer, wine, cheese, smoked meat)
hypertensive crisis if inhibited.
SE: hypertensive crisis (possibly with tyramine but ↓ risk), levodopa SE, dizziness, hallucinations, insomnia, orthostatic hypotension,
syncope, arrhythmia, GI upset/bleeding.
CI: meperidine, other opioids.
Catechol-O-methyltransferase (COMT) inhibitors
Examples (x-capone): tolcapone
Mechanism: Selective reversible inhibitor of COMT; main enzyme for peripheral and central metabolism of catecholamines including
levodopa to O-methyldopa (doubles levodopa t1/2). It can be combined with selective MAO-B inhibitor (selegiline).
SE: liver toxicity (jaundice, lethargy, fatigue, appetite loss, clay colored feces, monitor ALS/AST), orthostatic hypotension, hallucinations,
diarrhea, levodopa SE, rhabdomyolysis.
Mechanism: antiviral agent used to prevent influenza. It dopamine pre-synaptic reuptake, dopamine synthesis and release. Some
anticholinergic effect ( tremor, ridigity, bradykinesia). Fast acting drug (effect within few weeks). Drug tolerance occurs (d/c for a few
weeks or use only when needed).
SE: anticholinergic SE, hallucinations, dizziness, seizures, CHF, reversible skin rash (livedo reticularis), blood effect, insomnia, ∆
CI: effect of anticholinergics, HCTZ/triamterene excretion blood level.
Require needle insertion in the brain possible hemorrhage.
Deep brain stimulation: implant frequency electrode into target site and connect lead to SC pace maker functional inhibition of
target regions in the brain.
Globus pallidus internus pallidotomy: surgical resection of parts of the globus pallidus.
Retal nigral transplantation: implantation of embryonic dopaminergic cells to replace degenerated neuronal cells.
Genetic studies: 10x in risk with family history. 50% chance in both of monozygotic twins.
Neurophysiologic theories: mainly due to dopamine. Serotonin and glutamate may play a role. Dopamine may in some brain
Psychosocial theories: may be triggers but not causes. Stress, interpersonal skills, bad family communications, socioeconomic
Population prevalence: 1%.
Using Diagnostic and Statistical Manual (DSM) of Mental Disorders. Diagnosis by exclusion after ruling out medical and mental causes
of psychosis. Symptoms: delusions, hallucinations, disorganized speech / behavior, negative symptoms (6 months + 1 month act ive
symptoms causing social or occupational dysfunction).
Types: paranoid (delusions of grandeur or persecution), catatonic (psychomotor disturbances), disorganized (incoherent responses),
residual (history but no acute psychosis), undifferentiated.
No known cure. Objective is to relieve symptoms and restore function.
Treatment: pharmacotherapy, psychotherapy.
Agent selection: based on patient history and drug safety. Atypical antipsychotics in new diagnosis or first episode (safer drugs).
Antipsychotics are more effective for positive symptoms. Maximum effect: 6-8 weeks. One episode d/c gradually after 6 months.
Multiple episodes: indefinite treatment.
Examples: phenothiazines (chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, trifluperazine), haloperidol,
Mechanism: block dopamine (D2) activity. Cause hyperprolactinemia.
Potency: potency extrapyramidal symptoms. potency sedation, anti-cholinergic, cardiovascular SE.
Efficacy: as good as the typical drugs for the positive but not the negative symptoms. Generally, more SE than the typical drugs.
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Acute dystonias: sudden muscle spasms (neck, jaw, back, eyes). Common in the first 2 days. Treatment: IV/IM anticholinergic
Akathisia: motor restlessness, inner tension and agitation, urge to move (pacing). Common in the first weeks or months. Treatment;
anticholinergic, beta blocker, BZD.
Pseudoparkinsonism: parkinsonism induce by dopmine blockade. Common in the first weeks or months. Treatment: anticholinergic
or switch to atyptical drug.
Tardive dyskinesia (TD): latent extrapyramidal effect (after months / years). Abnormal movement (face, tongue, shoulders, hipds,
extremities, fingers, toes, etc). Movements are fixed (dystonic) and rhythmic. It’s due to prolonged dopamine blockade dopamine
receptor up-regulation sensitivity to stimulation. Treatment: may be irreversible, d/c therapy, when dose symptoms may first
worsen due to dopmaine blockade and still up-regulated receptors, dose may initially mask symptoms but will remerge later. Best
approach is prevention (monitor).
Neuroleptic malignant syndrome (NMS)
Uncommon but sudden onset, serious and may be fatal. Symptoms: extrapyramidal effects, hyperthermia, tachycardia, BP,
incontinence. Management: d/c drug, bromocriptine or dantrolene (muscle relaxant), supportive therapy.
Examples: risperidone, olanzapine, clozapine, quetiapine.
Block serotonin more than dopamione-2 receptors.
Less extrapyramidal SE than typicals. No hyper-prolactinemia.
Treat negative symptoms better than typicals.
Clozapine: only drug with no EPS/TD. Only effective drug for refractory patients. However, use as last resort due to agranulocytosis
(monitor CBC weekly). It has anticholinergic SE.
SE by recptor type: histamine H1 sedation; serotonin 5-HT weight gain; dopamine D2 EPS / hyperprolactinemia; muscarinic
anticholinergic / cognitive / tachycardia; alpha-1 orthostatic hypotension / reflex tachycardia.
Rapid tranquilization: for acute psychosis with agitation and aggression. Use injectable typical drug (IM haloperidol).
Noncompliant patient: use long acting IM drugs every 3 weeks; either haloperidol decanoate or fluphenazine decanoate. Convert
existing oral dose to its injectable equivalent.
Switching drugs: cross taper and titrate ( old, new).
Adjunctive therapy: if 3 agent tried unsuccesfully use clozapine or augmentative therapy (BZD anixiolytics or modd stabilizers such
as lithium, valproic acid or carbamazepine).
46. Mood Disorders
Mood range: depressiondysthymia (dysphoria)euthymiaeuphoria (hypomania)mania
Dysphoria (dysthemia): mood depression below normal range but above depression.
Euphoria (hypomania): mood elevations above normal range but below mania extreme.
Euthymia: the range of normal fluctuation in mood
Mood disorders: sustained elevation or depression in mood that impairs ability to function in the society. Risk of suicide:x10-20.
Incidence: more in women (2x men). 15-20% chance in woman’s lifetime.
Etiology: Biogenic amine theory: due to depletion of serotonin and norepinephrine. Dysregulation theory: cyclic nature of
depression is due to impaired balance of neutrotransmitters not absolute ↓ or ↑. Familial history plays a role.
Clinical depression: ↓ mood,anhedonia, appetite ↑ ↓ , weight ↑ ↓, sleep ↑ ↓, psychomotor ↑ ↓, fatigue, worthlessness, guild, ↓ thinking /
Diagnosis: using Diagnostic and Statistical Manual (DSM) IV criteria. Patient must have persistent symptoms for 2 weeks.
Psychotherapy, pharmacotherapy, and electroconvulsive therapy.
Pharmacotherapy with antiderpssants is 50-60% effective. It has three phases: acute (6 wk, resolve symptoms), continuation (6-9
months, prevents relapse) and maintenance (3 or > years, prevents recurrence).
Drug selection: all drugs are equally effective with different mechanisms and SE. Select drug with SE profile that compl ements the
disease process. For example, depression with psychomotor agitation sedative antidepressant, depression with psychomotor
retardation activating antidepressant.
Therapy initiation: start with half of the lowest dose to minimize SE ↑ to target range in 1-2 weeks, then titrate based on response.
Lag time exists between therapy initiation and clinical response due to changes in postsynaptic receptor sensitivity. Resolution of
anxiety and insomnia in 1-2 week. Full effect in 4-6 weeks.
Serotonin syndrome: tremor, seizure, hyperreflexia, hypomania, agitation, fever, diarrhea, confusion. May occur when two serotonin
enhancing drugs are used concomitantly or close to each other (e.g. MAOI, SSRI).
Serotonin withdrawal syndrome: lethargy, myalgia, chills, dizziness, flu-like symptoms
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Tricyclic Amines (TCA)
Examples: amitriptyline, nortriptyline, protriptyline, imipramine, trimipramine, desipramine, doexpin
Serum concentrations are established for some drugs.
Mechanism: blocks serotonin and norepinephrine reuptake. Also bind to cholinergic, histaminergic, alpha-adrenergic receptors (SE).
SE: anticholinergic (blurred vision, dry mouth, constipation, urinary retention), alpha blockade (orthostatic hypotension), antihistamine
(sedation, take at bedtime), ↓ seizure threshold, ECG changes, lethal if overdoes.
Not first choice for depression. Other uses: neuropathic pain, insomnia.
Monoamine oxidase inhibitors (MAOI)
Examples: phenelzine, tranylcypromine, isocarboxazid.
Mechanism: ↓ monoamine oxidase block break down of biogenic amines ↑ serotonin and norepinephrine in the brain
Not first choice for depression. Only for depression with agitation, hypersomnia, anxiety.
↑ SE: orthostatic hypotension, weight gain, edema, sexual dysfunction. Isocarboxazid liver damage.
May result in accumulation of sympathomimetic amines hypertensive crisis CI with decongestants, foods with tyramines (aged
MAO: 2 wk washout period before start or when D/C.
Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine.
SE: stimulation similar to SSRI give in the morning, ↑ seizure esp with eating disorders.
Selective Serotonin Reuptake Inhibitors (SSRI)
Examples: fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylsertraline, fluvoxamine (for OCD).
Mechanism: selectively block serotonin reuptake ↑ level
↓ SE: stimulation and insomnia (give in the morning), GI, sexual dysfunction, (weight gain?).
Abrupt D/C serotonin withdrawal syndrome (except fluoxetine) D/C gradually.
Metabolized by cytochrome P-450 drug interactions.
Fluoxetine: norfluoxetine has long t1/2 5 wk washout period after D/C.
Mechanism: ↓ reuptake of epinephrine, serotonin, dopamine (similar to bupropion). CI: MAOI. Dose gradually.
SE: nausea, GI (take with food), sustained hypertension (monitor BP).
Low dose is commonly used for insomnia with stimulating antidepressants.
Mechanism: ↑ serotonin. ↑ SE: sedation, hypotension, GI
Structure is similar to trazadone. Mechanism: ↑ serotonin.
SE (↓ than trazadone): sedation, hypotension, GI, dry mouth.
Interaction: ↑ protein binding interact with warfarin, phenytoin. Cytochrome P-450 inhibitor ↑ drugs metabolized by P-450.
Mechanism: ↓ presynaptic alpha-2 receptors ↑ norepinephrine and 5-HT central concentration. Specific affinity to 5-HT1 receptors
↓ SE compared to SSI (no insomnia, agitation, sexual dysfunction). Blocks H1 sedation, and 5-HT2c ↑ appetite.
SE: sedation (take at bedtime), weight gain, dry mouth.
Incidence: 1% of the population. More common in female teens or early 20’s.
Etiology: Family history in 90% (genetics). Due to imbalance and fluctuation in neurotransmitter levels.
↑ norepinephrine manic episode, ↓ norepinephrine depression.
↓ GABA (gamma-aminobutyric acid, inhibitory neurotransmitter) mania, due to unopposed excitatory neurotransmitters
↓ calcium in CSF mania. ↑ calcium in CSF depression.
G protein: involved in signal transduction and activation of other neurotransmitters. Hyperactive G protein mood instability.
Glutamate binding to G proteins linked to NMDA is involved.
Psychosocial and physical stressors trigger early episodes.
Diagnosis: using DSM-IV and history of mania and depression.
Mania: elevated, expansive or irritable mood for 1 week. Grandiose ideations, expansive self-esteem, ↓ sleep, racing thoughts,
distraction, psychomotor agitation, dangerous activities.
Mixed episode (mood incongruent): mania and depression symptoms.
Bipolar I: manic or mixed episode.
Bipolar II: depressive and hypomanic episode.
Cyclothymia: depressive and manic symptoms for 2 years.
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Rapid cycling: four depressive, manic, hypmanic or mixed episodes in 12 months
Clinical course: untreated episodes last days to months. Interval between episodes: 1-2 years. Episode sequence is unpredictable.
Early onset bad prognosis.
Acute, maintenance and continuation phases (like depression).
Antipsychotics, antidepressants, and mood stabilizers may be used.
Antipsychotics: short term therapy during acute mania to ↓ psychosis and agitation.
Antidepressants: use for depression with suicidal tendency. Use cautiously to avoid triggering mania.
First line therapy (except for mixed episodes or rapid cycling).
Monovalent cation like Na and K. Citrate salt liquid, carbonate salt tablet.
Food may delay absorption. Take with food to avoid rapid rise in serum concentration and SE.
Highly distributed but takes 3 days delayed response.
Eliminated through the kidneys with no metabolism.
Mechanism: unknown. ↓ norepinephrine / serotonin, ↑ membrane stabilization, ↑ cAMP / cGMP (2
Dose: narrow therapeutic index. Can be used to acute mania (↑ and ↓ dose gradually, quick action for mania but slow for deperssion)
or preventative maintenance (mania, depression). Require Cp monitoring. If high dose psychosis, psychomotor agitation give
BZD or antipsychotics.
SE: ↑↑↑. Monitor Cp. Categorized into early, long term, and toxicity. Polydipsia, polyuria, nocturia, dry mouth, weight gain, ↓ libido,
Toxicity: use emesis, gastric lavage, hemo- or peritoneal dialysis but not charcoal.
CI: renal failure, pregnancy 1
Interactions: drugs that ↑ serotonin serotonin syndrome. With BZD, antipsychotics ↑ neurotoxicity.
Valproic Acid (VA)
Indications: anticonvulsant that works as a mood stabilizer. Can be used in acute episodes or as a mood stabilizer.
Forms: elixir sodium valproate, capsules VPA, enteric coated tabs divalproex, injections sodium valproate sodium
SE: ↑↑. Monitor Cp. Blood (agranulocytosis, thrombocytopenia), weight gain, liver / pancreas damage, GI upset (↓ in divalproex).
CI: sensitive to enzyme inhibitors and inducers.
Indications: anticonvulsant that works as a mood stabilizer. Use in bipolar if lithium fails.
Mechanism: modulate NEp and cAMP (G protein-linked 2
SE: CNS: drowsiness, dizziness, blurred vision, diplobia, nystagmus, confusion, headache. Dose related: blood dyscrasias, ↑ dose
gradually to avoid SE, GI upset (take with food). Non dose related: skin SE. Metabolic enzyme inducer (drug interactions, monitor Cp).
Complete monitoring (blood count, live function, BUN, electrolytes, TSH).
New Mood stabilizers (anticonvulsants) (gabapentin, lamotrigine)
Indications: both mood elevation during epilepsy. Not approved, though, for mood stabilization (no systematic data).
Lamotrigine: structure is similar to phenytoin and CBZ. Mechanism: block sodium-mediated release of glutamate and aspartate, may
also block GABA and Ach release. SE: dizziness, blurred vision / diplobia, GI upset, rash / photosensitivity.
Gabapentin: structure is similar to GABA (but no effect on GABA). Mechanism: unknown. ↑ dose gradually. Short t1/2 frequent
administration. SE: somnolence, dizziness, nystagmus, fatigue.
Use of dual mood stabilizers
Combination of lithium and CBZ or VPA. Watch for leukocytosis / leukopenia. Do not combine CBZ and VPA (↑↑ blood dyscrasias).
May also combine one of the three (older drugs) with one of the two newer drugs (above).
Mood stabilizers in pregnancy
Older drugs (lithium, VPA, CBZ) may cause birth defects. If necessary, use lithium only in 2
trimester. If necessary, give folic
acid with VPA to ↓ risk.
47. Asthma and COPD
Reversible chronic airway inflammation. It involves obstruction, ↑ airway responsiveness, episodic asthma symptoms. Pathologic
changes are not permanent.
Classification: mild intermittent, and persistent (mild, moderate, severe)
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Incidence: 15 million Americans (one third children). 50% of children outgrow asthma by mid-teens, may return to asthma later in life.
Allergens (pollen, dust mite, animal dander, mold, food), occupational exposures (chemicals, flour, wood, textile dust), viral respiratory
infections, exercise, emotions (anxiety, laughter, stress, crying), irritant exposure (odors, chemicals, irritants), environmental exposure
(weather change, cold air, smoke, sulfer dioxide), drugs (hypersensitivity, aspirin, NSAID, cholinergics (bethanechol), anti-adrenergics
Allergic rhinitis is twice as common in asthmatics.
Pathology / pathophysiology
Postmortem examination: smooth muscle hypertrophy, airway plugs (inflammatory cells, debris, proteins, mucus), vessel
vasodilatation, inflammatory cellular infiltrate, collagen deposition.
Major contributing processes
Inflammatory cells: such as mast cells, eosinophils, activated T cells, macrophages, epithelial cells secrete mediators.
Airway obstruction: due to bronchoconstriction, airway wall edema, mucus plug formation, airway remodeling, smooth muscle
hypertrophy, hyperplasia. Obstruction ↓ ventilation ventilation / perfusion (V/Q) imbalance hypoxemia and ↓ partial pressure
of arterial oxygen (PaO2).
Hyper-responsiveness: ↑ response to stimuli due to ↑ inflammatory mediators and infiltration by inflammatory cells.
Airway inflammation: contributes to hyper-responsiveness, obstruction, respiratory symptoms, ↓ muco-ciliary function, ↑ airway
permeability to allergens / irritants.
Autonomic neutral control: ↑ cholinergic sensitivity ↑ parasympathetic tone, reflex bronchoconstriction.
Airway remodeling: due to persistent inflammation in poorly controlled asthma collagen deposition and fibrosis permanent
Sequencing of events in asthma
Triggering: exposure to trigger (allergen, aspirin, virus, etc) antigen binds to IgE attach to activated mast cells. Early response:
begins in < 30 min and resolves in < 2hr, blocked by beta agonist or cromolyns. Late response: begins 6 hr after trigger, persistent
airway obstruction, inflammation, hyper-responsiveness, occurs in 50% of cases, may last several days, blocked by corticosteroids or
Signaling: inflammatory cells (mast cells, lymphocytes, eosinophils, macrophages, epithelial cells) release chemical signals (cytokines,
chemokines, eicosanoids, leukotrienes) attract more inflammatory cells.
Migration: influx of inflammatory cells (eosinophils, lymphocytes, monocytes, granulocytes); ↑ adhesion molecules attract cells to
Cell activation: required before cells can release inflammatory mediators. Eosinophils activation ↑ inflammatory mediators
smooth muscle constriction, initiate chemotaxis. Leukotrienes bronchoconstriction, ↑ mucus, ↑ vascular permeability, ↑
responsiveness. Other mediators recruit more inflammatory cells to the airways in the late asthmatic response.
Tissue stimulation and damage: due to release of inflammatory mediators from activated cells. Epithelial damage ↑ airway
responsiveness may cause remodeling.
