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PHLE- Module-4

Pharmacy (University of Bohol)

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MODULE 4

 PHARMACOLOGY &
PHARMACOKINETICS
 TOXICOLOGY
 INCOMPATIBILITIES & ADVERSE
DRUG REACTION

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PHARMACOLOGY
Pharmacology  Study of selective biologic activity of drugs
 Study of substances that interact w/ living systems through chemical processes, especially by binding to regulatory molecules &
activating or inhibiting normal processes
 Medical Pharmacology  is the area of pharmacology concerned with the use of chemicals
in the prevention, diagnosis, and treatment of disease, especially in humans.
Drugs  Articles recognized in the official USP, official Homeopathic Pharmacopeia of the US or the official NF, or any supplements to any of them
 Articles for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
 Articles, other than food intended to affect the structure or any function of the body of man or other animals
 Articles intended for use as component of any articles specified in clause 1, 2, or 3: but does not include devices or their components parts
or accessories.
 Substances that act on biologic systems at the chemical (molecular) level and alter their functions(Katzung)
 Drug receptors  The molecular components of the body with which drugs interact to bring about their effects
 Nature of drugs  Drugs are chemicals that modify body functions. They may be ions, carbohydrates, lipids, or proteins.
They vary in size from lithium (MW 7) to proteins (MW 50,000)
Branches of Pharmacology
Pharmacodynamics  is a branch of pharmacology that focuses on the study of biochemical & physiological effects of drugs & the
mechanisms by which they produce such effects.
” what the drug does to the body”
 deals with interaction of drugs w/ receptor  molecular consequences Biological effect
 study of the biochemical & physiologic effects of drugs in biological systems
Pharmacokinetics  is the quantitative measurement of drug absorption, distribution, and elimination (i.e., excretion and metabolism) and
includes the rate processes for drug movement into the body, within the body, and out of the body.
”What the body does to the drug”
 examines the moment of drug over time through the body
Pharmacotherapeutics  Rational use of Dugs in the management of diseases
Toxicology  branch that deals w/ the undesirable effects of chemicals on living systems, from individual cells to complex ecosystems
Classification of Drugs:
 Functional modifiers
 Alters certain physiologic functions & activities of body cells
 Examples:
 Sensation of pain (analgesics, anesthetics)
 Tachycardia (beta-blockers)
 Morphine  narcotic analgesic; pain perception
 Bevacizumab  for cancer; inhibit VRGF (vascular endothelial growth factor)  vascularization
 Replenishers
 Replaces/ replenish endogenous substance that are lacking/ deficient/ absent
 Example:
 DM type 1 (Insulin)
 Pernicous Anemia (Vit B12)
an autoimmune disease when immune system produces antibodies that target the parietal cells of the stomach that
leads in inhibiting/ decrease HCL & Intrinsic Factor (which are important in VitB12 absorption
having pernicious anemia can lead to Megaloblastic Anemia (cause neurologic effect)
Vit B12  absorbed in terminal ileum; sources: meat products
Causes of VitB12 deficiency:
a. Chronic use of Proton pump Inhibitor
b. H2 Blockers
c. Diphylobotrium latum (fish tapeworm)  competes in Vit B12 absorption
 Diarrhea (ORS)
 Diagnostic Agents
 Diagnosis or confirmation of diagnosis of certain diseases
 Example:
 Edrophonium (Tensilon®) Myasthenia gravis
 Pulmonary challenge test; diagnosis of bronchial asthma (Histamine)
 Radiopaque; to visualize the outline of the GIT (Barium sulfate)
 Dobutamine  Schemia
 Dobutamine/ Dipyridamole  used in pharmacologic stress testing
 Tc99m stratum
Thallium 201
Dx: Myocardial Ischemia  O2  cells are still viable
Myocardial Infarction  no O2 supply  cells are dead (necrosis)
 Chemotherapeutics Agents
 Agents used to kill/ inhibit growth of cells considered as foreign to the body
 Anti-infectives
 Anti-microbials
 Anti-neoplastics
 Anti-cancer

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Principles of Pharmacodynamics: Mechanisms of Drug Action

Classification of mechanisms based on the concepts of target proteins

i. Non target protein-mediated

a. Direct chemical interaction
 Chelating agents
o Dimercaprol for Pb, Ag, Hg, Ar
o EDTA (emergency treatment for hypercalcemia, control of Ven arrhythmia due to digitalis
o Calcium EDTA (Treatment of acute & chronic lead poisoning)
o Defuroxamine (Desferal) for Fe toxicity
 Neutralization reactions
o Antacids Mg++ & Ca++ for HCl
o Ammonium chloride
o Sodium bicarbonate
b. Colligative mechanism/mass effect
 Lactulose
 Mannitol (osmotic diuretic – renal tubule-early loop of henle)
Creates a n osmotic gradient across renal tubule
c. Counterfeit incorporation
 Affects gene transcription
 (purine & pyrimidine analogues; ex. Flucystosine, 5FU, & antimetabolites)

ii. Target protein-mediated

a. Structural proteins:
 Tubulin, proteins present in microtubules (colchicines, vinca alkaloids)
 Keratin (Griseofulvinincrease absorption w/ fatty food through pinocytosis)
b. Regulatory
1) Transport Proteins
(a) Voltage-gated Na channels  detect changes in environment
 Inhibited by: Local Anesthetics, Class I Antiarrhythmic, Phenytoin, Carbamazepine
(b) Voltage-gated Ca channels
 Blocked by CCBs (-dipine)
 Non-DHP (Verapamil, Diltiazem)
(c) Voltage-gated K channels
 Blocked by class III antiarrhythmic (Aminodarone)
 Sulfonylureas – Type 2 DM ; insulin secretagogues
2) Enzymes
 MAO (Moclobemide, Phenelzine, , Isocarboxazide, Tranylcypromine Selegeline) MPITS
M – Selective MAOA inhibitors
PIT  Non selective
S  Selective MAOB inhibitors
 COMT (-capones)  management in PD
 ACE (-prils) –aka Kininase
 COX (NSAIDs)
 AChe (Organophosphates)
3) Carrier Molecules (Na-K ATPase, K-H pump, Re-uptake 1)
 Na-K ATPase pump (Digoxin)
 K-H ATPase pump (proton pump inhibitors; -prazoles
4) Receptors

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Receptors  A molecule to which a drug binds to bring about a change in function of the biologic system
 Functional macromolecular component of a cell w/ a specific stereochemical configuration w/ which a ligand interacts in a lock
& key fashion initiating a chain of biochemical events that leads to a therapeutic effect
 Receptor site  Specific region of the receptor molecule to which the drug binds
 Receptor affinity of the drug  a factor that will determine the number of drug-receptor complexes formed.
 Inert binding molecule or site  A molecule to which a drug may bind without changing any function
Spare receptor  Receptor that does not bind drug when the drug concentration is sufficient
to produce maximal effect; present when Kd > EC50
 Effector  Component of a system that accomplishes the biologic effect after the receptor
is activated by an agonist; often a channel or enzyme molecule
Type I (Ionotropic) receptors; 9ligand-gated ion channels)
 Channel linked receptors
 Controls movement of ions in & out the cell
 Effect seen in milliseconds
Ganglionic blockers, Nn
Examples:
Trimethapan
o Nicotinic receptors (ligand-gated Na channel)
Mecamylamine
Benzodiazipine  Frequency
Hexamethoprim
Phenobarbital  Duration
Neuromuscular blockers, Nm
o Inhibited by NMBs & ganglionic blockers
succinylcholine
o GABAA receptors (CI channel)
o Inhibitory NT
o Facilitates iflux of CI inons resulting to hyperpolarization
o Stimulated by benzodiazepines, barbiturates)
Type II (Metabotropics) receptors (Signal transduction pathway or effector system)
 7-transmembrane spanning receptors (serpentine receptors)
 G protein linked
Gs  activate adenylyl cyclase: increase cAMP or the release of secondary messenger
 Beta receptors
“Kiss & Kick”
B1  increase contraction rate (heart)
1- Gq M1-Gq
B2  bronchodilation (lungs)
2- Gi M2-Gi
Gi  inhibit adenylyl cyclase; decreases cAMP
1-Gs M3-Gq
Alpha-2, 5-HT1A , muscarinic, histamine receptors
Go  unknown 2-Gs
Gq Increase phospholipase C activity (splits Phospatidylinositol 4,5-bisphosphate);
increase IP3, DAG, & cytoplasmic Ca2+
Ex, alpha-1 receptors, muscarinic
Gt  increase cGMP phosphodiesterase: decrease in cGMP
 Effects seen in seconds
Type III (Enzyme-linked) receptors  translocation of glucose trensportation
 Tyrosine kinase (insulin)
 Guanylyl cyclase (cGMP as 2nd messenger)
 Conversion of GTP to GMP DNA DNA RNA CHON MAOi
 Involved in the action of NO
 Effects seen in minutes
DNA synthesis Transcription Translation
 Example:
o Insulin receptors
o ANP receptor (Atrial natiuretic peptide)
Type IV (Gene-transcription-linked) receptors
 Nuclear or Cytoplasmic receptors
 Effects seen in several hours
 Examples
o Steroid receptors (glucocorticoids, minercorticoids)
o Thyroid hormone receptors
o Sex hormones
Type I, II, III (located in the cell membrane)
Type IV (cytoplasm/ nucleus)

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Properties of Receptors:
(a) Saturability  a finite number of receptors per cell, or per weight of tissue or protein is present as revealed
by a saturable binding curve
(b) Specificity  Lock & key fashion of drug-receptor interaction
 Dugs should be structurally complementary to the receptor
(c) Reversibility  The drug should bind to receptors then dissociate in its non-metabolized form
This distinguishes receptor-drug interaction from enzyme-substrate interactions
Drug-Receptor Interaction/ Drug protein target
 Affinity  ability to bind to a receptor
 Intrinsic activity  ability to generate a series of biochemical events leading to an effect/ biological changes

Mechanism of Drug Action:

Agonist  binds and causes a response (A drug that activates its receptor upon binding)
 whose responses resembles the effect of the endogenous ligands.
interact w/ specific cellular constituents, known as receptors, and elicit an observable biological response
have both affinity for the receptor & intrinsic activity
Example: Bethanecol directly stimulates cholinergic receptors & is thus an agonist
 Full Agonist  produces all the expected effect of the binding to a receptor to the target protein
Example: Morphine – opioid receptor
 Partial Agonist  have no intrinsic activity but have affinity
 cause opposite effect
produces some of the expected effect
 Interact w/ the same receptors as full agonist; however their affinity for the elicit the same maximum response
 Have lower intrinsic activity than full agonist; however their affinity for the receptor can be greater than , or less
than, or equal to that of full agonist.
Example: Nalbuphine (Nubaine) analgesic
has no bradicardiac effect
Inverse Agonist  a drug that inhibits baseline level of activity, in the absence of agonist)
 a ligand which produces an effect opposite to that of an agonist occupying the same receptor

Antagonist  Inhibit the actions of agonist

Pharmacological Antagonist lack intrinsic activity & produce effects by competitively & noncompetitively inhibiting the action of the
endogenous molecules of the receptors
A drug that binds without activating its receptor and thereby prevents activation by an agonist
a. Phamacologic – Pharmacodynamic Antagonists
Produces an effect opposite that an agonist by binding to same receptor
Epinephrine – Propanolol (B1 receptor)
Organophosphate – atropine (M receptor)
may be two types:
Competitive Antagonist  act by interfering w/ binding of the endogenous ligand to the receptor as the agonist
A pharmacologic antagonist that can be overcome by increasing the
concentration of agonist in a reversible manner
There is shift of the agonist log-concentration-effect curve to the right w/out a
change in the slope or aplitude
Example:Propanolol competes w/ catecholamines for binding w/ adrenergic B-receptor
Tamoxifen competes w/ estrogen receptors fro binding w/ estradiol
Noncompetitive Antagonsit (Irreversible)  acts by interacting w/ the non-ligand binding site of the receptor
(e.g, through covalent modification), such that normal binding of the
endogenous ligand to the receptor is irreversible inhibited
(A pharmacologic antagonist that cannot be overcome by
increasing agonist concentration)
Example:  Monoamine Oxidase (MOA) inhibitors such as tranyl cypranine
(Parnate) initially interact w/ MOA in a reversible manner but then form
covalent adducts that irreversible inhibit MOA
b. Pharmacologic – Pharmacokinetic Antagonist
produce an effect opposite that of an agonist or reduce the effect of the agonist by modifying the agonist’s ADME
Cholestyramine (bile acid binding resin)
 Can also bind digitalis, warfarin & Vitamin ADEK (reduce absorption)
Phenobarbital & Warfarin interaction
 Enzyme inducer (phenol) reduces effects of warfarin
c. Chemical Antagonist  react w/ one another, resulting in the activation of both compounds.
 antagonize other drugs by direct chemical interaction
[A drug that counters the effects of another by binding the agonist drug (not the receptor)]
Example: The anticoagulant heparin, an acidic polysaccharide, is chemically
antagonized by protamine, a basic protein, via an acid-base interaction.
Chelating agents can be used as antidotes for metal poisoning
Ethylenediaminetetraacetic acid (EDTA) chelates calcium & lead
Penicillamine chelates copper
Dimecaprol chelates mercury, gold, antimony, & arsenic
Deferoxamine  Fe oversoe

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d. Physiologic (Functional) Antagonist

act independently at different receptor sites often yielding opposing action.
(A drug that counters the effects of another by binding to a different receptor and causing opposing effects)
 produce antagonistic physiological action through binding at separate/different receptors.
The adrenergic & cholinergic nervous system frequently produce this type of antagonism
Example:  Epinephrine & acetylcholine action the sympathetic & parasympathetic autonomic nervous
system, respectively & their effects are antagonistic to each other.
 Epinephrine = Bronchodilation (B2) + Vasodilation (A1)
 Histamine = Bronchospasm + Vasodialtion
Inc HR due to Atropine (M blocker)
Dec HR due to B-blocker
e. Partial Antagonist  inhibit the endogenous ligand from binding the receptor but possess some intrinsic activity
Example: Nalorphine is partial antagonist for opiate receptor
f. Neutralizing Antagonist  occurs when two drugs bind w/ each other to form a inactive compound
Example: Digoxin- binding antibody used in digoxin overdose
acts by sequestering the drug resulting in the formation of an inactive complex

Types of Chemical Bonds; (Molecular aspects of Binding)

a) Covalent  strongest bond (irreversible effects)
b) Electrostatic  very common type due to the attraction between oppositely charged groups
c) Hydrogen  a strong interaction which arises from the sharing of hydrogen atom between an acidic & basic groups
d) Van der Waals  weak interaction between polar or nonpolar molecules
e) Hydrophobic  major driving force for nonpolar drug or receptor binding site

Regulation of Receptors:
I. Downregulation/ desensitization/ refractoriness  may explain the development of tolerance to drugs
 maybe homologous (receptor itself) or heterologous
(include downstream proteins that participate in the signaling)
 Downregulation vs. Desensitization (reversible after laps of time)
II. Upregulation/ supersensitivity

Dose- response relationship (dose-response curves)

o Classical Receptor Occupancy Theory Ariëns and Stephenson:
KA Response = f (ENtotal . Xa/ (Xa + Ka)
A = R AR stimulus response is an equation showing
Receptor Occupancy  is given by the Langmuir Adsorption Isotherm: [A]/([A]+ Kd) Relationship between occupancy
where Kd= dissociation constant of drug-receptor complex of receptor & response to the
Total Receptor-mediated stimulus: drug
A
× Efficacy × R receptor number
A + Kd
1. Graded dose-response curve  shows the relationship between the degree of response w/ dose,
ie lowering of BP
(a) Efficacy  is the capacity to produce an effect
 represents the ability of a drug to accomplish a specified effect
o Ceiling effect  maximum achievable response
o Ceiling Dose  minimum dose that produces the maximum effect (maximum allowable dose)
(b) Potency  is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
reflects the amount of drug (the dose) required to cause an effect.
 (EC50) dose that produces 50% of the maximum response.
(c) Slope  degree of change in response w/ dose
(d) Variability, in effectiveness of a drug given to the same Px at different times can be due to:
o Physiological factors (circadian rhythm)
o Pathological factors (disease states/ health status)
o Drug-induced variation (receptor down-regulation)
o Variation in a population of Px (Genetic/ environmental)
2. Quantal dose-response curve (shows how a population respond (quantal event) to a given dose; ie prevention of convulsion, arrhythmia,
or death)
plots the cumulative # of respondents may it be beneficial effect w/ increasing dose.
 Selectivity of Drug Action
The ratio (relationship) between the dose of a drug required to produce undesired effects (toxic or lethal) & the dose required to
produce the desired effects (therapeutics)
1. Therapeutic Index  is a relative measure of the safety & effectiveness in laboratory studies.
 used to indicate the ability of adrug to produce the desired therapeutic effect relative to a toxic effect.
 TD50 (Median Toxic Dose) the minimum dose that is toxic of the population
 ED50 (Median Effective Dose)  the minimum dose that is effective for 50% of the population
2. Margin of Safety  is more practical term to describe the relative safety & effectiveness
 is the ratio of the:
 TD0.1 (Minimal Toxic Dose)  the minimum toxic dose for 0.1% of the population
 ED99.9 (Minimal Effective Dose)  the minimum effective dose for 99.9% of the population

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Variation in Drug Responsiveness:

 Idiosyncracy (genetic differences which affects the drug metabolism)
 Hyporeactive vs. Hyperreactive
 Tolerance & Tachyphylaxis
 Mechanism of variation in Drug Responsiveness
 Alteration in the concentration of drug that reaches the receptor
o Some may be predicted on the basis of age, weight, sex, disease state, or kidney & liver function of the px.
 Variation in concentration of endogenous receptor ligand
o Propanolol will markedly slow the HR of Px whose catecholamines are elevated (pheochromocytoma) but will affect the
resting HR of a marathon runner
 Alteration in number or function of receptor
o Downregulation/ upregulation of receptors
o May be used to explain withdrawals from long term use of drugs
 Changes in components of response distal to receptor
o Clinically, changes in these post receptor processes represent the largest & most important class mechanisms that causes
variation in responsiveness.

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Principles of Pharmacokinetics

Pharmacokinetics  The actions of the body on the drug, Processes: L  Liberation

including absorption, distribution, metabolism, and A  Absorption
D  Distribution
elimination. M  Metabolism
Elimination of a drug may be achieved by metabolism or by E  Excretion
excretion. R  Response
Transport Processes: Transport  mechanism of the drug which it moves across the cell membrane.
1. Passive Diffusion
 Movement of molecules from region high to low (along concentration gradient;)
 Non-energy requiring (no external energy)
 Major absorption process of most drugs (Predominant transport process)
 Slowest process (inversely proportional to the membrane thickness)
 Important process for small lipophilic molecules
 Ex: Aspirin
Factors affecting process:
Most Drugs are absorbed or transported by passive
(a) Fick’s law of diffusion 𝑄 = 𝐴 × 𝑑 (𝐶1 – 𝐶2)/ℎ
diffusion, which depends on:
Where:
-pKa value of the solution
Q= flux (movement of molecules)
-pH of the Solution
A= surface area of membrane
-Lipid solubility of the unionized form
d= diffusion coefficient
C1= higher concentration (soure)
C2= lower concentration (destination)
h= thickness of the semi-permeable membrane
(b) Concentration gradient determines Permeability Coefficient
the ratio of the number of molecules crossing per unit time to the concentration gradient
(c) Particle size
(d) Liposolubility degree of ionization (relationship of pKa, pH & form of the drug)
partition coefficient
2. Carrier-mediated transport
Features:
(a) Saturability
 Follows saturable kinetics (Michaelis-Menten, Enzyme kinetics)
 Ex. ASA <600 mg/day (1st day)
 ASA >600mg/day (0th order)
(b) Selectivity
 Carriers have a specific stereochemical configuration, & will only allow transport of molecules that have
configuration that fit into the carries binding site
(c) Subject to competition/ inhibition
 Ex. Isoniazid & Vit B6
 Must be taken hours apart (About 2-3 hrs)
 Otherwise will compete for the carries & will inhibit each other
(d) “poisoning”
Example of carrier-mediated transports:
(1) Active Transport  movement against concentration gradient (low to high)
 requires energy (energy-consuming) The Ileum sac of Guinea Pig is used
 fast transport process for testing of Active Transport.
 important for polar molecules
 Ex: Na-K ATPase pump (sodium pump)
(2) Facilitated Transport  movement along concentration gradient
 no energy required
 Ex: Vit B12 (Cyanocobalamin), glucose uptake
3. Carrier Mediated Intestinal Transport
1.) Vesicular Transport  process of engulfing particles
 doesn’t require aqueous solution to be absorbed
 Ex: Sabin Polio Vaccine
Forms: Phagocytosis  engulfment of large particles
Pinocytosis  engulfment of small particles
 cell drinking
 energy requiring
 important for large lipophilic molecules
 Ex: Griseofulvin, Vit ADEK (these drugs must undergo micelle formation)
Processes: Endocytosis Absorption of material across a cell membrane by enclosing it in cell membrane material and
pulling it into the cell, where it can be released.
Ex: Taking up of Glucose by the Insulin Receptor.
Exocytosis  Expulsion of material from vesicles in the cell into the extracellular space
 accomplished the primary mechanism of neurotransmitter release
Permeation  Movement of a molecule (eg, drug) through the biologic medium
Drug permeation Most drugs are administered at a site distant from their target tissue. To reach the target, they must
permeate through both lipid and aqueous pathways. Movement of drugs occurs by means of
aqueous diffusion, lipid diffusion, transport by special carriers, or by exocytosis and endocytosis

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2.) Convective (Pore) transport  transport thru water filled pores

Factors affecting transport:
(a) Pore size (diameter is 7-10 A) allows passage of substances w/ MW around 150-400 (small substances only)
(b) Charge of the pore lining (allows passage of ions w/ opposite charge)
(c) Electrochemical gradient (same as concentration gradient)
(d) Solvent drag- solvent may drag in ions or molecules through the channels
3. Ion-Pair Transport  mechanism by which you transport drug w/ large ions

Note: Passive, Carrier-mediated, Convective transport (Drug must be in aqueous solution)

Pinocytosis (drugs must be in micellar forms)

Liberation
 Dosage form to solution
 Release of Drug from the Dosage form
 should be in aqueous solution
 dissolution (rate-limiting step)
 highly modifiable\able process
 For drugs to be absorbed they must be liberated from the dosage form & from an aqueous solution
 Factors affecting liberation
o Formulation dependent factors (Tablet hardness, dissolution, & disintegration)
 Exceptions: Parenterals, Solutions

Effects: 1. Formulation of salt alkali metal (soluble group)

2. Formulation of prodrug
in-vitro  in-vivo
Advantages: 1.) enhances drug absorption
Example: enalapril (ester) esterase enalaprilat (carboxylic group)
2.) Facilitates the drug reaching its target site
3.) alter drug solubility
chloramphenicol (water-solubility)
chloramphenicol palmitate ( slightly water-solubility)
4.) Facilitate formulation of dosage form
methylprednisolone  methylprednisolone acetate  methylprednisolone Na succilate
(slightly H2O-soluble) (H2O-insoluble) (H2O-soluble)

Depot phase  liberates the drug to slower rate

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Absorption
 from site of administration to systemic circulation
 is a physical phenomenon
Kinetic  rate & extent of drug entry into the systemic circulation
Physiologic  rate & extent of disappearance of drug from site of administration
A drug may be absorbed physiologically but not pharmacokinetically (ex: Metoprolol)
Factors affecting absorption:
 Pharmaceutical factors (particle size, physical state of the drugs)
chemical structure
Ex: Aminoglycosides  the only bactericidal among protein synthesis inhibitor
 polar drugs
 side effect: nephrotoxicity
variation in particle size
Nature of crystalline form
Polymorphism exist two or more crystalline forms
 Amorphous  more soluble than crystalline
 Crystalline
Example: Insulin short acting = 30-90 minutes after administration
= 100% amorphous
Intermediate = NPH (Neutral Protamine of Hagedorn)
= 5-6 hours
= 30% amorphous + 70% crystalline
Long = 12-24 hours
= 100& crystalline
Anhydrous vs. Hydrous
more soluble less soluble
hydrolysis resistant
Tablet coating
Ex: Enteric Coated  prevent GI irritation
 protects drug from stomach aid
 enhances absorption
 Fick’s law of diffusion
 Gastric Emptying Time (Factors that increase/ decrease GET)
when gastric emptying time increase, Factors Influencing Gastric Emptying:
the gastric emptying rate decreases, 1. Volume of Liquid intake
the absorption rate decreases. 2. Type of Meal
Factors GET (GER) Factors GET (GER) 3. Osmotic Pressure
 High CHON/ fat  Spicy foods 4. Physical state of Gastric content
5. pH of the Stomach
 Cold food  Extreme temp. of meal
6. Drugs to be taken
 Gastric ulcers  Gastrectomy
7. Body position
 Stress  Depression
8. Viscosity of stomach content
 Vigorous exercise  Mild Exercise
9. Emotional States
 Lying on the left side  Lying on right side 10. Disease State
 Drugs (Antidiarrhea-  motility enhancing agents: 11. Presence of bile salts
antimotility agents) metoclopramide 12. Exercise
 Hunger domperidone 13. Age of a person
cisapride]
 Diabetes Mellitus
Mechanism of Absorption of Drugs (in
order of their importance):
1. Passive Diffusion
Gastric-Emptying  rate limiting step for absorption of oral solution
2. Convective/Pore Transport
3. Active Transport
 Dose size administered
4. Facilitated Transport
 pH of the absorbing environment (affects ionization of the drug) 5. Ion pair Transport
 area of the absorbing surface (lungs biggest SA, small intestines 6. Vesicular Transport
 degree of perfusion
 Physical factors that affect absorption
 Blood flow
 Surface area for absorption
 Contact time

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Distribution
 transport or net tansfer of drugs from the systemic circulation to the site of action
describes the movement of drug molecules across different body compartment
Physiologic Factors affecting distribution:
Cardiac output: volume of blood pumped by the heart per minute
 Px with CHF may have delayed drug effect due to poor distribution
Regional blood flow  (% of CO that reaches specific tissue)
 Fraction of the CO going to particular organs/ tissues
 Organs w/ high RBF (liver (25%), kidney(25%), lungs(100%), brain)
 Organs with low RBF (bone, adipose)
 Capillary Permeability  Capillary delivery oxygenated blood to tissues; smallest vein
two important parameters of drug distribution:
o PB (Protein binding)
o Vd (volume of distribution)
 Protein Binding limits the access of drugs to certain body compartment
 binding of the serum proteins
 decreases distribution
 Free form (unbound) can reach the site of action, metabolized, excreted
 Bound form (serves as reservoir)
 Examples of proteins & substrates
o Albumin  weak acidic (dominant)
o Alpha 1 glycoprotein  weak basic drugs
o Globulin  binding formones
 Significant protein binding= 80%; Penicillins have >97%PB
 Significant of PB
o Provide slow release form of a drug (repository, resulting to extended affect)
o Limits access to certain body compartment
o Can make the drug prone to drug-drug interaction
 Examples of drugs with high protein binding:
o Diazepam, Diditoxin, Indomethacin, Tolbutamine, Warfarin, Midazolam
o These drugs cam compete w/ each other
o Results to increase effect (toxicity) of the object drug
o The known importance of protein binding:
Transport function  reflected w/ drugs of low solubility in water
Buffer function  to maintain a relatively constant concentration

Drugs that are more than 90% bound to plasma proteins:

- Amitryptilline
- Chlorpromazine
- Cloxacillin
- Flurazepam
- Lidocaine
- Lorazepam
- Naproxen
- Phenylbutazone
- Penicillin
- Phenytoin
- Propanolol
- Warfarin

Decrease Albumin Level:

- Pregnancy
- Nephrotic Syndrome
- Trauma
- Chronic Liver Disease
- Burns

Factors affect the protein binding drugs:

- Pregnancy
- - Hypoalbuminemia
- - Uremia

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 Volume of distribution  is the hypothetical volume of fluid where drug is disposed

the ratio of the amount of drug in the body to the drug concentration in the plasma or blood
Extent of Distribution of drugs is effected by:
 Plasma protein binding
 pH
Rate of Distribution of drugs is effected by:
 Blood perfusion
 Membrane permeaility
 Hypothetical volume of body fluids necessary to dissolve a given amount of drug to a concentration equal to that in
the plasma
 Theoritical Volune
 Application Vd
1. Loading Dose
𝑑𝑜𝑠𝑒
𝑉𝑑 =
𝐶𝑝
2. Predict the location of drug
 Significance:
o May be used to compute loading dose
o Identification of most likely compartment of dictribution of a given drug
 Correlation with body fluids:
o Total body fluids = 60% of BW (Males)
= 50-55% of BW (Females)
o Intracellular fluids = 40%
o Extracellular fluids = 20% *Water compartment
Interstitial = 15%  where drugs can be found
Intravascular = 5% 1. Plasma compartment
o Approximate Volume of Distribution of a drug in an ADULT  high-molecular weight &
Ex: For a 70 Kg Px highly protein bound
o Total/Whole body fluids =40/42 L 2. ECF  low molecular weight &
o Intracellular fluids = 25-30 L hydrophilic
o Extracellular fluids = 10-20 L 3. Total body water
o Interstitial = 10.5 L  low molecular/ hydrophobic
o Intravascular = 3.5 L
o Circulatory system = 5mL
 Examples of drugs with high Vd:
 Atropine, CHloroquine, Digoxin, Fluoxetine, Imipramine & TCAs, beta blockers
 Examples of Drugs with low Vd:
 Chlorpropamide, Furosemide, Tolbutamine, Valproic Acid, Warfarin
 Significance: Management of Toxicities/ drug overdose
 Drugs w/ low Vd= hemodialysis (alternative treatment)
 Drugs w/ high Vd = hemodialysis (useless)
(Katzung) Apparent Volume of Distribution and Physical Volumes
Apparent Volume of Distribution (Vd) is an important pharmacokinetic parameter that reflects
the above determinants of the distribution of a drug in the body. Vd relates the amount of drug in
the body to the concentration in the plasma.
Average values for some physical volumes within the adult human body.
Compartment Volume (L/kg BW)
Plasma 0.04
Blood 0.08
Extracellular 0.2
Total Body water 0.6
Fat 0.2-0.35

 Distribution phase  The phase of drug movement from the site of administration into the tissues
 The Larger the Volume of Distribution, the more extensive the distribution