Acute exacerbations: occur suddenly or gradually, usually at night or early morning. Shortness of breath, tachypnea, tachycardia,
wheezing at end of exhalation, chest tightness, cough.
Chronic poorly controlled severe asthma: chronic hyper-inflation, barrel chest.
Signs of respiratory distress: cyanosis (↓ PaO2 / ↑ PaCO2), use of accessory muscles, inability to speak in sentences, ↓ mental
status, PEFR < 50% of normal.
Potentially fatal asthma: history of sudden severe exacerbations, poor self-perception of asthma, history of intubation or ICU
admission, visits to ER or hospitalization for asthma, frequent beta agonist use (>2 canisters / month).
Pulmonary function tests: determine degree of obstruction, may be normal between exacerbations. Forced expiratory volume in 1
second (FEV1): ↓ during exacerbation. Air trapping and lung hyperventilation ↑ residual volume (RV), ↑ total lung capacity (TLC).
Peak expiratory flow rate (PEFR): correlates with FEV1, used to monitor therapy, triggers, need for emergency care. Measure PEFR
in early morning before medications, and may be again midday. Diurnal variation > 20% in PEFR indicate ↑ responsiveness, and poor
Blood analysis: ↑ WBC count during acute exacerbation, eosinophilia, leukocytosis (due to WBC demargination due to corticosteroids).
Sputum analysis: may reveal eosinophils, clumps of epithelial cells, bacterial if infected, mucous in small airways.
Pulse oximetry: noninvasive measure of degree of hypoxemia during acute exacerbation. It measures oxygen saturation in arterial
blood (SaO2) and pulse.
Arterial blood gas: help gauge the severity of exacerbations. Early stages hyper-ventilation ↓ PaCO2 fatigue of respiratory
muscles. Respiratory acidosis: poor prognostic sign respiratory fatigue ↓ respiratory rate ↑ PaCO2.
ECG: may show sinus tachycardia, especially in the elderly.
Chest radiograph: may show pneumonia, hyperinflation.
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Allergy skin and radioallergosorbent test: identify possible allergic triggers.
Status asthmaticus: severe asthma exacerbation that fails to respond to therapy life threatening. Symptoms: ↓ consciousness,
cyanosis, ↑ PaCO2, PEFR < 100 L/min or FEV1 < 1 liter. Treatment: oxygen, inhaled beta agonist, anticholinergic, IV steroids. If
respiratory acidosis tracheal intubation, mechanical ventilation.
Pneumothorax: acute exacerbation with air accumulation in the pleural space. Symptoms: chest pain, dyspnea, cough, anxiety, lung
collapse. Treatment: oxygen, pleural air aspiration, analgesics.
Atelectasis: airway obstruction ↓ gas exchange during respiration collapsed lung. Symptoms: worsening dyspnea and anxiety,
hyperventilation, ↓ breath sounds, cyanosis. Treatment: postural drainage, chest percussion, coughing / breathing exercise,
bronchodilators, bronchoscopy to remove secretions.
At home: depends on EFV or PEFR. If < 50% of personal best aggressive treatment. Limit inhaled albuterol to 3 treatments of 3
buffs by MDI at 20 min intervals or one nebulizer treatment. If response is poor use oral corticosteroid, go to ER if needed.
In the hospital: inhaled albuterol, mechanical oxygen ventilation (up to 90% saturation), anticholinergic, oral or IV corticosteroids,
Step-down approach: aggressive. Start treatment one step above assessed severity for rapid control, review every 3 months. Then,
do gradual step-wise reduction in treatment.
Step-up approach: start treatment at the same step as assessed severity, and adjust upward as needed. Always, control environment
to avoid triggers. If daily or ↑ use of inhaled albuterol consider long-term therapy (e.g. anti-inflammatory). A rescue course of
systemic corticosteroids may be used.
Exercise-induced bronchospasm (EIB)
Warm-up period helps prevent EIB. Prevent EIB by using short acting beta agonist (albuterol) 15 min before exercise, long acting beta
agonist (salmeterol) 45 min before exercise, or cromolyn sodium 1 hr before exercise. Keep albuterol handy.
Chronic asthma (NIH guidelines)
Severe persistent: ↑ dose inhaled steroid + ↓ dose oral steroid + long acting bronchodilator (inhaled or oral salmeterol, SR
Moderate persistent: inhaled steroid + long acting bronchodilator for nigh time symptoms (inhaled or oral salmeterol, SR theophylline)
(drop oral steroid).
Mild persistent: only one of the following: ↓ dose inhaled steroid, inhaled cromolyn, SR theophylline, leukotriene modifier.
Mild intermittent: no daily medications. Albuterol for attacks.
Short acting: albuterol (R- and S- isomers), levalbuterol (only active R-enantiomer), metaproterenol, pirbuterol, for acute exacerbation
and EIB prophylaxis.
Long acting: salmeterol, formoterol for asthma maintenance, EIB prophylaxis, nocturnal symptoms, ↑↑ albuterol use, COPD.
Mechanism: stimulate beta 2 receptors ↑ adenyl cyclase ↑ cAMP bronchodilation, ↑ mucociliary clearance, ↓ inflammatory cell
SE: tremors (due to B2 activation in skeletal muscles), gluconeogenesis (↑ glucose), activation of Na K ATPase, cardiac stimulation
(due to partial B1 stimulation: palpitation, tachycardia), nervousness, headache.
Administration: inhalation ↓ systemic SE (preferred over oral). Always use salmeterol with inhaled steroid, except for EIB prophylaxis.
May combine long and short acting.
Tachyphylaxis: occurs due to regular use. It’s due to down-regulation due to moving of beta receptors from cell surface to inside the
cell. Effect may be reversed with steroids.
Paradoxical bronchoconstriction: due to cold-Freon effect or use of adjuvants.
↑ bronchial hyperactivity: due to irritants such as methacholine and histamine. May be due to albuterol’s S-isomer.
Drug interactions: hypertensive crisis with MAO inhibitors, TCA and methyldopa. Beta blockers (e.g. propranolol) bronchospasm.
Combined with sympathomimetics ↑ heart effect, vasoconstriction (prevent by alpha blockers, phenolamine).
Mechanism: Bind to glucocorticoid receptors in the cell cytoplasm alter gene transcription ↓ inflammatory response, ↓ airway
hyper-responsiveness, ↓ mucus.
Use: in case of allergic component. Added only when anticholinergic / beta agonist combo is ineffective.
Systemic steroids: used for rapid response during acute exacerbations (few hours).
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IV steroids: hydrocortisone and methylprednisone. Alternative to oral steroids to prevent respiratory arrest in hospitals. Switch to oral
steroids after stabilization.
Oral steroids: prednisone, prednisolone. Used in emergencies if possible when there is no risk of respiratory arrest. Used i n burst
doses for a week. Dose tapering may be required.
Inhaled steroids: fluticasone, flunisolide, triamcinolone, beclomethasone, budesonide. Used for chronic treatment, not for acute
exacerbations. Less SE and less efficacy. ↑ steroid penetration into bronchial tree by giving bronchodilator several minutes prior.
Systemic steroids SE: hyperglycemia, ↑ BP, CHF, peptic ulcer, immunosuppression, chronic infections, osteoporosis, glaucoma,
depression, psychosis, cataract, skin changes. If long term, minimize SE by giving morning dose or alternate day dosing.
Inhaled steroids SE: fungal infection, voice hoarseness, dry mouth. May ↓ children growth velocity, but uncontrolled asthma also
retards growth. Systemic SE with large doses. Gargle and wash mouth after use to ↓ fungal infections, systemic absorption.
Interactions: enzyme inducers (rifampin, barbiturates, hydantoins) ↑ steroid metabolism. Oral contraceptives, estrogens, enzyme
inhibitors ↓ steroid clearance. ↑↑ hypokalemia with thiazide and loop diuretics, amphoterecin ↑ digitalis toxicity. Cyclosporine ↑
Leukotrienes: derivatives of fatty acids formed by lipoxygenase. No ring structure. Covalently linked to 2-3 amino acids. Slow reacting
substances of anaphylaxis. ↑ eosinophil and neutrophil migration, ↑ leukocyte adhesion, ↑ neutrophil and monocyte aggregation, ↑
capillary permeability, ↑ smooth muscle contraction, ↑ mucous secretion, bronchoconstriction, .
Effect: anti-inflammatory and bronchodilation ↓ steroid dose.
Leukotriene receptor antagonists (x-lukast)
Examples: zafirlukast, montelukast
Mechanism: prevent interaction of leukotrienes with receptors by ↓ cysteinyl leukotriene-1 block effect of histamine in asthma and
Take zafirlukast on empty stomach (max absorption).
SE: ↓↓, can be used in children. GI upset, dizziness.
Churg-Strauss syndrome: eosinophilic vasculitis angiitus when steroids are d/c or ↓.
DI: enzyme inhibitor, ↑ effect of warfarin / theophylline.
Lipoxygenase inhibitor (Zileuton)
Mechanism: blocks 5-lipoxygenase ↓ leukotrienes synthesis from arachidonic acid.
SE: liver dysfunction and ↑ ALT (monitor, esp in alcoholics). Others (mild): headache, GI upset, myalgia.
DI: ↑ effect of warfarin, theophylline, propranolol.
Mast cell stabilizers (Cromolyn, nedocromil Na)
Effects: Nonsteroidal anti-inflammatory. Less effective than steroids. Used only for asthma maintenance, EIB prevention.
Mechanism: ↓ mast cell degranulation, ↓ inflammatory cells.
SE: ↓↓, used in children. Wheezing, coughing, nasal congestion, throat irritation / dryness.
Methyl xanthines (theophylline)
Use: alternative to B-agonists and steroids in acute attacks and to long acting B-agonist in persistent asthma. Combine with inhaled
steroids control night or early morning symptoms.
Effects: ↓ mucus, ↑ mucociliary transport, ↑ respiration, anti-inflammatory, ↑ renal diuresis.
Mechanism: ↓ phosphodiesterase ↑ cAMP, antagonize adenosine receptors. Less bronchodilation than B-agonists.
Oral (SR): ↑ compliance. ↓ fat tissue distribution, calculate dose based on lean body weight. Gradually titrate dose upward.
IV: rare. Start with loading dose, then maintenance infusion.
Theophylline anhydrous oral solids, theophylline monohydrate oral solutions. Aminophylline IV.
SE: palpitations, restlessness, nervousness, insomnia, seizures, GI upset, diarrhea, dizziness. Do not use in pregnancy.
Therapeutic drug monitoring: monitor SE, serum level, other drugs use. Clearance is age and condition specific.
Interactions: multiple drug and other interactions. ↑ clearance (↓ level) with smoking, ↑ protein. ↓ clearance (↑ level) with age (↑↑ or
↓↓) , fats and carbohydrates, CHF.
CI: peptic ulcer or uncontrolled seizure.
Postganglionic muscarinic block bronchodilation.
Use: more effective in COPD than in asthma.
Ipratropium sodium: quaternary ammonium compound. Used with or as an alternative to beta agonist in acute attacks. Slow onset
and long duration compared to beta agonists give regularly. SE: ↑ intraocular pressure if touches the eye, ↓ anticholinergic.
Atropine aerosols, glycopyrrolate (quaternary ammonium compound): rarely used due to ↑ SE and ↓ efficacy. Used in nebulizers
Antihistamines: if patient has allergic rhinitis. Prevent release of histamine mediated response that influence asthma.
Antibiotics: used to treat infections (change in volume, color, viscosity of sputum). Sputum cultures are useless because COPD are
chronically seeded. Chronic antibiotic preventative used can be considered in case of frequent exacerbations. M. pneumoniae or
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Legionella pneumophilia macrolide . C. pneumoniae oral doxycycline. Pneumonia in the hospital 2
cephalosporin or beta-lactam with b-lactamase inhibitor.
Magnesium sulfate (IV): cause little bronchodilation, ↑ respiratory muscle strength in hypomagnesemic patients.
Immunotherapy: may ↑ lung function, ↓ symptoms.
Humidified O2: ↓ flow rate helps reverse hypoxemia (use if PaO2 < 55 mmHg), esp. at night/during exercise. Goal: SaO2 > 90%.
Heliox: helium / oxygen mixture that is less dense than air ↑ ventilation during acute attack.
IV fluids: and electrolytes are given if volume is depleted.
Environmental control: avoid allergens and triggers. Use allergen-resistant mattresses / pillow encasements, ↑ filtration vacuum
cleaners, avoid ferry pets, carpets and draperies.
Vaccines: used to prevent infections that may trigger asthma (e.g. influenza and polyvalent pneumococcals).
Drug delivery options
MDIs: accurate with good technique and a spacer. A facemask may be needed for children. Wait 1 min between buffs.
Spacers and holding chambers: ↓ drug deposition in the upper airway, ↓ oral absorption, ↓ local / systemic SE. Spacers are
important for ↑ dose steroids or if hand-lung coordination is poor.
Nebulizers: require ↓ patient coordination. Disadvantages: cost, time consuming, ↑ size, inconsistent drug delivery. Used in ↑ dose
beta agonists, anticholinergics, cromolyn in children.
Dry powder inhalers: more common, avoid the use of Freon propellants, easier to use. First load the dose, and then inhale rapidly.
No spacers. Keep away from moisture.
Definition: excessive mucus production by the tracheo-bronchial tree edema and bronchial inflammation airway obstruction.
Pathophysiology: respiratory tissue inflammation vasodilation, congestion, mucosal edema ↑ mucus. Neutrophils infiltration.
Cilia impairment. Cartilage atrophy. Airways become blocked by thick, tenacious mucus secretions sputum rich productive cough.
Normally sterile airways become colonized by Strept pneumoniae, H influenza, Mycoplasma. Recurrent viral / bacterial infections ↓
body defenses, ↑ mucus accumulation, ↓ ciliary activity. Airway degeneration ↓ gas exchange exertional dyspnea. Hypoximia, ↑
Physical findings: chronic productive cough after age 45 (first in winter, worse in the morning). Progressive exertional dyspnea,
obesity, wheezing, prolonged expiration, right ventricular failure, cyanosis (called “blue bloater”)
Diagnostic tests: hypoxemia ↑ erythropoiesis polycythemia (↑ RBCs). ↑ WBC due to infections. Sputum: thick, colored (if
infected), ↑ neutrophils, microorganisms. Arterial blood gas: ↓ PaO2 (hypoxemia), ↑ PaCO2 (hypercapnia). ↓ FEV1. Right ventricular
hypertrophy and cor pulmonale in ECG.
Definition: permanent alveolar enlargement and destruction of the alveolar walls, ↓ alveolar surface area.
Pathophysiology: Inflammation, ↑ mucus secretion alveoli air trapping. tissue damage ↓ space into which normal lung tissue
expands.. Alveoli merge ↑ space for air trapping. Alveolar wall destruction small airways collapse. Hypercapnia and respiratory
acidosis are uncommon because of compensatory ↑ in respiratory rate.
Physical findings: cough is chronic but less productive than in chronic bronchitis, starts at age 55. Exertional dyspnea is progressive,
constant, more severe than in bronchitis. Other findings: weight loss, tachypnea, prolonged expiration, ↓ breath sounds. Patient usually
maintain good oxygenation through tachypnea “pink buffer”.
Diagnostic tests: small chance of ↓ AAT in blood or infections in sputum. ↓ PaO2 and ↑ PaCO2 in arterial blood gas, ↓ FEV1.
Smoking: causes pulmonary hyperactivity and persistent airway obstruction. Alpha-1 antitrypsin (AAT) is a serine protease inhibitor
↓ neutrophil elastase. ↑ risk of COPD when smoking is combined with genetic ATT deficiency.
Others: exposure to irritants (sulfur dioxide, polluted air, noxious gases, dusts), family history, social, economic factors.
Pulmonary hypertension: lung congestion ↓ pulmonary vascular bed space pulmonary hypertension cor pulmonale (right
ventricular hypertrophy) right heart failure.
Acute respiratory failure: advanced emphysema brain respiratory center damage ↓ cerebral oxygenation ↑ PaCO2
hypoxia, respiratory acidosis respiratory failure.
Infection: chronic bronchitis trapping of excessive air, mucus, bacteria and ↓ coughing and deep breathing infection.
Polycythemia: ↑ in RBCs hypercoagulate state, embolism, stroke.
Anticholinergics: First line treatment for COPD.
Beta blockers, corticosteroids, theophylline, O2, etc (see above)
Mucolytics: such as acetylcysteine ↑ sputum clearance, ↓ mucus plugs. May cause bronchospasm.
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Expectorants: such as guaifenesin. Avoid potassium iodide.
Chest physiotherapy: loosens secretions, re-expand lungs, ↑ efficacy of respiratory muscle. More important in outpatient.
Physical rehabilitation: ↑ exercise tolerance and ↑ diaphragm and abdominal muscle tone.
Smoking cessation: and avoidance of irritants. Use drugs with behavior intervention for maximum success.
Surgery: lung volume reduction therapy
48. Rheumatoid Arthritis
Definition: chronic, systemic, autoimmune, inflammation of the synovial joint.
More common in women (2-3:1). 2% of the population.
Four of the following criteria have to be met
1. Morning stiffness for 1 hour before improvement
2. Three joints have fluid or soft tissue swelling
3. One joint in the hand joints must be swollen.
4. Symmetric arthritis: involvement on both sides of the body.
5. Subcutaneous (rheumatoid) nodules
6. ↑ serum rheumatoid factor
7. Radiological erosion or decalcification of bones
May also include extra-articular organ manifestations (GI, infections, etc)
Human leukocyte antigen (HLA-DR4) + environmental factor inappropriate immune response chronic inflammation
Tumor necrosis factor (TNF) ↑ in RA and Crohn’s disease.
Infections may ppt RA in predisposed patients, e.g., polyarthritis with lyme disease
Vasodilation, edema, sensation of heat, loss of function, ↑ production of thick boggy synovial fluid, effusion accumulation.
Pannus: exuberant synovial thickening due to inward overgrowth of enlarged synovium across the surface of articular cartilage
cartilage degradation, bone loss, x-rayed marginal erosions, bone rubbing, pain.
Variable and unpredictable, polycyclic course (intermittent remissions) or progressive course (relentless rapidly advancing
destructive deforming inflammation permanent join deformities progressive functional decline, ↓ range of motion, work disability,
loss of 4-10 years of life expectancy.
Early symptoms: aching, joint pain, fatigue, then hand and feet synovitis (swelling, warmth, tenderness).
Morning stiffness: maximal pain and stiffness on awakening (30 min)
Diagnosis and clinical evaluation
Mainly clinical joint evaluation with lab and x-ray results.
Rheumatoid nodules: firm, round, rubbery masses in the SC of joints prone to pressure (e.g. elbows).
X-ray: soft tissue swelling, osteoporosis, erosions.
Laboratory findings: ↑ Rheumatoid factors (antibodies) especially IgG and IgM, ↑ erythrocyte sedimentation rate due to
inflammation, microcytic anemia, antinuclear antibody test.
Monitoring parameters: morning stiffness duration, number of affected joints, severity of pain, range of motion, deformity and
circumference of joints, time to walk 50 feet, depression, weight loss, sedimentation rate.
A balanced daily program of rest and exercise (↑ muscle strength and joint motion). Use lightweight splints during night (or even day) to
align joints. Avoid complete immobilization. Consider joint replacement.
Symptomatic pharmacological therapy
First line agent, first as analgesic and then ↑ dose for inflammation. Dose: 4-5 g daily.
SE: bleeding and ↓ platelet function (7 days after d/c), tinnitus in ↑ doses, GI (↓ by enteric coating or taking with food)
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Examples: salsalate, choline salicylate safer for aspirin sensitive patients. ↓ anti-inflammatory effect, ↓ respiratory SE, ↓ effect on
Examples: naproxen, ibuprofen, sulindac, piroxicam. May be better tolerated than aspirin. Try for 2 weeks before change.
Chemistry: x-en propionic acids, others acetic acids.
Avoid in asthmatics may trigger bronchospasm.
↑ bleeding time /↓ platelet function (effect reverse quickly if d/c)
GI upset, ulceration, hemorrhage (↓ platelets). ↓ GI ulcers by using misoprostol (Cytotec, ↑ SE: diarrhea) or H2-antagonists. Ibuprofen,
naproxen ↓ GI SE available OTC. Piroxicam ↑ GI SE, CI in elderly.
↓ renal blood flow renal failure (esp with diuretics or CHF).
Temporary CNS effects (headache, drowsiness, confusion, anxiety, etc) esp. with indomethacin. Avoid in the elderly.
Rofecoxib, celecoxib, valdecoxib. Anti-inflammatory, analgesic, antipyretic with ↓↓ GI SE.
Second line agents
Known as Slow Acting Anti-rheumatic Drugs (SAARD) or Disease Modifying Anti-Rheumatic Drugs (DMARD). They modulate
immune response to ↓ progression of erosion. All slow are acting (min 3 months for effect), except methotrexate. Used w/ NSAID. All
have ↑↑ SE.
First line for severe RA. Immunosuppressive folic acid antagonist and antineoplastic. Give a weekly dose, oral or IM.
Aspirin ↓ methotrexate secretion ↑ toxicity
SE: GI, bone marrow suppression, hepatitis, ↑ infection.
Give folic acid supplements. CI in creatinine < 40. Pregnancy X.
Purine analogue immunosuppressive antimetabolite. Converts to 6-mercaptopurine ↓ purine synthesis cytotoxicity to dividing
cells lymphocyte proliferation.
SE: GI, hepatitis, bone marrow depression. Also for leukemia.
Antidote: Leucovorin Ca
(tetrahydrofolic acid derivative)
IM: gold sodium thiomalate, aurothioglucose. SE: proteinuria.
Oral: auranofin. SE: metallic taste, diarrhea, GI, stomatitis
General SE: blood toxicity, rash.
Gradual build up of dose. Try for a min of 6 months
↓ immune response. Taken on empty stomach to ↑ absorption. Dosing: do low-go slow. ↑ SE: rash, fever, proteinuria, hematologic,
Hydroxychloroquine (Plaquenil): antimalarial for mild RA. ↓ SE: Retinal toxicity (retinopathy) due to drug deposition in the cones
monitor for vision acuity. GI upset.
Sulfasalazine (Azulfidine): very effective in slowing progress of joint damage. SE: GI, rash, rare blood dyscrasias, hepatitis
Cyclophosphamide (Cytoxan): Toxic antineoplastic prodrug. SE: ↑↑, hemorrhagic cystitis (treat with mesna), bone marrow
depression, sterility, alopecia.
Etanercept / Infliximab: TNF-alpha inhibitor ↓ TNF (cytokine) binding to inflammatory cell surface. Biological Response Modifier.
Given SC. SE: respiratory infections, autoantibody formation. NO effect of kidney function.
Leflunomide: immuno-modulator. Mechanism: ↓ dihydroorotate dehydrogenase (critical for pyrimidine synthesis). SE: rash, diarrhea,
alopecia, rash, anemia. Pregnancy X.
Mycophenolate mofetil: immuno-suppressant. SE: diarrhea, GI, hematologic. Used to prevent cardiact and renal allograft rejection.
Other drugs: chlorambucil, cyclosporine, minocycline.
Prednisone. Last resort. They do not alter the course of RA. Used for acute flare ups, before action of slow acting drugs kicks in,
systemic RA symptoms, or in case of intolerance to other drugs. Can be used as intra-articular injection if symptoms are localized. SE:
GI bleeding, slow wound healing, hyperglycemia, hypertension, osteoporosis.
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Capsaicin: for symptomatic treatment. It’s the pungent ingredient of hot pepper. Mechanism: depletes and prevents accumulation of
substance P, a chemical mediator in pain transmission from the periphery to CNS (sensory nerve fibers). It produces a sensation of
warmth. Use: joint pain, arthritis tenderness, neuralgia, psoriasis. SE: erythema (reflex vasodilation), histamine release.
Counter-irritants: methyl salicylate, menthol, allyl isothiocyanate, produce a mild inflammatory reaction. Effect may be actually
due to the massage during application not the drug itself.
Combination second line therapy
Step-down bridge approach: combo of antimalarial, oral gold, parenteral gold and methotrexate. Remove medications and taper
dosage after 3 months to the antimalarial alone.
Saw-tooth strategy: use second line agent early and serially substitutes with other agents before previous agents lose efficacy.
Graduated-step paradigm: combo therapy only for patients at active disease. Escalate treatment as needed.
49. Hyperuricemia and Gout
Hyperuricemia: ↑ serum uric acid > 7 mg/dl.
Gout: recurrent acute attacks of urate crystal-induced arthritis. It may include tophi-deposits of monosodium urate.
Incidence: 1% of the population, almost all men. ↑ risk with alcoholism, obesity.
Uric acid synthesis: purine xanthine oxidaze urice acid (adenine and guanine are purine bases). One gram in the body. No
biological function. 66% daily turnover.
Uric acid elimination: 66% through the kidneys, 33% through the GI.
At urine pH (acidic, 4-5) poorly soluble free uric acid. At physiologic pH (7.4) uric acid as monosodium urate salt.
Asymptomatic hyperuricemia: ↑ serum uric acid but no symptoms of arthritis. May be harmless. Drug treatment may be unnecessary.
May develop gout later. Maintain good urine output to prevent stone formation, ↓ purine foods, monitor.
Primary: due to defect in purine metabolism or uric acid excretion. It is due to uric acid ↑ production or ↓ renal clearance or both.
Under-excretors (90%): excrete < 600 mg/day on a purine restricted diet.
Secondary: renal failure (↓ excretion), hematologic diseases (↑ nucleic acid breakdown to uric acid).
Drug induced gout:
Ethanol ↑ production and ↓ secretion.
Aspirin and salicylates ↓ uric acid tubular secretion (↓ excretion).
Diuretics (except spironolactone)volume depletion / ↓ tubular secretion.
Cyclosporine, pyrazinamide, levodopa ↓ urate renal clearance.
Ethambutol, nicotinic acid compete for urate secretion ↓ excretion
Cytotoxic drugs ↑ nucleic acid turnover.
Gouty arthritis develop when monosodium urate crystals deposit in the join synovium inflammatory response gout attack join
swelling, redness, warmth, tenderness tophi (urate deposits) joint deformity, disability, renal impairment.
Renal complications: Acute tubular obstruction: due to uric acid pptn in the ureters and collecting tubes. Urolithiasis: uric acid
stones due to low urine pH. Chronic urate nephropathy: urate deposits in the renal interstitium.
Acute gouty arthritis
Painful arthritic attacks of sudden onset. Triggers: trauma, cold exposure. Initial attack is abrupt and usually occur at night or early
morning very hot swollen, tender joints. Podagra: attack in the metatorso-phalangeal joint. Attacks last 1-2 weeks (longer as the
disease progresses). May include fever, chills, malaise.
Diagnosis: Urate needle-shaped crystals in synovial fluid (-ve birefringence). Serum ↑ urate, ↑ erythrocyte sedimentation rate, ↑
leukocytes. Dramatic therapeutic response to colchicine. Acute attack pattern with remission periods.
Immobilize affected joints. Start anti-inflammatory drugs immediately. Start urate-lowering drugs after attack is over.
Colchicine: drug of choice for ↓ pain and inflammation and ending the attack. Mechanism: antimitotic, ↓ chemotaxis of leukocyte to
inflamed area, ↓ phagocytosis and ↓ urate deposition. Orally or IV (never IM or SC due to irritation). ↑ SE: diarrhea, GI, bone marrow
depression, irritation if given IM.
NSAIDs: if first choice is colchicine is not tolerated or not started immediately. Examples: indomethacin, naproxen, sulindac. SE: GI,
CNS headache and drowsiness / dizziness. Take with food. Aspirin ↓ dose ↓ uric acid secretion, ↑ dose ↑ uric acid secretion.
Corticosteroids: Methylprednisolone acetate given intra-articular with diagnostic / therapeutic aspiration. Prednisone (oral),
Triamcinolone acetonide (IM) or methylprednisolone (IV).
Symptom free period between attacks.
Non-drug urate lowering: ↓ high-purine diet (meats, legumes), ↓ obesity, ↓ alcohol. Limited effect.
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Prophylaxis: ↓ dose colchicine or NSAID.
Urate lowering therapy (<6 mg/dl): lifelong treatment.
Allopurinol (isopurine): ↓ production. Mechanism: ↓ xanthine oxidese (↓ xanthine hypoxanthine uric acid). Long acting active
metabolite: oxypurinol. Preferred over uricosurics in case of renal impairment (↓ dose). SE: reversible rash (↑ incidence with ampicillin),
exfoliative dermatitis treat with prednisone, Stevens-Johnson syndrome. May ↑ gout attacks if given during the attack due to
mobilization of stored urate (give colchicine). May dissolves tophi.
Uricosurics ↑ excretion. Examples: sulfinpyrazone, probenecid (benzoic acid derivative). Mechanism: ↓ uric acid reabsorption
at the proximal convoluted tubules. Do not initiate during acute attacks or give with colchicine. During the first 6-12 months may ↑
attacks. Maintain ↑ fluid intake, urine output and alkaline urine to ↓ risk of renal urate pptn. Build up dose gradually. Action is
antagonized by salicylates. SE: GI, blood dyscriasis (sulfinpyrazone). CI: urinary tract stones.
Chronic tophaceous gout: ↑↑ urate pool. Large SC tophic. Allopurinol / probenecid combo.
50. Peptic Ulcer Disease
Peptic ulcer disease (PUD): circumscribed lesions of upper GI mucosa.
Gastro-esophageal reflux disease (GERD): retrograde movement of gastric contents from stomach into esophagus. When reflux
leads to inflammation and/or ulcerations, it’s called reflux (erosive) esophagitis.
Dyspepsia: persistent / recurrent, pain / discomfort in upper abdomen.
Duodenal ulcers: develop in the first cm of duodenum (bulb).
Gastric ulcers: common in the antrum or antral-fundal junction.
Stress ulcers: from serious trauma or illness, major burn, sepsis.
Zollinger-Ellison syndrome: severe peptic intractable ulcer with extreme gastric hyperacidity and gastrionoma (non-beta islet cell
tumor). Diagnosed by ↑ fasting plasma gastrin concentration.
Stomal (marginal) ulcers: after ulcer surgery or subsequent ulcer recurrence after symptom free period.
Drug-associated ulcers: chronic ulcerative drug users (e.g. NSAID’s)
Reflex esophagitis: recurrent symptoms (heartburn), altered epithelial morphology. Heartburn may radiate to the neck. Other
symptoms: belching, chest pain, asthma, cough, hoarseness, laryngitis.
Epidemiology: Duodenal ulcers: 7% incidence. Gastric ulcers: 0.05%. May have both gastric and duodenal ulcers. Onset: 30-50
years. 45% of the population experience heartburn once a month. 15% take indigestion drug twice a week. Prevalence of dyspepsia:
25% (3% of doctor consultations). Hospitalization / mortality for peptic ulcer are ↓.
Description: Duodenal ulcers < 1 cm diameter. Gastric ulcer: slightly larger. Edges are sharply demarcated. Surrounding mucosa is
inflamed and edematous. Scar may form after healing. Gastric ulcers may be malignant (10%).
Helicobacter pylori (campylobacter pylori): gram negative spiral bacteria with multiple flagella living in the gastric mucosa. Produces
urease hydrolyzes urea into ammonia neutralizes gastric HCl bacteria survives. H pylori prevalence ↑ with age. 15% of
positive persons develop ulcer. H pylori is present in 90% of gastric and duodenal ulcer and cancer cases. Eradication may help ulcers
Genetics: ulcer prevalence with first degree relative is 3x the normal rate. May be due to H pylori presence. Blood type O have ↑
NSAIDs: chronic use ↓ COX-I ↓ PG synthesis (cytoprotective to mucosa). Also, allow H
back diffusion into mucosa injure
Smoking: ↑ incidence of ulcer, ↓ ulcer healing and ↑ incidence of relapse. Nicotine ↓ biliary and pancreatic bicarbonate secretion, ↑
stomach emptying into the duodenum.
Alcohol: known mucosal irritant, especially at concentrations > 20%.
Coffee: peptides in regular and decaf coffee ↑ gastrin release ↑ gastric juice flow. A direct coffee-ulcer link is not proven.
Associated disorders: ↑ incidence with hyper-parathyroidism, emphysema, rheumatoid arthritis, alcohol cirrhosis.
Advanced age: pylorus degradation ↑ bile reflux into the stomach ↑ ulcers.
Corticosteroids: NO link between corticosteroids and ulcers.
Psychological factors: minor factor, contrary to the opposite belief.
Ulcers occur due to imbalance between factors protecting gastric mucosa and factors causing mucosal corrosion.
Protective factors: thick mucosal mucus is a barrier between luminal acid and epithelial cells. This barrier ↓ inward movement of
hydrogen ions and allow neutralization by bicarbonate ions in fluids secreted by the stomach and duodenum. Alkaline and neutral
pancreatic biliary juices buffer acid entering duodenum from the stomach.
Corrosive factors: gastric mucosa is unable to resist corrosion by irritants such as HCl and pepsin. Mucosal barrier may not be intact.
Physiologic factors: Duodenal ulcer: ↑ gastric emptying rate, ↑ post-prandial acid secretion, ↑ serum pepsinogen I, ↑ pepsin
secretion, ↑ # of acid producing parietal cells. Gastric ulcer: ↓ gastric emptying rate, ↓ mucosal resistance, ↑ serum gastrin, ↓
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GERD: reflux occur via transient lower esophageal sphincter relaxation (TLESR). People with GERD ↑ TLESR frequency.
Dyspepsia: caused by PUD, GERD, gastric cancer, biliary tract disease.
Only 50% of patients experience classic ulcer symptoms. Pain: heartburn, aching, burning, cramping. May be due to chemical
stimulation or spasm. Duodenal ulcer pain: more localized and often peaks between 12-2 AM. Gastric ulcer pain: less localized.
Food: may ↓ duodenal ulcer pain but ↑ gastric ulcer and GERD pain. So, duodenal ulcer patients may gain weight and gastric ulcer
patients may lose weight. Pain occurs 1.5-3 hr after meals in duodenal but only 1 hr after meals in gastric ulcer.
Disease course: usually chronic with remissions and exacerbations. Relapse may be more common in spring and autumn. Test for
and eradicate H pylori and use maintenance drugs to ↓ recurrence.
Blood test hypochromic anemia. Stool test occult blood in chronic ulcers. Gastric secretion tests hyper-HCl secretion in
duodenal ulcers, normal or subnormal HCl secretion in gastric ulcer. Upper GI barium x-ray: reveals ulcer crater. Upper GI
endoscopy: most conclusive test. Biopsy: may be necessary to detect malignancy. H pylori status: using non-invasive (serology or
breath test, false negative breath test with PPI, antibiotics or bismuth compounds) or invasive (histological bacterial visualization or
urease activity test) tests.
Clinical picture: fresh blood vomit, bloody / tarry stool, coma, hypovolemic shock (heart rate > 110, systolic BP < 100).
Management: ensure airway, breathing, circulation. IV crystalloids or colloids (e.g. hetastarch), monitor / correct electrolytes, gastric
lavage, vasoconstrictors, antacids, H2 antagonists, PPI, vasopressin (GI muscle and blood vessel contraction).
Sudden acute upper abdominal pain, rebound tenderness, and finally, peritonitis and shock. Symptoms may ↓ with time (dangerously
misleading). Emergency surgery is needed.
Occurs due to inflammatory edema, spasm or scarring.
Clinical picture: postprandial vomiting / bloating, appetite / weight loss, abdominal distension.
Management: continuous gastric suction, monitor fluids and electrolyte status, perform saline load test to measure degree of
obstruction. Liquids feeding and daily aspirations may be needed.
Dumping syndrome: rapid gastric emptying in 10% of patients after partial gastrectomy.
Clinical picture: weakness, dizziness, anxiety, tachycardia, flushing, sweating, abdominal cramps, nausea, vomiting, diarrhea. Occur
between 15 and 120 minutes after the meal.
Management: eat six small meals, ↑ protein and fat and ↓ carb. Ingest fluids 1 hr before or after a meal but not with it. Give
anticholinergics to delay gastric emptying.
Other complications: reflux gastritis, stomal ulceration, diarrhea, malabsorption, early satiety, iron deficiency anemia.
Dyspeptic symptoms after 8 wk therapy. Perform gastroscopy and biopsy to exclude: Crohn’s disease, TB, lymphoma, carcinoma.
Treatment: only PPI offer maximum acid ↓. Eradicate H pylori. D/C NSAID. Perform surgery if all fails.
70% of ulcers recur in a year (90% in 2 years) after healing and therapy d/c. Use long-term maintenance therapy in: concomitant
disease, 4 relapses / year, many risk factors (old, male, NSAID, alcohol, smoking, family history, history of complications). H pyloric
eradication ↓ need for continuous therapy.
As effective as H2 antagonists. Examples: magnesium, aluminum and calcium salts. Antacids are not widely used for PUD. Continue
therapy for only 7 weeks. Typically given 2 hours after meals at bedtime. Effect lasts for 3-4 hours.
Mechanism: Neutralize gastric acid ↑ gastric pH ↓ pepsin activity and ↑ mucosal barrier heat and treat ulcer pain.
Non-systemic antacids: such as magnesium or aluminum are preferred over systemic antacids (e.g. sodium bicarbonate) to avoid
Liquid antacid: ↑ buffering capacity than tablets but not as convenient.
Antacid mixtures: such as aluminum hydroxide and magnesium hydroxide ↓ each drug dose and ↑ effect. Side effects are negated
(aluminum constipation, magnesium diarrhea).
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Calcium carbonate: not preferred ( acid rebound, delayed pain relief and ulcer healing, constipation, hypercalcemia). It may
produce milk-alkali syndrome esp with milk (hypercalcemia, alkalosis, kidney damage).