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Metabolism aka biotransformation

 lipophilic into more water-soluble or polar, pharmacologically inactive, & readily excretable form
Objectives: conversion of xenobiotics to a form less toxic, polar & readily excretable.
Exceptions:
o Inactive (prodrug) to active form Kinetic of Metabolism:
o Phenacetin to Acetaminophen 1st order  concentration dependent kinetic
o Prontosil to Sulfadiazine imporatant in maintenance of your steady
o Enalapril to Enalaprilat state
o Allopurinol to alloxanthine constant fraction of a drug
o Active to active metabolites Example: 100mg80mg64 …… 20%
o Diazepam to Nordiazepam to Oxazepam 0th order  concentration independent
o Atracurium to laudanosine  increase in the rate of metabolism
o Eserine to Rubreserine saturable kinetic/Michaelis-Menten
o Codeine to Morphine constant amount
o Non-toxic to toxic form Example: 100mg80mg60 …… 20mg
o Malathion to Malaoxon
o Acetaminophen(Paracetamol) to NAPQI
Location:
o Primarily in the liver
o Kidney (Imepenem metab by dihydropeptides in the kidney)
o Intestines
Drugs that are
o Blood
Extensively
First-pass metabolism
𝐶𝐿𝑙𝑖𝑣𝑒𝑟 Metabolized by First
Extraction ratio : 𝐸𝑅 = ; where Q is hepatic blood flow (about 90L/hr in a 70kg patient) Pass Effect:
𝑄
Systemic bioavailability : 𝐹 = 𝑒𝑥𝑡𝑒𝑛𝑡 𝑜𝑓 𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑓 × (1 − 𝐸𝑅) -Lidocaine
Drugs with extensive FPE (high ER): propanolol, catecholamine, meperidine, morphine, pentazocine -Isoproterenol
First-pass Effect (presynaptic elimination) describes the phenomenon whereby drugs may be metabolized -Nitroglycerin
(not chemically degraded) following absorption but before reaching systemic circulation -Morphine
Hepatic first-pass effect  may occur following P.O. & deep rectal administration -Meperidine
 may be avoided by using sublingual & buccal routes of administration -Prpoxyphene
Pulmonary first-pass effect  cannot be avoided by intravenous, buccal or sublingual routes. -Propanolol
Phases (Matabolic Reactions) -Salicylamide
1. Phase I  Reactions that convert the parent drug to a more polar (water-soluble) or more reactive -Entazocined
product by unmasking or inserting a polar functional group such as –OH, –SH, or –NH2
 usually involves conversion of drugs to active from by addition or unmasking of a functional group.
 Oxidation, Reduction, Hydrolysis
dominant among phase I reaction
Phase I Drug-Metabolizing Reactions (Functionalization Reaction
A. Oxidation – dominant
Reaction Type Typical Drug Substrates
Oxidations, CYP450 dependent
 Hydroxylation
Aromatic Hydroxylation Phenobarbital, Propanolol, Phenytoin, Warfarin, Ethinyl Estradiol
Aliphatic Hydoxylation Pentobarbital, Chlorpromazine, Ibuprofen
 N-dealkylation Caffeine, Morphine, Theophylline
 O-dealkylation Codeine, Dextromethorphan, Indomethacin
 N-oxidation Meperidine, Acetaminophen, Nicotine
 S-oxidation Chlorpromazine, Cimetidine, Thioridazine, Omeprazole
 Deamination Amphetamine, Diazepam

A partial list of drugs that significantly INDUCE P450-mediated drug metabolism in humans:
CYP Family Important Inducers Drugs Whose Metabolism Is Induced
Induced
1A2 Benzo[a]pyrene (from Acetaminophen, Clozapine, Haloperidol, Theophylline, Phenobarbital, Rifampin,
tobacco smoke), Omeprazole Tricyclic Antidepressants, (R)-Warfarin, Tamoxifen
Carbamazepine,
Charcoal-broiled foods,
Cruciferous vegetables,
Omeprazole
2C9 Barbiturates, Especially Barbiturates, Celecoxib, Chloramphenicol, Doxorubicin, Primidone, Rifampin
Phenobarbital, Phenytoin, Ibuprofen, Phenytoin, Chlorpromazine, Steroids, Tolbutamide, (S)-Warfarin
2C19 Carbamazepine, Diazepam, Phenytoin, Topiramate, Tricyclic Antidepressants, (R)-Warfarin
Phenobarbital, Phenytoin,
Rifampin
2E1 Ethanol, Isoniazid Acetaminophen, Enflurane, Ethanol (Minor), Halothane
3A4 Barbiturates, Antiarrhythmics, Antidepressants, Azole Antifungals, Phenytoin, Rifampin,
Carbamazepine, Pioglitazone, St. John's Wort Benzodiazepines, Calcium Channel Blockers,
Corticosteroids, Efavirenz, Cyclosporine, Delavirdine, Doxorubicin, Efavirenz, Erythromycin, Estrogens, HIV
Protease Inhibitors, Nefazodone, Paclitaxel, Proton Pump Inhibitors, HMG-Coa
Reductase Inhibitors, Rifabutin, Rifampin, Sildenafil, Ssris, Tamoxifen,
Trazodone, Vinca Alkaloids

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A partial list of drugs that significantly INHIBIT P450-mediated drug metabolism in humans.
CYP Family Inhibitors Drugs Whose Metabolism Is Inhibited
Inhibited
1A2 Cimetidine, Fluoroquinolones, Acetaminophen, Clozapine, Haloperidol, Theophylline, Tricyclic
Grapefruit Juice, Macrolides, Antidepressants, (R)-Warfarin
Isoniazid, Zileuton
2C9 Amiodarone, Chloramphenicol, Barbiturates, Celecoxib, Chloramphenicol, Doxorubicin,
Cimetidine, Isoniazid, Metronidazole, Ibuprofen, Phenytoin, Chlorpromazine, Steroids, Tolbutamide,
Ssris, Zafirlukast (S)-Warfarin
2C19 Fluconazole, Omeprazole, Ssris Diazepam, Phenytoin, Topiramate, (R)-Warfarin
2D6 Amiodarone, Cimetidine, Quinidine, Antiarrhythmics, Antidepressants, Beta-Blockers, Clozapine,
Ssris Flecainide, Lidocaine, Mexiletine, Opioids
3A4 Amiodarone, Azole Antifungals, Antiarrhythmics, Antidepressants, Azole Antifungals,
Cimetidine, Clarithromycin, Benzodiazepines, Calcium Channel Blockers, Cyclosporine,
Cyclosporine, Diltiazem, Delavirdine, Doxorubicin, Efavirenz, Erythromycin, Estrogens, HIV
Erythromycin, Fluoroquinolones, Protease Inhibitors, Nefazodone, Paclitaxel, Proton Pump
Grapefruit Juice, HIV Protease Inhibitors, HMG-Coa Reductase Inhibitors, Rifabutin, Rifampin,
Inhibitors, Metronidazole, Quinine, Sildenafil, Ssris, Tamoxifen, Trazodone, Vinca Alkaloids
Ssris, Tacrolimus
Suicide inhibitors are drugs that are metabolized to products that irreversibly inhibit the metabolizing enzyme.
 Ethinyl Estradiol
 Norethindrone CYP3A4 responsible for the highest
 Spironolactone fraction of clinically important
 Secobarbital drug interactions resulting from
 Allopurinol metabolism
 Fluroxene
 Propylthiouracil
Oxidations, CYP450 Independent
 Amine Oxidation (MAO) Epinephrine
 Dehydrogenation Aldehyde, Chloral Hydrate, Ethanol, Olefins, Aromatic
B. Reduction
Reductions
 Nitro-Reduction Chloramphenicol
 Carbonyl-Reduction Naloxone
C. Hydrolysis
Hydrolyses
 Esters Aspirin, Clofibrate, Procaine, Succinylcholine
 Amides Indomethacin, Lidocaine, Procainamide
2. Phase II (Conjugation Reactions)
 increase water solubility by conjugation of the drug molecule w/ a polar moiety such as glucuronate, acetate, or sulfate
 almost always involved in the inactivation of drug & formation of its polar form.
 allows attachment to small, polar & ionizable endogenous compounds
 allow the termination or attenuation of a biologic activity
serve to protect the body against chemically reactive compounds or metabolites
Reaction Type Typical Drug Substrates
(a) Glucuronidation Acetaminophen, Diazepam, Digoxin, Morphine, Sulfamethiazole, Chloramphenicol (kernicterus)
Expression of glucoronosyl transferase is inducible (Phenobarbital)
 Available source of D-glucuronic acid
 Responsible for functional groups that can combine enzymatically w/ glucuronic acid
 Require an active center as the site of conjugation
(b) Acetylation Clonazepam, Dapsone, Isoniazid, Mescaline, Sulfonamides, Hydralazine, Procainamide
Expression of glucoronosyl transferase is subject to genetic polymorphism
Fast Acetylators Slow Acetylators
-Eskimos -Egyptians
-Orientals (Filipinos/Asians) -Mediterranean Jews
(c) Glutathione Ethacrynic Acid, Reactive Phase I Metabolite of Acetaminophen
Conjugation Neutralizes chemically reactive substances
 Back-up mechanism for paracetamol toxicity
(d) Glycine Conjugation Deoxycholic Acid, Nicotinic Acid (Niacin), Salicylic Acid
(e) Sulfation Acetaminophen, Estrone, Methyldopa
 Only phase II reaction present in neonates (only well-developed metabolic pathway in neonates)
(f) Methylation Dopamine, Epinephrine, Histamine, Norepinephrine, Thiouracil
 Important in biosynthesis of many endogenous substances like epinephrine & melatonin
 Constitutes only a minor pathway for conjugating drugs or xenobiotics,
Paracetamol (Acetaminophen) sulfation NAPQI glutathione conj. Mercapturic acid
N-acetylparaquinoneimine (hepatotoxic form)

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Enzyme inhibiton-induction
Enzyme-inducers  stimulate the release of CYP450
Consequences: Low therapeutic levels of active drug
( decrease efficacy) Enzyme Inhibitors Enzyme Inducers
Prodrug (increase in efficacy) “sickfaces.com” “GPP PARK Sa Mall”
Toxic metabolite (increase toxicity)  Sodium valproate  Griseofulvin
Cross-induction  stimulated by auto & foreign induction  Isoniazid  Phenobarbital (Barbiturates)
Foreign-induction  stimulates another drugs  CImetidine  Phenytoin
Auto-induction  stimulate its own metabolism (Carbamazepine)  Ketoconazole  Phenylbutazone
Enzyme-inhibitors  competitive inhibition  Fluconazole  Alcohol (chronic)
Consequences: Active object drug (increase efficacy; intoxicity)  Alcohol (Acute)  Rifampicin
Prodrug (decrease in efficacy)  Ciprofloxacine  Carbamazepine
Toxic metabolite (decrease toxicity)  Erythromycin  Sulfonlurea
 Sulfanamide  Meprobamate
 Chloramphenicol
 Omeprazole Herbs: St. John’s wort
 Metronidazole

 Herbs:
 Grape fruit
 Valencia oranges

Genetic Polymorphism  variation in the DNA sequence that is present at an allele frequency of 1% or greater in apopulation
 variation in the expression of enzymes
(rapid/slow acetylators, CYP polymorphism)
1. CYP 2D6 polymorphism (increased risk of cardiotoxicity)  Thioridazine & antidepressants (Poor Debrisoquin Metabolizer)
CYP 2D6  most studied
2. Acetylation  HIPS: Hydralazine, Isoniazid, Procainamide, Sulfonamide(causes Steven Johnson Syndrome
(very notorious in causing SLE)
Isoniazid  peripheral neuropathy; Isoniazid toxicity (treated with Vitamin B6)
Genetic Polymorphism variation in the expression of enzymes
EM – Extensive Metabolizers
PM – Poor Metabolizers
UM – Ultra Rapid Metabolizers
NAT2  N-acetyltransferase
HIP: hydealazine, INH, Procainamide
 cause Drug-induced SLE
Fast acetylators: Asia – Extensive Metablozers
Slow Acetylators: Caucasian – Poor Metabolizers
CYP2D6
Tamoxifen
CYP2D6 PM -  effect
Endoxifen UM -  effect
Codeine
CYP2D6 PM -  effect
Morphine UM -  effect

Sites of Biotransformation/ Metabolism

 Liver
 Stomach
 Intestine
 Lungs
 Skin
 Kidney
Factors affecting drug Metabolism
Age Differences
Species & Strain Differences
Hereditary or Genetic Factors
Sex Differences
Enxyme Induction
Enzyme Inhibition

Regioselectivity  denotes the selective metabolism of two or more similar functional groups, or two or more similar atoms that are
positioned in different regions of a molecules

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Elimination  final loss of the drug from the body; constitutes metabolism & excretion
General Requirements: water-soluble (polar)
Routes of excretion: Renal, Biliary, Lungs, Skin, Mammary, Intestinal
Total body clearance  drug elimination rate divided by plasma drug concentration
Renal drug excretion major route for polar, water-soluble, drug w/ lo MW (<500g/mol)
a. Glomerular Filtration  passive process by which small molecules & drugs are filtered through glomerulus
b.(Proximal) Tubular Reabsorption follows Fick’s Law of Diffusion.
Lipid-soluble/ non-ionized  are reabsorbed from the lumen back to systemic circulation
c. (Distal) Active Tubular Secretion  is a carrier-mediated active transport
Probenezid – Penicllin (competes for tubular excretion)
Renal Clearance  volume of drug in the plasma, that is removed by kidney
Renal primary site of excretion of polar drugs with MW NMT 400-600
Dependent on GFR (glumerolus filtration rate)
GFR passive Malpighian Body/ Nephron
afferent efferent  the actual unit in the kidney where
Tubular secretion = active transport lemimination & reabsorption takes place
Tubular reabsorption = passive Urine date: too, [dDu/dt]maxo, Duoo
Determination of GFR  Inulin clearance (substance is freely Plasma Data: tmax, Cmax, AUCo oo
excreted but is not reabsorbed nor
secreted
Creatinine Clearance (CLCr) primary marker of renal function; ratio of creatinine excretes
measurement of GFR
Creatinine  end-product
24 hr urine collection
ClCr= Creatinine Determine urine creatinine, plasma creatinine, & 24hr urine volume
Clearance(mL/min) CLCr= [UrineCr] x Vol or urine (mL) Renal Impairment Based on Creatinine Clearance
CCr= Serum Creatinine [PlasmaCr] 1,440 mins (estimated creatinine clearance)
(mg/dL) Cockroff & Gault Equation (for adults)
Normal Renal Function >80mL/min
CLCr(Male)= ( 140Age ) BW in Kg Mild Renal Function 50-80 mL/min
Note: if unit given is 72 x Plasma Cr in mg/dL Moderate Renal Function 30-50 mL/min
mol/L (convert to CLCr(Female)= 0.85 (CLCr of male) Severe Renal Function <30 mL/min
mg%) Schwartz & Associates (for children) ESRD( end-stage Requires dialysis
Mg%= (mol/L) / 88.4 CLCr= 0.55 body length (cm) renal disease)
CCr
Ex: 75 yo female weighing 60Kg w/ a CCr mg/dL. If the regular dose of Gentamicin is 240 mg OD, at what dose should this
be adjusted for this patient?
Adjusted dose= CLCr(Px) x regular dose where: N CLCr= 100mL/min
CLCr (Normal)
CLCr (female)= 23.02mL/min; Adjusted dose= 55mg IV OD

Biliary: polar with MW exceeding 400-600; becomes important pathway when there is no significant enterohepatic recycling
Biliary excretion – enterohepatic recirculation
is the phenomenon that drugs emptied via bile into the small intestines can be
reabsorbed from the intestinal lumen into systemic circulation.
Ex: Tetracycline, penicillin, rifampicin, digitoxin
Ex. of drugs w/ enterohepatic recirculation: Morphine, Ethynylestradiol
Hepatic Clearance  volume of plasma-containing drug that is cleared by the liver per unit time
Extraction ratio is the fraction of drug that is irreversibly removed by an organ or tissue as
the plasma-containing drug perfuses that tissue
Blood flow  1.5L/min; altered by exercise, food, disease, drugs
Intrinsic Clearance  CLint, the ability of the liver to remove the drug independently
of blood flow
Lung: for volatile drugs
Skin/ sweat
Intestines
Mammary glands

 Volume of Distribution (Vd)= CL/Kel

Rate of Elimination = CL x Cp
= Kel x Vd x CP
Clearance (CL)= rate of elimination/C
= Kel x Vd where: Kel=0.693/t1/2
=(0.693/t1/2) x Vd
 t1/2 =(0.693 x Vd) CL
0.693
half-life(t1/2)  time required to decrease the concentration by 1/2; t1/2=
𝑘
 Elimination phase The phase of drug inactivation or removal from the body by metabolism or excretion

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Oral Drug Administration

Drug is Gastrointestinal tract Mesenteric Hepatic portal

swallowed circulation vein

Systemic Circulation Liver

Bioavailability & Bioequivalence

Bioavailability (F)  measures of both rate & extent of drug entry into the systemic circulation
 The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation
Relative Bioavailability  comparison of the AUC of a test drug against the AUC of standard
 is the availability of the drug from a drug product as compared to a recognized standard
Relative bioavailability = [AUC] A
[AUC] B
Absolute Bioavailability  comparison of the AUC of a test drug to an IV
 is the systemic availability of a drug after extravascualr administration (eg, oral, rectal, subcutaneous,
transdermal) compared to IV dosing.
Absolute bioavailability: F= [AUC] PO/ dose PO
[AUC] IV/ dose IV
Two methods in determining bioavailability:
o Drug plasma concentration vs. time graph
o Cumulative urinary extraction data
The important Bioavailability (F) parameter:
Cmax = max drug plasma concentration (measure the extent and rate of absorption)
Tmax = time needed to reacx
AUC = Area under the curve
 measure the extent of drug absorption (most important)
 is the integral of drug blood level over time from zero to affinity.
The graphic area under a plot of drug concentration versus time after a single dose or during a single dosing interval
Plasma level time curve: D
a.) Onset of Action  time to reach MEC F
b.) Duration  time remain above MEC
C E
c.) Intensity  proportional to the number of receptors B
d.) MTC  minimum toxic concentration
e.) MEC  (minimum effective concentration) The plasma drug concentration below which a patient's A
response is too small for clinical benefit
f.) therapeutic window  between MEC & MTC
Peak & trough  The maximum and minimum drug concentrations achieved during repeated dosing cycles
𝑜𝑜
Area Under First Statistical Moment Curve  mathematically defined by 𝐴𝑈𝑀𝐶 = 0 𝑡 − 𝐶 − 𝑑𝑡,
I,e., it is the area under the curve observed for the product of time & concentration versus time
Bioequivalence  when pharmaceutical equivalents or alternatives displays comparable bioavailabilities
 is achieved if its extent & rate of absorption are not statistically significantly different from those of the standard when
administered at the same molar dose
 the absence of a significant difference in the rate & extent to which the active ingredient or active moiety in pharmaceutical
equivalent or alternatives becomes available at the site of drug action when administered at same molar dose under similar
conditions in an appropriately designed study (FDA,2003)
Bioequivalence requirement  The FDA considers two product BE if the 90% Cl of the relative mean Cmax, AUC(0-t), and AUC(0-) of
the test to reference should be within 80% 125% in the fasting state.
Pharmaceutical alternatives Same therapeutic moiety/API
Different salts, esters, or complexes
Different dosage forms
Different strength
Ex: tetracycline phosphate 250mg  tetracycline HCl 250mg
Pharmaceutical Equivalence Same active ing.
Same dosage form
Same salts or esters
Same route of administration
Same strength/concentration
Ex: Chlordiazepine HCl 5mg cap (branded)(generic)
Pharmaceutical Substitution Process of dispensing pharmaceutical alternatives
Example: Ampicillin suspension & ampicillin capsules
Nifedipine 5mg cap & nifedipine 20mg GITS tab
Therapeutic Alternatives Different active ing.
Same therapeutic effect or pharmacologic class
Example: Ibuprofen aspirin
Therapeutic Equivalence Are pharmaceutical equivalents contain identical amounts of the same active drug ing.
In the same dosage form & route of administration.
Therapeutic Substitution Process of dispensing a therapeutic alternative

Compartment Models: AUC, t1/2, Cmax, Tmax

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Loading dose Maintenance dose

 Maintenance dose
Dose given to maintain a steady stae of drug concentration in the body
Dosing rateSS= rate of elimination
= CL x TC
If drug is given by a route that has a BA less than 100%
Dosing rateoral= Dosing rate/ Foral
If intermittent dose are given:
Maintenance dose= (Dosing rate/ F) x Dose Interval
 Loading dose
LD = Vd x TC
Maintenance Models in PK
Order of reaction (Kinetics)
First order

Zero order

Compartment Models
One compartment model Two compartment model

Where:
Ka= absorption or admin rate constant
Kcl= elimination rate constant
Cp= plasma concentration
Where:
K12 &K21=transfer rate constant

Models & Compartment

Models  mathematic description of a biologic system
 used to express quantitative relationships
Compartment  a group of tissue w/ similar blood flow & drug affinity
 is nor a real physiologic or anatomic region
Openone compartment model instantly distributed
 for an extravascular administration
Opentwo compartment model  does not instantly distributed
 for an intravascular administration
Central Compartment  sum of all body regions in which the drug concentration
is in instantaneous equilibrium
Disposition  loss of drug from the central compartment
 distribution  metabolism  excretion
Peripheral Compartment  sum of all body regions in which the drug eventually distributes
but is not in instantaneous equilibrium
Subdivided into: Shallow & Deep Comparment
Noncompartment methods  requires comparison of the area under the curve
Mean Residence Time (MRT)  aka “Mean Transit Time” or “Men Sojourn Time”
 average time for the drug molecules to residue in the body
Mean Absorption Time (MAT)  the difference between MRT & MRTIV
after extravascular route is used
Steady-state Vd  ration of the amount of drug in the body at steady state
& average steady state drug concentration

Units:
O-order: conc. /time Suspension  exhibit a zero order reaction.
1st order: 1/time Solution & Radioactive substances exhibit a first order reaction.
2nd order: 1/conc. time

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Nonlinear Pharmacokinetics  aka. “capacity-limited”, “dose-dependent”, saturation pharmacokinetics

at high concentration = may show zero-order
at low concentration = may show first-order How to determine if behavior is 1 or 2 compartment:
1. Graphic Method
Graph (IV) Determine Cmax
Draw a line connecting the last 3-4 teminal points
If the Cmax is below the line (1
compartment)
2. Natumen Method
Divide all the terminal points into 2 sets
Graph (EV,oral) Draw straight line for each of the sets of points
Determine the slope of the lines
Determine the slope difference = (V1  V0)/V1x 100
If slope difference is less than 10% (1
compartment)
3. AUC method
Determine the total AUC
Determine AUC above the back-extrapolated line
connecting the downward points
Determine %AUC above the line = (AUC above line/
Total AUC) x 100
If %AUC is less than 5% (1compartment)

Noncompartment Methods: (requires comparison of the areas under the curve

▪ Mean Residence Time (MRT)  aka “mean transit time” or “mean sojourn time”
 average time for the drug molecules to reside in the body.
▪ Mean Absorption (MAT)  the difference between MRT & MRTIV after extra route is used.
▪Steady-state VD  ration of the amount of drug in the body at steady state & average steady-state drug concentration

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Dose Calculation
(a) Half-life
t1/2=0.693/Kel
Determination of elapsed half-life: # of elapsed t1/2=total time/ t1/2
Ex: Compute for the amount of drug remaining in the body 6hr after administration of a 500 mg single IV dose, if the t1/2 of the drug is
2hrs?
3 of elapsed t1/2 = 6hrs/2hrs = half-life elapsed= 12.5% remaining drug
Amount remaining = 0.125(500mg)=62.5mg
A given drug is administered as 1000mg single IV dose. 10 hrs after administration, the total amount in the body is 250mg. what is
the t1/2 of the drug?
Determine % remaining = (250mg/1000mg)x 100= 25%
Determine the corresponding elapsed t1/2 of 25%=2 t1/2
# of elapsed t1/2=total time/ t1/2
2= 10hrs/ t1/2
t1/2= 5hrs
(b) Continuous IV infusion
Steady state=concentration of drug in the plasma is maintained w/in a specific range
Time to reach SS is dependent only on the t1/2
In SS the rate of admin= rate of elimination
So: same as the rate of infusion (RO)= rate of elimination
RO = CL x CP
RO = (Kel x Vd) x CP
Since SS is achieved, the CP=CSS
So: RO= CL x CSS
RO= (Kel x Vd)x CSS
(c) Multiple IV bolus
The rate of administration = dose size per given dosing interval
Ex: 80mg IV q8
Rate of admin = 80mg /8
Rate of admin = DM / T where: DM (maintenance dose); T (interval)
Since, rate of admin = rate of elimination
DM / T = CL x CSS
= (Kel x Vd) x CSS
DM = CL x CSS x T
= (Kel x Vd) x CSS X T
(d) Multiple extravascular/ oral doses
Ex: 500mg tab q12
Rate of admin = F. DM/ T where: F (bioavailability)
F. DM/ T = CL x CSS
= (Kelx Vd) x CSS
DM = (CL x CSS x T) /F

Ex: If the desired therapeutic concentration of theophylline is !)mg/L, at what dose should theophylline be given, a. IV & b.oral, for a
Px weighing 70Kg. Theophylline has a t1/2=8hrs & a Vd = 0.5L/Kg. The desired dosing interval is 12hrs. The BA of oral tabs is 0.9.

(IV intermittent bolus)

DM = (Kel x Vd) x CSS x T
= (0.693/8hrs) (0.5L/Kg)(70Kg)(10mg/L)(12hrs)
=363.8 mg

(oral dose)
DM = (CL x CSS x T) /F
= 363.8/ 0.9
= 404.2 mg

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Biopharmaceutics  deals with the physical & chemical properties of the drug substance, the dosage form, and the body & the biological effectiveness of
a drug upon administration.
Biopharmaceutics Classification System (BCS)
CLASS Solubility Permeability Comments
Class 1 High High Dissolves rapidly & well-absorbed
Class 2 Low High Dissolution limited & well-absorbed
Class 3 High Low Permeability limited
Class 4 Low Low Difficult in formulating a drug product

Clinical Pharmacokinetics  is the application of pharmacokinetics principles

for the rational design of an individualized dosage regimen.
Objectives: a. Maintain of an optimum drug concentration at the receptor site
b. Minimization of any adverse or toxic effect
Toxicokinetics  application of pharmacokinetic principles to the design, conduct
& interpretation of drug safety evaluation studies
Population Pharmacokinetics  Study of sources & correlates of variability in drug concentrations
among individuals who are the target patient population

Important Terms
Modern Biopharmaceutics  is the study of the relationship of the physic chemical properties & in vitro behavior of the drug & drug product
Bioequivalent drug product  are pharmaceutical equivalents that have similar bioavailability
 Drug Product  finished dosage form that contains active ing
Drug product selection  process of choosing or selecting the drug product in a specified dosage form
Equivalence  Relation in terms of Bioavailability, therapeutic response, or a set of established standards of one drug product to another.
Chemical equivalents  are pharmaceutical equivalents
Generic Name  established, nonproprietary, or common name of the active drug in a product
 Chemical Name  name used by organic chemist to indicate chemical structure of the drug
Brand Name  trade name; privately owned by a manufacturer
ANDA (Abbreviated New Drugs Application)  filed by manufacturer for approval to market generic
NDA (New Drug Application)  sponsor request for marketing
Reference listed Drug  RLD; is generally branded name drug that has a full NDA
 Identified by FDA as the drug product on which an applicant relies when seeking approval of an ANDA

Rate-limiting step  slowest step in a series of kinetic processes

Parenteral Routes
Intra-arterial Joint space
Intrasynovial Joint fluid are
Intrathecal Spinal column IM  exhibits depot effect
Intra-arterial Arteries
Intracardiac Heart
Intravenous, IV Into the vein
Intramuscular, IM Into the muscles
Intradermal, IB/ Intracutaneous Into the skin
Subcutaneous, SC/ Sub-Q, SQ/ Under the Skin
hypodermic

Receptor Site Theory

Lock & Key Hypothesis States that the drug molecules must “fit into a receptor” like a key fits into a lock” (intrinsic activity
Induced-fit Theory postulates a complementary relationship between the drug molecule & its active site
provides for mo\uttual conformational changes between the drug & its receptor
Hypothesis of Clark Percentage of receptors occupied
 advances the idea that maximum pharmacologic effect can be obtained if all the receptor occupied
Hypothesis of Ariens & Occupation Theory
Stephenson State that effectiveness lasts as long as the receptor is occupied
Hypothesis of Paton Rate Theory
States the effectiveness does not depend on the actual occupation of receptor of the drug, but upon obtaining the
proper stimulus

Fick’s Law Diffusion/ passive diffusion

Cockroft & Gault Creatinine clearance differences base on patient’s weight, age & sex
Noyes-Whitney Equation Dissolution rate
Henderson-Hasselbalch Equation Buffer equation
describes the relationship between the ionized & non-ionized form of a drug as a function of PH & pKa
Vanslyke Buffer Capacity
Fluid Mosaic Theory States that cell membrane is made up of bi-lipid layers & fluid protein molecules
Jellife Equation creatinine clearance may be computed for adults w/ unstable renal funstion

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Drug Evaluation & Regulation

Mutagenic An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually tested in microorganisms
with the Ames test
Carcinogenic An effect of inducing malignant characteristics
Teratogenic An effect on the in utero development of an organism resulting in abnormal structure or function; not generally heritable
Placebo An inactive "dummy" medication made up to resemble the active investigational formulation as much as possible but lacking
therapeutic effect
Single-blind study A clinical trial in which the investigators—but not the subjects—know which subjects are receiving active drug and which are
receiving placebos
Double-blind study A clinical trial in which neither the subjects nor the investigators know which subjects are receiving placebos; the code is held
by a third party
IND Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in humans; requires animal
data
NDA New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use. Requires data from clinical trials as
well as preclinical (animal) data
Phases 1, 2, and 3 Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA
of clinical trials
Positive control A known standard therapy, to be used along with placebo, to evaluate the superiority or inferiority of a new drug in relation
to the others available
Orphan drugs Drugs developed for diseases in which the expected number of patients is small. Some countries bestow certain commercial
advantages on companies that develop drugs for uncommon diseases

FDA ratings of drug safety in pregnancy.

Category Description
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later
trimesters), and the possibility of fetal harm appears remote
B Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal
reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in
women in the first trimester (and there is no evidence of a risk in later trimesters)
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled
studies in women, or studies in women and animals are not available. Drugs should be given only when the potential benefit justifies
the potential risk to the fetus
D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if
the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective)
X Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience
or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in
women who are or may become pregnant

Major Concept Description

Drug safety and Standards of safety and efficacy for drugs developed slowly during the 20th century and are still incomplete. Because of
efficacy heavy lobbying by manufacturers, these standards are still not applied to nutritional supplements and many so-called
alternative medications.
Preclinical drug All new drugs undergo extensive preclinical testing in broken tissue preparations and cell cultures, isolated animal organ
testing preparations, and intact animals. Efforts are made to determine the full range of toxic and therapeutic effects.
Clinical drug trials All new drugs proposed for use in humans must undergo a series of tests in humans. These tests are regulated by the FDA
and may be accelerated or retarded depending on the perceived clinical need and possible toxicities. The trials are often
divided into 3 phases before marketing is allowed.

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PHARMACOTHERAPEUTICS
Pharmacotherapeutics  is the study of rational drug use in the management of disease.
AUTONOMIC PHARMACOLOGY
Anatomy & Physiology of ANS
Nervous 2 neuron system
System presence of ganglia outside ANS
*ganglia  any neurons outside the ANS
Central Periphera
Nervous l Nervous Central Nervous system  composed of brain & spinal cord
System Sytem Peripheral Nervous System  includes neurons located
outside brain & spinal cord
Afferen Afferent  bring information from periphery to the CNS
Efferent Efferent  carry signals from brain & spinal cord
t
to the periphery
Somatic Autonomic Preganglionic Neuron  first nerve cell;
Sytem System located within the CNS
Postganglionic neuron emerge from the brain & spinal
Enteric cord & make a synaptic connection
ganglia

Sympathetic Somatic Efferent Neurons  involve in the voluntary control

of functions such as contraction of the
skeletal muscles essential for
Sympatheti
locomotion
c Autonomic  regulates the everyday requirements;
responsible for the control of involuntary muscles
(organs) except skeletal muscles
Sympathetic  leave CNS, via a chain of ganglia
Cranial Nerves: close to the spinal cord
I. Olfactory Parasympathetic  leave the CNS from the brain &
II. Optic lower portion of the spinal cord
Enteric  increase gastric secretion
III. Oculomotor
IV. Trochlear
Three parts:
V. Trigeminal 1. Presynapse synthesis, release & storage of
VI. Abducens Neurotransmitter;  NT release
VII. Facial Presynaptic receptor  a receptor located on the nerve ending
VIII. Auditory from which the transmitter is released into the
synapse; modulates the release of transmitter
IX. Facial 2. Synaptic Cleft  where neurotransmitters release
X. Auditory/ Vestibuulocochlear  some of the metabolism also happen
XI. Glossopharyngeal Neurotransmitter  stores in vesicles
XII. Vagus because amine containing, protect
XIII. Spinal accessory against MOA, COMT
XIV. Hypoglossal Enzyme  Acetylcholine acetylcholinesterase

Acetyl CoA Choline
3. Post Synapse
Postsynaptic receptor  a receptor located on the distal side
of a synapse, for example, on a
postganglionic neuron or an autonomic
effector cell

Dilation  enlargement of expansion

of a hollow organ or cavity
Constriction  compression of an organ
or causes a hollow organ

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Autonomic Nervous System (Characteristics)

Criteria Sympathetic (Adrenergic) Parasympathetic (Cholinergic)
1. Anatomy
a. Origin Thoracic & lumbar region of the Brain & Sacral area of Spinal cord
spinal cord (Thoracolumbar) (Craniosacral: III, VII, IX, X)
b. Location of ganglia Close/ near to spinal cord Within or near target organ
c. Length of Fibers
Preganglionic Short Long
Postganglionic Long Short
d. Preganglionic fiber branching Extensive Minimal
e. Distribution Wide Limited
f. Type of response Diffuse Discrete
2. Neurotransmitter
a. Preganglionic Acetylcholine Acetylcholine
b. Postganglionic NE, Epi, Dopamine Acetylcholine
3. Receptors
a. Ganglionic Nicotinic Nicotinic
b. Target organ/ Neuroeffector 1, 2, 1, 2 Muscarinic, Nicotinic
4. Responses
(Actions on Effectors/ target organ)
a. Heart Tachycardia (increase contractility) Bradycardia (decrease contractility)
b. Eyes Mydriasis (dilated) Meiosis (constricted)
c. Lungs Bronchodilation Bronchoconstriction
d. Gut sphincter Contraction (closure) Opening
Gut walls Relaxation Contraction
e. Urinary bladder
Detrussor Relaxation Contraction
Trigone & Sphincter Contraction (closure) Relaxation (opening)
f. Sweating From Apocrine Gland From Ecrine Gland
g. Genetalia
Male Stimulation of Ejaculation Stimulation ofErection
Female Relaxation of Uterus
h. Blood Vessel
Skeletal Muscles Dilation
Skin, Mucous membrane, Constriction
Splanchnic
i. Lachrymal gland Stimulation of Tears
j. Salivary Gland Thick, viscous secretion Copious, watery secretion
k. Adrenal Medulla Secretion of Epi & NE
l. Kidney Secretion of Renin:
1 increase
2 decrease

Sympathetic (Adrenergic) Parasympathetic (Cholinergic)

“alice in the wonderland syndrome” D diarrhea
Dry as a bone anhydrosis
U urination
dry mouth
Hot as hell hyperthermia
M meiosis
-decrease sweating
Red as a beet vasodilation
B bradycardia
/flushing, tachycardia
Blind as a bat cycloplegia (blurring of vision) B bronchial spasm/ contraction
mydriasis, Glaucoma
E Emesis
Mad as a hooter CNS: agitation L Lacrimation
confusion S Salivation
psychosis
S Sweating

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Receptor Characteristics
The major receptor systems in the ANS include: Cholinoceptors, Adrenoceptors, & Dopamine Receptors

SYMPATHETIC RECEPTORS:
 Adrenergic  A nerve ending that releases norepinephrine as the primary transmitter;
 also, a synapse in which norepinephrine is the primary transmitter

Adrenoceptors A receptor that binds, and is activated by, one of the catecholamine transmitters or hormones
(norepinephrine, epinephrine, dopamine) and related drugs
 Also referred to as adrenergic receptors, adrenoceptors are divided into several subtypes:
Alpha Receptors  are located on vascular smooth muscle, presynaptic nerve terminals, blood platelets, fat cells
(lipocytes), and neurons in the brain.
 are further divided into 2 major types, 1 and 2.
Beta Receptors  are located on most types of smooth muscle, cardiac muscle, some presynaptic nerve terminals,
and lipocytes as well as in the brain.
are divided into 3 major subtypes,  1, 2, and 3.
Dopamine Receptors (D, DA) are a subclass of adrenoceptors but with rather different distribution and function.
are especially important in the renal and splanchnic vessels and in the brain. Although at least 5 subtypes
exist, the D1 subtype appears to be the most important dopamine receptor on peripheral effector-cells. D2
receptors are found on presynaptic nerve terminals. D1, D2, and other types of dopamine receptors also occur in
the CNS.
Dopaminergic  A nerve ending that releases dopamine as the primary transmitter;
 also a synapse in which dopamine is the primary transmitter
Characteristics of some important ADRENOCEPTORS in the ANS.
Receptor G Location Major Functions Second
Protein Messenger
Alpha1 (1) Gq Effector tissues: smooth muscle, glands Ca2+(BP) , causes contraction, secretion IP 3, DAG
Smooth Muscles: Contraction
vascular SM: cutaneous splanchnic Vasocontriction
prostatic & bladder Urinary Retention ( closure of internal
sphincter of the bladder)
radial muscles of iris (eyes) Mydriasis (dilation of pupil)
ciliary muscles Cycloplegia
Pilomotor Goosebumps
Peripheral NS Increased peripheral resistance
Alpha2 (2) Gi Presynapse: Central NS Vasodilation ( NE release; cAMP
Acetylcholine; Insulin)
sedation; depression
Post synapse: Peripheral NS Vasoconstriction
Beta1 (1) Gs Cardiac muscle (heart) Tachycardia cAMP
+Inotropism (increase cardiac contractility)
+Dromotism (increase heart rate)
+Chromotism (increase electrical conjunction
across the heart) velocity of AV nodes
JG/ Juxtaglomerular (Kidney) Increase renin release
Beta2 (2) Gs Smooth Muscle, Relaxation cAMP
Vascular Smooth Muscles Vasodilation
Skeletal Muscles Contraction (intracellular movement of K)
Liver  Glycogenolysis (Increase Release Of Glucagon)
Heart Tachycardia (heart rate, force)
Lungs Bronchodilation
Uterus Uterine Relaxation
Peripheral NS Slightly Decreased Peripheral Resistance
Beta3 (3) Gs Adipose cells  Lipolysis cAMP
Dopamine Gs Smooth muscle Relax renal vascular smooth muscle cAMP
Peripheral
D1 Renal vasculature Vasodilation (GFR  dieresis)
Splanchnic blood vessels
D2 GIT GIT motility (loss of peristalsis)
constipation
Central: D2D4 CNS behavioral changes
Perception regulation
modulation of motor activities

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PARASYMPATHETIC RECEPTORS:
 Cholinergic  A nerve ending that releases acetylcholine; also, a synapse in which the primary transmitter is acetylcholine

Cholinoceptors Also referred to as cholinergic receptors, these molecules respond to acetylcholine and its analogs.
 are subdivided as follows:
Muscarinic Receptors receptors respond to muscarine (an alkaloid) as well as to acetylcholine.
The effects of activation of these receptors resemble those of postganglionic parasympathetic nerve stimulation.
Location: autonomic effector cells (including heart, vascular endothelium, smooth muscle, presynaptic nerve
terminals, and exocrine glands).
Evidence (including their genes) has been found for 5 subtypes, of which 3 appear to be important in
peripheral autonomic transmission. All 5 are G-protein-coupled receptors.
Nicotinic Receptors  are located on ion channels and respond to acetylcholine and nicotine,
another acetylcholine mimic (but not to muscarine) by opening the channel.
The 2 major nicotinic subtypes are located in ganglia and in skeletal muscle end plates. The nicotinic receptors
are the primary receptors for transmission at these sites.
Characteristics of the most important CHOLINOCEPTORS in the Peripheral Nervous System.
Receptor Mechanism Location Major Functions/response
M1 Gq-coupled Nerve endings IP 3, DAG cascade
(nerve that supplies GIT) GIT Acid secretion
M2 Gi-coupled Heart, some nerve endings cAMP, activates K+ channels
(nerve that supplies Heart) bradycardia, dromotism
M3 Gq-coupled Effector cells: smooth muscle, glands, endothelium IP3, DAG cascade
Smooth muscles:
Circular muscles (eyes) miosis
Contraction
Ciliary muscles (eyes) accommodation (cyclospasm)
Lungs Bronchospasm/ Contraction (bronchoconstriction)
Exocrine Glands:
Lachrymal Glands Lacrimation
Salivary Glands Salivation
Sweat Glands (Ecrine) Sweating
Gastric
GIT walls Relaxation
GIT sphincter Increase gastric peristalsis
Gut walls Contraction
Urination
Gut sphincter Opening
Urinary Bladder
Detrussor  Contraction
Trigone Relaxation; voiding
Glands (Exocrine) Increased secretion (thermoregulatory sweating,
lacrimation, salivation, bronchial secretion,
gastrointestinal glands)
NN Ion channel ANS ganglia, CNS Complex stimulatory effects, for example, nicotine
(neural)
(stimulate by (elevation of mood, alerting, addiction),
opening of physostigmine (convulsions); excessive
inwardNa concentrations may cause coma
channel)
Parasympathetic neurons
Stimulation
Sympathetic neurons
NM Ion channel Neuromuscular end plate (skeletal muscles) Depolarizes, evokes action potential
(muscular)
Contraction
*NM (muscular)  belongs to somatic NS (excluding in ANS)
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3 inositol-1,4,5-trisphosphate

Autonomic effector cells or tissues  Cells or tissues that have adrenoceptors or cholinoceptors which,
when activated, alter the function of those cells or tissues, for example, smooth muscle, cardiac muscle, glands
Baroreceptor reflex  The neuronal homeostatic mechanism that maintains a constant arterial blood pressure;
the sensory limb originates in the baroreceptors of the carotid sinus and aortic arch;
efferent pathways run in parasympathetic and sympathetic nerves
Homeostatic reflex  A compensatory mechanism for maintaining a body function at a predetermined level,
for example, the baroreceptor reflex for blood pressure

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I. AUTONOMIC DRUGS
 Sympathetic Drugs  “Fight or Flight" stimulus
Adrenergic Agonists (Sympathomimetics)
Phenylethylamine N-methyl transferase =
A. Direct-Acting Adrenergic Agonists directly act on receptors Norepinephrine  Epinephrine
Nonselective Agoniststimulate , , D (one or more receptors) Metabolite of NorEpi/Epi:
Natural Catecholamines:  <  Low doses: -receptors; High doses:  +  3-Methoxy-4hydroxy mandelic acid /
Vanillylmandelic Acid (VMA)
Epinephrine Adrenin®, 1st line cardiac stimulant (in advance life support)
For anaphylactic shock (too much vasodilation)
Decrease systemic absorption of anesthetic. Dopamine & NorEpi  most useful for
Epinephrine+ Management of Glaucoma hypodynamic septic
Epicaine® shock w/ Hypotension
Lidocaine  Hormone released from adrenal medulla, neurotransmitter in CNS
local vasoconstrictor
Norepinephrine Inotrop®, Levolin®, Levophed®, Norepin®, Norphed® 1st line inotropic agent in the management of Septic Shock
Dopamine Cardiofast®, Dokard®, Dopamax®, Myocard® 1st line bronchodilator in acute asthma attacks
Selective Agonist  stimulate one type of receptor
- nonselective agonist
Isoproterenol  alternative inotropic IV infusion for shock states or acute Heart Failure
1- selective agonist
Dobutamine Cardomin®, Dobuject®, Dobulex®, Dobutrim®  DOC in Management of Cardiogenic shock & acute HF
2- selective agonist
Ritodrine
Tocolytics used to control premature labor (for relaxation of uterus)
Isozsuprine Duvadilan®, Duvaprine®, Isoxilan® Asthma- COPD (Chronic Obstructive Pulmonary Disease)
Terbutaline Bricanyl®, Bricalin®, Pulmonyl®
Short-acting 2- selective agonist
Salbutamol/ Albuterol Activent®, Ventolin® 1st line bronchodilators
Salbutamol + Ipratopium Combivent®, Duavent® in acute asthma attack Anti-asthma:
Salbutamol + Guaifenesin Pulmovent® Reliever  for acute attacks
Controller  for maintenance
Metaproterenol Alupent®
Pirbuterol 2  entry of K into the cell
Long-acting  2- selective agonist  cause hypokalemia then Arrhythmia
Salmeterol Salmeflo®  for symptomatic of bradycardia
Salmeterol + Fluticasone in diskus Seretide®  Alternative controllers in
Bronchial Asthma SE: Tachycardia, Palpitations, Hypokalemia, Tremors,
Formoterol Atock®, Foradil® management of Hyperkalemia Tolerance
Formoterol + budesonide Symbicort®
1- selective agonist
Phenylephrine + Chlorphenamine + Paracetamol Bioflu®, Neozep®, Decolgen Forte® 1  nasal decongestant
Phenylephrine + Paracetamol No drowse Decolgen®  Management of hypotension
 local vasoconstrictor w/ local anesthetic
Phenylephrine + Brompheniramine Dimetapp®  Management of Arrhythmia (Methoxamine)
Phenylephrine + Dextromethorphan + Paracetamol Tuseran Forte® SE:
Propylhexedrine Exacerbate HTN due to vasoconstricting effect,
Methoxamine rebound congestion
precipitate urinary retention tolerance
Oxymetazoline Drixine®
must be given less than 5days
Tetrahydrozoline
Xylometazoline Otrivin®
Tetryzoline Eye-mo red eyes®, Visine Refresh®
2- selective agonist
Clonidine Catapres® 2  effects: Presynaptic Methyldopa  upon entering the body, it will be converted
Apraclonidine Uses: Mx of HTN to alpha-methylnorepinephrine
Nasal Spray effect on hemolytic anemia, especially on toxic
Brimonidine Alphagan® doses (Comb’s Test – test for hemolytic anemia)
Alternative Mx for ADHD
Brimonidine + Timolol Combigan® HTN: Urgensive =180/100 AntiHTN for pregnant
Methyldopa Aldomet® Emergency = organ/tissue Gestational Hypertension (like:hydralazine, Labelol, Nifedipine)
Guanfacine complications
SE: sedation, depression, hepatotoxicity (CI: Elderly)
Guanabenz
D1- selective agonist
 adjunct or alternative in Mx of HTNsive crisis
Fenoldopam  vasodilator
SE: diuresis
B. Indirect-Acting Adrenergic Agonists  only affect the levels of catecholamines
Ephedrine MOA: Stimulate release of NE into the cleft SE: Exacerbate hypertention
(Ma-huang, USES: Nasal Decongestant Risk for Tachycardia
Ephedra) Mx of acute Hypotension (Hypotension in surgery)
C. Centrally-Acting Adrenergic Agonists
alternative for ADHD USES: Mx of ADHD (Attention deficit
Amphetamine /Methamphetamine  Sympathomimetic drug that facilitates the release of Hyperactive Disorder)
catecholamines from adrenergic nerve endings Anorexiant
Methylphenidate/ Mephenidate Concerta®, Ritalin® DOC for ADHD Narcolepsy
Phenylpropanolamine SE: Increase Risk of Addiction
Phentermine Duromine®
 causes Risk for Pulmonary Hypertension
Phenmetrazine Preludin®NA
hemorrhagic
Phenylpropanolamine/ PPA stroke
PPA + Chlorphenamine + paracetamol Disudrin®, Sinutab Strength ®

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 Catecholamines  are phenylethylamine w/ orthodihydroxy substitutions in the phenyl ring.

 Two Carbons  can separate the amino from the phenyl ring that will produce maximal sympathomimetic activity
 Beta-1 receptor agonist selectivity  is conferred in beta phenylethylamine structure.

Adrenergic Antagonists (Sympatholytics)

A. Alpha Blockers
Nonselective Blockers Blockers  Vasodilation
a. Irreversible: Phenoxybenzamine DOC for Carcinoid Syndrome
CLINICAL USES:
b. Reversible:Phentolamine Regitine® Mx of HTN, especially w/ Pheochromocytoma as initial Therapy
Selective 1Blockers (zosin) Mx of urinary retention in BPH (Benign Prostatic Hyperplasia)
 -blockers are most appropriate, especially in male elderly
Prazosin
Mx of erectile dysfunction
Doxazosin Alfadil XL® Mx of Raynauds syndrome (finger are unduly reactive)
Alfuzosin Xantral®, Fozal®, Profuzosin®
Terazosin Hyzin®, Hykor® IMPORTANT SE: Orthostatic/ Postural Hypotension & Syncope
(First-dose Phenonemenon)
Tamsulosin Harnal®, Prozelax®, Pimax®
Selective 2Blockers
Yohimbine/ Rauwolscine/ -yohimbine
B. Beta Blockers
I. Based on Selectivity
Non-Selective: the rest of the olos & alols
1 Selective : [BBEAAM]
Bisoprolol Concore® Blockers DOC for CSAP (Chronic Stable Angina Pectoris)
Bisoprolol + Hydrochlorothiazide Ziac®  1st line drug for HTN esp. if with prior history of MI
 *its overdose, can be managed w/ Calcium Supplementation
Betaxolol Betoptic®, Kerlone®, Oxol®
Esmolol MOA: Block , in heart
Acebutolol Ability to decrease rennin release (JG cells)
Atenolol Tenormin®,
CLINICAL USES: Mx of Angina Pectoris
Atenolo + Chlorthalidone Tenoretic® Mx of arrhythmia
Metoprolol Neobloc®, Angimel®, Cardiotab® Mx of sympathetic symptoms of hyperthyroidism
II. Based on Intrinsic Sympatomimetic (agonist) activity [CLAP] Mx of Glaucoma
Mx of stable CHF(Congestive Heart Failure)
Carteolol Mikelan®
Mx hypertension
Labetolol Prophylaxis for Migraine
Acebutolol SE: Mask symptoms of Hypoglycemia (use with caution for DM patients)
Pindolol Bradycardia
Heart Block
III. Based on Membrane Stabilizing Activity [PPALM] Dyslipidemia
Pindolol Hyperuricemia
Propanolol Inderal® Rebound Hypertension
Acebutolol CI: CHF (Congestive Heart Failure)
If taking Calcium Channel Blocker(has same effect w/ Beta Blockers
Labetolol
Metoprolol Bisoprolol, Esmolol, Atenolol, Metoprolol  cardioselective
I. Based on the Presence of Alpha-Blocking Activity Acebutolo  least likelihood of casing rebound tachycardia & hypertension
Mixed - Blockers among -blockers
Esmolol  has the shortest duration of action (t ½ = 10 minutes)
Labetalol  can be used as treatment for the mx of cardiac manifestations of
Carvedilol Betacard®, Cardipres®, Carvid®, Xicard®, Psicardiol® Teophylline or Caffeine overdose
Carvedilol, Bisoprolo, Metoprolol  in low dose, have been proven in clinical
trials to be useful in the mx of stable
CHF
Chinese patients  are most likely to be more sensitive to the effects of -
blockers

Clinical applications of blockers.

Application Drugs Effect
Hypertension Atenolol, propranolol, Reduced cardiac output, reduced renin secretion, other
metoprolol, timolol, others
Angina pectoris Propranolol, others Reduced cardiac rate and force
Arrhythmia prophylaxis after Propranolol, metoprolol, Reduced automaticity of all cardiac pacemakers
myocardial infarction timolol
Supraventricular tachycardia Propranolol, esmolol, Slowed or blocked atrioventricular conduction velocity; blocked reentry
acebutolol
Heart failure Carvedilol, labetalol, metoprolol Decreased mortality, mechanism poorly understood
Hypertrophic cardiomyopathy Propranolol Slowed rate of cardiac contraction
Migraine prophylaxis Propranolol Mechanism not understood
Familial tremor, other types of Propranolol Reduced 2 alteration of neuromuscular transmission; possible CNS effects
tremor, "stage fright"
Thyroid storm, thyrotoxicosis Propranolol, esmolol Reduced cardiac rate and arrhythmogenesis; reduced conversion of T4 to T3
Glaucoma a Timolol, others (topical) Reduced secretion of aqueous humor

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 Parasympathetic Drugs  “Rest & Digest" stimulus

SE: DUMBBELSS
Cholinergic Agonists (Parasympathomimetics)
A. Direct-Acting Cholinergic Agonists stimulate directly cholinergic receptors
Choline Esters Acetylcholine hydolyzed by Achase
Acetylcholine prototype
no clinical use because of widespreasd effects & rapidly hydrolyzed by Acetylcholinesterase
Primary transmitter at cholinergic nerve endings (preganglionic ANS, postganglionic parasympathetic, postganglionic sympathetic to
thermoregulatory sweat glands, and somatic neuromuscular end plates)
Bethanechol (Urecholine®)
USES: Bladder and bowel atony, for example, after surgery or spinal cord injury
Betanecho & CarbacholResistant to Acetylcolinesterase
Butanechol
Methacoline diagnosis of asthma
Carbachol (Ophthalmic topical: Isopto carbachol®)
(Ophthalmic intraocular: Miostat®, Carbastat®)
for glaucoma
Cholinergic alkaloids
Pilocarpine (Isopto Carpine®) Tertiary Amines:
(SR inserts: Ocusert Pilo-20®, Ocusert Pilo-40®) Well Absorbed
 causes contraction of ciliary muscle fibers attached to the trabecular meshwork & sclera spur. -Pilocarpine
 opens the trabecular meshwork to enhance aqueous humor outflow -Arecoline
alkaloids from Pilocarpus sp. Quaternary Amines:
USES: Sjögren's syndrome (increases salivation) Less Absorbed
Arecoline from betel nut (Areca catechu) -Muscarine
Muscarine Alkaloid found in mushrooms (Amanita muscaria)
Nicotine Major overdose: convulsions, paralysis, coma
Lobeline
Cevimeline (Evoxac®)
Varenicline (Chantix®)
B. Indirect-Acting Cholinergic Agonists  only affect the levels of catecholamines
Short-acting anti-cholinesterase CLINICAL USES:
Edrophonium Tensilon® Dx & Mx of Myasthenia Gravis(mostly)
MOA: Inhibitor of cholinesterase; Mx of Atropine poisoning
amplifier of endogenously released Ach Mx of neuromuscular blocker toxicity
USES: Diagnostic agent for Myasthenia Gravis Mx of Glaucona
Mx of ileus
Intermediate-to-long-acting (Carbamates)  carbamic acid esters of alcohols Mx of urinary retention & BPH
bearing quaternary or tertiary ammonium groups Mx of Alzheimer’s Diseas
Neostigmine Prostig®, Prostigmin®
quaternary amine; poorly absorbed
USES: Antidote for Tubocurarine Poisoning
Tx Myasthenia gravis
Physostigmine aka, Eserine
Tertiary amine; more lipid soluble; well absorbed
USES: Reversal of severe atropine poisoning (IV);
occasionally used in acute glaucoma (topical)
Pyridostigmine Pyrinon®, Mestinon®, Regonol®
USES: Treatment of myasthenia gravis
Galantamine Reminyl®
Ambenonium Mytelase®
Demecarium Himorsol®
Very long-acting (Organophospates)  organic derivative of phosphoric acid
Ecothiophate Phospholine® USES: Tx of open-angle glaucoma
Malathion A-lices® Insecticide and scabicide (topical)
Parathion Insecticide only
Isofluorophate
Miscellaneous, for Alzheimer's disease
Rivastigmine Exelon®
Tacrine Cognex® 1st line treatment for Alzheimer’s Disease
Donepezil Aricept®, Donezepil®

Biosynthesis of Catecholamines Synthesis & Release of Acetylcholine

1. Tyrosine uptake 1. Synthesis of Acetylcholine
2. Tyr  DOPA (Tyrosine hydroxylase) transport of choline inhibited by
3. DOPA  Dopamine (DOPA decarboxylase) hemicholinium
4. Vesicular uptake of Dopamine 2. Uptake into Storage vesicles
5. Dopamine  NE (Dopamine -hydroxyl) protected from degradation
NE  Epi (PENMT) -Phenylethanolamine-N-methyltransferase) 3.Release of Neurotransmitter
6. Release botulinum toxin- blocks release
spider venom- promotes release
4. Binding to Receptor
Reactions involved: Methylation 5. Degradation by Acetylcholinesterase
Hydroxylation Ach  Acetate + Choline
Decarboxylation 6 Recycling of Choline

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Cholinergic Antagonists (Parasympatholytics) SE: Alice in the wonderland Syndome

A. Anti-muscarinic
CNS-Acting (for Motion-sickness) Anti-muscarinic CLINICAL USES: Mydriatic (cycloplegia)
Mx of Bradycardia
Scopolamine (Buscopan®, Transderm-Scop®) Organophosphate overdose
aka Hyoscine CI: History of Hyperplasia
alkaloid from henbase )Hyoscyamus niger) Glaucoma
Anti-motion sickness via transdermal patch; sedative *Diphenoxylate addition to atropine to prevent addiction
tertiary amine(exert CNS effects)
Biperiden Akineton®
Benztropine Cogentin®
Trihexyphenidyl Artane®
Mydriatic-Cycloplegic
Atropine Anespin®, Isopto Atropine®  DOC for cholinergic toxicity Effects:
aka Hyoscyamine -Cycloplegia (Contraction of ciliary muscles)
prototype antimuscurinic -Mydriasis (relaxation of the papillary constrictor
muscles)
-Tachycardia (blockade of vagal slowing of the
heart)
Homatropine Lesopen®, Isopto Homatropine®
Tropicamide
for ophthalmic examination
Tropicamide + Phenylephrine Medriacyl®, Sanmyd-P®
Cyclopentolate
Bronchodilator (Relaxant of Bronchial smooth muscles)
Ipratropium Br Atrovent®
Oxytropium  DOC bronchodilator for COPD (Chronic Obstructive Pulmonary Disease)
Tiotropium Spiriva®
M1-selective blocker (adjunct in hyperacidity)
Pirenzepine Gastrozepin® USE: Peptic disease (not available in USA)
Telenzepine
M3-blockers (useful for GIT & urinary bladder hyperactivity)
Hyosine-N-butylbromide Buscopan®
Hyosine-N-butylbromide + Paracetamol Buscopan Venus®
Dicycloverine Relestal®
Glycopyrrolate Robinul®
Clidinium
Clidinium + Chlordiazepoxide Librax®
Dicyclomine Bentyl®
Methscopolamine Pamine®
B. Anti-nicotinic
Neuromuscular Blockers /irreversible
Succinyl choline Depolarizing/ noncompetitive  Flaccid Paralysis
Isoquinoline derivatives Non-Depolarizing/ reversible  Fetanic Paralysis
Atracurium Atracor®. Tracrium® CLINICAL USE: Skeletal muscle relaxants during surgey
Mivacurium SE: Succinyl  rhabdomyolysis (massive release)
Steroidal derivatives Curare cause anaphylactoid reaction (not IgE mediated)
Pancuronium Pavulon® NA
Succinylcholine  may cause malignant hyperthermia
Vecuronium Norcuron®
Ganglionic Blockers
Hexamethonium
Mecamylamine Inversine®  for Nicotine Toxicity
Trimethaphan camsylate Arfonad®  expected to produce Hypotension
Regenerator
Pralidoxime Pralidoxime
 DOC for organophosphate poisoning
Diacetyl Monoxide
Atropine

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II. AUTOCOIDS
stamine  aka -imidazolylethylamine; 1H-imidazole-4-ethenamine
Basophils & mast cell; ECL; (*Histidine  major source of Histamine)
H1: Physiologic antagonis: Epinephrine H2: Prototypic Antagonist:
Pharmacologic antagonist: H1-antihistamine Cimetidine
Prototypic antagonist: Diphenhydramine Triple Response of Lewis following
Serotonin  happy hormone; responsible for mood regulation Intradermal Inj of Histamine:
Tryptophan decarboxylation hydrolase 5HT -Sensory nerve ending stimulation
producing flare
5HT1A Presynapse To inhibit further release
-Local flushing due to dilatation of
5HT1D Peripheral Blood Vessels Vasoconstriction
blood vessels
5HT2A Smooth Muscle vascular Uterine Contraction -Endothelial cell contraction
5HT3 Chemoreceptor Trigger Zone Emesis leading to exudation of fluids
5HT4 GIT Peristalsis
Kalidin no agent, but its analogues/ drugs can mimic, block or modulate other autocoids
Bradykinin  function as an algesic
Eicosanoids  aka “Arachidonic Acid”; Eicosatetranoic Acid; 20-carbon polyunsaturated FA
Prostaglandin  PG: PGE1, PGE2, PGF2 ; derivatives of Prostanoic Acid Products of Eicosanoids through
Leukotrienes LT: LTB, LTC, LTD ; for inflammation & bronchoconstriction Cyclooxygenase enzyme:
- Prostglandins
Prostacyclin PGI2
-Prostacyclins
Thromboxane TXA2
-Thromboxanes

 Anti-histamines
H1- Anti-histamines H1 receptor stimulation leads to:
MOA: Block H1 receptors especially in Mast Cells - Extravascular smooth muscle contraction
CLINICAL USES: allergic rhinitis - Vascular smooth muscle relaxation
allergic contact dermatitis - Endothelial cell contraction
1st Generation/ Sedating
MOA: Competitive pharmacologic block of peripheral and CNS H1 receptors plus - and M-receptor block.
Anti-motion sickness effect
CLINICAL USES: Hay fever, angioedema, anti-motion sickness; used orally as OTC sleep aid; used parenterally for dystonias
Ethanolamine  most sedating; has significant anticholinergic; used as sleeping pills; mx of EPS(atropine-like effects)
Diphenhydramine  can block Na channel in excitable membranes bringing about a local anesthetics effect
Diphenhydramine+ Calamine Benadryl®, Caladryl®
Dimenhydrinate Gravol®
Carbinoxamine Palgic®
Doxylamine Unisom®
Ethylenediamine (Ethylenediamine moiety  contained in Piperazine, Imidazolines, & Phenothiazine-type)
Pyrilamine
Tripelennamine
Piperazine
Hydroxyzine Iterax®  converted to Cetirizine(active metabolite)
Meclizine Bonamine®, Dizitab®
Antimotion sickness
Cyclizine Valoid®
Alkyl amines  adjunct in cold medications
Brompheniramine  propylamine derivative
Brompheniramine + Phenylephrine Dimetapp®
Chlorpheniramine Antamin®  result from the chlorination of pheniramine in the para position of phenyl ring
Chlorpheniramine-containing Bioflu®, Neozep®, Sinutab®, Decolgen forte®
Phenothiazine
Promethazine Phenargan®, Phenerzin®, Promet®, Zinmet®  as anesthetic
Cyproheptadine Periactin® for serotonin syndrome; has significant blocking effects on 5-HT receptors
2nd Generation/ Non-sedating
MOA: Competitive pharmacologic block of peripheral H1 receptors. No autonomic or anti-motion sickness effects
CLINICAL USES: Hay fever, angioedema
Less sedating
Cetirizne Alnix®, Zyrtec®
Acrivastine Benadryl allergy relief®
True non-sedating
Loratadine Allerta®, Claritin®, Clarihist®, Zylohist®,
Cardura ®, Lorid® Only antihistamines allowed for Pilots
Fexofenadine Fenafex®, Telfast®
Desloratadine Aerius®
Levocetirizne Xyzal®