Acid neutralizing capacity (ANC): number of mEq of a 1 N solution of HCl that can be brought to a pH of 3.5 (99% neutralization) in
15 minutes. For duodenal ulcers, 50 mEq/hr or 125 mEq/day of antacid is needed for neutralization.
Use calcium and magnesium carefully in renal disease (e.g. elderly).
Sodium bicarbonate is CI in hypertension, CHF, renal disease, edema.
Use aluminum carefully in patients with dehydration, GI obstruction.
Calcium carbonate + alkali (sodium carbonate) + milk = milk-alkali
Long term aluminum hydroxide use hypo-phosphatemia, osteomalacia. Aluminum hydroxide is used to treat hyperphosphatemia.
Generally, take other drugs 30-60 min before antacids.
Avoid antacids (polyvalent cations) with tetracycline (↓ absorption), cipro.
May destroy enteric coating leading to premature release in the stomach.
Interfere with absorption of: ranitidine, cimetidine, iron, digoxin, phenothiazines, anticholinergics.
↓ effect of sucralfate.
H2 receptor antagonists
Preferred in mild-moderate GERD due to lack of effect on GI motility.
Mechanism: competitively ↓ action of histamine at parietal cell H2 receptors ↓ volume and H+ concentration of gastric acid.
General SE: nausea, dizziness, renal damage (adjust). Absorption is ↓ with antacids (give 1 hr before antacids). All available oral or IV.
Cimetidine: first drug, ↓ gastric acid by 50%. SE: liver damage, hematologic (thrombocytopenia, agranulocytosis, aplastic anemia),
weak androgenic (gynecomastia), confusion. Cytochrome P-450 inhibitor ↓ metabolism of phenytoin, theophylline, Phenobarbital,
lidocaine, warfarin, imipramine, diazepam, propranolol, procainamide.
Ranitidine: more potent drug, ↓ gastric acid by 70%. Used with bismuth citrate and clarithromycin to eradicate H pylori.
Famotidine: most potent, ↓ gastric acid by 94% for 10 hr.
Nizatidine: newest drug, similar to ranitidine. Oral.
DI: ↓ absorption of drugs requiring acidic pH (e.g. ketoconazole).
Non-absorbable disaccharide containing sucrose and aluminum.
Mechanism: adheres to the base of ulcer crater forming a mucosal protectant barrier against acids and bile salts (esp. in duodenal
ulcers). Acidic pH is required for polymerization.
SE: constipation. Give 1 hr before meals and at bedtime for 6 weeks.
Interactions: antacids ↓ sucralfate mucosal binding, give 45 min apart. Surcralfate ↓ absorption of digoxin, iron, phenytoin, cimetidine,
Examples: atropine, propantheline. No proven value in ulcer healing
Mechanism: ↓ basal and stimulated gastric acid and pepsin secretion. Most effective at night in large doses with antacids delay
gastric emptying. Or, take 30 min before food (↓ acid by 40%)
SE: dry mouth, blurred vision, urinary retention, constipation, tachycardia
CI: gastric ulcer (they prolong gastric emptying), narrow angle glaucoma.
Mechanism: PG E1 analgoue ↑ mucus protect gastric mucosa against NSAID damage, ↑ bicarbonate, ↓ acid. NSAID ↓
prostaglandins ↓ bicarbonate and mucus secretion damage.
Use: QID prevention of NSAID induced gastric ulcer in ↑ risk patients.
SE: diarrhea, GI pain (take with food).
CI: abortifacient, pregnancy category X.
Proton pump inhibitors
Examples (x-prazole): omeprazole, lansoprazole, esmoprazole, rabeprazole, pantoprazole. Omperazole sulfenamide is the active
Mechanism: forms a stable disulfide bond with sulfhydryl group near potassium binding site on luminal side of gastric proton pump H
ATPase pump shuts down.
Very rapid ulcer healing and symptom control compared to other drugs (e.g. H2 blockers). 90% acid reduction for 24 hr with no
Omeprazole is better than ranitidine or misoprostol for preventing or healing NSAID ulcers. Omperazole can be used in infants.
SE: headache, diarrhea, GI pain / upset, flatulence. Take before food.
Interactions: ↓ absorption of drugs requiring acid pH (ketoconazole, ampicillin, iron). Omeprazle may ↓ or ↑ cytochrome P-450
Examples: bismuth subsalicylate (Pepto-Bismol), ranitidine bismuth citrate (RBC), colloidal bismuth subcitrate (not FDA approved).
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Mechanism: bismuth prevents adhesion of H pylori to gastric mucosa, ↓ H pylori growth, ↓ release of proteolytic enzymes.
Use: most effective in combination with PPI or antibiotics.
SE: CNS/neutrotoxicity, dark stool / tongue, headache, diarrhea, rash, salicylism in ↑ doses (tinnitus, hyperpyrexia, confusion,
Antibiotics for H pylori: metronidazole, tetracycline, clarithromycin, amoxicillin, bismuth subsalicylate, omperazole / lansoprazole.
Optimum regimen: bismuth subsalicylate QID + metronidazole QID + tetracycline QID + omperazole QD = 2 wk 90% eradication.
Example: metoclopramide, erythromycin, cisapride (d/c due to ↑ incidence of arrhythmia / torsades).
Mechanism: ↑ ACh release ↑ gastric emptying (no effect on acid secretion).
SE: diarrhea, GI upset, headache.
Interactions: antifungals (ketoconazole, itraconazole, fluconazole, miconazole) ↓↓ cisapride metabolism severe arrhythmia.
Rapid gastric emptying can affect absorption of narrow therapeutic drugs.
CI: arrhythmia, CHF, ischemic heart, renal failure, respiratory failure.
Diet / social modification
Milk may ↑ gastric acid (used to be recommended, no more). Milk leaves the stomach quickly no extended buffering.
Small frequent meals may ↑ ulcer pain by causing acid rebound (used to be recommended, no more)
Strict dietary limitations are now considered unnecessary.
Avoid certain foods: caffeinated drinks, alcohol, smoking, NSAIDs.
Used in complicated, incapacitating ulcer unresponsive to therapy.
Vagotomy: severs a branch of the vagus nerve ↓ HCl secretion.
Antrectomy: removes the antrum ↓ some acid secreting mucosa.
Others: gastrectomy, funoplication.
1. Dysfunction in metabolism of fat, carbohydrate, protein, insulin
2. Dysfunction of blood vessels and nerves function and structure
2-10% of US population (half undiagnosed)
General common symptoms: polydipsia, polyuria, dry skin, polyphagia, fatigue, frequent skin / vaginal infections, visual disturbances.
1. Type 1 (Insulin-Dependent, Juvenile-Onset, Ketosis-Prone)
Insulin production/secretion is destroyed. Usually in children and adults <30. Prone to ketoacidosis (accumulation of ketone bodies).
Dependent on exogenous insulin replacement. 10% of all diabetes.
Etiology: a. Genetics: ↑ w/ family history. Linked to Human Leukocyte Antigen (HLA) system. b. Environment: virus (e.g. rubella),
toxic chemical triggers genetics / autoimmunity. c. Autoimmunity: anti-insulin and anti-beta-cell antibodies usually present
Clinical presentation: abrupt onset, acute presentation. Unintentional weight loss w/ or w/o ketoacidosis.
2. Type 2 (Non-Insulin-Dependent, Adult-Onset)
Endogenous insulin is normal, ↑ or ↓. May or may not need exogenous insulin. 90% of all diabetes (esp. in the elderly). Adults >30.
80% are also obese. Not prone to ketosis except during stress (infection, surgery, trauma).
Etiology: a. Genetics: 90% concordance between monozygotic twins. 15% chance in offspring of diabetics. b. ↓ beta cell: ↓
insulin. c. Insulin site defect insulin-resistant tissue (insensitivity)
Clinical presentation: develops gradually. Evidence of damage to retina, kidneys, peripheral vasculature.
3. Gestational (pregnancy)
Glucose intolerance detected during (late) pregnancy (3% of pregnants). Test tolerance 6 wk post-partum. Usually returns to normal.
4. Other types (Secondary Diabetes)
Due to disease of pancreas, genetics, endocrinopathies (Cushing’s), drugs (thiazides, loops, corticostroids, hyperglycemia)
5. Diabetes insipidus: Cause: pituitary disease with ↓ production of antidiuretic hormone (ADH) kidney can’t conserve water,
lithium (↓ sodium reabsorption). Symptoms: polyuria (20 L / d), severe thirst, polydipsia, watch for dehydration. Treatment: anti-
diuretic hormone (vasopressin) analogs desmopressin (oral), lypressin (nasal), maintain fluids / electrolytes. (Desmopressin is also
used in Hemophilia A and von Willebrand’s disease).
Normal glucose regulation
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Structure: endocrine hormone secreted by beta-cells of pancreas. It is a 51-amino acid chain with two polypeptide chains and two
inter-chain disulfide bonds. It is derived from proinsulin (86 amino acids). Proinsulin can be used to determine the purity fo insulin
Mechanism: glucose ATP closes potassium channels membrane depolarization calcium influx fusion of insulin
granules insulin release. Insulin and glucose activate N/K ATPase force potassium into the cells hypokalemia.
Glucose effects: ↑ glucose transport across cell membranes, ↑ glucose storage as glycogen in muscles / liver (glycogenesis),
↓ glucose formation from glycogen in muscles / liver (glycogenolysis), ↓ glucose formation from amino acids (gluconeogenesis)
↓ breakdown of fatty acids to ketone bodies (lipolysis) (insulin prevents ketoacidosis absent in type II DM), ↑ adipose (fat)
tissue formation from triglycerides and fatty acids.
↑ incorporation of amino acids into proteins
Counter-regulatory hormones: glucagon (from pancreas alpha-cells), epinephrine, norepinephrine, growth hormone, cortisol.
Glycogen: carbohydrate consisting of branched chains of glucose units. Principal form of carbohydrate storage, mainly in the
liver and muscles. Breaks down easily to glucose when needed.
Abnormal glucose regulation
Insulin insufficiency, resistance hyperglycemia. Liver: ↑ glycogenolysis, ↑ neoglucogenesis, ↓ glycogenesis. Muscle (peripheral
tissue): ↓ glucose uptake cells use protein as energy source protein breakdown ↑ carbohydrates / glucose ↑
Renal glucose threshold: 180 mg/dl. ↑ BG concentration exceeds kidney’s glucose reabsorptive capacity glucose excreted
into urine (glucosuria) osmotic diuresis dehydration, electrolyte abnormalities coma, death.
Diabetic Ketoacidosis (DK) (Type 1)
No insulin to break glucose triglycerides breakdown (lipolysis) free fatty acids and glycerol. ↑ glycerol ↑ liver glucose
production ↑ hyperglycemia. Free fatty acids acidosis breakdown in the liver ketone bodies kidney excretion
ketonuria exceeds kidney excretion limit ketonemia coma, death. A ketone body: acetoacetate converted in the liver to
acetone excreted through the lungs acetone fruity breath. ↑ anion gap (Na
Ketone bodies urine detection: add sodium nitroprusside and ammonia purple color. May also occur in severe vomiting or
Initially, the body compensates for acidosis by ∆ breathing patterns (Kussmaul: rapid deep breathing) and by blood buffering systems
If Type 2 DM Hyperglycemic hyperosmolar nonketotic syndrome (HHNK), presence of even ↓ insulin prevents fat breakdown,
ketonemia, ketoacidosis (Ketosis-resistant).
Diagnostic criteria: 1. Random BG > 200 mg/dl with classic DM symptoms (polydipsia, polyuria, polyphagia, weight loss). 2. Fasting
BG > 125 mg/dl. 3. 2-hour BG > 200 mg/dl during an oral glucose tolerance test (OGTT) using 75 g anhydrous glucose in water.
DM predisposition: Impaired fasting glucose (IFG): fasting BG 110-125 mg/dl. Impaired glucose tolerance (IGT): 2-hr OGTT BG
Gestational diabetes: testing is done at 26 weeks in all women (unless ↓ risk: normal weight, no family history, and <25 year).
Glucose tolerance: 50 g, after 1 hr if > 140 glucose tolerance: 100 g, 3 hr.
Goals of management: euglycemia with no symptoms, prevent acute complications, prevent vascular and neuropathic disease,
prevent / treat risk factors (↑ BP, ↑ blood lipids), normal life expectancy and quality of life.
Patient education and self care
↓ Modifiable risk factors: smoking, ↑ BP, ↑ blood lipids, BMI > 27.
Identify BG patterns: effect of diet, exercise, medications on BG.
Foot care: ↑ lower-extremity complications due to neuropathy, peripheral vascular disease, trauma, infections. Inspect shoes and feet
skin color and integrity daily. Clean feet daily and dry well. Do not use hand to sense water temperature if neuropathic (sensation loss).
Trim nails. Moisturize dry skin but NOT between the toes. Wear well fitting shoes and cotton socks. Avoid walking barefooted. Do not
self-treat skin foot conditions.
Skin care: dry skin is common due to diuresis and dehydration or anhidrosis (autonomic ↓ in perspiration,) use aqueous non-
alcoholic moisturizers. ↑ skin infections due to ↑ BG and ↓ circulation. Always use sunscreen (sun burn ↑ BG). Avoid skin
trauma. Keep skin clean and regularly inspect for abrasions, swelling, pain.
Dental care: DM accelerates periodontal disease. Should effectively brush and floss, and have an annual exam.
Eye care: DM is the leading cause of visual impairment and blindness. Should have annual dilated eye exam.
Assessment of glycemic control
Self monitoring of blood glucose (SMBG): allows assessment of response to factors affecting BG (diet, drugs, stress, etc). Gives
immediate feedback to adjust diet, exercise, insulin, etc.
Urine glucose testing: only retrospective information (not recommended).
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Urine ketone monitoring: more important during illness, infection, trauma (even for type 2), type 1 patients with BG consistently >250
mg/dl, pregnant diabetics, patients on a diet to lose weight.
Hemoglobin A1c test (glycol-hemoglobin, glycosylated hemoglobin): long term BG monitoring, reflects average BG over 7-16
weeks. Stable for 120 days (RBC lifespan). Perform 1-2x / year. Hemoglobin A1c < 7% is targeted (normal = 6% (130 mg/dl), if >8%
additional intervention). BG ~ A1c x 20-30. Glycosylated fructosamine test: measures BG control over 3 weeks. Useful for short-term
follow-ups (e.g. pregnancy).
Acute changes in glycemic control
Mild to moderate hyperglycemia
BG 200-250 mg/dl. Rapid onset (hr). No metabolic abnormalities.
Acute: due to illness, emotional distress, or ↑ dietary calories.
Rebound (Somogyi effect): rebound hyperglycemia following severe/prolonged hypoglycemia, e.g. overnight insulin reaction).
May be ↑ BG pattern in early morning due to counter-regulatory hormones.
Moderate to servere hyperglycemia
BG > 250 mg//dl. Few days duration with acidosis or ketosis (Diabetic Ketoacidosis, DKA).
Common in children with undiagnosed Type 1 DM.
Precipitating factors: stress, infection, ↑ alcohol consumption, improper insulin therapy, dietary noncompliance.
Physical findings: Kussmaul’s respirations, acetone breath odor, dehydration, dry skin, ↓ consciousness (confusion, coma),
abdominal pain. Can be deadly.
Therapy: insulin IV infusion (Regular), fluid / electrolyte replacement.
BG > 500 mg/dl. ↑ serum osmolarity. Duration: days/weeks.
Mostly in Type 2 DM. Higher mortality rate than DKA.
Precipitating factors: conditions that ↑ insulin requirement and predispose to dehydration (burns, GI bleeding, CNS injury, MI), use of
glucogenic drugs (steroids, glucagon, thiazide diuretics), high glucose products (peritoneal dialysis, enteral nutrition).
Physical findings: ↑↑ dehydration, ↑ serum osmolarity (> 280 mOs), no ketosis / acidosis (hyperglycemic hyperosmolar nonketotic
syndrome, HHNK), polyuria, polydipsia, hypotension, tachycardia, palpitations, rapid respiration, nausea, vomiting, abdominal
discomfort, ↓ CNS function (confusion, coma, seizures, myoclonic jerking).
Therapy: insulin, fluid / electrolyte replacement.
Mild hypoglycemia symptoms: adrenergic (tachycardia, palpitations, shakiness), cholinergic (sweating), mild CNS glucopenia (↓
concentration, dizziness, hunger).
Moderate hypoglycemia: ↑ CNS effect confusion, motor impairment, no unconsciousness.
Severe hypoglycemia: coma, seizure, motor impairment.
Pseudo- hypoglycemia: hypoglycemic symptoms perceived (mostly adrenergic) but BG is normal.
Hypoglycemia unawareness: no or little symptoms but BG is low. Sweating or neurologic impairment is noticed.
Precipitating factors: excess insulin or oral hypoglycermic, delayed or ↓ food, ↑ exercise, alcohol, drug interaction ↓ BG, ↓
progesterone in menstruation, new insulin bottle with full potency, gastroparesis (delayed stomach emptying), change in insul in injection
site (↑ absorption if SC near exercising muscle).
Treatment of hypoglycemia: if conscious 10-15 g fast acting simple oral carbohydrate (milk, juice, regular soda), 3 g glucose
tablet or hard candy, honey, glucose gel. Repeat in 10-15 min if BG is not back to normal. If unconscious IV glucose (10-15%
dextrose) or glucagons injection (1 mg IM, SC, or IV).
Atherosclerosis: coronary, cerebrovascular, peripheral
Peripheral vascular disease: pain, chronic “cold feet”, insufficient circulation to heal distal lesions gangrene
Hypertension: with diabetes ↑↑ cardiovascular disease, stroke, transient ischemic events. Causes acceleration of retinopathy,
nephropathy, atherosclerosis. Hyperinsulinemia / insulin resistance diabetic hypertension.
Coronary artery disease: autonomic neuropathy Silent myocardial infarction (atypical, no chest pain).
Management: daily ↓ dose aspirin, ACE inhibitor (for ↑ BP), cardio selective beta blocker (for cardiac disease).
Consequence of microvascular changes, leading cause of new blindness. Treatment: laser photocoagulation.
Nonproliferative (background) retinophathy: retinal microaneurysms, blot hemorrhages, retinal edema, hard exudates, macula
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Preproliferative retinopathy: ↑ abnormality of tiny vessels, retinal ischemia, white patches of oxygen-starved retina (soft or cotton-
Proliferative retinopathy: lack of oxygen weak vessel grow or proliferate (neovascularization) from retinal surface to vitreous cavity.
Fragile vessels may bleed into vitreous cavity hemorrhage obscured vision scar tissue and new vessels grow vitreous pull
on the retina retinal detachment.
Most common cause of End Stage Renal Disease (ESRD)
↑ microalbuminuria, positive dipstick (clinical) albuminuria, proteinuria / ↑ BP, ↓ glomerular filtration, ↑ creatinine.