H2- Anti-histamines H2 receptor stimulationj leads to:

MOA: Block H2 receptors especially in Parietal cells of the stomach - Gastric acid secretions
CLINICAL USES: Alternative drug for PUD & GERD
Potency: (most to least) Famotidine  Nizatidine = Ranitidine  Cimetidine
Cimetidine Tagamet®
Ranitidine Zantac®, Ulcin®
Famotidine H@ BLOC®, Hista-Bloc®
Nizatidine Axid®, Nolcer®  have an almost complete oral bioavailability

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Serotonin & Related Drugs

5-HT1A Partial Agonist
Buspirone Buspar®  anxiolytic
5-HT1D Full Agonist
Sumatriptan Sumigran®, Imigran®
Naratriptan Naramig® MOA: 5-HT1D agonist; causes vasoconstriction; modulates neurotransmitter release
CLINICAL USES: Migraine and cluster headache(same w/ 5-HT1B)
Zolmitriptan Zomig® CI: Patient w/ Ischemic Heart Disease because of their Vasospastic Effect
Rizatriptan Maxalt®
5-HT2A Agonist
Ergotamine Ergomar®
Methylergometrine/ Methergine Methergin®
Ergonovine Ergotrate®  oxytoxic
Dihydroegotamine Migrana®
5-HT2 Antagonist
Ketanserin MOA: Competitive 5-HT2 and 1-receptor block
CLINICAL USE: Hypertension, carcinoid tumor (not available in United States)
5-HT3 Antagonist
Granisetron Kytril®, Sancuso® MOA: Pharmacologic antagonist; blocks chemoreceptor trigger zone and enteric nervous system 5-HT3 receptors
Ondansetron Zofran®, Nozuka® CLINICAL USE: Chemotherapy and Postoperative Vomiting

5-HT4 Partial Agonist

Tegaserod Zelnorm® MOA: Partial agonist at 5-HT4 receptors
CLINICAL USE: Constipation-dominant irritable bowel syndrome (restricted use)
Toxicity: Diarrhea, Ischemic Colitis

 Prostaglandins & Other Eicosanoids

Leukotrienes
LTB4 MOA: Chemotactic factor in inflammation
TOXICITY: Inflammatory Mediator
LTC4, LTD4 MOA: Bronchoconstrictors important in anaphylaxis; cause edema
Leukotriene antagonists
Lipoxygenase inhibitor MOA: Blocks synthesis of leukotrienes
Zileuton CLINICAL USE: Asthma prophylaxis
TOXICITY: Liver enzyme elevation
Leukotriene receptor inhibitors MOA: Block CysLT1 receptor; reduce bronchoconstriction in asthma
Montelukast CLINICAL USE: Asthma prophylaxis
Toxicity: Liver enzyme elevation
Zafirlukast SE: Churg-Strauss Syndrome (a form of eosinophilic vasculitis)

Thromboxane
TXA2 MOA: Activates TP, receptors, causes platelet aggregation, vasoconstriction

Prostacyclin
PGI2:
Epoprostenol Flolan® MOA: Activates IP receptors, causes vasodilation, reduces platelet aggregation
CLINICAL USES: Vasodilator in pulmonary hypertension, antiplatelet agent in extracorporeal dialysis
TOXICITY: Hypotension, Flushing, Headache
PGI2 analog, treprostinil: parenteral for pulmonary hypertension

Prostglandins
PGE1
Alprostadil Caverject®, Muse®  injectable form for erectile dysfunction
 used as a palliative treatment to maintain neonates w/ ductus arteriosus
Misoprostol Cytotec® MOA: Activates EP receptors, causes increased HCO3– and mucus secretion in stomach; uterine contraction
CLINICAL USES: Protective agent in peptic ulcer disease; abortifacient ; Cytoprotectant
TOXICITY: Diarrhea, Uterine Cramping
PGE2
Dinoprostone Cerviprime®  natural prostaglandin, used to terminate pregnancy from 12th week through the 2nd trimester.
MOA: Low concentrations contract, higher concentrations relax uterine and cervical smooth muscle
CLINICAL USES: Abortifacient; for induction of labor-causes uterine contraction; cervical ripening
TOXICITY: Cramping, fetal trauma
PGF2
Latanoprost Xaltan® MOA: Increases outflow of aqueous humor, reduces intraocular pressure
CLINICAL USE/S: Glaucoma
TOXICITY: Color change in iris

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III. NSAIDS & related drugs

Cyclooxygenase inhibitors (NSAIDs)

Nonselective COX-1, COX-2 inhibitors used as analgesic & anti-inflammatory
Salicylates
Aspirin Aspilet® TOXICITY: Gastrointestinal (GI)
 325mg/day, 1st line in the primary & secondary prevention of acute thrombotic events toxicity, nephrotoxicity, and
 absorbed in the stomach & in the small intestines in the unhydrolyze form increased bleeding time at
EXCRETION:<600mg/d -1ST order; >600mg/d- 0th order therapeutic levels;
(its excretion, enhance w/ alakalination of the urine; follows Michaelis Menten Elimination Kinetics) hypersensitivity reaction due
MOA: Irreversibly inhibits COX-1 and COX-2; reduce synthesis of prostaglandins/ to increased leukotrienes;
Acetylation of COX-1 and COX-2 results in decreased prostaglandin synthesis tinnitus, hyperventilation
CLINICAL USES: Analgesia, antipyretic(Inh. CNS response to Interleukin-1), anti-inflammatory, metabolic acidosis,
Antithrombotic(irreversible acetylation of COX enzyme in platelets); prevention of colon cancer hyperthermia, coma in
3.2-4g/day  usual adult dose of Aspirin for its Anti-Inflammatory Effect overdose
SE: GI discomfort, GI ulceration, CNS salicylism, vertigo, Hypersensitivity reaction=Reye’s Syndrom, Asthma
Reye’s Syndrome  manifest as hepatic failure & encephalopathy Serum Salicylate Levels:
happen when there is a previous or current viral infection Low Toxic (50-80 mg/dL)
ADMINISTRATION: Must be given w/ or after heavy meal -Hypeventilation
Or take proton-pump inhibitor before taking aspirin -Respiratory Alkalosis
RISK FACTORS: Taking multiple NSAIDS: causes Gastritis (blood in the stools) -Tinnitus & Vertigo
Concurrent use of Glucocortcoids: Increase inhibition of cytoprotectant action of COX Moderate Toxic(80-110mg/dL)
-Metabolic Acidosis
-Dehydration
-Hyperthermia
Pyrazolone derivatives
Phenylbutazone SE: Hematologi toxicities - Aplastic Anemia, Agranolocyte; ATN(Acute tubular necrosis)
Oxyphenbutazone CI: Drug allergy, Blood Dyscrasias, Hypertension
Sulfinpyrazone Anturane® Aromatic Hydroxylation  involved in biotransformation of Phenylbutazone to Oxybutazone
Indole derivatives
Indomethacin Infree®, MOA: Inhibits COX1 than COX2(preferred for the mx of pain of an acute attacks of gout); Increase gastric ulcers
VI-Gel® BENEFICIAL: PDA/ Patent Ductus Artriosus  failure to close ductus
Pyrolle alkanoic acid derivatives
Tolmetin Tolectin®
Oxicam derivatives
Piroxicam Feldene® MOA: Inhibits COX1 than COX2 (represents a class of acidic inhibitors of prostaglandin synthetase, although it does not
antagonize PGE2 directly)
Phenylacetic acid derivative
Sulindac Clinoril® sulfur-containing drugs Indications: 0 Arthritis
causes SJS (Steven Johnson Syndrome) Osteoarthritis
Ankylosing Spondylitis
Diclofenac Voltaren®, Cataflam®, Diclogen®
Alclofenac
Etodolac Etoflam® has minimal anti-inflammatory aactivity that are primarily indicated as analgesic especially in
Ketorolac  replace morphine the mx of post-operative pain
Nabumetone Relafen® All known NSAIDs are weak acids, except Nabumetone
Fenamates
Mefenamic Acid Dolfenal®, Gardan®, Ponsran® not anti-inflammatory must be given for not more than 5 says
Flufenamic Acid not antipyretic never give it to children
Meclofenamic Acid but only an analgesic more toxic than aspirin
Propionic Acid Derivative
Ibuprofen Advil®, Dolan FP®,  is an arylacetic acid derivative
Medicol®, Midol®,  appears comparable to aspirin In the tx of RA, with a lower incidence of side effects
 also been approved for use in primary dysmenorrheal
Nuprin®, Motrin®  prescribed for Hemophiliac Patient for RA
 exists both as R- & S- enantiomers (S-enantiomer is the only active form)
SE: Renal Failure
Ibuprofen+Paracetamol Alaxan®
Ketoprofen Orudis®
Flurbiprofen Ocufen® ophthalmic solution
Naproxen Flanax®, Naprosyn®
Selective COX-2 inhibitor
Meloxicam Mobic®
Specific COX-2 inhibitor (Advantage: Less incidence of gastric irritation or ulceration)
Celecoxib Celebrex®, Celcoxx® MOA: Selectively reversibly inhibits COX-2
CLINICAL USE/S: Analgesia, antipyretic, and anti-inflammatory
Eteroxib Arcoxia® Toxicity: Nephrotoxicity; hypersensitivity due to increased leukotrienes; less risk of GI toxicity than nonselective
NSAIDs; greater risk of thrombosis than nonselective NSAIDs
Rofecoxib (Vioxx®)  have been withdrawn from the market or are marketed w/ ―black box‖ warning because of
its increase risk of Thrombosis & cardiac death

Aspirin, Other salicylates, Tolmetin  contraindicated w/ GOUT (effect on urate levels: <2g/dL hyperuricemia/ >2g/dL uricosuric acid)
COX-1 isozymes  is widely distributed & constitutively expressed
COX-2 isozyme  present only during inflammation upon stimulation by cytokines & growth factors, & by inflammatory & immune cells

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 Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

DMARDs  alters/ slows down joint destruction
 SAArTs (slow-acting antirheumatic drugs
Methotrexate Zexate®, Alltrex® 1st line DMARDS in RA
 Important to pyrimidine synthesis
MOA: Cytotoxic to rapidly dividing immune cells due to inhibition of dihydrofolate reductase
Inhibit AICAR (aminoimidazole carboxanide tribonucleotide)
Inhibits DNA transcription
CLINICAL USE/S: Anticancer, rheumatic disorders
SE: Hepatotoxicity (Folic Acid- hepatoprotectant)
TOXICITY: Nausea, Mucosal Ulcers, Hematotoxicity, Hepatotoxicity, Teratogenicity
ALTERNATIVE: Leflunamide
Anti-Malarial Agents
Chloroquin Chloromax®
Hydroxychloroquine Plaquenil®
Gold Compounds
Auranofin Ridaura®
Aurothiomalate Myochrysine® SE: hypersensitivity reaction
Aurothioglucose Solganal®
Sulfasalazine Azulfidine® has 2 metabolites:
Sulpapyridine
I-aminosalicylate (IBD)
Biologic Agents
Adalimumab Humiral® MAB (Monoclonal Antibodies)
Inflximab Remicade® Inhibit TNF- & also block inflammation.
subjecting patients to inflammation
Etanercept Enbrel®
Leflunomide Arava® alternative of Methotrexate
Azathioprine Imuran® metabolize into 6-mercaptopurine
Penicillamine Cuprimine® for copper toxicity/ Wlison’s Disease is a degradation product of penicillin-type antibiotics
alter the function of WBC  also useful in treating Lead poisoning & RA
for progressive rheumatoid Arthritis

 Drugs for Gouty Arthritis

Gout  increase level of uric acid
 Deposition of uric acid in subcutaneous tissue
Uric Acid  strong negative birefringent needles of (MSU) - monosodium urate
Formation of Uric Acid : Purine hypoxanthine xo xanthine xo uric acid
w/ allopurinol alloxanthine cannot be converted to uric acid
Acute Gout
Colchicine Goutnil®, Rhea® 1st line treatment of acute gout (usual dose: 15mg once a week)
 Microtubule assembly inhibitor (decreases macrophage migration and phagocytosi)
MOA: Inhibitionof AICAR (aminoimidazolecarboxamide)
CLINICAL USE/S: Chronic and acute gout, familial Mediterranean fever
TOXICITY: Diarrhea, Severe Liver & Kidney Damage in Overdose(mimimized w/ Leucovorin)
NSAIDs
Glucocorticoids (GC)
Methyl Prednisolone to inhibit inflammation
systemic management of RA,
Life threatening SLE (Systemic Lupus Erythematus)
Intrasynovial
Chronic Gout
Colchicine  1st line initial treatment of chronic gout
 after 2-3 weeks
MOA: Inhibits the synthesis of Microtubules
Allopurinol Zyloprim®, Drug of choice for chronic gout
st
Alpurase®, 1 line hypourecemic agent in chronic gout
 Xanthine oxidase inhibitors
Allurase®, acts as suicide substrate
Purinase®, MOA: Active metabolite irreversibly inhibits xanthine oxidase and lowers production of uric acid
Lopric®, CLINICAL USE/S: Chronic gout; Adjunct to cancer chemotherapy; Mx of recurrent renal urate stones
Loricid® TOXICITY: GI Upset, Hypersensitivity Reactions, Bone Marrow Suppression
Probenecid Benuryl®  Uricosurics (induce loss of uric acid in urine
Sodium Bicarbonate to increase uric acid secretion
MOA: Inhibition of renal reuptake of uric acid
CLINICAL USE/S: Chronic gout, prolongation of antimicrobial drug action
TOXICITY: Exacerbation of acute gout, hypersensitivity reactions,
inhibits renal tubular secretion of weak acids such as methotrexate
Sulfinpyrazone Anturane® Uricosurics
Similar to probenecid
Penicillamine Cuprimine®

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IV. ANALGESICS

Non-Narcotic Analgesics
NSAIDs
Acetaminophen/ Biogesic®, MOA: Selective, reversible inhibition of COX-2 results in decreased prostaglandin synthesis (weak inhibitor)
Paracetamol Tylenol®, CLINICAL USE/S: (Equivalent to Aspirin -Analgesia, Antipyretic) and (has non Anti-Inflammatory)
TOXICITY: 150mg/kg
/para-aminophenol Calpol®,
Nephrotoxicity; hypersensitivity due to increased leukotrienes;
Tempra®, less risk of GI toxicity than nonselective NSAIDs; greater risk of thrombosis than nonselective NSAIDs
Kidilets®, IMPORTANT TOXIC METABOLITE: NAPQI (N-acetylparaquinone)
Naprex® ANTIDOTE: N-acetylcysteine
Maximum Daily Dose for Adults: 4 grams

Opioids/ Opiates
Opioid Effects:
Opioids  semi-synthetic or synthetic compunds Analgesic Other Effects:
Opiates  natural compound Euphoria CNS-Tolerance
Opioid Receptors: Mu ()  dominant Receptor Sedation Peripheral Effects: Vasodilation
Hypotension
 responsible of most Opioid Effects Biliary tree- contraction
Respiratory GIT-less of peristalsis -constipation
Kappa( ) affords additional analgesia for women Depression Mast cells- release of histamine
Delta () additional analgesia Bradycardia (anaphylactoid reaction)
Opioid Receptors  are activated by endogenous peptides, Vasodilation Drugs dependence (addiction)
including endorphins such as:
Convulsion  are not observe in tolerance of opioids
-endorphins have affinity for  receptor Constipation
Enkephalins  for  receptor Mioisis Tolerance  developed in 2-3 weeks
Dynorphins  for  receptor
Uses: Pain States, Acute Pulmonary Edema(Congestion), Anesthetic Adjunct, Antidiarrheal, Cough Suppresant, Antiemetics
CI: Pregnancy, Partial Agonist,
History of Head Trauma or Increase Intracranial Pressure
Narcotic Analgesics  MOA: mimic or increase the release of endogenous opioid peptides.
Natural opium
Morphine Morin®, is the standard by which you compare opioid activity (can tx acute pulmonary edema-reduce venous return)
MST Continus® only 25% bioavailable (40 mg Oral Dose = 10 mg IV Dose)
 Prescription Limit for Cancer Patients: 3,000 mg Morphine Sulfate
Codeine prodrug
has less activity compared to morphine
 USES: Antitussive, Mx for Moderate pain state
Thebaine precursor substrate of Naloxone
Semisynthetic
Heroin diacetyl morphine or diamorphine
diamorphine
common drug of abuse
Apomorphine Apokyn® non-narcotic/ non-analgesic
USES: POD, emetic
Hydromorphone Jurnista® derivatives of morphine
Oxymorphone Opana® 10-12x more potent than morphine
same efficacy w/ morphine
Oxycodone OxyContin®, OxyNorm® same efficacy w/ codeine
Hydrocodone Vicodin® 8-10x more potent w/ codeine
derivatives of codeine
 Prescription Limit for Cancer Patients: 1,200 Oxycodone HCl
Synthetic Derivatives
Methadone same efficacy w/ morphine
has greater bioavalability(F), has longer duration of action,
has less rapid development of tolerance than morphine
USES: to wean-off patient addicted to Heroin or Morphine
Meperidine Demerol®  ADV: has no CNS & biliary effect
 has analgesia ( is not associated w/ Biliary Colic, Hypotension, Bradycardia)
converted to normeperidine
Problem: can cross blood-brain barrier so it causes seizures as
convulsion
Diphenoxylate
for diarrhea (antidiarrheals)
Diphenoxylate + atropine Lomotil® other countries
Diphenoxylate  always given w/ Atropineto discourage the abuse of DIphenoxylate
Loperamide Diatabs®, Imodium®, Lomotil®
Alfentanil Alfenta® same efficacy as morphine
Sulfentanil Sufenta® 100x more potent than morphine
100% bioavailability(F)
Tramadol Tramal®, Ultram® weak opioid agonist (synthetic analogue of Codeine)
Tramadol+Paracetamol Dolcet® for mild pain states
derivative of codeine
only opioid that does not require S2 prescription
Pentazocine Talwin®  Kappa ()

Abstinence Syndrome  is seen w/ abupt withdrawal of an opioid agonist in a patient taking the drug chronically, in newborn of a mother illicitly taking
heroin during pregnancy, & administration of Nalbuphine or Naloxone on a patient chronically taking on morphine

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Opioids, Opioid Substitutes, & Opioid Antagonists

Subclass Mechanism of Action Clinical Applications Pharmacokinetics & Toxicities
(Receptors) Interactions
Strong agonists
Fentanyl Strong agonists; variable Severe pain, anesthesia (adjunctive); Hepatic metabolism; duration: Respiratory depression,
Hydromorphone and agonists dependence maintenance (methadone) 1–4h (methadone 4–6 h) constipation, addiction
iability
Meperidine
Morphine
Methadone
Oxymorphone
Partial agonists
Codeine As above, but lower affinity Mild-moderate pain; cough (codeine); Genetic variations in As above, but weaker
Hydrocodone analgesic combinations with NSAIDs metabolism
and acetaminophen
Mixed agonist-antagonist
Buprenorphine Partial agonist and Moderate-severe pain; dependence Long duration (buprenorphine); Like strong agonists but
antagonist maintenance, reduces craving for nalbuphine (parenteral only) can antagonize their
alcohol (buprenorphine) effects
Nalbuphine Kappa agonist and Has analagesic efficacy equivalent to
antagonist Morphine
Antagonists
Naloxone Antagonists at all receptors Opioid overdose; dependence Duration: naloxone 2 h; Rapid antagonism of all
Naltrexone maintenance (naltrexone) naltrexone and nalmefene >10 opioid actions
h
Nalmefene
Antitussives
Codeine Mechanism uncertain Acute debilitating cough Duration: 0.5-1 h Reduce cough reflex;
Dextromethorphan patrial agonists toxic in overdose
Tramadol Weak agonist; inhibits Moderate pain; adjunctive to opioids in Duration: 4-6 h Toxic in overdose
norepiniphrine and 5-HT chronic pain states (seizures)
transporters

Drugs of Abuse
Signs and symptoms of overdose and withdrawal from selected drugs of abuse.
Drug Overdose Effects Withdrawal Symptoms
Amphetamines, Agitation, hypertension, tachycardia, delusions, hallucinations, Apathy, irritability, increased sleep time,
methylphenidate, cocainea hyperthermia, seizures, death disorientation, depression
Barbiturates, benzodiazepines, Slurred speech, "drunken" behavior, dilated pupils, weak and rapid Anxiety, insomnia, delirium, tremors,
ethanolb pulse, clammy skin, shallow respiration, coma, death seizures, death
Heroin, other strong opioids Constricted pupils, clammy skin, nausea, drowsiness, respiratory Nausea, chills, cramps, lacrimation,
depression, coma, death rhinorrhea, yawning, hyperpnea, tremor

Drugs Used to Treat Dependence and Addiction

SUBCLASS MOA EFFECTS CLINICAL APPLICATION
Opioid antagonists
Naloxone Antagonists of Reverse or block effects of opioids Naloxone: opioid overdose
Naltrexone opioid receptors Naltrexone: treatment of alcoholism
Synthetic opioid
Methadone Slow-acting Acute effects like morphine Substitution therapy for opioid addicts
agonist at opioid
receptors Toxicity: Like morphine re acute and chronic effects including withdrawal
Partial -receptor agonist
Buprenorphine Partial agonist at Attenuates acute effects of morphine and other strong opioids Substitution therapy for opioid addicts
opioid receptors
N-receptor partial agonist
Varenicline Agonist at ACh-N Blocks "rewarding" effects of nicotine Smoking cessation
receptor (22)
subtype Toxicity: Nausea and vomiting, psychiatric changes, seizures in high
dose
Benzodiazepines
Oxazepam Modulators of Enhance GABA functions in CNS; safest alternative for elderly Attenuate withdrawal symptoms
Lorazepam GABAA receptors including seizures from alcohol and
other sedative-hypnotics
NMDA receptor antagonist
Acamprosate Antagonist at May block synaptic plasticity Treatment of alcoholism (in
glutamate combination with counseling)
NMDA receptors Toxicity: Allergies, arrhythmias, variable BP effects, headaches, and
impotence; hallucinations in elderly
Cannabinoid receptor agonist
Rimonabant Agonist at CB1 Decrease GABA and glutamate release in CNS Treatment of obesity; off-label use for
receptors smoking cessation
Toxicity: Major depression; increased suicide risk

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V. DRUGS FOR COAGULATION DISORDERS

DRUGS FOR COAGULATION DISORDERS

Antithrombotic (Anticlotting drugs) Prothrombotic (drugs that facilitate clotting)

Anticoagulants Replacement Factors
Antiplatelets Vitamins K
Fibrinolytics/ Thrombolytics Antiplasmin drugs

Clot Formation:
1. Vascular event  Coagulation Cascade – “zymogen”
 Vasoconstriction  Coagulation Factor/
 Vasodilation Clotting Factor
2.Cellular event/ types of Thrombosis synthesis by liver
a. Platelet migration aggregation  synthesis to zymogen, as
 Aggregation inactive factor I – XII
 Adhesion Examples: Prothrombin  Thrombin
Factors: Fibrinogen  Fibrin
Proaggregants (PLT)
Antiaggregants (endothelium) Intrinsic pathway Extrinsic Pathway
Receptors: Glycoprotein IIb, IIIa
b. Activation of Coagulation Cascade
Glycoprotein IIb, IIIa
Va, VIIa
responsible for interplatelet binding Factor X Factor Xa
Glycoprotein Ia/ Ib VIIIa
responsible for adhesion vascular surface
Ia – bind w/ collagen
Ib – bind w/ Von willebrand Factor FII
Red Thrombus  for after 6-12 hours formation of white thrombus Prothrombin Factor IIa
 Golden period of Coagulation
Thrombin
Stimuli for Thrombosis
endothelial injury
presence of foreign matter in the blood/ blood vessel
Factor I
stasis of blood Factor Ia
Fibrinogen
platelet plug  final product
1 hemostasis Fibrin
White thrombosis
Fibrin  form a mesh work over the white thrombus
 temporary & unstable
(glue)
 to make its stable, there will be an
attract cell (RBC)
Activation of Coagulation Cascade
product: Red Thrombus (secondary homeostasis)
-stable & permanent
-6-12 hours
Three factors that ingluence the formation of Pathologic Clot:
Regulatory Mechanisms:
Virchow’s Triad:
1. Antithrombin  endogenous anticoagulant
- Abnormalities of Blood Flow
2. Protein  anticoagulant
- Abonormalities of Surface contact with Blood
3. Plasmin  serine protease (enzyme aacting on protein)
- Abnormalities of Clotting component
 produced as plasminogen, as inactive form
activated by converting,
Embolus  small part of clot using TPA (Tissue-typePlasminogen Activator)
Thrombosis  formation of fibrin blood clot

Pro-aggregants: Anti-aggregant: Plasminogen

 Serotonin(5-HT)  Prostaglandin (PGI2)
 Thromboxin A2 (TXA2)  PGE1
 ADP  cAMP Antiplasmin
Fibrinolytics
Drugs
Replacement Factor
Clotting factors
Factor VIII Plasmin
MOA: Key factor in the clotting cascade
CLINICAL USES: Hemophilia A

Hemophilia A  lack of Clotting factor VIII

Hemophilia B  lack of Clotting Factor IX Thrombin
Degradation Fibrinogen Fibrin Fibrin Split
Product Products

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Antithrombotic (Anticlotting drugs)

Anticoagulant
Direct Thrombin Inhibitor: directly interfere with action/ destroy factor
Hirudin/  derive form medicinal leeches
Lepirudin – DNA  for the Mx of HIT (Heparin Induced Thrombocytopenia)
MOA: Binds to thrombin's active site and inhibits its enzymatic action
recom. form CLINICAL USE/S: Anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
of Hirudin TOXICITY: Bleeding (monitor with aPTT); anaphylactic reactions
Bivalirudin Angiomax®  Given to patient post-PTCA to prevent thrombosis (PTCA – percutaneous transluminal coronary angioplasty)
Argatroban alternative drug for Mx of HIT
Indirect Thrombin Inhibitor: primarily affect the synthesis of thrombin or its formation
Heparin  (mucopolysaccharide) Hemastat®, Heptin® Bleeding associated w/ the use of Heparin is best
anticoagulant of choice(activates antithrombin III) managed w/ administration of Protamine
initiating anticoagulant therapy Sulfate & stopping therapy
 also for long term use or extended anticoagulation therapy
 anticoagulation for pregnancy
 when used subcutaneousl, there is no need to monitor activity in most cases
SE: Bleeding, HIT (heparin-induced thrombocytopenia)-caused by idiopathic reaction against heparin,
alopecia, thrombocytopenia, osteoporosis with chronic use
CLINICAL USE/S: Venous thrombosis/ deep vein thrombosis(DVT),pulmonary embolism, myocardial infarction,
unstable angina, adjuvant to percutaneous coronary intervention (PCI)/ acute coronary syndrome
MONITORING PARAMETER: activated Partial Thromboplastin Time (aPTT)
CI: Patients w/ Hemophilia
Regular/ Unfractioned Heparin (IV, SQ) MOA: Forms an active complex w/ anti-thrombin III that inactivates factor IXa, Xa, XIa, XIIIa
Low molecular weight / Fractioned Heparin (SQ) MOA: Forms an active complex w/ anti-thrombin III that inactivates factor Xa
Enoxaparin More selective anti-factor X activity, more reliable pharmacokinetics with renal elimination,
protamine reversal only partially effective, less risk of thrombocytopenia
Dalteparin
 Fondaparinux: Effects similar to LMW heparins
Tinzaparin
Warfarin Coumadin®, Zyparin® MOA: Inhibits vitamin K epoxide reductase (inactive from of Vitamin K) and thereby interferes with production
of functional vitamin K-dependent clotting and anticlotting factors (II, VII, IX, X)
TOXICITY: teratogen
MONITORING PARAMETER: Prothrombin Time (PT) - (recommended PT: 3-4/ 2-3)
Antiplatelet
st
Thromboxane synthesis Inhibitor: (<325mg/day)  1 line in the primary & secondary prevention of acute thrombotic events
Aspirin MOA: Nonselective, irreversible acetylation of COX in platelets
CLINICAL USE/S: Prevention and treatment of arterial thrombosis
TOXICITY: Gastrointestinal Toxicity, Nephrotoxicity; Hypersensitivity Reaction due to Increased Leukotrienes;
Tinnitus, Hyperventilation Metabolic Acidosis, Hyperthermia, Coma in Overdose
ADP inhibitor :
Clopidogrel MOA: Active metabolite irreversibly inhibits platelet ADP receptor(pro-aggregants)
CLINICAL USE/S: Acute coronary syndrome, prevention of restenosis after PCI, prevention and treatment of arterial thrombosis
Ticlopidine Ticlid®, Tikpid® Older ADP receptor antagonist with more toxicity,
particularly Leukopenia and Thrombotic Thrombocytopenic Purpural (weekly WBC monitoring is needed)
Phosphodiesterase Inhibitors: Dipyridamole Persantin® MOA: Inhibits adenosine uptake and inhibits phosphodiesterase enzymes that degrade cyclic
nucleotides (cAMP, cGMP) can cause Coronary steal phenomenon
Glycoprotein IIb/ IIIa Inhibitors
Abciximab Reopro® MOA: Inhibits platelet aggregation by interfering with GPIIb/IIIa binding to fibrinogen and other ligands
Tirofiban Aggrastan® CLINICAL USE/S: Used during PCI to prevent restenosis; acute coronary syndrome; post PTCA
Eptifibatide, tirofiban: Reversible GP IIb/IIIa inhibitors of smaller size than abciximab
Eptifibatide Integrilin®
Fibrinolytics  activate plaminogen to plasmin, a serine protease that catalyzes breakdown of fibrin & fribrinogen
Streptokinase  comes from Streptococcus species of bacteria  Bacterial protein that forms a complex with plasminogen that rapidly
can be given after 2 years from current administration converts plasminogen to plasmin. Subject to inactivating antibodies and
enhances the conversion of plasminogen  plasmin allergic reactions
Anisoylated Plasminogen – Streptokinase Activator Complex (APSAC)
Tissue Plasminogen Activator (t-PA) MOA: Converts plasminogen  plasmin, which degrades the fibrin in thrombi
Natural: Alteplase CLINICAL USE/S: Coronary artery thrombosis, ischemic stroke, pulmonary embolism; Thrombolytic
TOXICITY: Bleeding especially Cerebral Hemorrhage
Recombinant: Reteplase, Tenecteplase  Reteplase, Tenecteplase: Similar to alteplase but with a longer half-life
Urokinase Abbokinase

Prothrombotic (drugs that facilitate clotting)

Vitamin K
Phytonadione (Vit. K1) MOA: Increases supply of reduced vitamin K, which is required for synthesis of functional vitamin K-dependent clotting
Menaquinone (Vit. K2) and anticlotting factors
CLINICAL USE/S: Vitamin K deficiency, reversal of excessive warfarin anticlotting activity,
Menadione (Vit. K3) Prophylaxis against hemorrhagic disorder of Newborn
Antiplasmin
Epsilon aminocaproic acid: Tranexamic Acid Hemostan® MOA: Competitively inhibits plasminogen activation
(prevent conversion of plaminogen to plasmin)
CLINICAL USE/S: for Excessive fibrinolysis, reduce the severity of hemarthroses
Minimize post-surgical/ post-dental procedur,
TOXICITY: Thrombosis, Hypotension, Myopathy, Diarrhea

Acetanilide  Antifibrin
 Acetophenetidine
 Phenacetin
Phenprocoumon  limit its climincal use in the mx of thrombosis due to its
primary drawback, its half-life.

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VI. DRUGS FOR LIPID DISORDERS

Nieman- Pick Like Enter the portal

Transporter circulation CHYLOMICRONS
(NPC1 L1 Transporter) (LIVER)

Lipoprotein
Lipase

(INCOMPLETE) (COMPLETE)
Blood vessel VLDL repackaged Liver Monoglycerol + 2 fatty Acids Glycerol
or Or +
Systemic Diglycerol + 1 fatty Acids 3 fatty Acids
circulation
Lipoprotein IDL
Lipase (Intermediate
Density LDL
Lipoprotein)

Role of the Liver

Liver  only organ that metabolizes cholesterol
 upon metabolizing cholesterol in Liver, it will be converted into Bile Acids
maintains a certain amount of bile acid in the body.
Sources of Cholesterol in the Body:
de novo synthesis of cholesterol (acetate mevalonate) Normal Value
Acetyl CoA  HMG-CoA HMG-CoA Reductase mevalonate Total Cholesterol 3.88 – 5.15 mmol/L
Cholesterol  Cyclopentanophenanthrene (CPPP) HDL <3.38 mmol/L
LDL <1.04 mmol/L
Secondary Sources of Cholesterol Triglycerides <2.82 mmol/L
increase or synthesis of hepatic LDL receptor Hyperchlerolemia, Hypertriglyceridemia
LDL bad cholesterol may cause,
 primary role/function: brings cholesterol from the liver Atherosclerosis  obstruction of blood flow
to the systemic circulation Risk Factors: Female (age >55)
HDL good cholesterol Male a (age >45)
 primary role/ function: sequester cholesterol from Family History
systemic circulation back to the liver Obesity

DRUGS FOR LIPID DISORDERS

Statins  1st line in the Mx of Hypercholesterolemia
 for coronary heart disease
 largest amount of evidence on the benefits of lipid-lowering therapy
Short-acting MOA: Inhibit HMG-CoA reductase Lovastatin & Simvastatin  vulnerable to myositis
Fluvastatin Lescol® CLINICAL USE/S: Atherosclerotic vascular disease  depend on P450-3A4
(primary and secondary  active form: -hydroxy acid
Simvastatin Zocor® prevention); acute coronary Pravastatin  doesn’t metabolized w/ P450-3A4
Lovastatin syndromes Other Statin  have less reliance on this enzyme
Long-acting Rhabdomyolysis Atorvastatin & Rosuvastatin  have long half-lives making
TOXICITY/SE: Hepatoxicity (hepatic dysfunction), bight dosing unecessary
Atorvastatin Lipitor® Rhabdomyolysis/ Myopathy,teratogen
Rosuvastatin Crestor® INSTRUCTIONS: Take it Before Bedtime
Can be taken w/ or w/out meals
Fibrates  1st line in the Mx of Hypertriglyceridemia Statins & Fibric Acid
Gemfibrozil Lopid® (Fibric Acid Derivatives) Combination
Fenofibrate Liphantyl®, Lofibra® MOA:Stimulate lipoprotein lipase/ PPAR- agonists can increase the risk of
CLINICAL USE/S: to lowere VLDL, Hypertriglyceridemia, Low HDL cholestero myopathy &
Clofibrate SE: increase risk of Bile Stone or Gallstone formation cause Rhabdomyolysis; rhabdomyolysis
Increase incidence liver cancer w/ Clofibrate used
Nicotinic Acid (Niacin) Niaspan®  is associated w/ cutaneous vasodilation & sensation of warmth after an initial dose which may be reduced w/ the
Vitamin B3 use of 300mg dose Aspirin taken an hour before the dose
 is tolerated poorly because it induces Flushing(can be inhibited by Aspirin)
MOA: Decreases VLDL synthesis and LDL cholesterol concentrations; increases HDL cholesterol
CLINICAL USE/S: Low HDL cholesterol, elevated VLDL and LDL
TOXICITY/SE: Hepatotoxicity, Gastrointestinal Irritation, Flushing, Hyperuricemia, may Reduce Glucose Tolerance
Bile Acid binding resins  add on treatment to statins for hypercholesrolemia
Cholestyramin Questran®  anion-exchanger
Colestipol Colestid® MOA: Prevents reabsorption of bile acids from the gastrointestinal tract
CLINICAL USE/S: Elevated LDL cholesterol, pruritus
SE: Steatorrhea, Increase Gallstone Formation; Inhibit absorption of fat-soluble subsatnces
TOXICITY: Constipation, Bloating
NPC1L1-like transportre inhibitors
Eztimibe Ezetrol® MOA: Reduces intestinal uptake of cholesterol by inhibiting sterol transporter
CLINICAL USE/S: Elevated LDL cholesterol, phytosterolemia
TOXICITY: Rarely, Hepatic Dysfunction, Myositis

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VII. CARDIOVASCULAR DRUGS

Hypertension

Factors affect Blood Pressure

BP Determinants: BP= CO X SVR – Systemic vascular Resistance SVR= Stroke Volume CO= HR X SV
PVR – Peripheral Systemic Resistance amount of blood that HR heart rate
TPR – Total Peripheral Resistance is pump out of the SV – Stroke volume
BP: Two Mechanism of BP regulation heart every beat volume of blood pump
1. Baroreceptor reflex Mechanism = cardiac afterload by the heart per beat
vasodilation
CO – cardiac output
vasoconstriction – (increase BP) Application: volume of blood pump
Barorecptors VasoC Arteiolar  BP by the heart per minute
Carotid arteries  CVA (central vasomotor area) Vein  BP
 sends sympathetic signals to the heart
NE  vasoC  BP SV = contributors of SV:
and to the bloodvessels: HR (vasoconstriction) CC  Cardiac
  (+)CC  BP
Aortic arch  detect P; vol  (+) stretch
HR  BP Contractility
2. RAAS - (Renin- angiotensin Aldosterone System) (CC, SV)
 responsible for long term BP regulation VR  Venous Return
Arteriolar vasodilators:
Renin  is realsed in JG/ Juxtaglomerular (Kidney) cardiac preload
SE: Reflex tachycardia
 an enzyme released by the kidneys that breaks down proteins and end diastolic
Tx:  - blockers
helps regulate blood pressure ventricular volume
Peripheral Edema
Renin is release: Stimulus: B activation the amount of
Tx: Diuretic
Renal Hypoperfussion blood goes back to
preloader
Renal Hypotension the heart during
Angiotensinogen renin Angiotensin I ACE Angitensin II ACE, ARBs diastole
Causes: Vasoconstriction  are preload & VR = Factors of VR
NE release afterload reducers/ VT – Venous Tone
aldosterone unloaders VT: VasoC
secretion VT: VasoD
NA & H2O retension VT: VR
K excretion FC  Fluid Content
Effect: elevation of BP of Blood
Angiotensin II  has 8 amino acids FC VR
Aldosterone (by Adrenal Cortex, zoma glumerolosa) FC VR

SBP DBP Systolic  heart contraction: the contraction of the heart,

<120 <80 Normal during which blood is pumped into the arteries
120-139 80-89 PreHypertension Diastolic  expansion of heart on each beat: the rhythmic
140-159 90-99 Stage 1 expansion of the chambers of the heart at each
>160 >100 Stage 2 heartbeat, during which they fill with blood

Special Hypertension Conditions:

a. HTN in pregnancy
Chronic Hypertension  less than 20weeks gestation For Pregnancy Hypertensive:
Gestational Hypertension  greater the 20weeks of gestation Methyldopa
Pre-eclampsia  a gestational hypertension but w/ albuminuria Nefidipine
Rclampsia  a pre-eclampsia w/ seizure or convulsion Labetalol
 DOC : Magnesium Sulfate Hydralazine
b. Hypertensive Crisis: For Hypertensive Emergencies:
Hypertensive Urgency = 180/100 Enalaprilat
Hypertensive Emergency = Papilla edema Diazoxide
Acute hearing Failure Sodium Nitroprusside
Acute Renal Failure
Encephalopathy

Sodium Nitroprusside  activation of Guanylyl

cyclase w/ increase in
CGMP

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Drugs Used in Hypertension

Diuretics  causes urinary loss of Na & H2O
Proximal convoluted : Carbonic Anhydrase inhibitors; Osmotic Diuretics
Loop of Henle: Furosemide; Loop Diuretics
early Loop of Henle: Osmotic Diretics
Distal Convoluted Tubule: Thiazides
Carbonic Anhydrase Inhibitors (-zolamide)1st line Mx of Open-angle glaucoma
sulfonamide; sulfamoyl group responsible in invitro carbonic anhydrase inhibitory activity
& for the production of a diuresis in vivo.
Acetazolamide Cetamid®, MOA: Inhibits carbonic anhydrase in proximal convoluted tubule of the kidneys
Zolmide® & ciliary bodies of the eyes
 short-lived natriuretic & diuretic effect, don’t last for more that three days
Diamox®
 increase aqueous humor production
Brinzolamide Azopt® CLINICAL USE/S: Glaucoma; mountain sickness; edema with Metabolic Alkalosis;
Dorzolamide Seizure disorder, especificcaly Metazolamid
Dorzolamide + Timolol Trusopt®, Cosopt® SE: Metabolic acidosis; sedation, paresthesias. Hyperammonemia in cirrhosis
Sulfa-associated side-effects: SJS, aplstic anemia, hemolytic anemia, hypersensitivity reaction
Dichlorphenamide CI: -COPD = Chronic Obstrcutive Pulmonary Disease (already has metabolic acidosis)
-chronic liver disease
-patient w/ a history of TCA’s Hypersensitivity

Acetazolamide is most useful for the mx of Nephrolithiasis due to idiopathic hypercalciuria

 has been found to be useful for the management of catamenial seizures
(seizures during menses)
 use for Glaucoma to reduce reabsorption of hydrogen
Osmotic Diuretics
Mannitol MOA: Cretaes an osmotic gradient at the eater permeable regions of the renal tubule (PCT, early Loop of Henle)
CLINICAL USE/S: Mx in increased Intracranial Pressure or Edema
SE: Hyponatremia followed by hypernatremia; headache, nausea, vomiting; dehydration;
Massive loss of wqter (hypovolemia)/ hypernatremia since doesn’t los sodium
Loop Diuretics  high ceiling, highly effective diuretics, most effective among diyretics
which ahave become preferred due to theior ability to increase sodium excretion by 20-25% of the filtered oad & to maintain their efficacy until
renal function is severely impaired
sulfanamide = Frosemide, Bumetanide
sulfonylurea = Torsemide
Phenoxyacetate = Ethacrynic Acid (only loop diuretic does not contain Sulfur)
+ + –
Furosemide Lasix®, Diuspec®, Fusemex® MOA: Inhibit Na /K /2Cl transporter in thick ascending limb of loop of Henle.
Bumetanide Burinex® Cause powerful diuresis and increased Ca2+ excretion
CLINICAL USE/S: Heart failure, pulmonary edema, severe hypertension; other forms of edema;
Torsemide Pulmonary congestion; oligoric/ aneuric/ acute renal failure; hyperkalemia;
Ethacrynic Acid hypercalcemia; anion poisoning
SE: Electrolyte Imbalance, Hyperglycemia, Dyslipidemia, Hyperuricemia,
Metabolic Hypokalemic Alkalosis; Ototoxicity; Hypovolemia
CI: Gout
efficacy is reduced by nonsteroidal anti-inflammatory drugs.
 Ethacrynic acid: Like furosemide but not a sulfonamide and has some uricosuric effect
Chem. Name of Furosemide: 4-chloro-N-furfuryl-5-sulfamoyl anthranilic acid
is useful as a rapid-acting intravenous agent in reversing acute pulmonary
edema
 ototoxic
Thiazide Diuretics  1st line in Mx of HTN(as montherapy or combination therapy8) in nephrogenic diabetes insipidus
Structure: Benzothiadiazine-1,1-dioxide nucleus
Benzothiazides (sulfur-containing)= HCTZ, Chlorthiazides
Thiazide-like compound= Indapamide, Chlorthalidone, Metalazone
+ –
Hydrochlorothiazide (HCTZ) MOA: Inhibit Na /Cl transporter in distal convoluted tubule.
Hydrochlorothiazide + Losartan Hytaz®, Combizar®, Hyzaar® Cause moderate diuresis and reduced excretion of calcium
CLINICAL USE/S: Mx of nephrogenic diabetes insipidus
Hydrochlorothiazide + Valsartan Co-diovan® SE:, Electrolyte imbalance; sulfonamide Effect;
Chlorothiazide metabolic Effects: Hyperglycemia, Hyperuricemia, Dyslipidemia
CI: Gout
Potassium-sparing diuretics
Aldosterone Antagonist = Spirinolactone, Eplerenone
Direct Na-CL transporter = Amiloride, Triamterene
+
Spirinolactone Aldactone® MOA: Steroid inhibitors of cytoplasmic aldosterone receptor in cortical collecting ducts; reduce K excretion
loss when using other diuretics; Aldosteronism; CHFw/ Conn’s Syndrome
+
Eplerenone CLINICAL USE/S: Excessive K
SE: Hyperkalemia; Gynecomastia (spironolactone only)/ Anti-Androgenic Effect
Amiloride MOA: Inhibitor of ENaC epithelial sodium channels in cortical collecting duct, reduces Na+ reabsorption and K+ excretion
+
Triamterene CLINICAL USE/S: Excessive K loss when using other diuretics; usually in combination with thiazides
SE: Hyperkalemia
Triamterene  is the primary compound selected from a host of pteridine analogues & resembles the structure of the folic acid & certain
dihydrofolate reductase inhibitors
MOA of Amiloride  Pyrazinoyl Guanidine Diuretic that inhibits the electrogenic entry of 2% to 3% of the filtered load of Na into the
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Sympathoplegics
Centrally-acting Anti-HTNsive
Clonidine Catapres®, Catapin®, Melzin®
Methyldopa Aldomet®, Dopamet®  is converted first to -methyldopamine & -methylnorepinphrine which stimulate central alpha-2 receptors
 SE: Sedation
Guanfacine
Guanabenz
Peripheraly-acting sympathoplegics:
Reserpine
Guanethidine
Guanadrel
Ganglionic Blockers
Alpha Blockers
Beta Blockers  can actually worsen an Active Angina Pectoris
 reduce myocardial oxygen demand by reducing myocardial contractility making them useful for Chronic Stable Angina Pectoris

Vasodilators for Hypertensive emergencies

Arteriolar Vasodilators
Hydralazine Apresoline®, Aprezin® MOA: K+ channel opener in smooth muscle, secretory cells
Minoxidil Regrow®, Relive®, Minoxidil Isac® CLINICAL USE/: Diazoxide  hypoglycemia due to insulin-secreting tumors
 pure arteriolar vasodilator
Diazoxide SE: Hyperglycemia; edema, excessive hypotension; reflex tachycardia; peripheral edema
Minoxidil- hypertrichosis or hirsutism (extended use: hair growth stimulant)
may minimize when combined w/Diuretic & -blocker
CI (hydralazine): Patient w/ Ischemic Heart Disease
 Hydralazine  causes SLE-like symptoms
Mixed Arterial & Venous dilators
Na Nitroprusside (Fe, NO2, CN) 1 line in HTNsive emergencies
st
Na Nitroprusside Nipride®
Nitrovasodilators/ Organic Nitrates  a fast-acting vasodilating agent
 also commonly used for sevrere deconsated congestive heart failure (CHF)
(to be discussed in angina)
MOA: increase CGMP levels (Releases NO from drug molecule)
Special Precaution: Protect form sunlight, use freshly prepared preparations
SE: Excessive hypotension; prolonged infusion may cause thiocyanate and cyanide toxicity

Calcium Channel Blockers  all CCBs are Natriuretic & Diuretic

 Drugs for Angina at rest.
Intrinsically Short-acting
Long-acting= amlodipine
Modified long-acting= felodipine, Verapmil, Nefidipine
Dihydropyridine (dipine)  close & open state
Nifedipine Adalat®, Adalat GITS®, Calcibloc®, Odipin® MOA: block the L-type Ca channel in arteriolar smooth muscles
Nimodipine Nimotop® CLINICAL USE/S: Hypertension, angina, arrhythmias
SE: (Reflex Tachycardia)Excessive Cardiac Depression;
Amlodiipine Lopicard®, Provasc®, Stamlo®, Vasalat®, Normasc®, Amvasc Peripheral Edema; Significant degree of Constipation
Felodipine Plendil®, Versant SR®
Non-Dihydropyridine  open state
Verapamil Calan® MOA: block the L-type Ca channel in arteriolar smooth muscles and myocardium
Verapamil + Trandolapril Isoptin®, IsoptinSR®, Tarka® SE: Bradycardia; Peripheral Edema
Verpamil  has greater activity on Ca channel in myocardial tiisues
Diltiazem Dilzem®, Dyalac®  Verapamil + Trandolapril (Isoptin®, IsoptinSR®, Tarka®)  DOC for Prinzmetal Angina

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Angiotensin Modifiers
ACE Inhibitors (-pril)  Base treatment of CHF Effects: 1. Decrease vasoconstriction
 1st line Mx of HTN in CKD & DM 2. increase bradykinin (vasodilating effect)
st
1 line for albuminuria reflex for cough reflex
 inhibit kinin metabolism (in the lungs) 3. increase prostaglandin
Sulfhydryl = Captopril CI: Bilateral renal artery stenosis; Hyperkalemia; Pregnancy
Phosphinyl = Fosinopril
Carboxyl NSAIDS  reduce the efficacy of ACEi in the mx HTN
active ACE: Captopril, Lisinopril, Enalaprilat IV
Prodrug: Enalpril, Perindopril, Ramipril
Captopril Capotec®, Primace®, Prilat®, Tensoril®, Vasostad® MOA: inhibit Angiotensin Converting ENzyme
Fosinopril BPNorm CLINICAL USE/S: Hypertension, diabetic renal disease,
heart failure
Lisinopril SE: Hyperkalemia; Teratogen; Cough(Idiosyncratic Dry Cough);
LIsonopril + Hydrochlorothiazide Zestril®, Zestoretic® Renal Failure in Infants
Enalaprilat
Enalapril Renitec®, Hypace®, Vasopress®, Hypril® Enalapril  exhibits pharmacodynamic interaction w/ the
Thiazide Diuretics leading to reduced diuretic
Perindropil effect
Perindropil + Indapamide Conversyl®, Novaril®, Perigard-4®, Preterax®
Angiotensin Receptor Blockers (ARBs: -sartan)
Losartan Cozaar®, Hylos-50®, xartan®, Provisar®, Lifezar® MOA: Blocks AT1 receptors
Candesartan
Candesartan + HCTZ Blopress®, Candez®, Blopress Plus®
Valsartan Diovan®,
Valsartan+ HCTZ Co-Diovan®
Valsartan+ Amlodipine Exforge
Renin Inhibitor
Aliskerin (Tekturna®, MOA: Renin inhibitor; reduces angiotensin I synthesis /(binds to CLINICAL USE/S: add-on to ACE-inhibitors or ARBs fro HTN
Rasilez®) rennin preventing interaction of rennin to angiotensin SE: Angioedema, renal impairment, dry cough, rashes

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Drugs for Angina Pectoris

Ischemia : decrease in Oxygen
Infarction : no oxygen
Determinants of Cardiac Oxygen Requirement
Diastolic Factor: Blood Volume
Venous Tone
Systolic Factor: Peripheral Resistance
Heart Rate
Heart Force
Ejection time
Major determinant: Myocardial Fiber Tension (the higher the tension, the greater the oxygen requirement)

Nitrovasodilators Primary MOA: Dentrification by glutathione S-transferase leads to

Nitirc Oxide potent vasodilator release of nitrite ion which is then converted to nitric
Very short-acting: last only for 5-10 minutes oxide, a molecule that activates guanylyl cycles
Amyl Nitrate (inhalational)  for acute angina leading to increase cGMP
Short-acting: last 10-30minutes
Isosorbide Dinitrate Uses: For mx of acute angina (sublingaual, inhalational)
Nitoglycerin SL Prinzmetal (type of chest pain)= DOC: CCBs
Intermediate-acting: 5-8 hours For chronic
ISDN PO, NTG-SR For hypertensive emergencies
Long-acting: 10-24 hours For add-on CHF; ISDN+ hydralazine
ISDN SR, ISMN For Acute pulnmonary edemy
Initial mx of CN poisoning: Amyl Nitrite
Amyl Nitrite
Relief of Angina Pectoris MOA of NitroVasodialtors:
Isosorbide dinitrate Isobar®, Isodil®, Nitrosorbon®, Isoket spray® Reduction in Myocardial
Nitroglycerin Nitrostat®, Deponit NT,NItonal®, Transderm-Nitro 5 ®, oxygen demand & cardiac
Isosorbide Mononitrate Isomonit®, Isonate®, Monosorb®, Vasotrate®, Imdur® preload

SE: Hypotension, Migraine-like HA, Tolerance(due to sulfhydryl

moieties)

Veins  the tissues exhibit the greatest sensitivity to

Nitrovasodilators at the lowest effective doses
Isosorbide Mononitrate  does not undergo first-pass effect
(100 % bioavailability)
Amyl Nitrite  for Cyanide Poisoning
=induce conversion of hemoglobin to
methemoglobin (methemoglobinemia) which can
lead to cyanosis
Beta Blockers  DOC/ 1st line maintenance treatment for CSAP (Chronic Stable Angina Pectoris)
Calcium Channel Blockers  Non-DHP – alternative for CSAP
Long-acting – Alternative for CSAP
Short-acting – for Prinzmetal Angina

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Drugs for Heart Failure

Inotropics
Cardiac Glycosides: Digoxin Lanoxin®, Lanox®, Cardioxin® MOA: Blocks the Na-K ATPase thereby increasing intracellular sodium & preventing calcium
extrusion
Primary Indications: Control the rate of Ventricular response in atrial fibrillation
Useful in Pregnant patient w/ CHF
Mechanical EFFECTS: (+) Inotropism(contaction of heart muscles);
Intracellular Ca2x dromotism
Decrease conduction velocity in the AV node
Electrical EFFECTS: Decrease in the refractory period of atrial muscles
Increase in the refractory period of the AV node
Increase in the automaticity of atrial tissues & the AV node
Conditions that may augment the Effects of Digitalis Glycosides:
-Hypokalemia
-Hypomagnesemia
-Hypercalcemia (Concurrent administration of Calcium gluconate)
-Hypoxia (Reduced oxygenation of myocardial tissues)
SE: Heart: Bradycardia, Arrhythmia (VT)
Non-Cardiac: Nausea, Vomiting, ophthalmic effect (blurring of vision)
Pharmacokinetic Parameters: In about 10% of patients, use of antibiotics can lead to
increased oral bioavailability as the bacteria in the intestines
normally reduce systemic absortion of Digoxin.
Toxicity: Digitalis binding antibodies
Potassium Supplements  are given if the patient is hypokalemic
Cholestyramine  capable to binde to digitalis glycosides
 may also help prevent absorption & reabsorption of digitalis in
the bile
Fab-Fragment  for patient with very high serum digoxin levels
for suicidal overdose w/ Digoxin
 give Digibind®, Digifab®  antibody fragments that bind digitalis
Digoxin Digitoxin
F 70-75% 90%
T1/2 36-40%
Protein binding 20-40% 80%
Vd 6.3L 6L
Excretion renal hepatic
 Toxic Plasma Concentration of Digoxin: 2ng/mL

 Quinidine  decrease the renal clearance of Digoxin

 Na-K pump  affected by Digitalis Glycosides & Oabain

B1 agonist
Dobutamine Dobunex®, Cardomin® CLINICAL USE: Mx of acute heart failure or acute
Dopamine Dopamax®, Dokard®, Cardiofast®, Myocard®, Intropin® exacerbation of a CHF
Phosphodiesterase
Amrinone MOA: Inhibits PDE enzyme (increase levels of cAMP)
Milrinone CLINICAL USE: mx of Acute Heart Failure or Exacerbation of CHF
SE: Arrhythmia, Hypersensitivity, thrombocytopenia
Unloaders
Preload  first amount of the bloodgoes back to the heart
Afterload  systemic vascular resistance
ACE inhibitors & Angiotensin Receptor Blockers  (main treatment) very effective forcongestive heart failure: preload, afterload
Diuretics preload unloader
Vasodilators  ISDN + hydralazine
ISDN  preload
Hydralazine  afterload
Beta Blockers: Metoprolol, Bsoprolol, Carvidilol only
Brain natriuretic peptide (BNP) analogue: Nesiritide Natrecort® Effect: Massive Vasodilation
-IV CLINICAL USE: Mx of AHF (acute heart Failure)

Dopamine exhibits a wide range of effects;

-Doses of 2-5 g/kg/min  increases renal blood flow through its
dopaminergic effects.
-Doses of 5-10 g/kg/min  increase cardiac output through its -adrenergic
stimulating effect
 is seleted for its positive inotorpic effects on
treating the patient w/ HF
-Doses of 10-20 g/kg/min  increase peripheral vascular through -
adrenergic stimulating effects.

Dopamine  3,4-dihydroxyphenylethylamine
 acts directly as  &  resptors
 biosynthetic precursor of norepinephrine & Epinephrine
 used to treat Hypotension

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Anti-Arrhythmic Drugs
Vaugh-williams Classification
Class I (Na Channel Blockers)
Class Ia prolong action potential  work by blocking the rapid inward sodium current & thereby slow down the rate of rise of the cardiac tisue’s action
potential
 prolong the duration of the action potential & dissociates from the channel w/ Intermediate Kinetics
Procainamide Pronestyl® causes SLE-like symptoms
Quinidine Quinidex® cause Cinchonism (maniofestated by gastrointestinal disturbances. In severe cases, Nausea, Vomiting, Diarrhjea,
Headache, Confusion, Delirium, Photophobia,
Diplopia, & psychosis may also occur)

Disopyramide Norpace®
Class Ib  Shorten the duration of Action potential capable of shortening repolarization or the refractory period, as they weakly affect the repolarization rate.
Lidocaine DOC in the treatment in Ventricular Fibrillation
decrease efficacy over time
Metabolie: Xylidide  competes Lidocaine fro binding
LIdocaine + Epinephrine Xepacaine®, Xylocaine®, Nobucaine®, Enducaine®, Epicaine®
Phenytoin Dilantin®, Lantidin®, Fenitin® SE: Gingival Hyperplasia
Nystagmus
Tocainide Tonocard®
Mexiletine Mexitil®
Class Ic  No effect on action potential  strongly depress depolarization but have a negligible effect on the duration
 dissociates from the channel w/ slow kinetics
Profenone Rythmol®
Encainide Enkaid®
Moricizine Ethmzine®
Flecainide Tambocor®
Class II (Beta Blockers)
Propanolol Inderal®
Esmolol Brevibloc®
Acebutolol Sectral®
Class III (Potassium-channel blockers)
Amiodarone Myodial®, Cordarone®, Arrythgo® 1st treatment in Ventricular Tachycardia/ Atrial Fibrillation
iodine-containing (32%)
has a prolong action potential
 must be associated w/ ALT level measurement
SE: First two weeks: hypothyroidism
After two weeks: Hyperthyroidism
Wolffe-Chaikoff Effect
Bradycardia
Important SE: Hepatotoxicity, Pulmonary Fibrosis
Sotalol Betapace
Bretylium
Ibutelide Corvert
SE: Torsade de pointes
Dofetilide Tikosyn
Class IV (Calcium channel Blockers)
Verapamil  is primarily indicated for the tx of chronic paroxysmal Supraventricular Tachyaarhythmias
 only Ca channel blocker w/ proven clinical role in arrhythmia therapy
Diltiazem
Miscellaneous Agents:
Adenosine Cardiovert® 1st line treatment in acute episodes of Supraventtricular Tachycardia
5 seconds t1/2
SE: Bronchospasm
Magnesium ion 1st line in the mx of Torsades de Pointes
Potassium ion for Digitalis toxicity and other arrhythmias if serum K is low

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VIII. DRUGS FOR THE RESPIRATORY SYSTEM

Drugs for Colds

Viruses: Adenovirus
Coronavirus
Rhinovirus
(self limiting 5-7 days)
Common Colds
Nasal Decongestants (local vasoconstrictors)  fro 5 days only (if exceed, lead to tolerance)
Effect: Vasoconstrition; Urinary Retension
Side Effect:
PO= exacerbation of HTN
Precipitate urinary retention in patient BPH
Tolerance
A1 agonists: Loss of responsiveness to a given dose of a drug
Phenylephrine Mydfrin®
Phenylpropanolamine  was out of the market
Cold medications: increase hemorrhagic stroke
Dextromethorphan + Paracetamol Tuseran Forte® centrally acting sympathomimietic
Chlorphenamine Maleate + Paracetamol Decolgen Forte®, Bioflu® together with: Amphetamine
Methylphenidate
Phenyltoloxamine citrate + Paracetamol Sinutab PE® Phentermine
Phenylpropanolamine+ Chlorphenamine + Paracetamol Sinutab Extra Strength Phennetrazine
Propylhexedrine
Oxymetazoline
A2 agonists:
Colindine
Apraclonidine
Brimonidine
Allergic Colds
Nasal decongestants
H1-antihistamines

Drugs for Cough & Mucus Production

Mucoregulators  only produce a placebo-like effect
Bromhexine Bisolvon® MOA: Increases the water portion of the mucus thus decreasing viscosity of mucus
Carbocisteine Solmux®
Ambroxol Mucosolvan®
Mucolytics  decrease the viscosity of bronchial secretions for easier expectoration
N-acetylcysteine Fluimucil®, Mucomyst®, MOA: Break sulfide linkages between mucus molecule
Hidonac®, Exflem® NAC has –SH, for formation of glutathione
to detoxify the paracetamol maetabolite that causes toxicity (NAPQI)
Expectorants
Guiafenesin (glycerol guiacolate) Robitussin MOA: Stimulate bronchial glands to secrete more of the water portion of the mucus
Expectorant: Mgt of chronic bronchitis
inflammation of bronchi & increase mucous production
COPD: Chronic bronchitis
Amphysema  loss of decrease on elasticity of alveoli
there will be air trapping of carbon dioxide that lead to respiratory acidosis.
CI with COPD patient: Diuretics (Carbonic Anhydrase inhibitors)
prevent reabsorption of Bicarbonate (bicarbonaturia)
lead to metabolic
acidosis
Anti-tussive/ cough suppressant
MOA: Inhibit the cough center at the CNS
Peripheral-acting
Butamirate citrate Sinecod®  Peripheral-acting antitussive
MOA: decrease sensitivity of peripheral receptor
Centrally-acting
Codeine Robitussin AC®  Centrally-acting antitussive
Noscapine MOA: Hyperpolariztion of cough receptor
Narcotic  codeine; noscapine
Dextromethophan Robitussin DM®, Tuseran Forte® Non-narcotic  dextromethrphan
USES: Management of harmful cough (TB) – suffer from hemophysis(blood in the sputum)
Useful Cough (Iron-Productive)
Excessive Cough