ACE inhibitors helpful, ↓ protein intake, treat UTI. For ESRD fluid / electrolyte restriction, dialysis.
Peripheral neuropathy: esp. in sensiomotor nervous system. Symptoms first in distal lower extremities then upper extremities
(Stocking-glove distribution). Signs: impaired perception of pain / temperature numbness / tingling, impaired balance, ↓
proprioception (perception of body parts movement), motor nerve damage muscle weakness / atrophy.
Autonomic neuropathy: genitourinary neurogenic bladder, sexual dysfunction. GI gastroparesis, nocturnal diarrhea, fecal
incontinence, chronic constipation. Cardiovascular orthostatic hypotension, cardiac denervation.
Foot, skin and mucous membranes
Due vascular changes and peripheral neuropathy alter nerves that control blood flow and skin hydration
Infection by staph, beta-hemolytic strept, fungus cutaneous infection (furunculosis, carbuncles), Candida (genital, upper thighs,
under breast), cellulites, lower-extremity vascular ulcers
Atrophic round painless lesions, diabetic dermopathy (red-brown popular spots) esp. in lower extremities.
Necrobiosis lipoidica diabeticorum (ulcerative necrotic lesion)
Peripheral neuropathy loss of protective sensation, inability to detect minor trauma ulcers
Infection, injury, neuropathy, vascular disease gangrene
Sensory exam of feet (protective sensation) 10 g monofilament
Protective footwear (deep sole shoes, molded shoes, orthotics)
Significant interactions affecting glycemic control
Hyperglycemia (direct glucogenic effect): corticosteroids, furosemide, thiazides, sunburns, nicotinic acid, phenytoin, pentamidine,
protease inhibitors, sympathomimetics, isoniazid, sulfinpyrazone, theophylline toxicity.
Hypoglycemia: MAO-I, fluoxetine, salicylates (↑ dose), alcohol, fenfluramine, pentamidine
Prolonged hypoglycemia / masking hypoglycemic symptoms: B1 beta blockers (e.g. propranolol)
Medical nutrition therapy (MNT)
Carbohydrate counting: 50% of total calories. DM therapy may include pre-meal short acting bolus insulin (lispro, regular, semilente).
Otherwise, maintain consistent CHO intake.
Fat: limitations on type and amount. Critical for weight loss and treating hyperlipidemia. Target: < 30% of calorie intake and < 300
Protein: important in end stage renal disease and may delay dialysis.
Fiber: bran, beans, fruits, vegetables may help BG and lipids.
Alter diet based on stress, illness, exercise, etc.
Spaced meal intervals help match hypoglycemic therapy effect.
Careful exercise ↑ cell glucose uptake ↓ BG
Careful if patient has severe retinopathy.
Patients with cardiovascular disease or over 45 cardiovascular evaluation and stress test.
Aerobic activity: e.g. swimming, walking, running, preferred due to positive effect on BG (↓), cardiovascular, BP, lipids, circulation,
Anaerobic activity: e.g. weight lifting, should be avoided. Potential negative cardiovascular, BP, retinopathy effects.
Insulin and insulin analogues
For type 1 DM and only uncontrolled type 2.
Mechanism / structure: see above
Factors ↑ insulin requirement: infections, weight gain, puberty, inactivity, hyperthyroidism, Cushing’s disease
Factors ↓ insulin requirement: renal failure, weight loss, ↑ exercise, nutrient malabsorption, hypopituitarism, adrenal insufficiency.
Concentration: U-100 or U-500 for insulin resistance.
Source: human, bovine, porcine, synthetic (Lispro insulin, Humalog), or a mixture. Human insulins are made by enzymatic conversion
of terminal amino acid of porcine insulin (Novolin, semisynthetic), or by recombinant DNA (Humulin). Human insulin ↓ antigenicity.
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Short-acting: Lispro synthetic, shortest onset and duration. Regular soluble insulin with neutral pH, only clear insulin (IV), only
insulin that can be mixed freely. Semilente (prompt insulin zinc suspension) finely divided amorphous prep, use acetate buffer, mix
only with other lente, similar duration to Regular, Aspart insulin analogues.
Intermediate-acting: NPH (isophane insulin suspension) similar to protamine zinc but with no excess protamine. Lente (insulin zinc
suspension) mixture of 70% ultralente crystals and 30% semilente powder.
Long-acting: Protamine zinc use phosphate buffer. Ultralente (extended release zinc suspension) large crystalline. Glargine
insulin analogue (very long acting).
Pre-mixed insulin: 50/50 Regular/NPH, 70/30 Regular/NPH, 75/25 Lispro/Protamine Lispro regular as pre-meal bolus and NPH
intermediate for later control of hyperglycemia. Other mixtures can be prepared extemporaneously for tailored ratios.
DM Type 1 example: pre-breakfast is 2/3 of total daily dose (TDD) 1:2 short : intermediate. Bedtime is 1/3 of TDD 1:2 like pre-
breakfast. Or give pre-supper rapid/short and then bedtime intermediate.
DM type 2 example: bedtime only or 2-3 daily injections.
Subcutaneous: for routine administration. Absorption of regular insulin is fastest from abdomen > arm > buttock > thigh. Monitor
variations in absorption. Randomly rotate injection site to avoid lipohypertropy. If ↑ variations avoid random rotation of injection site.
Exercise, hot showers, baths, massages ↑ blood flow to injection site. Abdomen is least likely to have ↑ absorption preferred
site for pre-exercise insulin.
Continuous Intravenous (insulin drip): provide Regular insulin for acute hyperglycemia, ketoacidosis, HHNK, or during surgery.
Continuous SC infusion (insulin pump): short acting insulin is infused continuously during the day to deliver ↓ doses (basal insulin).
Bolus dose (determined by algorithms) is delivered by the patient before each meal. Offers tighter glycemic control. Used for diabetics
with ↑ BG fluctuations, irregular work schedules, lifestyles, or meals. Require frequent SMBG (BG self-monitoring) and training.
SE: hypoglycemia (tachycardia, sweating, hunger, convulsions and insulin shock), hypersensitivity, injection site local irritation.
Drugs (all acidic): Sulfonyrlureas: First gen: chlorpropamide, tolbutamide, acetohexamide, tolazamide, more lipid-soluble, more
potent. Second gen: glyburide, glipizide, glimperide. Also repaglinide.
Mechanism: block ATP-sensitive potassium channels ↑ insulin pancreatic release (primary), and also as sensitizers with time
Use: Type 2 (useless in type 1, require functioning beta cells).
Chlorpropamide: longest duration of action. CI in liver and kidney disease. ↑ SE severity and frequency, disulfiram-reaction (also
Use insulin instead during stressful conditions (↑ risk of hyperglycemia due to ↑ counter-regulatory hormones release).
SE: severe / prolonged hypoglycemia (esp. in the elderly, w/ glipizide / glyburide), GI upset, sulfa sensitivity, sun sensitivity, headache,
rash, tachycardia, hematologic problems, cholestatic jaundice.
CI: allergy to sulfa drugs, pregnancy, lactation.
Altered protein binding of sulfonylureas: alcohol, salicylates, NSAID’s, methyldopa, chloramphenicol, MAO-I, clofibrate, probenecid.
Therapy failure: due to ↓number of functioning beta cells. Primary: failure to control BG within 4 weeks. Secondary: initial control of
BG, but fails to maintain control, due to progression of DM.
Repaglinide: less hypoglycemia.
Drugs: biguanides (metformin, basic drug), thiazolidinediones (rosiglitazone, pioglitazone).
Mechanism: anti-hyperglycermic not hypoglycemic. ↑ sensitivity to insulin, (metformin work on liver, ↓ hepatic glucose
production, gluconeogenesis), (glitazones ↑ sensitivity / ↓ insulin resistance in muscle and adipose tissue). Thiazolidinediones
bind to PPARs.
Use: significant insulin resistance.
Biguanides SE: fatal lactic acidosis, metallic taste, GI upset, ↓ vitamin B12, no hypoglycemia. May be fatal if at ↑ risk of lactic
acidosis (liver / kidney disease, hypoperfusion, hypoxia, radiography). Phenformin was d/c.
Glitazones SE: liver toxicity / failure (monitor), weight gain, edema, GI upset, no hypoglycemia. Troglitazone was d/c due to liver
toxicity. CI: liver disease. May resume ovulation in premenopausal women. Highly protein bound (99%).
Drugs: acarbose (polysaccharide), miglitol (basic monosaccharide)
Mechanism: inhibit intestinal enzyme alpha-glucosidase ↓ absorption of complex carbohydrates (starch, dextrins, disaccharides).
Use only glucose or lactose for correcting hypoglycermia if it occurs.
Use: significant post-prandial hyperglycemia. Minimal effect on pre-prandial or fasting BG. Good combination with insulin
secretagogues. Take with first bite of meal.
SE: GI (diarrhea, abdominal pain, flatulence) due to undigested carbohydrates in the lower GI, no hypoglycemia. CI: GI conditions
(inflammatory bowel, colonic ulcer, obstructive bowel, intestinal gas), liver cirrhosis (monitor liver function), pregnancy.
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52. Thyroid Disease
Thyroid hormone regulation / function
Thyrotropicn-releasing hormone (TRH): secreted by the hypothalamus, triggers the release of TSH through negative feedback
Thyroid stimulating hormone (TSH): released by the anterior pituitary gland, controls thyroid hormone secretion and transport.
Thyroid gland produces thyroxine (T4), triiodothyronine (T3) (both for growth, development, metabolic rate), and calcitonin (↓ blood
Thyroid hormone is transported in the circulation by thyroxine-binding globulin (TBG), and albumin. Protein binding protects hormone
from premature metabolism, excretion, and prolongs its t1/2.
Metabolism: T4T3 conversion in pituitary gland, liver, kidneys.
Degradation: by deiodination feces / urine excretion.
Function: Activate mRNA and ↑ protein synthesis or catabolism (↑ dose). ↑ growth, development, ↑ basic metabolic rate, ↑ blood flow,
↑ cardiac output, ↑ heart rate, fine muscle tremor, fatigue wakefulness, ↑ lipid mobilization and degradation, ↑ bone remodeling (rate of
resorption > rate of formation).
Dietary iodine: critical for thyroid hormone synthesis, reduced to inorganic iodide then exracted from plasma by the thyroid by iodide
trapping (iodide pump).
Organification: oxidation of iodide by peroxidase. Synthesis starts with iodide-tyrosine binding modoiodo then dioiodo-tyrosine.
Thyroid function studies
Serum total thyroxine (TT4):
Most direct reflection of thyroid function by indicating hormone availability in tissues. Total (free and bound) T4 is determined by radio-
immunoassay (sensitive, rapid).
TBG ↑ during pregnancy misleading results (bound T4).
↑ TT4 hyperthyroidism, and vice versa
Serum total triiodothyronine (TT3):
Measures total (free and bound) T3. TT3 rise before TT4, useful for early detection. ↑↑ in hyperthyroidism (more than T4), responsible
for symptoms. Pregnancy ↑ TT3.
Resin triiodothyronine (RT3U):
Evaluates the binding capacity of TBG. Clarifies whether abnormal T4 is due to thyroid disorder or abnormal protein binding. If
abnormal thyroid in the blood RT3U changes in same direction (↑ in hyperthyroid). If abnormal protein binding RT3U changes in
opposite direction (↓ in hyperthyroid).
Serum thyrotropin (TSH) assay:
Serum TSH assay: most sensitive test for hypothyroid, but nor reliable in hyperthyroid (TSH is suppressed).
Sensitive TSH assay: uses monoclonal antibodies known as immuno-radiometric or immunometric (IMA) method (vs. the older radio-
immunoassay). ↑ sensitivity, ↑ cost, more commonly used to control over treatment of replacement therapy.
Free thyroxine (T4) index (FTI):
Not a separate test but rather an estimation of free T4 level by a calculation involving serum T4 and RT3U. ↑ FTI hyperthyroid or ↓
Strategies for testing
Most common and ↓ expensive: TT4, RT3U, FTI.
Thyroid disease screening for healthy population is not cost effective. Screen only target population (elderly, chronic disease
Use FTI and Sensitive TSH for disease diagnosis.
Primary hypothyroidism: due to gland destruction or dysfunction caused by disease or therapy (radiation, surgery).
Secondary hypothyroidism: due to ↓ TSH secretion (pituitary disorder). Thyroid gland is normal but not enough TSH stimulation.
Tertiary hypothyroidism: ↓ TRH (hypothalamus) to stimulate pituitary
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Hashimoto’s thyroiditis: chronic autoimmune thyroiditis.
Treatment of hyperthyroidism: e.g. radioactive iodine, subtotal thyroidectoym, antithyroid drugs.
Goiter: enlargement of the thyroid gland. Endemic goiter: due to inadequate dietary iodine (malnutrition). Sporadic goiter: due to
foods or drugs containing progoitrin (inactive hydrolysis active goitrin) ↓ oxidation of iodine to iodide. Goitrogenic drugs:
propylthiouracil (PTU), iodides, cobalt, lithium, phenylbutazone. Other causes: thyroiditis, thyroid cancer.
Signs and symptoms
Vague early symptoms: lethargy, fatigue, sensitivity to cold, weight gain, constipation. Later: features of Myxedema such as dry flaky
inelastic sin, coarse hair, puffy face / hands / feet, eyelid droop, slow speech / thought, ↓ libido, coma (if not controlled).
Life threatening condition in old patient with undiagnosed hypothyroidism
Precipitating factors: alcohol, sedative / narcotic use, antithyroid overdose, d/c thyroid replacement, infection, cold exposure, radiation,
Symptoms: coma, hypothermia, ↓ respiratory rate failure, hypometabolism fluid / electrolyte retention fluid retention,
hyponatremia, ↓ heart rate / contractility, ↓ heart output.
Treatment: rapid restoration of T3 and T4 to normal levels. IV bolus levothyroxine, oral liothyronine, then oral levothyroxine.
Desiccated thyroid preparations: not commonly used anymore. Different preparations are not bioequivalent (varying amounts of
actives depending on source (bovine, ovine, porcine).
Fixed ratio (liotrix) preparations: standard ratio of T4/T3. T3 is, however, unnecessary (T4 converts to T3) cause SE tremor,
headache, palpitations, diarrhea.
Levothyroxine: agent of choice, predictable results, no T3. Individual variable response to different preparations care if to switch.
Use ↓ dose for elderly or chronically ill patients. Results start after 2 wk, full response after 4-5 months (TSH levels ↓ to normal levels).
Careful in the elderly and in case of cardiac disease. Start with ↓ doses.
Watch for cardiac complications (palpitations, arrhythmia, angina).
Monitor thyroid levels (T4, RT3U, FTI, sensitive TSH).
Long term levothyroxine therapy can cause thyrotoxicosis.
Accelerated bone loss due to over treatment nontraumatic fracture.
CI: cholestyramine (bile acid sequestrant) ↓ thyroxine bioavailability. Separate drug by 6 hours.
Hyperthyroidism / thyrotoxicosis
Grave’s disease (diffuse toxic goiter)
Most common form. Occurs usually in young women.
Autoimmune disease, antibodies (long-acting thyroid stimulators, LATS) bind to and activate TSH receptors (does not actually increase
Symptoms: enlarged goiter, exophthalmos, stare, nervousness, irritability, anxiety, insomnia, heat intolerance, ↑ sweating, ↑ appetite, ↓
weight, muscle tremor / weakness, tachycardia, palpitations, diarrhea.
Plummer’s disease (toxic nodular goiter)
Less common. Common in the elderly. Caused by adenoma nodules autonomously secreting excessive thyroid.
Symptoms: same as Grave’s with nodular masses rather than diffusion enlargement.
Jodbasedow phenomenon: hyperthyroid due to ↑↑ iodine ingestion or amiodarone.
Factitious hyperthyroidism: due to abusive ingestion of thyroid replacement drugs to lose weight.
Beta blockers – propranolol
Propranolol ↓ peripheral symptoms (tachycardia, sweating, tremor, nervousness). It also ↓ peripheral T4T3 conversion
Examples: propylthiouracil (PTU), methimazole.
Mechanism: interferes with thyroid hormone synthesis by ↓ iodide oxidation. PTU ↓ peripheral T4T3.
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Dosing: initial dose (2 mo), maintenance dose (12 mo), gradual withdrawal (2 mo). Restart therapy if signs of hyperthyroidism appear.
Monitor serum thyroid, FTI and goiter size.
SE: skin rash, urticaria, pruritus, hair loss, skin piementation, drowsiness, myalgia, arthralgia. Severe SE: blood (agranulocytosis,
granulocytopenia, thrombocytopenia), monitor blood count.
Radioactive iodine (RAI)
Mechanism: thyroid gland picks up the radioactive element iodine-131 as it would regular iodine. Radioactivity destroys cells.
Advantages: ↑ cure rate (100%), avoid surgical risks, ↓ cost
Disadvantages: risk of delayed hypothyroidism, delayed effect.
SE: only for women past childbearing years. Response is hard to gauge (too much, too little).
Partial removal of the thyroid gland. Last resort.
Advantages: ↑ success rate, rapid cure.
SE: thyroid storm, permanent hypothyroidism.
Hypothyroidism: may follow Grave’s disease.
Thyroid storm (thyrotoxic crisis): is a sudden exacerbation of hyperthyroidism caused by rapid release (leakage) of thyroid hormone
(↑↑ T4) fever, tachycardia, restlessness, tremor, hyper-meabolism dehydration, shock, death if not treated rapidly. Precipitating
factors: thyroid trauma, surgery, radiation, infection, sudden d/c of antithyroid therapy. Treatment: PTU, methimazole, proproanolol,
potassium iodide (↓ intrathyroidal iodine intake), supportive therapy (rehydration, cooling, AB, rest, sedation).
54. Cancer Chemotherapy
Principles of oncology
Tumors arise form a single abnormal cell, which continues to divide indefinitely. Characteristics: no growth control, can invade local
tissues, can spread (metastasize).
Second leading cause of death in the US.
Affects 30% of all people at some point in life.
Some forms of cancer are curable if detected / treated early.
Viruses: Epstein-Barr virus, hepatitis B, human papilloma viruses.
Environmental / occupational exposures: ionizing / UV radiation, chemicals (benzene, asbestos, vinyl chloride).
Life-style: ↑ fat, ↓ fiber diet, ethanol, tobacco.
Medications: alkylating agents, immunosuppressants.
Genetics: inherited mutations, cancer-causing genes (oncogenes).
Detection / diagnosis
Warning signs: CAUTION. Change in bowel / bladder habits, A sore that does not heal, Unusual bleeding / discharge, Tissue
thickening or lumps (e.g. breast), Indigestion of difficulty swallowing, Obvious change in a wart or mole, Nagging cough or hoarseness.
Guidelines for screening: for asymptomatic people mammography (breast cancer), fecal occult blood test (colon cancer), Pap
smears (cervical cancer).
Tumor markers: biochemical indicators of the presence of neoplastic proliferation in serum, plasma, other body fluids. Not definitive.