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Drugs for Bronchospastic Disorders

Based on Effects:
Relievers  management of acute exacerbation SABA
Controllers  prevention of acute exacerbation  steroids; LABA
Based on Mechanism of Action:
1. Bronchodilators
2. Mast cell Stabilizers
3. Anti-inflammatory
Brochodilators
2 agonist
SABA (Short-acting) 1st line reliever in BA & alternative reliever in COPD SE: Tremors
Salbutamol Brecanyl® subcutaneously given as mx of acute episodes of bronchospasm
Terbutaline subcutaneously given as mx of recalcitrant acute exacerbation of bronchial asthma
to increase heart rate in sympotomatic hypertension
LABA (Long-acting)  1st line controller (w/ inhaled GC) for COPD
Salmeterenol  is not suitable for acute breakthrough attacks of bronchospasm
Formeterenol
Bambuterenol
Methylxanthine
Theophylline Theodor®, Asmalon® MOA: Adenosine Antagonist;
Aminophylline PDE inhibitor;
Inhibit the late phase allergic reaction occurring 2-8 hrs after an acute attack
CLINICAL USE: Alternative bronchodilator in severe BA attacks (reduce nocturnal attack),
Respiratory Stimulant in COPD
Neonatal Apnea
SE: Cardiac: Palpitation
Tachycardia
Arrhythmia
CNS: CNS Stimulation
-agitaion
-confusion
-seizure
Diuresis (proximal renal tubule like osmotic diuretic, carbonic anhydrase inh.
Anticholinergics  1st line bronchiodilator in COPD
Oxytropium Anticholinergics primary used as relievers (more effective in COPD than in Bronchial Asthma)
Tiotropium  first line relivers of COPD
 altenative reliever of bronchial asthma
Ipratropium  can be safely given at high doses by inhalations
Ipratropium + Salbutamol Combivent® SE: Alice in the Wonderland Syndrome
Ipratropium + Terbutaline Berodual®
Mast cell Stabilizer controllers only; prophylaxis; 3-4 weeks
Nedrocromil MOA: Induce opening of inward Cl- channels leading to influx of Cl- into mast cells
Cromolyn Sodium/ Na Cromoglycate CLINICAL USE: Mx of allergic conditions
SE: may induce bronchospam (given SABA to prevent bronchospasm)
Cromolyn Sodium  inhibit the degranulation of mast cells in asthmatic patients, thereby preventing the
release oof the chemical mediators of anaphylaxis
Anti-inflammatory Agents
Leukotriene Modifiers:
Lipooxygenase Inhibitor CLINICAL USE: alternative controllers in persistent bronchial asthma
Zileuton Zyflo® Management of NSAIDs induced bronchial asthma
SE: Unmask the symptoms of Churgg-Straus Syndrome (eosinophilic vasculitis)
Leukotriene Receptor Blocker (LTD4 antagonist) can be treadted with steroids
Montelukast Montemax®, Singulair®
Zafirlukast Accolate®
Glucocorticoids
Locally-acting inhaled GC (Low dose)  1 line controllers for BA
st
Budesonide Pulmicort®
Beclomethasone Systemic GC(parenteral)  1 st
line in status asthamticus
MOA: Inhibit the synthesis of phospholiase A2
Fluticasone Inhibit the late phase allergic reactions
Triamcinolide Inhibit the release of interleukin by the macrophages
Prednisone Inhaled Corticoids  adjunctive controllers; COPD
SE: oral candidiasis  vocal cord nodules
Prednisolone
Oral thrush  hoarseness
Hydocortisone Solucortef® Prevention of oral candidiasis: gargling (3-4x); use of spacers
Methylprednisolone Solumedrol® PO: Prednisone; Prednisolone
are given not more thant 10days(if exceed, aderanl suppression)
Short Course Therapy: Acute BA Exacerbation
Exacerbation: Early phase  airway obstruction (brochodilation)
Late Phase  2-8hrs ; inflamation
IV: Methylprednisolone; Hydrocortisone
management of severe acute asthma exacerbation

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IX. DRUGS FOR GASTROINTESTINAL DISORDERS

Drugs for Peptic Ulcer Disease

Antacids
Aluminum Hydroxide+ Magnesium Hydoxide Maalox® MOA: Chemical Neutralization
Aluminum Hydroxide+ Magnesium Hydoxide + Dimethicone Maalox IMPORTANT SE: Mg – Diarrhea, Al – constipation, Ca – renal stones
Plus®
Aluminum Hydroxide+ Magnesium Hydoxide + Simethicone Kremil-S®
Sodium Bicarbonate + Calcium Carbonate+ Sodium Alginate Gaviscon®
Sodium Bicarbonate Rhea®
H2-receptor Antagonist
Proton Pump Inhibitors (aka Benzimidazole)
Omeprazole Losec® MOA: Inhibit H-K ATPase pump If Dopedogrel is given w/ PPI
Lansoprazole Prevacid® USES: Mx of GERD (Gastrointestinal reflux disease) the effect of Dopidogrel will decrease,
Acid Peptic Disease since it blocks the CYP2C19
Esomeprazole Nexium® Gastrtis (due to NSAIDs use) ACS (Acute Coronary Syndrome)
Pantoprazole Pantoloc® SE: Diarrhea tx: Clopedogrel+ PPI (Pantoprazole)
Rabeprazole Vit B12 Deficiency (to decrease risk of stress-
 Gastric Infection induced gastritis)
NOTE: formulated as enteric coated tablets since they ACS: Acute manifestation of CAD
get degrade in an acidic environment Chest pain lasting for 20min & is not relieve by
Formulation: Acid –Labile  enteric coated tablets rest & nitrates
Three conditions under ACS:
Intruction Before Use: ―Take this medication once a day unstable angina
before Breakfats‖ STEMI (st-elevation MI)
NSTEMI (non-ST elevation MI)
Prostaglandins
Misoprostol Cytotec® PGE1 Analogue (cytoprotectant effect in the GI mucosa)
Mucosal Protectants
Sucralfate Iselpin® MOA: forms a protective barrier between the acidic environment of the stomach the epithelium by lining the
Colloidal Bismuth Subitrate stomach wall
 Sucralfate  used as short term therapy of ulcers
Triple Drug Therapy to Eradicate H. Pylori
Omeprazole + Clarithromycin + Metronidazole/Amoxicillin
Bismuth subsalicylate + Metronidazole + Tetracylcine
Ranitidine/ Bismuth subcitrate+ Tetracycline+ Clarithromycin/ Metronidazole
Quadruple Drug Therapy to Eradicate H. Pylori
Omeprazole + Bismuth subsalicylate + Metronidazole+ Tetracycline

GERD (Gastrointestinal Reflux Disease)

s/sx: heartburn epigastric pain (4-6 weeks)
Risk factors: Obesity, Tight Clothing, Food

GI intolerance  hyperacidity Magaldrate  used as gastric antacid & is

() mucosal damage official as its oral suspension
Px: taking NSAIDs after a full meal & tablets
GI ulcers/ bleeding gastritis
(+) mucosal damage
Px: *PPI, H2 blockers, Misoprostol
Metronidazole  has activity against
anaerobic organism &
against most protozoan
PUD (Pepetic Ulcer Disease)
Causes: Helicobacter pylori infection
Phase 1 tx: 4-6 weeks
1. Eradication by giving (PPI)Omeprazole + Clarithromycin + Metronidazole/Amoxicillin
2. Ulcer healing phase: PPI = 2-4 weeks
Risk Factors fro NSAID-induced PUD disease
old age
multiple NSAID used
dose NSAID
glucocorticoids

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Drugs for Diarrhea

Oral Rehydration Salts/ Oral Glucose-Electrolyte Solution (Oresol®)
Antimotility agents(Opioids)
Diphenoxylate cross BBB Oral Rehydration Powder
Diphenoxylate + atropine  is a dry mixture of Sodium
Chloride, Sodium Bicarbonate,
Loperamide Imodium®, Diatabs®  does not cross BBB; GI motility
or Sodium Citrate, Potassium
Paregoric Chloride & Dextrose
Opium tincture  used to treat Chronic Diarrhea
Difenoxin
Adsorbents
Kaolin-Pectin mixture
Polycarbophil
Attapulgite (kaopectate) MOA: adsorbs H2O
Antisecretory
has antibacterial Effect (adsorbs bacterial toxins that cause diarrhea)
Bismuth Subsalicylate Peptobismol® cause discoloration of stool (black)
Enzymes Lactase®
Bacterial replacement Lactobacillus®
Octreotide

Drugs for Constipation

Bulk-forming Laxatives
Fibers ( fruits, vegetable)
MOA: adds bulk to the feces by absorbing water that causes the swelling of cellulose molecules
Bran Methyl Cellulose
absorbs H2O swell distention of colon peristalsis
Psyllium (C-lium®, Psyllium; Carboxy methylcellulose  non-absorbable compounds
Metamucil®)
Osmotic Laxatives (saline laxative)
Lactulose (Lilac®) create an osmotic gradient in the intestinal lumen
Sorbitol prevent H2O reabsorption  high consistency stools
Magnesium hydroxide/ citrate/sulfate MOA: as an osmotic agent in the intestinal lumen by inviting water molecules into the lumen
Glycerin(suppository)
Stimulant Laxatives (irritant laxative)
Bisacodyl Dulcolax®
Phenolphthalein directly irritate the GI tract leading to peristalsis
anthraquinone except CHrysarobin (Keratolytic) senna Melanosis Coli  a dark pigmentation of the colonic
Cascara Sagrada
MOA: stimulates mucosal nerves in the colon mucosa that results from long-term
Sennosides Senokot® SE: may cause dependence on laxatives use of Anthraquinone laxatives.
Casanthrol
Castor Oil
Stool Softeners/ Emollient Laxatives
not good for acute constipation; good for patients who should not strain by passing a hard stool
Docusate Na - (Stool Softener)
Mineral Oil – (Emmolient)
MOA: surfactants which facilitates mixing of water & oily materials
CLINICAL SE: prevent constipation in post MI patient & those who underwent rectal surgery

Drugs for Vomiting

Dopamine Antagonist  may cause secondary
Prochlorperazine
Chlorpromazine
IMPORTANT SE: Extrapyramidal symptom, Sedation, Depression
Promethazine
Metoclopromide Plasil®, Reglan®
Selective Serotonin Receptor Inhibitors
Ondansetron Zofran®, Nozuka®
Granisetron Kytril®
Dolasetron
Palonostron
Antihistamine-Anitcholinergic Agents
Dimenhydrinate Gravol®, Dramamine®
Diphenhydramine Benadryl®
Meclizine Bonamine®, Dizitab®
Scopolamine
Cannabinoids: Marijuana, Nabilone, Dronabinol
Corticosteroids: Dexamethasone
Benzodiazepines: Lorazepam
Substance P/ Neurokinin 1 Receptor Antagonist: Aprepitant
Pyridoxine

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Inflammatory Bowel Disease: Ulcerative Colitis (patches in Colon) st

1 : 5-aminosalicylate
nd
Crohn’s Disease (there’s a patches 2 ; Glucocorticoids
rd
from the mouth to anus) 3 : Biological Agents (TNF inh.): Adalimumab, Infliximab

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X. ENDOCRINE DRUGS

Links between hypothalamic, anterior pituitary, and target organ hormones or mediators
Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone(s) or
Mediator(s)
Growth hormone (GH, Growth hormone-releasing hormone (GHRH) Liver, muscle, bone, Insulin-like growth factor-1 (IGF-1)
somatotropin) (+) Somatostatin (–) kidney, and others
Thyroid-stimulating hormone Thyrotropin-releasing hormone (TRH) (+) Thyroid Thyroxine, triiodothyronine
(TSH)
Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+) Adrenal cortex Glucocorticoids, mineralocorticoids,
androgens
Follicle-stimulating hormone Gonadotropin-releasing hormone (GnRH) (+)b Gonads Estrogen, progesterone, testosterone
(FSH)
Luteinizing hormone (LH)
Prolactin (PRL) Dopamine (–) Breast —

Hypothalamic- Pituitary Hormone

Hypothalamic
GnRH  Agonist of the LH receptor
is released in pulses by the hypothalamus to induce secretion of FSH & LH by the pituitary
CLINICAL USE: Stimulatory Dosing: Management of Hypothalamic Hypongonadism,
Luteinizing hormone (LH) analogs Inhibitory Dosing: Management of Hormone-sensitive disease
Gonadorelin SE: Male: femination; Female: Muscurization
Goserelin
 Leuprolide  a synthetic nonapeptide analogue of naturally occurring gonadotropin-releasing hormone, used for
Buserelin palliative treatment of advanced prostatic cancer
Leuprolide
Follicle Stimulating Hormone Growth hormone receptor antagonist
Follitropin Gonal-F®, Puregon® MOA: Agonist of the follicle-stimulating hormone (FSH) receptor
CLINICAL USE: Controlled ovulation hyperstimulation in women; infertility due to hypogonadism in men
Somatostatin MOA: mimics the hormone somatostatin which is an inhibitory hormone
Agonists CLINICAL USE: Mx of acromegaly
Mx of Tumors associated with oversecretion of target hormones (Zollinger – Ellison Syndrome)
Octreotide Mx of carcinoid syndrome
Lanreotide Mx of esophageal varice
Pasireotide  delta secrete somatostatin
Vapreotide
Anterior Pituitary
ACTH  release occurs in pulses that peak in the early morning hours & after meals
Agonists
Corticotrpin
Cosyntropin
Tetracosactide
GH CLINICAL USE: for growth hormone Deficiency
Somatropin Prepuberty : dwarfism
Post puberty:  risk of cardiac mortality
Sermorelin Excess: Pre-puberty: Pituitarty Gigantism
Somatrem (recombinant) Genheal®, Post Puberty: acromegaly
Humatrope®, Features: Macrognathia (large jaws),Macroglossia (large tongue),
Norditropin®, Wides space teeth, Broadened nose, Thickened Lips, Large Joints
pituitary adenoma (tumor pit. Gland) secretion
Scitropin®
pheochromacytoma  tumor/ hyperplasia in the adrenal medulla  NE, Epi
TSH
Thyrotropin
Posterior Pituitary  produced by hypothamlamus, stored in the posterior pituitary gland
Oxytocin PItocin®, Syntocin® CLINICAL USE: Induction and augmentation of labor;
Carbetoxin control of uterine hemorrhage after delivery;
Demoxytocin stimulate lactation as nasal spray
mx of postpartum hemorrhage
Antagonist: Atosiban
Vasopressin Minirin® antidiuretic hormone; Arginine Vasopressin (AVP)= V1(bloodvessels-vasoC); V2(Kidney-H@O reabsorption)
CLINICAL USE: MX of Pituitary(central) diabetes insipidus; Hemophilia A and von Willebrand disease
Desmopressin (analogue)
EXCESS: cause SIADH (Syndrome of Inappropriate ADH Secretion : (malignancies-ccancer, CNS disorder)
Tx: Demeclocycline (an example of tetracycline) most photosensitizing among tetracycline
Antagonist: Conivaptan, Demeclocycline, Lixivaptan, Mozavaptan, Nelivaptan, Relcovaptan, Satavaptan, Tolvaptan

Regulation: Circadian Rhythm/ Sleep-wake pattern

Pituitary-derived growth Hormone
entrained to sleep
Peak during sleep: GH  has been historitically associated w/
Peak durng waking up: ACTH, Cortisol Creutzfeldt-jakob disease, a fatal
neurogenerative disease caused by
Chronic Gonadotropin  is a gonad-stimulating polypeptide hormone Prions.
obtained from the urine of pregnant women

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Zones of Adrenal Cortex

1) Zona glomerulosa  secretes mineralocorticoids
2) Zona fasciculate  secretes glucocorticoids
3) Zona reticularis  synthesizes androgens

Mineralcorticoids (aldosterone) Glucocortecoids (Cortisol)

 
RAAS CRH Cortisol  is capable of
  targeting intranuclear
Angiotensin II ACTH receptors secondary to
renin  its ability to diffuse
Angiotensiin I Corisol through lipid membranes
ACE
Angiotensin II morning: increase secretion of cortisol
 before waking up: ACTH secretion
Aldosterone: Reabsorption: NA+/ H20/ HCO3 upon waking up: peak of ACTH secretion
Excretion: K/Cl/H Start of cortisol secretion
Hyperaldosteronism: 2 hrs after peak of ACTH
Hypernatremia  Peak of cortisol
Hypervolemia Effects of Glucocorticoids:
Metabolic alkalosis (problem in Physiologic
concentration HCO3) <10-20mg / day of cortisol
Hypokalemia metabolism of macromolecules
HypoCl increase vascular/ bronchial responsiveness to catecholamines
Pharmacologic
USES: Corticoids >10-20 mg/day of cortisol Adverse effects:
Rheumatologic Disorders anti-inflammatory 1. risk of infection
RA – given thru intasynovial immunosuppresant 2. Cushing’s Syndrome
2-3x a yr, q 4-6 months inhibition od cell division Moon Face
SLE – life-threatening catabolism of bone / CHON Buffalo Hump
Tx: Methylprednisolone IV infusion Truncal Obesity
1g OD x 3days, infused in 30 min-1hr Easy Bruising
Inflammatory bowel disease 3.Poor Wound Healing
Sulfazalazine 4. Hyperglycemia
Sulfapyridine 5. Proximal Myopathy
5-amino salicylate 6.Adrenal Suppression
RA If the treatment
Dermatologic Disorder: Psoriasis, CA last 10-14 days

Adrenocortical Hormone
Glucocorticoids CLINICAL USE: Inflammatory diseases
Short-acting Transplant Rejection Inhibition Adrenal Suppression
Dermatologic Disease  is expected to occur when
Cortisol/ Hydrocortisone Hematologic Cancer glucocorticosteroids
Prednisone Premature labor therapy is extended
All preparations w/ PRED IMPORTANT SE: Cushing’s Syndrome (high levels of the hormone cortisol) beyond 2 weeks
in their name except Increased Risk of Infection  requires very low dosage
Hyperglycemia reduction when the therapy
(Fulprednisolone) Poor Wound Healing is to stopped & when the
Cortisone Adrenal Suppression dose reaches replacement
Intermediate Acting CI: Active Tuberculosis level
Fluprednisolone  necessitates giving of
Triamcinolone supplementary therapy at
times of stress like surgery
Paramethasone or trauma
Long-acting
 Beclomethasone  DOC for prophylaxis of Asthma
Dexamethasone
 Hydrocortisone  metabolize into Cortisone by Ketone Reduction
Betanethasone  Hydrocortisone + Fludrocortisone  is the appropriate maintenance theapy for patients w/ primary adrenal
insufficiency
 Chronic Glucocorticoids therapy can cause: Hypertension, Osteoporosis, Glucose Intolerance
 Dexamethasone Suppresion Test  is employed in the work-up of patients w/ Cushing’s syndrome to
diagnose the most probable etiology of the condition.
Mineralcorticoid CLINICAL USE: Adrenal insufficiency (Addison's disease)
Desoxycorticosterone
Fludrocortisone  Fludrocortisone  has the best mineralocorticoid effect
Aldosterone

Equivalent Doses: Hydrocortisone 20mg = Prednisone 5mg = Dexamethasone 0.75mg

Physiologic Dose of Glucocorticosteroids: Hydrocortisone (Cortisol) dose less than 10-20 mg/day
Pharmacologic (Supraphysiologic) Dose: Hydrocortisone (Cortisol) dose greater than 10-20 mg/day

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Thyroid Hormones

Thyroid Gland  made up of multiple follicles/ follicular cells, parafollicular cells, calcitonin(calcium-controlling hormone)
Thyroglobulin  the storage from of thyroid hormones. Calcium Homeostasis
Two Major Thyroid Hormones: inh. the Parathyroid Ca;
T3 (triiodothyronine)  most active form reabsorption of Hormones Po4
 is better absorbed after oral administration than T4 PO4
T4 (thyroxine) longer t1/2 increase the Vit D Ca;
preferred oral replacement since its half0life is longer & absorption in Po4
slower in onset. GIT
is deiodinated to T3 in the periphery
deposition of Calcitonin Ca;
Thyroid Function
CaPO4 in the Po4
controlled by atropic hormone, Thyroid-stimulating Hormone (TSH; Thyrotropin)
bones
governed by hypothalamic Thyrotropin-
Releasing Hormone (TRH)
action; mediated by cAMP & leads to stimulation of iodide uptake
 is the best monitoring guide for response to therapy
(Biochemical Goal of Therapy: To achieve a normal TSH)
Biosynthesis of Thyroid Hormones:
1. Active Uptake of Iodide
▪ Amiodarone  SE: Pulmonary fibrosis (pulmonary function test) Thyroid Hormone Deficiency
Hepatotoxicity (ALT)  Hypothyroidism  T4, T3
Thyroid abnormalities TSH
- Hypothyroidism  1st 10-14 days Subclinical Hypothyroism: T4, T3
- Hyperthyroidism  beyond 14 days No symptoms
▪Excess of Iodine  inh. the uptake of iodide to follicular cell  Hypothyroidism hypometabolic state;
- Wolff-chaikoff effect inh. organification hyposympathetic state
2. Peroxidase Mediated Steps SX: cold intolerance
1. Peoxidation of iodide to iodine or iodides to peroxidate Weight gain (despite a low appetite)
2. Organification iodination of thyroxyl residues of thyroglobulin sleeping time
TG- MIT monoiodotyrosyl Mental & Physical Slowing
TG-DIT  diiodotyrosyl residue Poor ressistance to cold
3. Coupling: MIT+DIT  T3 TG Bradycarida
DIT+MIT  T4 TG Children: Critinism, mental retardation, dwarfism
3. Proteolysis CAUSES: Iodine Deficiency
Post-procedural: Radiactive Iodine Therapy
T4 TG proteaseT4 + TG
-Thyroidectomy
T3 TG proteaseT3 + TG Autoimmune  Hashimoto’s Throiditis
4. Release of T4/T3  peripheral tissues Antibodies vs. own cells(peroxidase)
5. Peripheral conversion Drug-induced
T4 5-iododinaseT3  Hyperthyroidism  T4, T3
TSH
 aka Thyrotoxicosis
hypermetabolic state; hypersympathetic state
SX: Tremors
Diaphoresis
WeightLoss (despite increase appatite)
Heat tolerance (increase Heat production)
Tachycardia & cardiac arrhythmias
Nervousness
Palpiatation
Hypertension
CAUSES: Graves’s Disease
-hyperthyroism,
demopathy,
ophthalmopathy
Drug-induce : Amiodarone
Solitary Hyperfuction
ThyrotoxicosisFactitia
- T4, T3 –because of excessive intake
of Levothyroxine/ Levothyronine

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Drugs for Thyroid Disorders

Hypothyroidism
Levo-T4 (Levo-Thyroxine)  1 line hypothyroidism
st
Levo-T4 (Levo-Thyroxine) Levothyroid®, Synthroid®, Eltroxin®, st
Eltroxin®, Euthyrox®, Thyrax® Levo-T3(Levo-Thyronine)  1 line in myedema coma
MOA: Activation of nuclear receptors results in gene expression with
Levo-T3(Levo-Thyronine) RNA formulation and protein synthesis
Liotrix T4/T3 PHARMACOKINETICS: T4 is converted to T3 in target cells, the liver,and the kidneys;
T3 is 10 x more potent than T4
Sucralfate, Ferrous Sulfate & Aluminum hydroxide antacid
may interfere w/ the absorption of Levothyroxine that patient must be
advised on the proper interval of intake these agents.
Hyperthyroidism
Thionamides  1st line drugs for hyperthyroidism
PTU- propylthiuracil Rhea® PTU  safe for preganant
Methimazole Tapazole® MOA: Inhibit thyroid peroxidase reactions& the coupling of Iodotyrosine
Additional MOA (PTU): iodine organification, and peripheral conversion of T4 to T3
Carbimazole Neo- Mercazole® SE(both): Agranulocytosis :  Granulocyte,  Risk Of Infection (Fever, Sorethroat, Oral Ulcers)
*MX: Discotinue the Therapy
PTU Methimazole
Rapid onset Slow onset
Shorter duration of action Longer duration of action
Thyroid storm Maintenance
10x PTU dose of methimazole 10x more potent
SE: Hepatitis SE:Obstructive jaundice
(icterus)
Teratogenic
Inorganic Anions
Perchlorate Perchlorate  DOC in amoiodarone-induces hyperthyroidism
Thiocyanate (is not used anymore) MOA: inhibit iodides uptake (compete with iodide transport into cells)
CLINICAL USE: DOC in the managemebt of AMiodarone-induced Hyperthyroidism
SE: Aplastic Anemia
Iodides
SSKI (satutrated solution of Potassium MOA: Inhibit iodine organification and hormone release;
Iodide) Inducing Wolff-chaikoff Effect
EFFECTS: reduce size and vascularity of thyroid gland
Lugol’s Solution (strong Iodine Solution) CLINICAL USE: Initial Manangement of Throid storm; Preoperative control of hyperthyroidism
5% I2 (KI), H20 CI: pregnant  lead to fetal goiter
Breatfeeding (lactation)  lead to goiter
SE: Iodism: Conjunctivitis, Rhinitis, Sialadenitis
Radioactive iodine (131I) MOA: Radiation-induced destruction of thyroid parenchyma/
(emits -radiation that destroys follicular cells of thyroid glands)
--ray cause ablation of the thyroid gland
CLINICAL USE: Preffered Tx fro most cases of hyperthyroidism except during pregnancy
SE: Hypothyroidism (80%)- 6-12 Hrs
Quarantine: Patient within 72 hrs
CI: Pregnancy, Lactation
Radiocontrast dyes: Ipodate, Iopanoic acid
Dexametasone  inhibit the peripheral conversion of T4T3
Beta Blocker:  most widely used in the terapy of Thyrotoxicosis
Propanolo(Inderal®) MOA: Inhibition of receptors
Inhibition of peripheral conversion of T4 to T3
Control the sympathetic symptoms of Hyperthyroidism
CLINICAL USE: Thyroid storm
SE: Asthma, AV Blockade, Hypertension, Bradycardia

Consideration in Thyroid Hormone Replacement Therapy include:

Infants & children w/ congenital hypothyroidism require
higher dose per kilogram body weight than adults
Steady state levels of thyroxine takes about 6-8 weeks to
achieve after initiating therapy
Older adults & those w/ long-standing disease must be started
on lower than usual doses of levothyroxine

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Types of Sex Hormones/ Sexogens:

1. Estrogen  is essential for normal female reproductive development
 responsible for estrus
is responsible for the growth of the genital structures (vagina, uterus, and uterine tubes)
during childhood and for the appearance of secondary sexual characteristics and the growth spurt associated with puberty.
▪ Estradiol  major ovarian estrogen in women; most potent estrogen produced & secreted by the ovary
 principle estrogen in the premenopausal woman
Metaboiltes of Estradiol: Estrone  has approximately ½ the estrogenic potency of estradiol
 primary circulatingestrogen after menopause
Estriol  is significantly less potent than estradiol
present during pregnancy, because it is the principal estrogen produce by placenta
2. Progesteron  is the major progestin in humans produced in response to luteinizing hormone (LH) by both females & males
Females (secreted by the corpus luteum, primarily during second half of the menstrual cyle & the placenta)
Males (secreted by testes)
also synthesized by the adrenal cortex in both sexes
For females, responsible for thicking of endometrium lining that can accommodate implantation of a newly forming embryo
(gestational hormone)
▪Corpus luteus  responsible for progesterone production in females
3. Androgen  have anabolic &/or musculinizing effects in both males & females
▪ Testosterone  most important androgen in humans
 is synthesized by Leydig cells in the testes &,
in smaller amounts, by celss in the ovary of the female and by adrenal gland in both sexes
 responsible for the major changes in the male at puberty (growth of penis, larynx, and skeleton; development of facial, pubic, and axillary
hair; darkening of skin; enlargement of muscle mass). After puberty, testosterone acts to maintain secondary sex characteristics,
fertility, and libido. It also acts on hair cells to cause male-pattern baldness.