Include: prostate specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP).
Tumor biopsy: definitive test for cancer cells is pathology of a biopsy.
Imaging studies: x-ray, computerized tomography scans, MRI, positive emission tomography.
Lab tests: complete blood count, blood chemistries.
It is the categorizing of patients according to extent of the disease. Used to determine prognosis. Two system are used for neoplasm
TNM: T = tumor size (0-4), N = regional lymph node spread (0-3), M = presence of absence of distant metastases (0-1). Example:
AJC: by the American Joint Committee on staging. Scale: 0-IV.
Depends on tumor size, disease extent, treatment received.
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60% survive more than 5 years, but not all survivors are cured. “Complete response or remission” when no evidence of disease after
treatment. Slow growing tumors 10-15 disease free years.
Cell life cycle
Phases of the cell cycle
M phase (mitosis): cell divides into two daughter cells
G1 phase (postmitotic gap): synthesis of RNA and proteins
S phase (synthesis): synthesis of DNA
G2 phase (premitotic / postsynthetic gap): production of RNA and topoisomerisae I/II enzymes (important for DNA replication and
G0 phase (resting): cell is not dividing. Cells now are not sensitive to chemotherapy. Recruitment: resting cells re-enter actively
divided cell cycle caused by some chemotherapy agents.
Cell growth kinetics
Cell growth fraction: proportion of the cells in the tumor dividing or preparing to divide. Large tumor ↓ nutrients and blood supply to
some cells ↓ cell growth fraction.
Cell cycle time: average time for a cell that has just completed mitosis to grow and again pass through mitosis (divide). Cycle time is
specific for each individual tumor.
Tumor doubling time: time for the tumor to double in size. Large tumor ↓ cell growth fraction ↑ doubling time
Gompertzian growth curve: illustrates cell growth kinetics concepts.
Tumor cell burden
Number of tumor cells in the body. Number required for clinical symptoms: 10
(large number) tumor may be in plateau phase of
growth curve when detected. Body immunologic defenses may be able to keep tumor cells less than 1000 under control.
Each cycle of cancer chemotherapy kills a certain percentage of tumor cells (depending on the dose). When tumor cells are killed
Cells in G0 phase may be recruited to G1 phase tumor regrowth. Therefore, repeated cycles of treatment are required for complete
response or remission.
Drug reliance on cell cycle kinetics for cytotoxic effect
Phase specific agents: M vinca alkaloids / taxanes, G1 asparaginase / prednisone, S antimetabolites, G2 > bleomycin /
Phase nonspecific agents: effective when cell are at any phase of the active cycle. Examples: alkylating agents, cisplastin, antitumor
Cell cycle nonspecific agents: effective in all phases including G0. Example: nitrosoureas, radiation.
Combination of drugs that are active in different cell cycle phases will result in greater cell kill.
Cure: sought with aggressive therapy for long time to eradicate all disease. Example for leukemia: remission induction, attempt
maximal cell kill and therapy consolidation to eradicate all clinically detectable disease and get tumor cell count ↓ 1000.
Palliation: goal is to control symptoms when complete eradication of tumor is unlikely or if patient refuses aggressive therapy.
Adjuvant: given after more definitive therapy (e.g. surgery) to eliminate any remaining disease.
Neoadjuvant: goal is to ↓ tumor burden before surgery or radiation.
May be bases on body weight, BSA or AUC. BSA is preferred (correlates with cardiac output which determines renal / hepatic bl ood
flow / elimination). Adjust dose for liver or kidney dysfunction.
Dosing is usually given as short courses in cycles.
To overcome or prevent resistance, achieve cytotoxicity to resting and dividing cells, enhance biochemical effect, rescue normal cells.
Acronyms are often used to indicate certain combinations.
IV is the most common
Inrathecal: for methotrexate, hydrocortisone, cytarabine, thiotepa.
Response to chemotherapy
Does not always correlate with survival.
Complete response: disappearance of all disease (clinical, gross, microscopic).
Partial response: > 50 reduction in tumor size for a period of time.
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Response rate: defined as complete response + partial response.
Progression or no response: > 25 increase in tumor size or appearance of new lesions.
Classification of chemotherapeutic agents
Prototype: mechlorethamine (nitrogen mustard)
Mechanism: cross-linking and abnormal base-pairing of DNA strands ↓ DNA replication.
Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan.
Ethylenimines / methylmelamines: thiotepa, altretamine.
Alkyl sulfonates: bisulfan
Nitrosoureas: carmustine, lomustine, semustine, streptozocin.
Platinum coordination complexes: cisplatin, carboplatin
Substituted ureas: hydroxyurea
Others: procarbazine, temozolomide.
Most come from Streptomyces
Mechanism: alkylation (mitomycin) or intercalation. Intercalation: drug slides between DNA base pairs and ↓ DNA synthesis.
Anthracyclines: daunorubicin (daunomycin), doxorubicin (adriamycin, hydroxydaunorubicin), epirubicin, idarubicin.
Others: bleomycin, dactinomycin, mitomycin, plicamycin (mithramycin).
Structural analogs of naturally occurring substrates for biochemical reactions.
Mechanism: false substitution in production of nucleic acid ↓ DNA synthesis.
Adenosine analogs: cladribine, fluudarabine, pentostatin (deoxycoformycin).
Folic acid analogs (folate antagonists): methotrexate, trimetrexate, raltitrexed.
Purine analogs (purine antagonists): mercaptopurine, thioguanine
Pyrimidine analogs (pyrimidine antagonists): fluorouracil, capecitabine, cytarabine, gemcitabine.
Vinca prevent formation of the mitotic spindle arrest cell division. Examples: vinblastine, vincristine, vindesine, vinorelbine.
Camptothecins inhibit topoisomerase I. Examples: irinotecan, topotecan.
Podophyllotoxins inhibit topoisomerase II. Examples: etoposide, teniposide.
Taxanes ↑ microtubule assembly / stabilization ↓ cell division. Examples: taxol (paclitaxel), taxotere (docetaxel).
Androgens: testosterone, fluoxymesterone
Antiandrogens: bicalutamide, flutamide, nilutammide.
Antiestrogens: tamoxifen, toremifene.
Aromatase inhibitors: letrozole, anastrozole, exemestane, aminoglutethimide.
Corticosteroids: prednisone, dexamthasone
Estrogens: ethinyl estradiol, diethylstilbestrol.
Estrogen/nitrogen mustard: estramustine
Progestins: medroxyprogesterone, megestrol
Luteinizing hormone releasing hormone analogs: leuprolide, goserelin
Mechanism: enzyme that causes the degradation of essential AA asparagine to aspartic acid and ammonia. Normal cells can
synthesize asparagine but tumor cells can not.
Biologic response modifiers
Mechanism: alter the patient’s immune system to fight cancer or to ↓ SE of cancer treatment. Examples: Bacillus Calmette-Guerin
(BCG), Colony-stimulating factors (erythropoietin, filgrastim, sargramostim), interferons (alpha, beta, gamma), interleukins (IL-2, IL-11),
levamisole, monoclonal antibodies (rituximab, trastuzumab).
Toxicity of chemotherapeutic agents
Most toxic to the most rapidly proliferating cells (mucous membranes, cells, hair, GI tract, bone marrow).
Bone marrow depression
Most life threatening SE. Effect is dose related.
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↓ WBC (especially neutrophils; neutropenia) serious infections.
Colony stimulating factors: used to ↓ extent of neutropenia.
↓ platelets (thrombocytopenia) bleeding give platelet transfusion.
Anemia is not as common because RBC lifespan is 120 days.
Time course: onset 1 week, lowest count point (nadir) 2 weeks, count recovery 3 weeks.
Alopecia: partial or complete, can not be prevented.
Local necrosis: results from extravasation during administration of vesicant drugs immediate pain / burning + possible delayed
reaction tissue damage, necrosis, ulceration require plastic surgery. Treatment: cold for all drugs except vinca and taxanes (use
Skin changes: dryness, sun sensitivity (methotrexate, fluorouracil).
Nausea and vomiting
Most distressing SE from the patient’s viewpoint.
Acute, delayed or anticipatory.
Antiemetics are used for prophylaxis.
Vomiting dehydration, electrolyte imbalance, esophageal tears d/c therapy.
Common with methotrexate, fluorouracil (same as skin changes)
General inflammation of the oral mucosa or other areas of the GI with rapid turnover of cells.
Symptoms: erythema, pain, mouth dryness, lip tingling / burning, ulceration, bleeding infection, inability to eat.
Time course: starts in 1 week, resolve in 2 weeks.
Other SE: fluorouracil diarrhea, vincristine constipation.
Irreversible and may be fatal. Especially with bleomycin, mitomycin.
Symptoms: breath shortness, unproductive cough.
Acute: transient ECG abnormalities. Not important.
Chronic: irreversible CHF due to drugs or radiation.
Dexrazoxane: cardioprotective (use with doxorubicin).
Due to intrathecal or systemic therapy.
Autonomic / peripheral neuropathy: due to vincristine. Vincristine is fatal if given intrathecally.
Peripheral neuropathy / ototoxicity: due to cisplatin.
Arachnoiditis: due to intrathecal methotrexate, cytarabine.
Bladder toxicity due to cyclophosphamide and ifosfamide. Acrolein: metabolite of these drugs chemical irritation of bladder mucosa
bleeding. Prevention: aggressive hydration with frequent urination, mesna (binds to acroltein prevents it from contacting bladder
Hypersensitivity: may be life threatening (anaphylaxis).
Chills / fever: especially with bleomycin.
Hepatoxocity: ↑ liver function tests, jaundice, hepatitis.
Nephrotoxicity: ↑ serum creatinine, ↑ BUN, electrolyte imbalance. Use amifostine to protect the kidney if using cisplatin.
Secondary malignancies: such as leukemia, solid tumors, lymphoma.
Female infertility: may be temporary or permanent .
Other chemotherapeutic modalities
Surgery: can be diagnostic or therapeutic
Radiation: ↑ doses of ionizing radiation directed at the cancerous tissue. SE: stomatitis, myelosuppression, GI (nausea, vomiting,
It’s common to combine drugs, surgery and radiation.
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55. Pain Management
Pain: unpleasant sensory and emotional experience that usually is associated with structural or tissue damage. No objective
Acute pain: lasts < 30 days. Occurs after muscle strains and tissue injury. Self limiting, ↓ w/ time as injury heals, linear process with
beginning and end, ↑ autonomic NS: ↑ heart rate, ↑ breath rate, ↑ BP, mydriasis, anxiety.
Chronic pain: persistent or episodic, > 6 months.
Chronic non-malignant pain: complication of acute injury, disease (osteoarthritis, rheumatoid arthritis, fibromyalgia, degenerative
disorders). Cyclic, constant, does not improve w/ time. No ANS stimulation. Depression, insomnia, weight loss, sexual dysfunction
Chronic cancer pain: similar to non-malignant pain, depression, fear, anger, agony. Due to cancer therapy or tumor (bone metastasis,
compression of nerves, occlusion of blood vessels, obstruction of bowel, infiltration of soft tissue).
Breakthrough pain: intermittent, transitory ↑ in pain.
Principles of pain management
Comprehensive pain management: chronology, history, symptomatology, onset, location, intensity, duration, quality, distribution,
provoking factors, underlying disease / trauma, allergies, analgesic response, side effects.
Pain management targets: ↑ patient comfort (may aid healing in acute pain), break pain cycle (chronic pain), ↓ breakthrough pain,
improve sleep, well-being, self-esteem, mobility, psychology, etc.
Individual management regimens: dose, intervals, mode of administration, adjunct therapy. Avoid narcotics for chronic non-
malignant pain. Long acting analgesics (round the clock) for cancer pain. Intermittent prn short-acting analgesics for breakthrough and
acute pain. Reassess and change regiment as needed.
Non narcotic analgesics
General uses: antipyretic, anti-inflammatory (except acetaminophen), analgesic ceiling effect, no tolerance, no dependence. OTC:
aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen (low doses).
Due to PG inhibition. With all except acetaminophen, COX-II inhibitors, choline magnesium trisalicylate, etanercept.
Symptoms: dyspepsia, ulceration, bleeding, perforation.
Especially in the elderly, ulcers, smokers, alcoholics.
Avoid by combo therapy with GI protectants (PPI, misoprostol, H2-antagonists, antacids, sucralfate) or enteric coating (aspirin).
Exceptions: acetaminophen, choline mg trisalicylate, etanercept.
Inhibit platelet aggregation by reversibly inhibiting PG synthase. Aspirin is an irreversible inhibitor.
Contraindicated with anticoagulants (warfarin, heparin, etc)
PG inhibition, interstitial nephritis, impaired renin secretion, ↑ tubular water/Na reabsorption reversible abrupt oliguria
Chemistry: derivatives of salicylic acid (from Willow bark). Weak acids with excretion ↑ by ↑ pH. Aspirin is acetyl salicylic acid,
hydrolyses easily, unstable in water, moisture. Other salicylates: diflunisal, methyl salicylate (topical, wintergreen oil), salsalate,
mesalamine, olsalazine, sulphasalazine, sodium thiosalicylate (injection), choline salicylate (oral liquid).
Pharmacology: ↓ cyclooxygenase (COXI/II) ↓ local PG analgesic, antipyretic, anti-inflammatory. Aspirin is the only salicylate
that ↓ COX irreversibly by covalent acetylation. Also, ↓ platelet COX ↓ thromboxane A2 formation ↓ platelet aggregation /
Indications: analgesics (skeletal muscle pain, headache, neuralgia, myalgia, spasmodic dysmenorrhea), anti-inflammatory (arthritis,
rheumatic fever), antipyretic (avoid in children with viral infection Rye’s syndrome), prophylaxis of MI. Mesalamine, sulphasalazine,
olsalazine ↓ inflammation in inflammatory bowel disease, Crohn’s disease. Methyl salicylate topical counter irritant.
SE: GI upset (nausea, vomiting, discomfort, irritation, ulceration, hemorrhage), ↑ bleeding, delayed labor, ↑ depth of respiration,
hyperglycemia, glycosuria. Low dose (2 g) ↓ urate excretion (↑ blood level). High dose (5 g) opposite. Toxicity: salicylism
(tinnitus). Oral methyl salicylate can be fatal. Sulphasalazine male infertility. Acute hypersensitivity (asthma, rhinitis, urticaria, shock,
etc). May have cross-sensitivity to other NSAID
DI: Oral anticoagulants (due to platelet inhibition and gastric mucosal damage ↑ bleeding). Methotrexate: ↑ toxicity with
salicylates by blocking methotrexate renal tubular secretion.
Examples: (x-profen) ibuprofen, ketoprofen, fenoprofen, flurbiprofen, naproxen (sodium), indomethacin, piroxicam, diclofenac,
ketorolac (oral, IM), etodolac, oxyprazocin, tolmetin, sulindac, meclofenamate, mefanemic acid, nabumetone. COXII inhibitors:
celecoxib, rofecoxib, valdecoxib.
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Chemistry: Many are acid derivatives. Most are from propionic (x-en) or acetic acid. Others: fentamates, oxicams or anthanilic acid
derivatives. COX-II inhibitors pyrazole derivatives.
Pharmacology: COX-I produces PG cytoprotective of stomach lining. COX-II produces PG for pain / inflammation. NSAIDs: ↓
COXI/II ↓ local PG synthesis. COX-II inhibitors: ↓ COXII only.
Indications: NSAIDs: mild to moderate pain, rheumatoid arthritis, osteoarthritis, gout, additive analgesia with narcotics. COX-II
inhibitors: rheumatoid arthritis and osteoarthritis.
Ketorolac IM: for moderate to severe pain (strongest NSAID for analgesia) when narcotic are undesirable (addicts, respiratory
Indomethacin: strongest NSAIDS for inflammation, ↑ CNS SE. Use for ductus arterisous in premature infants.
SE: NSAIDs: GI upset (dyspepsia, mucosal erosion), CNS depression / drowsiness, ↓ platelet function, skin rash, kidney damage.
COX-II inhibitors: kidney damage, ↓ GI upset.
DI: NSAIDs ↓ effect of diuretics (due to ↓ renal perfusion). COXII inhibitors are CI in allergy to sulfonamides, aspirin, NSAID’s
Acetaminophen is the prototype (APAP, acetyl para-amino phenol). Also, phenacetin.
Mechanism: ↓ central PG analgesic, antipyretic. No peripheral PG blocking no effect on inflammation, platelets.
Use: alternative antipyretic, analgesic to salicylate. Unlike aspirin, safe as antipyretic for children with viral infections.
SE: ↓ at normal doses (skin rash). Acute overdose liver failure. Antidote: N-acetyl cysteine. CI: alcoholism.
Chemistry: prototype is phenylbutazone, its metabolite is oxyphenbutazone. Also sulfinpyrazone.
Mechanism: ↓ PG synthesis, stabilize lysosomal membrane analgesic, antipyretic, anti-inflammatory, uricosuric. Sulfinpyrazone
only uricosuric ↓ hyperuricemia in gout.
Use: (oxy)phenylbutazone short term treatment of rheumatoid arthritis and gout (not first choice).
SE: ↑ SE. blood dyscrasias (agranulocytosis, thrombocytopenia, anemias), GI uspet, ulceration, kidney damage, hyperglycemia, skin
rash, CNS (drowsiness, headache).
Narcotic analgesics (opioids)
Include natural opiate alkaloids and synthetic analogs
Derived from opium (oldest drug) from poppy seed capsule.
Morphine: phenolic hydroxyl group is critical for activity. Most important alkaloid (pharmacologically and quantitatively). Amphoteric
structure erratic oral absorption.
Agonists: morphine, codeine, heroin, oxycodone, oxymorphone, hydromorphone, hydrocodone, dihydrocodone, meperidine, fentanyl
(transdermal), propoxyphene, loperamide, methadone / levorphanol (both long t1/2), diphenoxylate, sufentanil, dezocine.
Antagonists: methyl group on nitrogen atom is replaced by bulkier group. Examples: naltrexone, naloxone, levallorphan (?).
Mixed agonists-antagonists: nalbuphine, buprenorphine, butorphanol, pentazocine, can ppt withdrawal symptoms if used after
Endogenous peptides (enkephalins, endorphins, dynorphins) provide self-pain relief. Opioid receptors: in the brain / spinal cord
(Types: μ, κ, σ, δ, ε)
Effects of mu receptor stimulation (morphine-like): analgesia, sedation, miosis, euphoria, physical dependence, respiratory depression,
Other actions: cough suppression, CTZ stimulation (nausea, vomiting).
Opioids mimic the action of endogenous opioid peptides at CNS opioid receptors ↑ pain threshold and tolerance.
Moderate to severe pain, acute or chronic, of visceral or somatic origin, e.g. MI, cancer, labor, etc. Pre-anesthesia and adjuncts during
anesthesia. Anti-tussives (codeine, dextromethorphan). Antidiarrheal (loperamide, diphenoxylate).
Pure antagonists are used as antidotes to reverse SE of agonists or agonists-antagonists (respiratory depression, CV depression,
drowsiness). Naltrexone is used for opioid addition.
Dose is increased gradually until the appearance of limiting SE
Mixed agonist-antagonist preferred for acute pain respiratory depression risk is ↑. Avoid with chronic opioids withdrawal.
Oral: preferred esp. for chronic stable pain. CR morphine and oxycodone available for continuous pain (e.g. cancer)
IM, SC: used post-operatively. Absorption is not predictable.
IV bolus: most rapid, predictable onset for breakthrough pain
IV infusion: to titrate pain relief rapidly for unstable chronic pain, esp. morphine.
IV PCA: for acute post-operative pain. Small doses delivered at frequent intervals (10 min).
Epidural / intrathecal: for acute post-operative pain and chronic cancer pain. Intrathecal dose = 0.1 epidural dose. Must be
preservative free due to neurotoxicity of parabens and benzyl alcohol. Intrathecal local SE: itching, urinary retention. Epidural: ↓ brain
level ↓ SE give if respiratory depression risk is ↑. Labor meperidine (less neonatal respiratory depression).
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Rectal: alternative to oral. Patient un-preferred, poor absorption.
Transdermal: CR fentanyl (3 days). Alternative to oral for chronic pain. Slow onset, require oral supplement.
Constipation: due to ↓ intestinal tone and peristalsis. After several days (↑ with codeine). Prophylaxis: laxative / stool softener
combo (bisacodyl / docusate) if to be used chronically.
Respiratory depression: most serious. Monitor respiratory rate if at risk. Use IV naloxone (antagonist) to reverse life-threatening
depression, but may ppt withdrawal if on chronic opiates.
Nausea / vomiting: due to central stimulation of chemoreceptor trigger zone, esp. in parenteral dosing for acute pain. May need anti-
emetic (hydroxyzine, prochlorperazine), but may ↑ sedation.
Sedation: dose-related and ↑ with other sedatives (BZD, anti-emetics). Tolerance develops if chronically used. May need CNS
stimulant (methylphenidate, dextroamphetamine). Different from physiological sleep (pain is controlled patient rests).
Anticholinergic: dry mouth, urinary retention.
Hypersensitivity: not true allergy. Itching or wheel at injection site due to histamine release, esp. with intrathecal or epidural.
Meperidine CNS excitation: seizure-like, esp. in renal failure patients. Due to accumulation of normeperidine metabolite.
Tolerance: to analgesic, sedative and euphoric effects. Combo with NSAID may help overcome this problem.
Other SE: miosis, euphoria, confusion / hallucinations, coma, orthostatic hypotension, arrhythmias, histamine release (itching,
vasodilation ↓ BP, bronchoconstriction).
Dependence: Withdrawal symptoms: anxiety, irritability, insomnia, chills, salivation, rhinorrhea, diaphoresis, nausea, vomiting, GI
cramping, diarrhea, piloerection. Long t1/2 less intense / delayed withdrawal. Reduce acute withdrawal by using antagonist
(naloxone) or agonist-antagonist (pentazocine).
Drug interactions: additive CNS depression (alcohol, anesthetics, antidepressants, antihistamines, barbiturates, benzodiazepines,
phenothiazines). Meperidine with MAO inhibitors hypertension, excitation, rigidity.
Oral, centrally acting, non-controlled, analgesic with weak opiate (mu) activity for moderate to severe pain. Chemically unrelated to
Mechanism: bind to opiate receptors ↓ norepinephrine, serotonin reuptake. Naloxone is a partial antagonist.
SE: GI (nausea, constipation, dry mouth), CNS (dizziness, drowsiness, headache), ↓↓ respiratory depression, histamine release.
DI: ↑ sedation with alcohol and hypnotics. Inhibits MAO avoid with MAO inhibitors ( seizures)
Glucosamine sulfate and chondroitin sulfate
For degenerative joint disease (arthritis)
Glucosamine: substrate and stimulant for biosynthesis of hyalouronic acid and glucosaminoglycans forming proteoglycans in structural
matrix of joints. SE: GI, drowsiness, headache, rash.
Chondroitin: substrate for formation of healthy joint matrix
Other drugs affect non-opiate pain pathways may help with certain types of pain (e.g. neurogenic / neurologic), or to ↓ SE
Examples: tricyclic antidepressants, anticonvulsants, BZD, neuroleptics, corticosteroids, antihistamines, amphetamines.
Non-pharmacological pain management
Include Cognitive Behavioral Interventions (education, instruction, relaxation, biofeedback, hypnosis), and Physical methods
(acupuncture, physical therapy, compression gloves, orthotic devices, heat / cold, massage, immobilization, exercise, rest,
transcutaneous electrical nerve stimulation (TENS)
56. Nutrition and the Hospitalized Patient
I. Nutritional problems in hospitalized patients
Pathologic state resulting from the relative or absolute deficiency or excess of one or more essential nutrients.
Chornic state (over months or years) that result from deficiency in the total calorie intake depletion of fat stores and skeletal proteins
to meet metabolic needs.
Visceral protein is preserved (normal serum albumin, prealbumin, transferrin).
Immune competence, wound healing and ability to handle short term stress are preserved
Aggressive nutritional repletion can result in metabolic distrubances (e.g. hypokalemia, hypophosphatemia)
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Acute pricess (within weeks) due to inadequate protein intake
Visceral protein depletion, impaired immune function
Hypermetaboism (e.g. trauma, infection, surgery) + protein deprivation kwashiorkor malnutrion, hypoalbuminemia, edema
Aggressive nutritional protein repletion is warranted
d. Mixed marasmus kwashiorkor
Severe protein-calorie malnutrition when marasmic patients are hypermetabolic
II. Nutritional assessment of metabolic requirements
A. Nutritional assessment
1. Subjective global assessment (SGA): relies on patient history
2. Prognostic nutritional index (PNI)
Derived from a formula that quantifies patient’s risk of developing complications based on markers of nutritional status such as: serum
albumin (visceral protein), triceps skn fold thickness and delayed hypersensitivity skin-test reactivity (immune competence).
PNI<40 low risk, PNI>50% high risk.
3. Body composition analysis: measure and compares the ratios of body compartments.
a. Bioelectrical impedence: calculates lean body mass based on resistance to electrical current. Inaccurate in critically ill patients,
and those with fluid or electrolyte abnormalities.
b. Dual energy x-ray absorptiometry: measures fat and lean body mass. Depend on hydration status
c. Total body potassium: uses whole body counter to measure potassum isotope concentrated in lean tissue measures lean
d. Total body water: measures lean body mass from deuterium total body water (impractical).
e. In-vivo neutron activation analysis: divides the body into compartments. Requires large dose of radiation.
4. Test of physiologic function:
Quantify malnutrition based on decrease in muscle strength due to amino acid mobilization.
a. Maximum voluntary grip strength: measured with isokinetic dynamometry and correlates to total body protein.
b. Electrical stimulation of the ulnar nerve: measures muscle contraction.
B. Metabolic requirments:
1. Energy requirments
Determined as nonprotein calories (NPC). Can be measued by:
a. Indirect calorimetry or Measured Energy Expendure (MEE)
Most accurate. Directly measures O2 consumption and CO2 production.
Energy requirment is directly related to oxygen consumption.
Respiratory quotient (RQ) = CO2 produced / O2 consumed
Oxidation of nutrients: carobohyrates RQ = 1.0, fat RQ = 0.7,
Lipogenesis: conversion of excess carbohyrate calories to fat, produces more CO2 than oxidation.
b. Estimated energy expendure (EEE)
Requires calculation of basal energy expendure (BEE) from Harris-Benedict equation. BEE is then multiplies by stress and substrate
c. Simple nomogram
Based on patient weight, least accurate. Range from 2535 Kcal/kg/day depending on degree of stress.
2. Protein (nitrogen) requirments
a. Nitrogen balance techniques
16% of protein is comprised of nitrogen
Nitrogen balance = 24hr nitrogen intake – 24hr nitrogen output
Nitrogen output = urine urea nitrogen + nonurea urine nitrogen (ammonia, creatinine) + nonurine nitrogen loss (skin/feces)
Positive nitrogen balance of 3-6 g is the goal (not for the renally impaired)
b. Nomogram method: estimates protein needs based on lean body weight (1.5-2.0 g protein/kg/day)
c. Nonprotein calorie to nitrogen (NPC:N) ratio: normally 125-150:1
3. Essential fatty acids (EFAs):
EFAs are polyunsaturated fatty acids not synthesized by humans.
Linoleic acid: principal EFA. It’s omega-6 polyunsaturated fatty acid.
Linoleic acid deficiency diarrhea, dermatitis, hair loss
Prevent EFAs deficiency by giving ~5% of patient’s calorie intake as linoleic acid from lipid emulstion.
Fat soluble: A, D, E, K; Water soluble: B, C
Vitamin A: essential for vision, growth, reproduction. IV form binds to plastic and glass.
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Vitamin D: regulate calcium / phosphorous homeostasis together with calcitonin and parathormone.
Vitamin E: antioxidant, ↓ oxidation of free unsaturated fatty acids. Need to ↑ Vitamin E in diets ↑ in unsaturated fatty acids.
Vitamin K: critical for synthesis of clotting factors.
Vitamin B1 (thiamine): coenzyme in phosphogluconate, structural component of nervous system membranes. Deficiency acute
pernicious beriberi. Prolonged deficiency Wernicke’s encephalopathy.
Vitamin B2 (riboflavin): coenzyme in oxidative phosphorylation. No intracellular stores maintained.
Vitamin B3 (niacin): conenzyme in oxidative phosphorylation. Deficiency pellagra.
Vitamin B5 (pantothenic acid): functional form is coenzyme A, essential for all acylation reactions.
Vitamin B6 (pyridoxine): coenzyme in enzymatic reactions. Deficiency when taking isonizid, penicillamine, cycloserine.
Vitamin B7 (biotin): synthesized by intestinal floar. Involved in carboxylation reactions.
Vitamin B9 (folic acid): folate cofactors are needed for purien and pyrimidine (DNA) synthesis. Deficiency in B12 deficiency in (B9)
folate megaloblastic anemia. Deficiency during pregnancy neural tube fetal defects.
Vitamin B12 (cyanocobalamin): large stores deficiency develops in years. Deficiency: megaloblastic (pernicious) anemia,
peripheral neuropathy (needed for myelin synthesis).
5. Trace minerals
Iron: necessary for hemoglobin and myoglobin production, enzymatic reactions (cofactor). Deficiency: hypochromic, microcytic anemi a,
Zinc: necessary for RNA, DNA synthesis and enzymatic reactions (cofactor). Deficiency: imparied wound healing, growth retardation,
hair loss, anorexia. risk of deficiency in long-term steroid therapy, mal-absorption, surgery.
Copper: necessary for heme synthesis, electron transport, wound healing. Deficiency: anemia, leukopenia, neutropenia.
Manganese: involved in protein synthesis
Selenium: for antioxidant reactions. Deficiency: muscle pain, cardiomyopathy.
Iodine: component of thyroid hormones. Deficiency: goiter
Chromium: critical for glucose use, insluin effect. Deficiency: hyperglycemia, glucose intolerance.
Molybdenum: essential to xanthine oxidase
100. The Patient Behavioral Deterimants
102. Drug Education
103. Patient compliance
Definition: extent to which an individual’s behavior coincides with medical or health advice. Noncompliance can be intentional or
About 50% of the population is noncompliant with drug therapy in some way.
Causes in the elderly: complicated drug regimen, inability to read labels, difficulty opening lids, etc.
Noncompliance can affect and bias the results of clinical studies.
Types of noncompliance
Not filling Rx: because they do not feel they need or want the Rx. Example: an infection with Tylenol is feeling better and improving.
May be because of cost.
Omission of doses: common for drug that are taken frequently for long time.
Wrong dose: amount of does or frequency of administration is incorrect.
Incorrect administration: for example, not using the right technique with aerosols, or wrong route of administration.
Wrong time: for example, drug taken at the wrong time in relationship to meals. Drugs such as tetracycline, fluoroquinolones,
erythromycin should be taken on empty stomach. Diuretic should be taken in the morning.
Premature d/c: common with antibiotics (symptoms subside) or chronic drugs such as for ↑ BP (asymptomatic).
Storage: improper storage and improper disposal of unused drugs.
Consequences of noncompliance
Over and under utilization have major economic impact.
Always, the benefits from ↑ compliance outweigh the costs of compliance enhancing programs.
Overutilization: may cause toxicity. Examples: double dose to make up for missed dose, if one pill is good then more must be even
Noncompliance is one of the most commonly missed diagnoses (e.g. poorly controlled BP).
Consequences of noncompliance are not always negative. Some patients are “intelligent noncompliant” where they alter the dose
based on SE emergence while treatment goals is still achieved.
Detection of noncompliance
Diagnosis of the problem is a key. Behavior may change with time.
Ideal detection takes place at the time and place of taking the medication.
Self-reports and interview: simplest, but overestimates compliance. “Most people have trouble remembering to take their medicine.
Do you have trouble remembering to take yours?”
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Pill count: commonly used in clinical studies. Pill dumping is a common problem (study participants try to deceive physicians).
Overestimate compliance. Change of weight of MDI can be used.
Achievement of treatment goal: examples: normal BP, BG, intraocular pressure. However, patients may load-up on medication or
use other regimens (diet) before doctor visit. This is called toothbrush effect (people toothbrush before dentist visit).
Computerized compliance monitors: most reliable indirect method. Started with electronic eye-drop dispensers. A microprocessor
is located in the cap of the container. Time and date are recorded every time the patient removes the cap. Very useful in clinical
Refill rate: commonly used in community pharmacy settings.
Direct methods are more reliable. Use of at least 2 methods is recommended.
Biological markers and tracer compounds: indicate patient compliance over extended period. Example: glycosylated hemoglobin
assesses BG control over the preceding 3-months.
Tracer compounds: small amounts of agents such as Phenobarbital or digoxin (long half life, indicate compliance for past weeks) are
added to drugs and measured in biological fluids.
Drug concentration in biological fluids: limited usefulness due to variability between individuals, does not indicate the timing of the
dose, can be fooled by loading-up prior to biological fluid sampling.
The noncompliant patient
No consistent pattern has been observed regarding noncompliance with certain age, education, occupation, socioeconomic status,
personality, race, severity or type of illness, etc.
Intentional noncompliance is more common in patients who used two or more drugs or two or more physicians.
Health Belief Model: developed initially to explain preventative health behaviors such as immunizations and prophylactic dental care.
It also applies to compliance with prescribed medical regimen.
Third Generation Model: focuses on health decisions.
Health Decision Model: combines decision analysis, behavioral decision theory, and health beliefs to give a model for health decisions
and resultant behavior.
Compliance and health beliefs: patient has to believe that: he has the illness diagnosed, illness can cause severe consequences to
daily functioning, treatment will ↓ present and future severity of condition, benefits or regimen outweigh perceived disadvantages and
Stimulus to trigger positive health behavior can be internal (patient’s concern) or external (interaction with physician or pharmacist).
Myths: “need to take medication only when experiencing symptoms”, “need to d/c medication occasionally to prevent dependence and
Other factors: patient who live alone are more noncompliant. Patient may have fear of dependence for any drug that is used
chronically. They may d/c or ↓ dose occasionally to prevent this or to prove to themselves that is not the case.
Factors associated with noncompliance
Psychiatric patient are more noncompliance due to an attitude or inability to cooperate.
Patients with chronic asymptomatic disease are more noncompliant (hypertension, hypercholesterolemia, tuberculosis).
Occurrence of significant symptoms upon d/c may ↑ compliance.
↑ disability caused by the disease ↑ compliance.
No general correlation between disease severity and compliance.
Multiple drug therapy: ↑ number of drugs ↑ noncompliance (e.g. in geriatrics). The similarity in appearance of drugs may lead to
confusion. Combination drugs may help but therapy should start with individual drugs and then switched to the combo when opt imum
dose is reached.
Frequency of administration: may cause interruption of normal routine or work schedule inconvenience, embarrassment, forget.
Very critical factor in compliance. However, patient may be skeptical about the effective of a QD drug.
Duration of therapy: rate of noncompliance ↑ as duration ↑.
Adverse effects: change dosage or use alternative drugs if possible. Big problem when the medication makes the patient feel worse
than before (e.g., BP drugs). Sexual dysfunction is common cause (e.g. with antipsychotics, antihypertensives). Just communicating
potential SE may cause the patient not to take the drug.
Asymptomatic conditions: includes lack of symptoms before the drug, lack of appearance of symptoms if drug is d/c, disappearance
of symptoms (antibiotics).
Cost: ↑ cost Rx not filled, ↓dose is taken, ↓frequency, prematurely d/c.
Administration: for example, incorrect measure of liquid medications, MDI use, oral antibiotic drops for ear infection instilled in the ear,
using suppository by the oral route.
Taste: common for oral liquid in children (e.g. liquid KCl).
Psychological support should be provided in a compassionate manner.
Patients are ↑ compliance with a physician they know and respect.
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Not appreciating importance of therapy: if therapy does not meet their own or taught expectations noncompliance.
Poor understanding of instructions: “as directed” should be avoided on label. “every 8 hours” is more specific than “three times a
day”. Auxiliary instructions are also key. Example: apply one nitroglycerin patch a day, patient got confused and added a new patch
without removing the old ones.
Identification of risk factors
All patients should be viewed as potential noncomlpiers. Evaluate the probability of being noncompliant based on the risk factors.
Development of treatment plan
Recommend longer acting drugs or dosage forms.
The more actively participating patient in the plan is more compliant.
Plan should be individualized.
Tailor regimen to ↓ inconvenience and forgetfulness by fitting it to regular activities in the patient’s schedule. Indicate specific times of
the day to take medications if possible.
Effective communication is the key for ↑ compliance.
Patients should be asked to repeat the instructions to show understanding.
Key points: name of medication, action, how much to take, when, for how long, food interactions, possible SE, what to do about SE,
Oral communication / counseling: more important than written, as it gives patient a chance to interact and ask questions. Ensure
privacy and ↓ distractions. Separate consultation area is ideal. Call the patient if possible if face to face is not possible.
Written communication: important is a future reference for the patient as he is not expected to remember all details. Written info ↑
compliance only for short term therapy (e.g. antibiotics).
Audiovisual materials: very useful in certain situations (e.g. insulin, sumatriptan, MDI).
Controlled therapy: it is recommended that patients start self-medication before hospital discharge to transition them from complete
dependence in the hospital to complete independence at home.
Special compliance programs: example: behavioral program for schizophrenics. Training include learning on obtaining information
about drug benefits, correct self-administration and evaluation of effects, identify SE, talking about issue with professionals. Programs
may be useful also for sight or hearing impaired patients.
Good knowledge about the illness and medication does not necessarily translate to ↑ compliance. Patients need to be motivated not
Information must be presented in a manner that is not coercive, threatening, or demeaning. Use special packaging or reminder
systems if possible. A contract approach may be useful with some patients where agreement is reached on specific actions.