Contraceptives  decrease fertility by a number of different mechanisms,

such as preventing ovulation, imparing gametogenesis or gametematuration, or interfering with gestation
Major Classes of Contraceptives:
1. Combination Oral Contaceptives (COCs)  contain Estrogen + Progesterone
 > 50mcg =  risk for Thromboembolism
SE: Thromboembolsm: myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism
CI: >35 yr old, Obese, Breast feeding, Smoke
Monophasic  constant amount
Biphasic  D1  D14; D15  D28 (two concentraton/ pill)
Triphasic  D1  D7; D8  D14; D15  D22 (three or more concentration/ pill)
 Oral Contraceptives are avoided in females above 35 years-old & among chronic smokers due to a higher risk of stroke
2. Trandermal Patch: containing Ethinyl Estradiol + Progestin (Norelgestromin)
applied each week for 3 weeks to the abdomen, upper torso or buttock; week 4 is patch-free, & withdrawal bleeding occurs
3. Vaginal Ring : Ethinyl Estradiol + Etonogestrel; inserted into vagina for 3 weeks & week 4 is ring-free , & withdrawal bleeding occurs
4. Progestin-only pills: usually Norethindone or Norgestrel ( called a “mini-pill”)
5.Progestin Implants: Norplant  4cm capsule placed in the upper arm, q 3-5 yrs
6. Progestin Intrauterine Device (Impregnated IUD): Levorgestrel, q 1 yr
7.Post-coital Pills (Morning after pills): contain high dose of progesterone, within 36 hours
8. Injectable: Depo-provera® ( Methoxy progesterone acetate), q 3months

Gonadal Hormones  primary use is for CONTRACEPTION

Estrogen
Natural Estrogen MOA: Activation of estrogen receptors leads to changes in the rates of transcription of estrogen-regulated genes
Estradiol (gene –activation)
SE/ TOXICITY: -Moderate toxicity: Breakthrough bleeding, nausea, breast tenderness
Estrone -Serious toxicity: Thromboembolism, gallbladder disease, hypertriglyceridemia, migraine headache,
Estriol hypertension, depression
Synthetic Estrogen -In postmenopausal women: breast cancer, endometrial hyperplasia (unopposed estrogen)
-Combination with cytochrome P450 inducer can lead to breakthrough bleeding and reduced contraceptive
-Steroidal:
efficacy
Ethinyl Estradiol  DES (Diethylstilbestrol)  clear cell carcinoma of the vaginal/ cervix
-Non-Steoidal Mestranol: A prodrug that is converted to ethinyl estradiol, contained in some contraceptives
DES (Diethylstilbestrol) Estrogen Esters (eg, Estradiol Cypionate): Long-acting estrogens administered IM and
used for hypogonadism in young females
Progestins
Norgestrel
Derivative:  can promote appetite
Hydoxyprogesterone caproate MOA: Activation of progesterone receptors leads to changes in the rates of transcription of
progesterone-regulated genes
Medroxyprogesterone acetate (Provera®) SE: Weight gain, reversible decrease in bone mineral density (high doses)
Megestrol Acetate
Breakthrough Bleeding  most common problem encountered in female patients using progestin-only oral
contraceptive pills
Androgens
Testosterone MOA: Androgen receptor agonist
Methyltestosterone CLINICAL USE: Male hypogonadism; weight gain in patients with wasting syndromes
Androgen replacement; GYnecollogic Disoreders such as endometrial bleeding, refractory anemia, osteoporosis
Danazol SE: -NA & H2O retention, CHolestatic Jaundice
Menotropins -In females, Virilization In men, High Doses can cause Gynecomastia, Testicular Shrinkage, Infertility

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MOA CLINICAL USES SE/ TOXICITY

Antiestrogens
SERMS
Tamoxifen Estrogen antagonist actions in breast Prevention and adjuvant treatment of Hot flushes, thromboembolism, endometrial
tissue and CNS; estrogen agonist hormone-responsive breast cancer hyperplasia
effects in liver and bone
Toremifene: Similar to tamoxifen
Raloxifene: Approved for osteoporosis and prevention of breast cancer in selected patients; antagonist effects in breast, CNS, and endometrium and
agonist effects in the liver
Clomiphene: Used for ovulation induction; antagonist effect in pituitary increases gonadotropin secretion
Receptor antagonist
Fulvestrant Estrogen receptor antagonist in all Adjuvant treatment of hormone-responsive Hot flushes, headache, injection site
tissues breast cancer that is resistant to first-line reactions
antiestrogen therapy
Aromatase inhibitors
Anastrozole Reduces estrogen synthesis by Adjuvant treatment of hormone-responsive Hot flushes, musculoskeletal disorders,
inhibiting aromatase enzyme breast cancer reduced bone mineral density
Letrozole: Similar to anastrozole
adjuvant therapy for hormone-sensitive breast cancer
Exemestane: Irreversible aromatase inhibitor (steroidal hormone agent, usefull in mx of advanced breast cancer unresponsiveness to Tamoxifen)
GnRH agonist  Leuprolide
GnRH receptor antagonist  Ganirelix, cetrorelix
Other
Danazol Weak cytochrome P450 inhibitor and Endometriosis, fibrocystic breast disease Acne, hirsutism, weight gain, menstrual
partial agonist of progestin and disturbances, hepatic dysfunction
androgen receptors
Antiprogestin
Mifepristone Progestin and glucocorticoid receptor Used in combination with a prostaglandin Gastrointestinal disturbances (mostly due to
antagonist (eg, misoprostol) for medical abortion coadministration of misoprostol); vaginal
bleeding, atypical infection
Antiandrogens
5-reductase inhibitors
Finasteride Inhibition of 5-reductase enzyme that Benign prostatic hyperplasia (BPH), male- Rarely, impotence, gynecomastia
converts testosterone to pattern hair loss
dihydrotestosterone
Dutasteride: Similar to finasteride
Receptor antagonists
Flutamide Competitive inhibition of androgen Advanced prostate cancer Gynecomastia, hot flushes, impotence,
receptor hepatoxicity
Bicalutamide, nilutamide: Similar to flutamide but lower risk of hepatotoxicity
Spironolactone: Mineralocorticoid receptor antagonist used mainly as a potassium-sparing diuretic (see Chapter 15); also has androgen-receptor
antagonist activity, used for the treatment of hirsutism
GnRH agonist  Leuprolide
GnRH receptor antagonist  Abarelix, degarelix
Synthesis inhibitor
Ketoconazole Inhibition of cytochrome P450 enzymes Advanced prostate cancer that is resistant Interferes with synthesis of other steroids;
involved in androgen synthesis to first-line antiandrogen drugs many drug interactions due to cytochrome
P450 inhibition

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Diabetes Mellitus chronic hyperglycemia Diagnosis:

Type 1 DM  absolute lack of insulin; early onset (below 30 yrs old) 1. FBS (Fasting Blood sugar)/ FPG ( Fasting Plasma Glucose)
 autoimmune condition  destruction of -cells of pancreas  a person must not to eat for 12 to 14 hours.
-cells (Produces insulin)  Diagnosis categories:
Islets of Langerhans Hypoglycemia: < 70 mg/dL
TX: Insulin normal range: 70 mg/dL to 99 mg/dL
Type 2 DM relative lack of insulin; late onset (above 30 yrs old) prediabetes: 100 mg/dL to126 mg/dL
1.  secretion of insulin by the -cells of pancreas Diabetes:  126 mg/dL
2. Insulin resistance (decrease sensitivity of insulin receptors) OGTT (Oral Glucose Tolerance Test)
3. Increase gluconeogenesis is a lab test to check how your body
gluconeogenesis  formation of glucose breaks down sugar.
from non-carbohydrate sources  most common glucose tolerance test
such as Fatty Acids cannot eat or drink anything after midnight
TX: Oral Antidiabetic Agents causes hypoglycemic agent before the test/ (8-10 hours before the test)
▪Insulin Secretagogues For the test, you will be asked to drink a liquid
Sulfonylureas containing a certain amount of glucose.
Meglitinides  blood will be taken every 30 to 60 minutes
 test takes up to 3 hours.
Type 1 Type 2  Diagnosis categories:
Age of Onset Usually during Frequently over age ▪ For a 50-gram oral glucose tolerance test
childhood or puberty 35 used to screen for gestational diabetes
Nutritional status at Frequently Obesity usually 1 hour:  140 mg/dL
time of onset undernourished present ▪ For a 75-gram oral glucose tolerance test
Prevalence 5 - 10 % of diagnosed 90-95% of diagnosed Normal: Fasting: 60 -100 mg/dL
diabetics diabetics 1 hour: less than 200 mg/dL
Genetic Moderate Very Strong 2 hours: less than 140 mg/dL.
predisposition Prediabetes: 140  200 mg/dL
Defect or Deficiency  cells are destroyed, Inability of  cells to Diabetes Mellitu:  200 mg/dL
eliminating the produce appropriate ▪ For the 100-gram oral glucose tolerance test:
production of insulin quantities of Insulin; Fasting: > 95 mg/dL
Insulin Resistance; 1 hour: > 180 mg/dL
other defects 2 hours: > 155 mg/dL
3 hours: > 140 mg/dL
Intravenous Glucose Tolerance Test (IGTT)  rarely used
2. RBS (Random Blood Sugar) aka casual blood glucose test
INSULIN is a blood sugar test taken from a non-fasting subject
▪  cells ( Islets of Langerhans) can be used in symptomatic diabetic patient
▪ Type 3 receptor (enzyme-linked) Polyuria
tyrosine kinase Polydipsia
Effects: Translocation of glucose transporter in the cell membrane Weight Loss
Anabolism  promotes: Lipogenesis  Diagnosis categories:
Protein Synthesis normal range: 80 - 140 mg/dl
Gluconeogenesis prediabetes: 140 - 200 mg/dl
SE: Hypoglycemia diabetes:  200 mg/dl
Tipodystrophy  prevented by rotation of injection sites 3. HBA1C (glycated hemoglobin)
monitor the control of the patient’s blood sugar
Immune Insulin Resistance  is said to be due to production of low levels of for the past 3-4 months
what type of insulin antibodies  Diagnosis categories:
Normal: < 5.7%
Pre-diabetes: 5.7% to 6.4%
Insulin  produce by using non-disease producing strain of E.coli by Eli lily
Diabetes:  6.5%
company as the first commercial application of the technique in
4. Platelet : Aspirin 7-10d
Pharmacognosy
 contains Chromium

Drugs that may reduce the effects of Drugs that may potentiate the
sulfonylureas, leading to loss of effects of sulfonylureas, leading
glucose control: to hypoglycemia:
• Atypical antipsychotics • Allopurinol
• Corticosteroids • Azole antifungals
• Diuretics • Chloramphenicol
• Niacin • Clarithromycin
• Phenothiazines • Monoamine oxidase inhibitors
• Sympathomimetics • Probenecid
• Salicylates
• Sulfonamides

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Drugs for Diabetes Mellitus

Insulin  MOA: Activate insulin receptor
 Zinc  improves stability & shelf life of insulin in commercial insulin preparations
Rapid acting insulin: SQ; 5 min before meals
Insulin Lispro Rapid onset of action in 5-15 minutes
Insulin Aspart
Insulin Glulisine
Short-acting insulin: SQ/IV; 20 min before meals
Regular Insulin (Humulin-R®) USES:To prevent Postprandial Hyperglycemia
Target Postprandial Glucose = < 180mh/dL
Target Preprandial Glucose = 90-130 mg/dL
Target HbA1C = < 7%
 Intermediate-acting insulin: USES: Insulin basal insulin secretion
Isophane Insuin/ NPH (neutral protamine Hagedorn) DOSE: BID: AM  2/3 of the dose
/Humulin N,/Insulatard, PM  1/3 of the dose
Lente Insulin  prepared by mixing 30% Semilente & 70% Ultralente Insulin
/Novolin N, /Novolin NPH, /NPH Iletin II
Lente Insulin
Long-acting insulin: SQ, OD Insulin Glargine (―peak-less insulin‖)  has a character release pattern that
Insulin Glargine USES: Provide basal insulin requirement shows no peak & a plateau serum insulin level
that is maintained for about 24 hours
Insulin Detemir .
Insulin Levemir
Insulin Secretagogues  known to induce Hypoglycemia among diabetic & euglycemic individuals.
 promote release of insulin by the remaining functional beta-cells of the pancreas
Sulfonylureas  MOA: block outward K+ channel  lead to to depolarization of  cells to release Insulin
CI: Liver disease, Renal Disease
Common SE: Hypoglycemia, Weight Gain
1 generation
st
2nd generation
Chlorpropamide longest t1/2  Less Potent, Glibenclamide(Euglucon®)
 More potent,
Tolbutamide most cardiotoxic More side effects Glipizide (Minidiab®) Less side effect
Acetahexamide SE: Disulfiram-like reaction Gliclazide (Diamicron®)
Tolazamide  safest for elderly Glimepiride (Solosa®)
Meglitinides Short-Acting
Repaglitide (Prandin®, Novonorm®) CLINICAL USE: Control 2hr post prandial Hyperglycemia
SE: Hypoglycemia
Nateglitide (Starlix®)
Insulin Sensitizers
Biguanides Metformin 1st line initial treatment of type 2 DM esp. among obees patients
Metformin (Gucophage®) very low risk of lactic acidosis SE: Diarrhea, Weight Loss, Lactic Acidosi
Phenformin  high risk of lactic acidosi ( out in the market) MOA: UNKNOWN Still not understood but possibly
enhances fatty acid oxidation (decreased hepatic gluconeogenesis)/
decreased endogenous glucose production
CLINICAL USE: 1st line tx of type 2 DM especially among obese Px.
CI: Chronic Alcoholics, Renal Failure, Hepatitis
Thiazolidinedione must not be given to patient w/ CHF (ClassIII-IV) MOA: Regulates gene expression by binding to PPAR-  /
Rosiglitazone (Avandia®)   risk of cardiovascular mortality Activate PPAR ( Peroxisome Proliferator-acting receptor ) Gamma
SE: Hepatotoxicity
Pioglitazone (Actos®)  bladder cancer
Troglitazone
Alpha-glucosidase Inhibitors  may be given to Type 1 DM patients as a combnation therapy with Insulin
Acarbose (Glucobay®, Gluconase®) Alpha-glucosidase Inhibitors  important in conversion of
Complex Carbohydrate  Simple Carbohydrate (absorbable)
Voglibose (Basen®)
MOA: Inhibit intestinal -glucosidases
Miglitol (Glyset®) Inhibit a variety of enzymes present in the brush-border of the mucosa of the wall intestine that are
responsible for the breakdown of complex polysaccharides & sucrose into asbsorbable
monosaccharides
SE: Flatulence, Hepatotoxicity (Acarbose)
st
ADMINISTRATION: After 1 bite of food (must be taken w/ food)
Incretin-acting drugs  NOTE: can cause weight loss
  insulin secretion;  glucagon secretion;  GI motility;  Gastric Emptying Time
GLP-1 analogue (Glucagon-like peptide-1)   risk hypoglycemia
Exenatide (Byetta®) ADMINISTRATION: Parenteral (SQ)
MOA: Analog of glucagon-like peptide-1 (GLP-1) activates GLP-1 receptors
SE: GI disturbances, headache, pancreatitis
DPP-4 inhibitor (Dipeptide peptidase IV)  responsible in metabolizing GLP- 1 to active ones
Sitagliptin (Januvia®) ADMINISTRATION: Oral
MOA: Inhibitor of the dipeptidyl peptidase-4 (DPP-4) that degrades GLP-1 and other incretins
SE: Rhinitis, upper respiratory infections, rare allergic reactions
Amylin Analogue  given SQ MOA: Analog of amylin activates amylin receptors
Pramlitide  cosecreted w/ insulin CLINICAL USE: Type 1 and type 2 diabetes
 enhances the effect of insulin SE:  risk of hypoglycemis
Glucagon  parenteral  useful for reversing the cardiac effects of an overdose of -blocking agents because of its ability to increase cAMP
production in the heart.
MOA: Activates glucagon receptors
CLINICAL USE/S: Severe hypoglycemia(not responding well to glucose),
 -blocker overdose(by increasing cAMP Levels as it binds to Glucagons Receptors in the Heart)
SE: GI Disturbances, Hypotension, Flatulence (most common)

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XI. DRUGS FOR OSTEOPOROSIS

Calcium Carbonate  salt of choice (highest elemental Ca) NOTE: should be taken with meals
SE: Constipation, Flatulence
Biphosphonate MOA: Bind to hydroxyapatite in bones & inhibits osteoclast adherence
Alendronate (Fosamax®) NOTE: Taken at morning with plain tap water 30 minutes before meals
& Should remain upright for 30 minutes
Risedronate (Actonel®) SE: Nausea, Abdominal Pain, Dyspepsia, GI Irritation, Ulcers,
Ibandronate Osteonecrosuis of the Jaw
Selective Estrogen Receptor Modulator (SERMs) MOA: estrogen agonist at bones but anatagonist in the breast & uterus
Raloxifene NOTE: Decreases breast CA risk like Tamoxifen
Calcitonin MOA: Decreases bone resorption (2nd line TX)
Estrogen & Hormonal Therapy MOA: Decrease osteoclast activity,
Inhibits PTH (parathyroid hormone),
Increase Vitamin D & calcium absorption,
Decrease calcium excretion
Phytoestrogens  isofalvonoids from soy beans & lignans from flax seeds (not sufficient when used alone)
Testosterone & Anabolic Steroids
Oral Methyltestosterone
Testosterone Implants
Parathyroid Hormone NOTE: Given SubQ every 28 days, should not be used with Bisphosphonates (Antagonistic Effect)
Terparatide

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XII. CNS DRUGS

Excitatory Neurotransmitter opens Na or Ca Channels/ influx  depolarization (more positive) nerve impulse
EX: NE, Dopa, Epi, Glutamate, Aspartate
Inhibitory Neurotransmitters  opens Cl channels  hyperpolarization (more negative)  no nerve impulswe
EX: Glycine, Gamma-aminobutyric Acid (GABA)
Anxiety  is an unpleasant state of tenson, apprehension, or uneasiness  afear thatseems to arise from sometimes unknown source.
Antianxiety Drugs  aka anxiolytic or minor tranquilizers

Types of Anxiety :
Generalized Anxiety Disorder  intense parsavasive worry over virtually every aspect of life
Obsessive Compulsive Disorder  recurrent obsessions & compulsions that cause significant distress & occupy a significant portion of one’s life
Post- traumatic Stress Disorder persistent reexperience of a trauma, efforts to avoid recollecting the trauma, & hyperarousal
Panic Disorder recurrent unexpected panic attacks that can occur with agoraphobia in which patients fear places in which escape might be difficult
Performance Anxiety/ Social Phobia: -blockers  intense fear of being scrutinized in social or public situations. Ex: giving a speech
Specific Phobia  intense fear of a particular obejects or situations (Ex; snakes, height); most common in psychiatric disorder

Hypnotic Drug  produces drowsiness & facilitates the onset & maintenance of a state of sleep resembling natural sleep
Sedative Drug  decreases activity, moderates excitement, & calms.

 SEDATIVES HYPNOTICS (Minor Tranquilizers)

Benzodiazepines most widely used anxiolytic
Short-Acting (2-8 hours) benzene ring A fused to a seven-membered diazepine ring B
MOA: Increase the frequency of GABA-mediated chloride ion channel opening/
Oxazepam (Serax®) Bind GABAA receptor subunits to facilitate chloride channel opening; membrane hyperpolarization
Triazolam (Halcion®) CLINICAL USES: Anxiety: Alprazolam ,Diazepam
Clonazepam (Klonopin®, Rivotril®) Seizures: Diazepam, Clonazepam, Lorazepam
Midazolam (Versed®,Dormicum®) Insomia: Flurazepam, Midazolam
Pre-operative sedation: Midazolam Benzodiazepine,Zolpindem, Barbiturates
Intermediate-Acting (10-20 hours) bind to molecular components of the
SE:Cross- Dependence; Drowsiness; Respiratory Depression;
Lorazepam (Ativan®) Anterograde Amnestic effect macromolecular complex GABA-A
Alprazolam (Xanax®, Xanor®) ANTIDOTE FOR TOXICITY: receptor-chloride channel present in
Temazepam (Restoril®) Flumazenil (Anexate®) GABA receptor antagonist neuronal membranes in the CNS
Estazolam (Benzodiazepine Antagonist) Chlorazepate  a prodrug that s
hydrolyzed to the active
Long-Acting (1-3 days)
metabolite, nordiazepam in the
Diazepam (Valium®, Anxionil®) Stomach
Flurazepam (Dalmane®) Desmethyldiazepam  major metabolite of
Chlordiazepoxide (Librium®) Diazepam
Quazepam (Doral®)
Chlorazepate
Barbiturates  former DOC of anxiety, Insomia
Ultra Short-Acting (20mins)  barbituric acid is 2,4,6-trioxohexahydropyrimidine
MOA: Increase the duration of GABA-mediated chloride ion channel opening/
Thiopental (Pentothal®) Bind to GABAA receptor sites (distinct from benzodiazepines); facilitate chloride channel opening
Methohexetal CLINICAL USE: Induction of Anesthesia, Seizures in Children, Anxiety
Secobarbital thiopental Anesthesia
Pentobarbital (Nembutal®) secobarbital insomnia and sedation
 Short-Acting (3-8 hours) phenobarbital seizure disorders in children
Amobarbital (Amytal®) Pentobarbital, Amobarbital  anxiety
SE: Drowsiness, Respiratory depression, Paroxical excitation, CYP450 inhibitor
Butabarbital (Butisol®)  risk of Dependence/ Addiction
Long-Acting CI: Porphyrin such as Acute intermittent porphyria, Variegate Porphyria, Symptomatic porphyria
Phenobarbital (Luminal®) Ultra-short acting  has a very short duration & very rapid onset of action
due to the increasing in the number of polar substituents (high lipid solubility)
 usually contain sulfur atom (become more lipid soluble, ex; Thiopental –lethal injection)
5HT-A partial Agonist act on 5HT1a (Gi); does not cause sedation & dependence
Buspirone (Buspar®) MOA: Partial agonist at 5-HT-1A receptors in the CNS and possibly D2 receptors
CLINICAL USE/S: Generalized anxiety states
SE: GI distress, tachycardia; paresthesias
Melatonin receptor agonist MOA: Activates MT1 and MT2 receptors in suprachiasmatic nucleus
Ramelteon CLINICAL USE/S: Sleep disorders, esp when sleep onset is delayed
SE: Dizziness, fatigue, endocrine changes
Newer hypnotics  act on BZD receptor
Eszopiclone MOA: Bind to GABAA receptor sites (close to benzodiazepine site); facilitate chloride channel opening
CLINICAL USE/S: Sleep disorders, esp when sleep onset is delayed
Zaleplon (Sonata®, Starnoc®) SE: Extension of CNS Depressant Effects; Dependence Liability
Zolpidem (Stilnox®, Ambien)
Chloral Hydrate  for pre-operative sedation
‖knockout drops‖
converted to trichloroethanol (active) via aldehyde reduction
Anti-Histamine
Diphenhydramine (Benadryl®)
Doxylamine (Unison®)
HYdroxyzine (Iterax®, Atarax®)

 Patients may be expected to have increased sensitivity to sedative-hypnotics leading t higher incidence of adverse effects or toxicity:
Elderly, Patients w/ Cardiovascular disease, Patients w/ Respiratory depression

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Psychosis  a psychiatric disorder such as schizophrenia or mania that is

marked by delusions, hallucinations, incoherence, and distorted perceptions of reality
hyperactivity of dopaminergic neurons in the mesolimbic area ; (due to increase dopamine levels (as in amphetamines)
tx w/ Dopaminergic Antagonist
Schizophrenia  type of psychosis that has strong genetic component & probably reflects some fundamental biochemical abnormality,
possibly a disfuntion of the mesolimbic or mesocortical dopaminergic neurons
1% of population, inheritable
▪Negative Symptoms : Blunted Effect (Flattening)
Alogia  poverty of speech (auditory) Anhedonia (lack of ability to feel pleasure; asociality)
Apathy
Impaired Attention
▪Positive Symptoms : Hallucination (auditory, visual, lactile, and/or olfactory hallucations; voices that are commenting)
Dilusions (persecutory, paranoid, grandiose, religious; thought broadcasting, thought insertion)
Bizarre Behavior (aggressive/agitated, odd clothing or appearance, odd social behavior, repetitive-sterotyped behavior)
Neurolyptic Drugs  aka Antipsychotic Drugs/ Major Tanquilizers

 Anti-Psychotics
Typical/ First Generation  Inhibit the Dopamine-2 receptors in the brain
Phenothiazines Chlorpromazine first neurolyptic drug used
Chlorpromazine (Torazine®, Laractyl®, Psynor®) Thioridazine  causes cadiotoxicity; formation of retinal deposits;
lead to blindness
Prochlorperazine (Compazine®) MOA: Block D2 receptor only (Block of D2 receptors ≫5-HT2 receptors)
Fluphenazine (Prolyxin®, Modezine®, Phlufdek®, Sydepres®) SE: Hyperprolactinemia
Thioridazine (Mellaril®, Melleril®) Movement Disorders
Perphenazine (Trilafon®) Neurolyptic Malignant Syndrome
Trifluoroperazine Extrapyramidal Effects (cause by blocking D in the nigrostriatal pathway)
-Acute Dystonias (sustained contraction of muscles
Trifluphenazine leading to twisting distorted postures)
Mesoridazine -Parkinson-like symptoms (pseudoparkinsonism)
Thioxanthene -Akathisia (Motor restlessness)
Thiothixene (Navane®) -Tardive Dyskinesia (involuntary movements of the
tongue, lips, neck, trunk, & limbs)
Butyrophenone  Prochlorperazine  can be administered rectally & acts directly at the chemoreceptor
Haloperidol (Haldol®, Serenace®) trigger zone (CTZ)
Haloperidol & the Piperazine Phenothiazines  are classified as high potency
antipsychotic & share similar effects
& side effects
Thioridazine  most cardiotoxic of the available antipsychotics
 most commonly associated w/ prolongation of the QT interval on ECG
which can lead to fatal arrhythmia
 causes retinal deposits to form which can lead to blindness
Chlopromazine  causes corneal deposition which does not lead to blindness
 is most commonly associated w/ seizures
Mesoridazine  is associated w/ a higher incidence of fatal poisoning
Atypical/ Second Generation
Aripiprazole (Abilify®) MOA: Block of 5-HT2 receptors ≫ D2 receptors Anticholinergic effect are commonly seen w/:
SE: Causes little or no movement disorders -Chlorpromazine
Clozapine (Clozaril®, Leponex®) -Thioridazine
Agranulocytosis (Clozapine, Chlorpromazine);
Olanzapine (Zyprexa®) Diabetes And Weight Gain (Clozapine, Olanzapine), -Prochlorperazine
Quetiapine (Seroquel®) Hyperprolactinemia (Risperidone); -Clozapine
Paliperidone (Invega®) QT Prolongation (Ziprasidone)
Risperidone (Risperdal®) Pigmentary Retinopathy (Thioridazine)
Ziprasidone (Geodon®, Zeldox®)  Clozapine  belongs to Dibenzodiazepine
 has the propensity to cause Agranulocytosis (requires WBC monitoring)
Molindone
Weight Gain is an expected complication of therapy w/ all the clinically antipsychotics except w/ Molindone
Extrapyramidal Effects –aka Neuroleptic-induced parkinsonism
Management: Anticholinergic : Benztropine (Cogentin®) First-Generation Antipsychotic
Biperiden (Akineton®) (Low potency) Sedation,
Trihexyphenidyl (Artane®) Chlorpromazine Orthostatic hypotension,
Diphenhydramine Prochlorperazine anticholinergic effects
Neurolyptic Malignant Syndrome (NMS)  cause of Dopaminergic antagonist Thioridazine
Manifestations: First-Generation Antipsychotic
Muscle Regidity (High potency) Neuroleptic malignant
Autonomic Disregulation: Unstable BP, Irregular heart beat Fluphenazine syndrome,
Malignant Hyperthermia  genetically determined Haloperidol Dystonic reactions,
Other Causes: Succinyl Choline (Nm Blockers) Pimozide Oculogyric crisis,
Halogenated Hydrocarbons Thioxene Pseudoparkinsonism
Management: Bromocriptine Trifluphenazine
Dantrolene (skeletal muscle relaxant)
 DOC for Malignant Hyperthermia Different Phenothiazines: (listed in terns of potency)
 Blocks Ca release from Sarcoplasmic Reticulum Piperazines (e.g. Trifluoroperazine, Fluphenazine)
Tardive Dyskinesia is considered as the most important unwanted effect of Antipsychotics. Piperidines
Its is probably due to Dopamine Receptor Hypersensitivity (relative Cholinergic Deficiency) Aliphatics
Poisoning w/ the Antipsychotic Drugs can lead to:
Hypotension,
Hypothermia,
Ventricular Arrhythmia

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Mood Disorders

5HT, NE

Bipolar  Major Depression + Mania

Cyclothymia  Dysthimia + Hypomania

Bipolar characterized by shifts between episodes of mania and depression

Depression  lack NE, serotonin, dopamine
Major Depression  a psychiatric disorder showing symptoms such as persistent feelings of hopelessness, dejection, poor concentration,
lack of energy, inability to sleep, and, sometimes, suicidal tendencies
Mania  a psychiatric disorder characterized by excessive physical activity, rapidly changing ideas, and impulsive behavior
Cyclothymia  a psychiatric disorder in which the patient has frequent, relatively mild mood swings between elation and depression
Dysthimia  depression with associated symptoms:
such as fatigue, low self-esteem, insomnia, and appetite disturbances but is not severe enough to amount to a psychosis
Hypomania  a condition of mild mania or overexcitement, especially when part of a bipolar manic-depressive cycle

 Anti-Depressants
Tricyclics Antidepressants (TCAs) “Triptyline”
Tertiary Amines  three ring nucleus Amitriptyline “Pramine”
Amitriptyline (Elavil®) Protriptyline Clomipramine
MOA: Inhibits Neronal reuptake of NE, Serotonin, Dopamine Nortryptyline
Clomipramine (Anafranil®) CLINICAL USE/S: Major depression (backup), Trimipramine
Imipramine (Tofranil®) chronic pain obsessive-compulsive disorder Desipramine
Doxepine (Aponal®) (OCD)—clomipramine Doxepine Imipramine
Trimipramine (Surmontil®) SE: Orthostatic Hypotension, Dry Mouth, Constipation, Blurrred Dosulepine/
Vision, Dothiepin
Dosulepine/ Dothiepin (Prothiaden®)
Urinary Retension, Cardiac Conduction Delays & Heart Block,
Secondary Amines Sexual Dysfunction
Desipramine (Norpramin®) Weight Gain (most common side effects of Tricyclic Antidepresssant)
Protriptyline (Vivactil®) N-demethylation  process involved in the biotransformation of Amitriptyline to Nortriptyline
Nortryptyline (Pamelor®) Nortrityline  active metabolite of Amitriptyline
Imipramine  has been found to be useful in the treatment of Nocturnal Enuresis (Bed Wetting)
due to its Anticholinergic Effects
Selective serotonin reuptake inhibitors (SSRIs) MOA: Block 5-HT transporters/ serotonin reuptake
Fluoxetine (Prozac®) CLINICAL USE/S: Major depression, anxiety disorders, OCD, PMDD, PTSD, bulimia, etc
SE: Headache, Agitation, Insomia, Impotence/ decrease libido(Sexual dysfunction)
Sertraline (Zoloft®) Serotonin Syndrome (resembles Malignant Hyperthemia) – Mx: Cyproheptidine
Parxetine (Paxil®, Seroxat®)  occurs when SSRI given w/ MAO-inhibitors
Fluvoxamine (Luvox®, Faverin®) For Children: Impaired memory, akathisia, Menstrual irregularity
Citalopram (Celexa®, Lupram®) Advantages of the SSRIs compared to the rest of the drugs used for depression:
Escitalopram (Lexapro®)  Lesser lethality w/ overdose
 Minimal Anticholinergic effects
 Generally, do not require dose titration
Serotonin-norepinephrine reuptake inhibitors (SNRIs) MOA: Block NE and 5-HT transporters
Venlafaxin (Effexor®) CLINICAL USE/S: Major depression, chronic pain, fibromyalgia, menopausal symptoms
SE: Anticholinergic, Sedation, Hypertension (Venlafaxine, Serotonin Syndrome
Desvenlafaxine
Duloxetine
 Selective Serotonin Reuptake Enhancer (SSRE)
Tianeptine (Stablon®)
 Monoamine oxidase inhibitors (MAOIs) (MPITS)
MOA: Inhibits MAO enzymes  MOA A  found in the intestinal
Selective MAO A tract
CLINICAL USE/S: Major depression unresponsive to other drugs
Moclobemide (Aurorix®) SE: Orthostatic Hypotension,  for metabolism of
Non-Selective MAOi Hypertensive Crisis (when given w/ +tyramine-rich foods-aged cheese, Norepinephrine,
Phenelzine (Nardil®) sour cream, yoghurt, red wint, chocolate, coffee) Serotonin,&
Isocarboxacid CI: Pickled Fish, Fava Beans, Cheese Tyramine
Moclobemide has a lesser risk of causing Hypertensive crisis  MAO B  found in the brain
Tranylcypromine (Parnate®)
w/ tyramine-rich food  for metabolism of
Selective MAO B Tranylcypromine: CI:Ephedrine, Phenylpropanolamine, Levodopa Dopamine
Selegeline (Eldepryl®)  to avoid Hypertensive Crisis
Tetracyclics  also called Noradrenergic & Specific Serotonergic Antidepressant (NaSSA)
Mirtazepine (Remeron®)
MOA: Mirtazepine blocks presynaptic 2 receptors; mechanism of action of others uncertain
Maprotiline (Deprilept®) CLINICAL USE/S: Major depression, smoking cessation (bupropion), sedation (mirtazepine)
Bupropion SE: Lowers Seizure Threshold (amoxapine, bupropion); Sedation and Weight Gain (mirtazepine)
Amoxapine
Reboxetine
5-HT2 antagonists MOA: Block 5-HT2 receptors
Nefazodone (Serzone®) CLINICAL USE/S: Major depression, hypnosis (trazodone)
SE: Nefazodone  hepatotoxicity
Trazodone (Desyrel®) Trazodone  Priapism (prolonged, painful erection) can lead to Necrosis

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 Anti-Manic Agents/ Mood Stabilizers

Lithium Lithium  1st line treatment & prevention of bipolar disorder;
DOC
can take the place of Na
- Na: Accumulation of Lithium  lead to lithium toxicity
- Na: increase excretion of Lithium  drug effect decrease
Causes Nephrogenic Diabetes Insipidus; sensitivity of V2 DCT
MOA: Uncertain, suppresses IP 3 and DAG signaling
EFFECT/S: No specific actions on ANS receptors or specific CNS receptors; no sedation
CLINICAL USE/S: Bipolar affective disorder;
prevents mood swings (prophylaxis)
SE: Tremor,Thyroid Enlargement, Leukocytosis, Edema , Renal Dysfunction,
Polyuria(can be seen even in usual dose & not considered a sign of Lithium Toxicity),
Pregnancy Category D
 Long term: Hypothyroidism

Conditions that can lead to sodium loss can enhance the toxicity of Lithium, include:
 Use of Thiazide Diuretics
 Diarrhea
 Vomiting
 Excessive Sweating
 Newer drugs for bipolar affective disorder alternative
Carbamazepine MOA: Unclear re: bipolar disorder
EFFECT/S: Ataxia and diplopia (carbamazepine);
Lamotrigine nausea, dizziness, and headache (lamotrigine);
Valproic acid gastrointestinal distress, weight gain, alopecia (valproic acid)
CLINICAL USE/S: Valproic acid competes with lithium as first choice in bipolar disorder, acute phase;
others also used in acute phase and for prophylaxis in depressive phase
TOXICITY: Hematotoxicity and induction of drug metabolism (Carbamazepine);
Rash (Lamotrigine);
Hepatic Dysfunction, Weight Gain, and inhibition of drug metabolism (Valproic Acid)
Valproic acid  give false-positive in urine ketone ttest

 Lithium salts  EBstein Anomaly/ Tricuspid valve malformation.