Labeling / auxiliary: must be clear, accurate and specific
Calendars / Reminder charts: helps the patient understand which medication to take and when to take it.
Special containers / caps: for example, system with four compartments for different time periods (morning, noon, evening, bedtime)
for each day of the week. Special caps can display the time of the day when the last dose was taken. It flashes / beeps when it is time
for the next dose.
Compliance packaging: defined as pre-packaged unit that provides one treatment cycle of the medication. Usually based on blister
packages. A good example is special packaging for birth control pills. Another example: prednisone decreasing dose regimen. Child-
proof caps may be a problem for the elderly or patients with arthritis.
Dosage forms: for example ER, XR and transdermal patches.
Self monitoring: by the patient of the treatment regimen, response parameters.
Pharmacist monitoring: based on inadequate frequency of refills, follow up by phone or mail reminders. Automatic phone call
reminder systems have been used. Brown bag program: elderly pull all medications in a bag and take them to a professional for
Directly observed treatment: watch patient swallow drug (e.g. in TB).
Innovative roles for pharmacists: home IV therapy, drug level monitoring, parenteral nutrition management, self-care counseling.
Pharmacy services may provide positive outcomes by ↓ morbidity, ↑ therapeutic control, ↓ cost of treatment by using efficient therapy, ↓
# of physician visits, ↓ rate of drug related hospitalization, ↓ incidence and intensity of SE.
Extra years of life for a patient population can be converted to dollars for society.
Technique Inputs Outputs
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Units (e.g. pharmacy hrs) Units (e.g. patients monitored)
Dollars Natural units
Cost utility analysis Dollars Utiles/preferences
Dollars Assumed equal
Cost benefit analysis
Medical care is an investment good (in human capital) and a consumption good.
Measure of investment benefit: present value of a person’s lifetime productivity.
Both inputs (costs) and outputs (benefits) have to be quantified in dollars.
Both $ amounts are discounted to their present value at a certain interest rate.
Economic value = present value of benefits – present value of costs.
Benefits may be difficult to measure or to convert to $, or both.
Benefits: defined as the ↓ in costs realized due to program implementation. Can be direct, indirect, or intangible.
Direct benefits: savings on direct costs in medical care. Easy to measure.
Indirect benefits: savings on indirect costs in the medical care. Difficult to measure. It’s avoidance of earnings and productivity losses
which would have been incurred without the health program.
Intangible benefits: difficult, if not impossible, to measure. Intangible costs are psychological (pain, suffering and grief).
Discount rate is the conversion of dollar amount to present values through the use of interest rate.
↑ discount rate: favors projects with benefits occurring in distant future.
↓ discount rate: favors projects with costs occurring in distant future.
Commonly used discount rate is the yield rate on long term gov bonds.
Mathematical models are used to calculate benefit/cost ratio.
Net Present Value (NPV): a new model for calculating benefits-costs. Very popular and currently recommended by many economists.
Rate of Return on Investment: calculates the interest rate from an initial program investment over a potential stream of benefits over
Cost effectiveness analysis
Alternative ways are compared for achieving results (↓BP, life expectancy).
Similar output measurements must be achieved to compare programs.
Cost Benefit Analysis Cost Effectiveness Analysis
Output: dollar values Output: units not dollars
Determines maximum benefit or investment Determines least cost combination
Assumes limited resources Assumes adequate resources
Fast comparison of programs Different ways to reach same objectives
Less flexible More flexible
A pharmacy service with positive benefit/cost ratio may be good for the society as a whole but not to every segment of the society.
Example: drug regiment that ↓ # of patient days in acute care is good for the society but may not be good for the hospital that depends
on patient stays for revenue.
Always consider who pays the costs and who receives the benefits.
Quality of life outcomes and patient decisions
Quality of life and satisfaction with service are critical. Elements may include: probability of success, associated pain, l ikely outcomes,
Example: the quality of years within life extension (healthy years?).
Example: untreated hypertension may not critical affect daily life, but a MI would ↓ quality of life.
Health-related quality of life (HRQL) is a humanistic outcome.
Using decision-analysis techniques, a decision tree can be made of what happens to the patient from diagnosis to cure.
The FDA has been leery of drugs that ↑ quality but ↓ life expectancy.
Diseases are associated with physical, mental and social impairments (which can be difficult to measure).
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Pharmacy Management (PDF files)
Accounting: process of collecting, recording, summarizing, using financial data
Auditing: accounting that deals with verifying that records are kept and computations are made.
Bookkeeping: process that documents flow of resources ($$, goods) into / out of the business, and claims of creditors / owners to
Dual effects of accounting: most transactions are recorded twice with the result of a balanced sheet.
T Account: with debt on the left and credit on the right. Debits = Credits.
Transactions: fiscal / financial events that are recorded.
Accounting period: period of time over which transactions are recorded, at the end of which income is measured. Usually 1 year. Not
always a calendar year.
Methods of recording transactions: Accrual: transactions are recorded at the time they occur. Cash: transactions are recorded
when cash transfers hands.
Revenue: measurement of goods sold or services rendered for which the business receives cash or the promise of cash.
Expenses: resources used up during a period of time to earn revenue.
Types of accounts: owner equity = assets - liabilities.
Assets: resources owned by the business, e.g. cash, account receivable, buildings, inventory, equipment, furniture, prepaid insurance.
Liabilities: debt owned by the business to creditors. It arises when business borrows cash (e.g. bank loan) or purchases goods or
services on credit. Examples: accounts payable, notes payable.
Owner equity (Net Worth): claim of the owners to the assets of the business after all creditors have been paid. It ↑ when owners make
investments in business or when revenue is earned. It ↓ when expenses are paid. Examples: contributed capital, sales revenue, service
revenue, expense accounts.
Expenses: not a liability because they are used up resources that require the immediate payment of cash for the amount in full,
otherwise liability. Prepaid expenses are assets because they’re resources that have not yet been used up.
Income = revenues – expenses.
Cost of Goods on Hand: on last day of accounting period physical inventory to determine cost of inventory not sold. No physical
inventory is needed if perpetual inventory is kept by computer systems.
Fixed assets: tangible, long-lived resources used in business operation, e.g. building, machinery, fixtures, equipment, etc.
Current assets: resources owned by the business which are expected to be realized in cash, sold or consumed in one year, e.g.
account receivable, inventory, etc.
Depreciation: wear and tear that occurs on fixed assets calculated as an expense. Most fixed assets, except land, are depreciated.
Contra (offset) accounts: reside directly below the fixed asset account to which they pertain.
Summary of operations, income earned during accounting period.
Constructed using revenue and expense account balances.
Revenue: sales of good and services
Cost of goods sold: such as inventory and transportation expenses.
Gross margin = revenue – cost of goods sold.
Net profit (income) = revenue – all expenses.
Net income = net profit – income tax
Presents the financial position of the business at a certain point in time
Constructed using all asset account, liability accounts, OE accounts
Retained earnings: link income statement and balance sheet.
Purchasing and inventory
Involves planning, organizing, controlling inventory for profitability
Inventory control objectives: ↓ investment, ↓ purchasing / carrying costs, balance supply and demand.
Inventory is the largest pharmacy investment critical to manage.
Total inventory costs = acquisition costs + stock out costs + carrying costs + procurement costs.
Acquisition costs: amount the pharmacy pay for the product.
Stock out costs: cost of not having the product available when needed
Carrying costs: storage, handling, insurance, loss/theft, damage, capital
Procurement costs: cost of placing orders, receiving items, stocking shelves, processing documentation
Objective of holding inventory: to guard against fluctuations in demand and later delivery, take advantage of bulk discount.
Goals of inventory management: minimize investment in carrying and procuring inventory by balancing supply and demand.
Inventory costs significant impact on financials. ↓ procurement and carrying costs, ↑ sales by avoiding stock-outs
Cash flow: prompt payment, ↓ COGS, ↑ gross margin
Inventory turn-over rate (ITOR) = COGS/average inventory. Target: ↑ ITOR to ↑ return on investment in inventory, ↓ investment in
inventory to free up capital for other ventures.
Inventory return on investment = net profit/average inventory.
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What to buy? product, manufacturer, competitor consideration.
Where to buy? consider order cycle time, minimum order required.
How much and when to buy? difficult to determine.
Cycle stock: inventory kept on hand to fulfill orders
Buffer/safety stock: inventory for case of supply/demand fluctuations.
Anticipatory/speculative stock: inventory for expected ↑ in demand
Steps of purchasing
Cost of goods sold (COGS): have dramatic effect on profits
Purchasing objectives: right product / variety, quality, quantity, price, time
1. Market research: to determine needs/wants of patients / prescribers, identify pharmacy image and business goals, space limitations,
potential sales. Determining needs: usage reports, other pharmacies, pharmacy employees, questionnaires, sales reps, published top
X drugs, formularies. Example: area with young families children items, older families elderly items. Consider special disease
management areas, e.g. asthma, diabetes.
2. Effective purchasing policies: Use “open-to-buy purchase budget”. Control total $ investment in inventory. Use prior year data to
forecast purchase budget for each month in the upcoming year, based on sales and COSG. Adjust (↑ / ↓) each month purchases
based on previous month sales and purchases. Gross margin = sales – COGS.
3. Selecting supply sources: must be dependable, prompt, frequent delivery, good return policy, ↓ frequency of out-of-stock, customer
service, price, financing arrangement. Options: wholesales, manufactures, buying groups, rack jobbers, etc. Wholesales:
advantages include storage of good until needed, rapid delivery, financing options, help with advertising promotions, store layout and
design. Rack jobbers: stock and maintain a specified assortment of goods (e.g. eyeglasses) in a fixture in the pharmacy.
Manufacturers: not common, large minimum purchases. Central purchasing groups: pool buying power of independent pharmacies
for better terms.
4. Negotiating terms: price, discounts, dating, return policy. Pharmacy margin = suggested retail price – pharmacy cost. Quantity
discounts: cumulative (generic rebate) or non-cumulative ($ or % per quantity). Cash discount: for prompt payment (typical: 2% if
paid in 10 days, net amount due in 30 days), or discount for Electronic Fund Transfer. Final price is calculated after subtracting trade,
quantity and cash discounts. Dating: time for discount and payment (prepayment, collect-on-delivery (COD), delayed). Returned
goods policy: full credit within x days, partial credit after y days, non-returnable after z days. Check shelves regularly for items not sold.
Consider using a returned goods service company (charge a fee).
5. Transferring merchandise title (?)
6. Receiving, marking, stocking: count shipment, check for damage, check invoices, mark prices (merchandise, computer), stock.
Stock depth considerations: average demand, review time, lead time, safety stock. Inventory control includes the following:
1. Visual: look at # of units in inventory and compare with how many should be carried, order more if needed.
2. Periodic: count stock on hand at certain intervals, compare to minimum target levels, order more if needed.
3. Perpetual: monitor inventory all the time (usually using a computer).
Computer systems: sales, analysis, trends, perpetual, automatic ordering, interface inventory and dispensing systems at point of sale.
Financial analysis / planning
Comparative analysis: express each financial statement component as percent of sales, and compare with Digest data.
Ratio analysis: compare financial ratios with ratios for the same company during recent years, and similar group of pharmacies in
NCPA Pharmacia Digest.
Solvency: overall ability to pay legal debts. Calculate Current and Acid Test ratio
Current Ratio = current assets / current liabilities. Target > 2
Acid Test Ratio = (Cash + account receivable) / current liabilities. Target > 1
Other solvency ratios: current liabilities / inventory, total liabilities / net worth, long-term liabilities / net working capital, fixed assets /
Efficiency: how well available capital is used. Inventory turnover ratio.
Inventory turn over ratio = COGS / average inventory. Target: 5-6.
Other efficiency ratios: net sales / inventory, account receivable and account payable collection period, net working capital turnover.
Profitability: the bottom line, important but not the only measure of success.
Return on net worth = net profit / net worth. Target 25%.
Net worth = total assets – total liabilities.
Net profit / net sales: target 5%.
Net profit / total assets. Target 15%.
Net profit / inventory. Target 20%.
Expenses: salaries, wages, rent, utilities, accounting / legal fees, taxes, licenses, insurance, interest, equipment, depreciation.
Balance sheet: includes assets and liabilities. Current assets: cash, account receivables, inventory. Current liabilities: account
payable, accrued expenses.
Components of price = ingredient cost + service cost (dispensing) + income.
Actual Acquisition Cost (AAC): price the pharmacy pays for the product. Varies depending on source, volume, incentives and deals,
type of pharmacy
Average Wholesale Price (AWP): NOT (?) the average price the wholesalers sell the product at. Cost assigned to product by
manufacturer, overstates AAC
Estimated Acquisition Cost (EAC): established by third party payers to estimate AAC. Usually a percentage of AWP (e.g. 90%).
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Service cost: average or per unit cost of providing a service. Covers expenses such as salaries, rent, utilities, depreciation. Includes
cost to dispense.
Direct costs: results directly from providing the service. No direct cost if service is not provided. Dispensing direct costs: labels,
containers, computer, delivery costs, patient education materials, pharmacy licenses.
Indirect costs: costs shared by all services, e.g. rent, utilities, salaries, benefits, advertising, etc.
Cost of providing a service = all direct costs + “fair share” of indirect costs.
Cost allocation: determining the fair share of indirect costs. Difficult. Estimate % of employees time and facility space devoted to
Cost to dispense (COD): total dispensing costs / expected Rx volume. It is an estimation of the average cost to dispense Rx.
Sensitive to volume.
Differential costs; differ among alternative courses of action, i.e. additional costs the pharmacy incurs for providing a new service.
Non-cost factors: demand, competition, image, quality signaling, goals, non-monetary costs.
Demand: quantity consumers will be at a certain price. Function of price.
Elasticity of demand: measures sensitivity of demand to price ∆.
Elastic demand: small ↓ in price results in big ↑ in demand. Sellers make money by lowering the price. Inelastic demand is opposite
(↑ price ↑ profit)
Consumers are more sensitive to price when: cost of product is large part of total cost, ↓ differences among products, comparisons are
easy, consumers can judge quality, switching costs are small, commodity.
Image: consumers can select based on perceptions of pharmacy image. Image is affected by: prices, size, location, services offered,
personnel, promotions, etc
Price as a signal of quality: more likely when consumers cannot judge quality, more for services than products.
Penetration pricing: ↓ price to ↑ sales volume. Loss leader pricing: ↓ Rx prices to ↑ OTC sales. Price skimming: ↑ price for superior
Management components: self, controllable surroundings, uncontrollable surroundings, external environment.
Management activities: satisfy various entities, deal with emergencies, purchasing, recruiting, accounting, training, planning,
negotiating, sales, dealing with regulatory officials.
Management actions: identify tasks, organize resources, monitor performance / task completion, plan for future requirements, deal
Functions of management actions: target setting, problem solving, leadership, team building, dealing with emergencies.
Management functions: controlling, directing, organizing, planning, staffing
Controlling: establish standards based on objectives, measure / report performance, take corrective / preventative actions.
Directing: motivation, communication, performance appraisal, discipline, conflict resolution.
Organizing: division of labor, delegation of authority, departmentalization, span of control, coordination.
Planning: vision, mission, objectives, coals
Staffing: recruiting, selecting, hiring, training, retaining
Know self, who we are, what we aspire to become, new info, what we need to know, who else need to work with us, etc.
Manager’s skills: intellectual, technical, ethical, interactive, emotional.
Intellectual skills: logical thinking, problem solving
Ethical skills: define right from wrong
Interactive skills: communicate intelligently and create an atmosphere that facilitates communication.
Most problematic issues: poor communication, developing people, empowerment, lack of alignment, entitlement, balancing work /
personal life, confronting poor performance, coaching senior management, cross-functional strife, fascination with programs.
Decision making: identify objectives, analyze relevant factors, consider all alternatives, selection best option, implement the decision,
evaluate the results
Management style: depends on organization, situation, personal values, personality, chance.
Self-development methods: observation, reflection, guided readings, attachments / visits, seeking feedback, seeking challenges.
Strategic planning: must complement strategic thinking / acting. Includes where we are going (mission) and how we get there
SWOT analysis: strengths, weaknesses, opportunities, threats.
Vision of success: mission, basic philosophy, core values, goals, strategies, performance criteria, decision rules, ethical standards.
Environment: stability, complexity, market diversity, hostility, competition
Cascade of information: should flow not only downward, but also upward
Project management failures: lack of focus / attention, inability to cope with different project characteristics, feeling being used /
exploited, lack of experience
Project management process: develop ideas and proposals, approve the project, project kick-off / start, monitoring / reporting /
Project management 10 commandments: concentrate on interfacing, organize project team, plan strategically / technically,
remember Murphy’s law, identify stakeholders, manage conflict, expect the unexpected, listen to intuition, apply behavioral skills, take
Project management functions: scope / quality / time / cost management
PDCA Cycle: Plan, DO, Check, Act
Problem solving: define the problem identify the criteria weight importance of criteria generate alternatives rate alternatives
on each criterion compute the optimal decision
Continuous Quality Improvement (CQI): philosophical / structural / healthcare-specific elements. Use PDCA cycle.
Philosophical elements: strategic focus (mission, values, objectives), customer focus (patient, provider, payer), systems focus.
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Structural elements: process improvement teams, top management commitment, statistical analysis, customer satisfaction measures,
benchmarking, seven tools (flow charts cause/effect diagrams, check sheets, histograms, etc).
Healthcare specific elements: epidemiological studies, governance processes (QA, committees, peer review), risk-adjusted outcome
measures, cost-effectiveness analysis.
Barrier to quality transformation: lack of constancy of purpose, emphasis on short-term profits, personal view system, management
mobility, using only visible figures, ↑↑ cost of employee healthcare, ↑↑ cost of warranty / insurance.
5. Extemporaneous Prescription Compounding
18. Nuclear Pharmacy
19. Pharmaceutical Care and Disease Management
21. Adverse Reactions and Post Market Surveillance
34. Clinical PK and Therapeutic Drug Monitroing
53. Renal Failure
57. Immunosuppressants in organ transplantation
58. Outcomes Research and Pharmacoeconomics
Health care system
Preferred Provider Organization (PPO): Broad network of providers available, generally management is less strict. 52%
Point of Service (POS): HMO plan with the option of going outside the narrow provider network if willing to pay higher cost-sharing.
HMO: Narrow choice of providers, tighter management. 26%
Types of outcomes:
Humanistic outcomes: Health Related Quality of Life, Patient Satisfaction, Caregiver Impact, Patient Preferences, Functional Status
Economic: Cost Analysis, Cost-of-Illness, Cost-Minimization, Cost-Benefit, Cost-Effectiveness, Cost-Utility
Clinical: Efficacy, Safety, Impact of therapy on “natural history” of the disease
Methods for setting health insurance rates
Experience rating: everyone in a specific area is charged the same premium based on the average cost of providing health services to
all people in the area
Community rating: premium adjusted individually according to a person’s or group’s average health history, risk, and past claim
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