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Epilepsy  also called seizure disorder, neurologic disorder / chronic brain disorder that briefly interrupts the normal electrical activity of the brain
to cause seizures, characterized by a variety of symptoms including uncontrolled movements of the body, disorientation or confusion,
sudden fear, or loss of consciousness.
To detect:
 Neuroimaging Techniques
Magnetic Resonance Imaging (MIR)  can detect brain lesions related to epilepsy
 should be used in all cases to exclude brain abnormalities
Positron-Emission Tomography (PET)
Scan & Single-photon-Emission Coherence Tomography (SPECT) offer functional views of the brain to detect hypometabolism or
Stable Xenon-enhanced X-ray CT relative hypoperfusion
EEG  measures the electrical activity of the brain, & helps to identify functional cerebral changes underlying structural
abnormalities
 finds its utility in classifying the seizure or as an additional diagnostic tool,
but EEG by itsel cannot rule seizures in or out
 the beast time to obtain its is during seizure episode

Types of Epilepsy:
1. Idiopathic Epilepsy no specific anatomic cause for the seizure; inherited
Tx: Antiseizure Drugs; Vagal Nerve Stimulation
2. Symtomatic Epilepsy  due to some causes such as illicit drug use, tumors, head injury, hypoglycemia,
meningeal infection, or rapid withdrawal of alcohol from an alcohol.
Tx: Antiseizure drugs; Vagal Nerve Stimulation; Surgery

Classification of Seizures
Partial Seizures (Focal) Generalized Seizures
 1 hemisphere of the brain of one hemisphere  (both) 2 hemisphere of the brain of one hemisphere
1. Simple Partial  there is no loss of consciousness 1. Tonicclonic (grand mal)  is marked by rapid nilateral muscle jerking, muscle
2. Complex Partial  there is loss of consciousness flaccidity, & hyperventilation. Sometime, incontinence,
Manifestations: tongue biting, heavy salivation, & tachycardia.
-glassy stare -Respirations are interrupted
-visual, auditory -The individual becomes rigid & falls
or olfactory hallucinations  last for a bout a minute
-automatism postical phase: Drowsiness
st DOC: Valproic Acid
1 line in mx of partial seizure: Carbamazepine
Avoid giving to patient less than 2 yrs old  cause hepatotoxicity
Phenytoin
2, Absence (petit mal) ”Blank Stares”
Other DRUGS:
 5-40s (not exceed 1 min)
Lamotrigine
 100 episodes per day
Oxacarbamazepine
 usually in <20 yrs old
Valproic Acid
DOC: Ethosuximide
ALTERNATIVE: Valproic Acid
3. Myoclonic & Atonic (px suffer frequent fall)
 type of seizure involves a brief, shock-like contraction of muscles which may
be restricted to a part one extremety or may be generalized.
TX: Clonazepam
4. Status Epilepticus  continuous seizure episode
DOC: Lorazepam (formerly Diazepam)
DOC for children: Phenobarbital
ALTERNATIVE: Phenytoin
Fosphenytoin (more water-soluble)
5. Acute Seizure
Tx: Diazepam
6. Febrile Seizure (by fever)
Tx: Phenobarbital

Phases of Seizure Activity:

1. Prodome  may precede the seizure by hours or days, & may be accompanied by behavious or mood changes
2. Ictal Phase  is theseizure itself
3. Postical Phase  takes place immediately after seizure
 accompanied by extensor plantar reflexes, lethargy, & confusion

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 Anticonvulsants The most dangerous effect of most drugs used for seizure is
Mechanism of Action: Respiratory Depression.
1. Sodium Channel Blockers: Phenytoin, Carbamazepine, Valproic Acid Stimulant cannot be used for tx (ineffective as antidotes)
2. Calcium Channel Blockers: Ethosuximide Alkalinization of the urine to hasten elimination is usually ineffective)
3. GABA-mediated: Benzodiazepines, Phenobarbital, Gabapentin, Tiagabine
Cyclic ureides
Phenytoin (Dilantin®, Epilantin®) MOA: Alters conductance of sodium, potassium, calcium
At high concentration, it also inhibits the release of Serotonin & norepinephrine
At therapeutic concentration, it inhibits generation of repetitive action potentials
CLINICAL USE/S: Generalized tonic-clonic and partial seizures
SE: Nystagmus, Fetal Hydantoin Syndrome, CYP450 inducer, Gingival Hyperplasia
Ataxia & Diplopia  early manifestations of toxicity, that would warrant reduction in the dose
NOTE: Cardiotoxicity is partly due to Propylene Glycol(used as Solubilizing Agent through IV/IM)
Fosphenytoin is queous & more soluble, requires no solubilizing agent
It is incompatible w/ Dextrose-containing IV fluids Maximum rate (IV)
Elimination of Phenytoin follows a first order kinetics at very low blood levels =50mg/min
but displays a zero order kinetics at high serum levels (saturable kinetics)
Phenytoin is most commonly associated w/ cosmetic changes making the drug less desirable to use
among adolescents, school-age children, & women
 are significantly increase the clearance of Theophylline
Phenobarbital/ Phenobarbitone (Luminal®) MOA: Increase duration of Chloride Channel Opening
CLINICAL USE/S: Generalized tonic-clonic and partial seizures  Phenobarbital & Phenylethylamalonide
SE: Sedation, Ataxia  one of the active metabolites of
Ethosuximide (Zarontin®)  DOC for Absence Seizure (Petit mal) Primidone
MOA: Closes Na channel
CLINICAL USE/S: Absence seizures
SE: GI Distress, Dizziness, Headache
Tricyclics
Carbamazepine (Tegretol®) MOA: Closes Na channel
CLINICAL USE/S: Generalized tonic-clonic and partial seizures
Additional CLINICAL USE/S: Also Used for Trigeminal Neuralgia
SE: Headache, Nausea, Vomiting, SJS, Leucopenia, CYP450 Inducer (Autoinduction of Metabolism)
Ataxia & Diplopia  most common side effects seen w/ the use of Carbamazepine which requires adjustment in the
dose of the drug
CI: Patient w/ history of Tricyclic Antidepressants hypersensitvity
Benzodiazepines
Diazepam MOA: Enhance GABA receptor responses Diazepam  DOC to prevent & arrest convulsion in anesthetic toxicity
Lorazepam CLINICAL USE/S: Enhance GABAA receptor responses Lorazepam  DOC for Status Epilepticus
SE: Sedation
Clonazepam MOA: Enhance GABAA receptor responses
CLINICAL USE/S: Absence and myoclonic seizures, infantile spasms
SE: Sedation
GABA derivatives
Gabapentin (Nerontin®) MOA: Blocks Ca2+ channels
CLINICAL USE/S: Generalized tonic-clonic and partial seizures
Also for Diabetic Neuropathy
SE: Ataxia, Dizziness, Somnolence
Pregabalin MOA: Blocks Ca2+ channels
CLINICAL USE/S: Partial seizures
SE: Ataxia, Dizziness, Somnolence
Vigabatrin MOA: Inhibits GABA transaminase
CLINICAL USE/S: Partial seizures
SE: Drowsiness, Dizziness, Psychosis, Ocular Effects
Miscellaneous
Valporic Acid + Na Valproate (Depakene®)  DOC for Generalized Tonic-clonic (grand mal)
Divalproex Na (Depakote®)  ALTERNATIVE for Absence Seizure (Petit mal) Valproic Acid
MOA: Closes Na channel; Blocks high-frequency firing (valproate)  has the ability to decrease the
CLINICAL USE/S: Generalized Tonic-Clonic, Partial & Myoclonic Seizures metabolism of Carbamzepine
SE: Nausea, Alopecia, Weight Gain, Teratogenic, Cyp450 Inhibitor, associated w/ Idiosyncratic
Gi Disturbance, Rare Pancreatitis & Hepatotoxicity Hepatoxcicty when given for
Lamotrigine (Lamictal®) MOA: Blocks Na+ and Ca2+ channels, decreases glutamate the tx of seizure in Children
CLINICAL USE/S: Generalized tonic-clonic, partial, myoclonic and absence seizures leass than 2 years of age & in
patient on multiple
Topiramate (Topamax®) has a higher incidence of kidney stones medications
is a sulfamte-substituted monosaccharide &
a weak carbonic anhydrase inhibitor
that can precipitate renal calculi
MOA: Na-Channel blocker, potentiates GABA
CLINICAL USE/S: Generalized tonic-clonic, absence and partial seizures, migraine
SE: Sleepiness, Cognitive Slowing, Confusion, Paresthesias
Tiagabine (Gabitril®) MOA: Blocks GABA reuptake (inhibition GABA uptake by inhibiting the GABA transporter)
CLINICAL USE/S: Partial Seizure
Magnesium Sulfate  for eclampsia (HTN + proteinuria + Seizures)
Leveliracetam MOA: Binds synaptic protein
CLINICAL USE/S: Generalized tonic-clonic and partial seizures
Zonisamide MOA: Blocks Na+ channels
CLINICAL USE/S: Generalized tonic-clonic, partial and myoclonic seizures

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Parkinson’s Disease a progressive nervous disorder marked by symptoms of trembling hands, lifeless face, monotone voice, and a slow shuffling walk.
 associated w/ depigmentation of substantia nigra
caused by the degeneration of dopamine-producing brain cells, Manifestations of PD: TRAPS
and is the commonest form of Parkinsonism. Tremor
 was first described by Dr. James Parkinson in 1817 as “skaing palsy” Rigidity
 dopamine; acetylcholine Akinesia
Postural Instability
Treatment: Dopamnie agonist Shuffing Gas
Acetylcholine antagonist
Bradykinesia  slowness in performing common voluntary
DOC: Levodopa (it doesn’t cross in the blood brin barrier)
movements, including standing, walking, writing &
Levodopa Dopa Decarboxylase DOPAMINE talking
Dopamine is also known as Prolactin Inhibiting Hormone Akinesia  is characterized by difficulty in initiating movements
Dyskinesia & Dystonia  are typically oral-facial movements,
grimacing, or jerky & writhing movement
of the trunk & extremities
 AntiParkinson Drugs
Dopamine Precursor  most effective drug; DOC
Levodopa +/- Carbidopa (Sinemet®)  most useful in controlling the bradykenia of Parkinsonism
 ( 3-hydroxy-L-tyronine)

MOA: Precursor of dopamine; Carbidopa inhibits peripheral metabolism via dopa decarboxylase
CLINICAL USE/S: Primary drug used in Parkinson's disease;
SE: Dyskinesia/ chorea, ―on & off‖, ―wearing-off‖,
hallucinations & psychosis,
 ‖wearing off phenomenon‖
Postural hypotension
– decrease in the effect of Levodopa
Transitory nausea & vomiting
due to formation of 3-O-methyldopa
Orthostatic Faintness
(which may exist after using it for 3-5 yrs)
Transient Depression of Granulocytes

NOTE: Levodopa can penetrate to the brain & decarboxylated to dopamine,

Levodopa is decarboxylated in the GIT thus carbidopa is given
(carbidopa inhibits peripheral decarboxylase)
Carbidopa – suicide substrate
 minimizes nausea & vomiting associated w /Levodopa
 has no intrinsic activity for parkinsonism
The presence of large neutral amino acids in food interfere w/ Levodopa’s transport across the
blood-brain barrier
 Carbidopa  is a peripherally acting inhibitor of aromatic L-amino acid decarboxylase
Dopamine Releaser  also used as an antiviral (Amantadine)
Amantadine (Symmetrel®) CLINICAL USE/S: for mild symptoms especially tremors, also used as antiviral for influenza
SE: Livedo Reticularis (Skin Discoloration), SeizuresiIn Overdose
Ergot-derived Dopamine Agonist  direct agonist of D2 receptors
Bromocriptine (Parlobitsdel®, Provasyn® ) may cause first-dose phenomenon that can trigger sudden cardiovascular collapse
 ergotamine derivative (from ergot Claviceps Purpurea),
Pergolide (Permax®) Also used in the treatment of hyperprolactinemia – galactorrhea, amenorrhea, impotence
adjuct to Levodopa Therapy
Retroperitonal Fibrosis is a common side effect of all ergot derivatives
Non-Ergot Dopamine Agonist MOA:
Pramipexole (Sifrol®) CLINICAL USE/S:
SE:
Ropinirole (Requip®)
MAO (Monoamine Oxidase) Inhibitors  1st line drug
Selegiline/ Deprenyl (Eldepryl®) adjuct to Leveodopa when patient experiences a ―wearing-off‖ phenomenon
 most patients experience side effects at doses higher than 30-40 mg/day
Rasageline MOA: Selective MAO B inhibitor
CLINICAL USE/S: Rasagiline for early PD; Both drugs adjunctive with L-dopa
SE: Serotonin syndrome with meperidine and possibly SSRIs and TCAs.
COMT (Catechol O-methyl transferase) Inhibitors MOA: Block L-dopa metabolism in periphery (both) and CNS (tolcapone)
Tolcapone (Comtan®, Tasmar®) Can convert Levodopa to 3-O-methyldopa
SE: Hepatotoxicity
Entacapone
Anticholinergic/ Antimuscurinics
Benztropine (Cogentin®) MOA: Block M receptors
CLINICAL USE/S: Improve tremor and rigidity not bradykinesia
Biperiden (Akineton®) SE: Typical atropine-like side effects
Trihexyphenidyl (Artane®)

 Drugs for Other Movement Disorders

 Drugs for Huntington's disease An inherited adult-onset neurologic disease characterized by dementia and bizarre involuntary movements
Tetrabenazine MOA: deplete amines
Reserpine CLINICAL USE/S: Reduce symptom (eg, chorea) severity
SE: depression, hypotension, sedation
Haloperidol MOA: D2 antagonist
CLINICAL USE/S: Reduce symptom (eg, chorea) severity
SE: extrapyramidal dysfunction
 Drugs for Tourette's syndrome  A neurologic disease of unknown cause that presents with multiple tics associated with snorting, sniffing,
and involuntary vocalizations (often obscene)
Haloperidol MOA: D2 receptor blocker
CLINICAL USE/S: Reduce vocal and motor tic frequency and severity
SE: Haloperidol: extrapyramidal dysfunction
Clonidine MOA: 2 blocker

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 Anesthetic Agents
General Anesthetics
Inhaled POSSIBLE MOA: Facilitate GABA-mediated inhibition; block brain NMDA and ACh-N receptors
Gas: PHARMACOLOGICAL EFFECTS: Increase cerebral blood flow;
Enflurane and Halothane decrease cardiac output.
Nitrous Oxide (N20) Others cause vasodilation;
Volatile Liquids: All decrease respiratory functions—lung irritation (Desflurane)
Halothane (Fluthane®) SE: Hypotension, Arrhythmia due Sensitization of Heart to Catecholamines, Malignant Hyperthermia
Isoflurane (Forane®, Aerrane®) Severe & life-threatening Hepatitis(Halothane)
Nephrotoxicity (Enflurane, Methoxyflurane)
Desflurane (Suprane®) DRUG INTERACTIONS: additive CNS depression with many agents, especially opioids and sedative-hypnotics
Enflurane (Ethrane®, Alyrane®) NOTE: used with other anesthetics to increase their uptake & analgesic activity
Sevoflurane (Sevorane®) Isoflurane  produces the greatest augmentation of the effect of neuromuscular
Methoxyflurane  Nitrous Oxide (N20)  Laughing gas; least potent; associated w/ Leukopenia
Methoxyflurane  most potent; For Labor (no longer used clinically)
Desflurane  least potent
 Halothane (Fluthane®)  for children- least/non-hepatotoxic, pleasant odor
 most potent based on the minimum alveolar concentration
sensitizes the myocardium to catecholamines which can lead to ventricular arrhythmia
when sympathomimetic drugs are concurrently administered
Solubility in the blood: Halothane > Enflurane > Isoflurane > Sevoflurane> Desflurane> Nitrous Oxide
Intavenous  for rapid induction of anesthesia; maintained with inhalational agent
Barbiturates  induce sedation
Thiopental (Pentothal®, Pentobrim®) POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors
PHARMACOLOGIC EFFECTS: circulatory and respiratory depression; decrease intracranial pressure
Thioamylal TOXICITY: extensions of CNS depressant actions; additive CNS depression with many drugs
Methohexital Theopental  can only be used to induce anesthesia but not to maintain anesthesia
Benzodiazepines used for sedation ; reduce anxiety & seizure;
Midazolam premedication when large doses of local anesthetics must be administered to reduce seizure
POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors
PHARMACOLOGIC EFFECTS: less depressant than barbiturates
SE: Postoperative respiratory depression reversed by flumazenil
Imidazole POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors
Etomidate PHARMACOLOGIC EFFECTS: Minimal effects on CV and respiratory functions
SE: No analgesia, pain on injection (may need opioid), myoclonus, nausea, and vomiting
Phenols for rapid onset, short duration hypnosis
Propofol (Diprivan®, Fresofol®) POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors
PHARMACOLOGIC EFFECTS: Propofol: vasodilation and hypotension; negative inotropy.
Fospropofol Fospropofol water-soluble
SE: Propofol: Hypotension (During Induction), Cardiovascular Depression
 Propofol (Diprivan , Fresofol®)  a preparation containing soybean oil & egg phospholipid
®

Dissociative provides dissociative anesthesia (analgesia, amnesia without loss of consciousness)

Ketamine POSSIBLE MOA: Blocks excitation by glutamate at NMDA receptors
PHARMACOLOGIC EFFECTS: Analgesia, amnesia and catatonia but "consciousness" retained;
(Ketalar®, Ketaject®, cardiovascular (CV) stimulation
Ketamax®, Quetanex®) SE: Increased intracranial pressure; emergence reactions; Distortion of reality & terrifying dreams
Opioids POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors
Fentanyl PHARMACOLOGIC EFFECTS: Marked analgesia, respiratory depression
SE: Respiratory depression—reversed by naloxone
Alfentanil
Remifentanil Nitrous Oxide + Droperidol + Fentanyl = ―neuroleptanesthesia‖
Morphine
Local Anesthetics  Common MOA: Inhibition of Voltage-Gated Sodium Channel
 NOTE: CO-administered with vasoconstrictor Epinephrine (1: 100,000)
 COMMON SE: lightheadedness, dizziness, seizures, shivering, respiratory depression, coma, bradycardia, hypotension
 All Local Anesthetics are vasodilators, except for COCAINE (vasoconstrictor)
Amides MOA: Blockade of Na+ channels slows in nerves, then prevents axon potential propagation.
Articaine (Ubistesin®) provides analgesia without loss of consciousness
CLINICAL APPLICATIONS: Analgesia via topical use, / injection (perineural, epidural, subarachnoid);
Bupivacaine (Marcaine®, Sensorcaine®, Senpivac®) rarely IV
Etidocaine (Duranest®) SE: CNS: excitation, seizures
Levobupivacaine (Sensibloq®) CV: vasodilation, hypotension,
Lidocaine (Xylocaine®) arrhythmias (bupivacaine)
Bupivacaine  most cardiotoxic
Mepivacaine (Carbocaine®, Mepivastesin®) Lidocaine  most neurotoxic when given as a spinal anesthetic
Prilocaine (Citanest®, Emla®)  has a relatively longer half-life
Ropivacaine (Naropin®)  DOC for Ventricular Tachycardia
Prilocaine  can predispose to the development of methemoglobinemia when given in large
doses during regional anesthesia
-Ortho-Toluidine  metabolite of Prilocaine
 when formed in the body in significant amounts can cause oxidation
of the iron I hemoglobin to the ferric form

Esters MOA: Blockade of Na+ channels slows in nerves, then prevents axon potential propagation
Benzocaine (Americaine®, United Home Burn Ointment®) provides analgesia without loss of consciousness
Additional MOA of Cocaine: Intrinsic Sympathomimetic Actions
Cocaine
CLINICAL APPLICATION/S: Analgesia, topical only for cocaine and benzocaine
Procaine (Novocaine®) SE: CNS: excitation, seizures; Cocaine vasoconstricts
Tetracaine (Pontocaine®) When abused has caused hypertension and cardiac arrhythmias
Chloroprocaine (Nesacaine®) Tetracaine, Procaine, & Chloroprocaine  are para-amino benzoic acid derivatives
Proparacaine (Alcaine®)  Allergic reaction is most likely to occur
Dibucaine (Nupercainal®) Butylcholinesterase  is responsible for the metabolism of ester-type local anesthetics
 The degree of anesthetic activity of an ester is higher if the acid group is Aromatic.

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 Drugs of Abuse
CNS Stimulants
Caffeine (1,3,7-trimethylxanthine) MOA: inh. phosphodiesterase  inc. cAMP inc. Adrenergic Action
Theophylline (1,3-dimethylxanthine)
Theobromine (3,7-dimethylxanthine)
Nicotine
For smoking cessation:
Nicotine Polacrilex gum (Nicorrete®)
Clonidine (Catapress®)
Bupropion (Wellbutrin®, Zyban®)
Vareniclinen (Champix®)
Amphetamines:
Methylphenidate (Ritalin®, Concerta®)
Methamphetamine (shabu, ice, meth)
Ecstacy (Metylenedioxymethamphetamine/ MDMA)
Phentermine (Ionamine®, Duromine®)
Bangkok pills (Phentermine+ Fenflurane)
Cocaine (Crack)
CNS depressants
Ethanol/ Ethyl Alcohol ANTI-ALCOHOLISM: Disulfiram (Antabuse®)
IMPORTANT SE: Wernicke-Korsakoff Syndrome
Benzodiazepines
Opioids
Heroin
Morphine
Hallucinogens
Phencyclidine (PCP, “angel dust”)
Lysergic acid diethylamide (LSD)
Marijuana (delta-9-tetrahydrocannabinol , 9-THC)

Drugs Used to Treat Dependence and Addiction

Subclass Mechanism of Effects Clinical Applications Pharmacokinetics, Toxicities,
Action Interactions
Opioid antagonists
Naloxone Antagonists of Reverse or block effects of Naloxone: opioid overdose Naloxone: Short half-life (1-2 h)
Naltrexone opioid receptors opioids Naltrexone: treatment of alcoholism Naltrexone: Half-life like morphine (4 h)
Synthetic opioid
Methadone Slow-acting agonist Acute effects like Substitution therapy for opioid addicts Variable half-life
at opioid receptors morphine Toxicity: Like morphine re acute and
chronic effects including withdrawal
Partial -receptor agonist
Buprenorphine Partial agonist at Attenuates acute effects of Substitution therapy for opioid addicts Long half-life (>40 h); formulated with
opioid receptors morphine and other strong nalorphine to avoid illicit IV use
opioids
N-receptor partial agonist
Varenicline Agonist at ACh-N Blocks "rewarding" effects Smoking cessation Nausea and vomiting, psychiatric
receptor (22) of nicotine changes, seizures in high dose
subtype

Benzodiazepines
Oxazepam Modulators of Enhance GABA functions Attenuate withdrawal symptoms Half-life 4-15 h; lorazepam kinetics not
Lorazepam GABAA receptors in CNS including seizures from alcohol and affected by liver dysfunction
other sedative-hypnotics
NMDA receptor antagonist
Acamprosate Antagonist at May block synaptic Treatment of alcoholism (in Allergies, arrhythmias, variable BP effects,
glutamate plasticity combination with counseling) headaches, and impotence; hallucinations
NMDA receptors in elderly
Cannabinoid receptor agonist
Rimonabant Agonist at CB1 Decrease GABA and Treatment of obesity; off-label use for Major depression; increased suicide risk
receptors glutamate release in CNS smoking cessation

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XIII. CHEMOTHERAPEUTIC DRUGS

CANCER  uncontrolled cell proliferation  tumor/ neoplasm

Malignant Tumor/ Cancer  metastasize or spread to other parts of the body
Benign Tumor/ Cancer  does not metatasize

CANCER DRUGS  CELL CYCLE

Cancer Chemotherapy Drugs (Katzung 9 ed)

th

Subclass Mechanism of Action Clinical Applications Acute Toxicities Chronic Toxicities

Alkylating agents
Cyclophosphamide Forms DNA cross-links, resulting Breast Cancer, Nausea &Vomiting Myelosuppression,
in inhibition of DNA synthesis and Ovarian Cancer, Alopecia,
function Non-Hodgkin's Lymphoma, Hemorrhagic Cystitis
Chronic Lymphocytic
Leukemia,
Neuroblastoma
Other major alkylating agents: Mechlorethamine, procarbazine, busulfan carmustine, lomustine, dacarbazine
Platinum analogs: Cisplatin, carboplatin, oxaliplatin

Antimetabolites
Methotrexate Inhibits DHFR, resulting in Breast Cancer, Head &Neck Mucositis, Myelosuppression
inhibition of synthesis of Cancer, Primary CNS Diarrhea
thymidylate, purine nucleotides, Lymphoma, Non-Hodgkin's
serine, and methionine Lymphoma, Bladder Cancer,
Choriocarcinoma
6-Mercaptopurine Inhibits de novo purine synthesis Acute myelogenous leukemia Nausea & Vomiting Myelosuppression,
Immunosuppression,
Hepatotoxicity
5-Fluorouracil Inhibits thymidylate synthase, and GI Cancers, Nausea, Myelosuppression,
its metabolites are incorporated Breast Cancer, Mucositis, Neurotoxicity
into RNA and DNA, all resulting in Head & Neck Cancer, Diarrhea
inhibition of DNA synthesis and Hepatocellular Cancer
function and in RNA processing
Other antimetabolites: Cytarabine, gemcitabine

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Plant Alkaloids (Cell cycle-specific agent)

Vinca alkaloids
Vincristine Interferes with microtubule Acute Lymphocytic Leukemia, None Neurotoxicity w/ Peripheral
function, resulting in impaired Hodgkin's & Non-Hodgkin's Neuropathy,
mitosis Lymphoma, Paralytic Ileus,
Wilms' Tumor, Myelosuppression,
Neuroblastoma Alopecia,
Inappropriate ADH Secretion
Other vinca alkaloids: Vinblastine, vinorelbine
Cantharatine  is the indole-containing moiety of the antitumor vinca alkaloids idolated from periwinkle Catharanthus roseus
Vindoline  is the indoline-containing moiety
Podophyllotoxins
Etoposide Analogue of Podophyllotoxin, Lung Cancer, Nausea, Alopecia,
inhibits topoisomerase II, resulting Non-Hodgkin's Lymphoma, Vomiting Myelosuppression
in DNA damage Gastric Cancer
first choice tx for small-lung
cancer
Other podophyllotoxins: Teniposide
Camptothecins
Topotecan Inhibits topoisomerase I, resulting Small Cell Lung Cancer, Nausea, Myelosuppression
in DNA damage Ovarian Cancer Vomiting,
Diarrhea
Other camptothecins: Irinotecan
Taxanes
Paclitaxel Interferes with microtubule Breast, Lung, Nausea, Myelosuppression,
function, resulting in impaired Ovarian, Vomiting, Peripheral Sensory Neuropathy
mitosis Gastroesophageal, Hypotension,
Prostate, Bladder, Arrhythmias,
Head & Neck Cancers Hypersensitivity
Other taxanes: Docetaxel

Antibiotics
Anthracyclines
Doxorubicin Oxygen free radicals bind to DNA Lymphomas, Nausea, Alopecia,
(Adrianamycin®) causing strand breakage; inhibits Myelomas, Arrhythmias Cardiomyopathy,
topoisomerase II; intercalates into Sarcomas, Myelosuppression,
DNA Breast, Lung, Ovarian And Cardiotoxic
Thyroid Cancers
Dactinomycin Intercalates in DNA Wilms’ Tumor, Nausea&Vomiting, Myelosuppression,
(actinomycin D) Ewing’s Sarcosoma, Anorexia, Alopecia,
Rhabdomyosarcosoma Erythema & Tissue Bone Marrow Depression,
(Childhood Tumors) Injury
Other anthracyclines: Daunorubicin, idarubicin, epirubicin, mitoxantrone Bleomycin  can cause Pulmonary Toxicity (Pulmonary Fibrosis)
Other antitumor antibiotics: Bleomycin, mitomycin, Dactinomycin  from S. verticillus
 occurs naturally as a blue copper complex

Monoclonal Antibodies
Tyrosine kinase inhibitors
Imatinib Inhibits bcr-abl tyrosine kinase Chronic Myelogenous Nausea, Fluid Retention w/ Ankle & Periorbital
and other receptor tyrosine Leukemia(CML), Vomiting Edema,
kinases GI Stromal Tumor Diarrhea,
Myalgias,
Congestive Heart Failure
Other tyrosine kinase inhibitors: Dasatinib, nilotinib
Growth factor receptor inhibitors
Trastuzumab Inhibits the binding of EGF to the HER-2/neu receptor + breast Nausea, vomiting, Cardiac dysfunction
(Herceptin®) HER-2/neu growth receptor cancer chills, fever,
(Metastatic Breast cancer) headache
Other growth factor receptor inhibitors: Cetuximab, panitumumab, gefitinib, erlotinib
Vascular endothelial growth factor (VEGF) inhibitors
Bevacizumab Inhibits binding of VEGF to its Colorectal, Breast, Hypertensin, Arterial Thromboembolic Events,
receptor, resulting in inhibition of Non-Small Cell Lung, Infusion Reaction Gastrointestinal Perforations, Wound
tumor vascularization Renal Cancer Healing Complications, Proteinuria

Hormones
Hormone agonists
Prednisone most commonly used glucocorticoid in cancer chemo.
Ketone Reduction  involved in biotransformation of prednisone to prednisolone
MOA: May trigger apoptosis. May even work on non-dicing cells.
CLINICAL USE: Many inflammatory conditions, organ transplantation, hematologic cancers
SE/ TOXICITY: Adrenal Suppression, Growth Inhibition, Muscle Wasting, Osteoporosis, Salt Retention,
Glucose Intolerance, Behavioral Changes
Hormone antagonists
Tamoxifen, MOA: Estrogen antagonist actions in breast tissue and CNS; estrogen agonist effects in liver and bone
Raloxifene CLINICAL USE: Prevention and adjuvant treatment of hormone-responsive breast cancer
SE/ TOXICITY: Hot Flushes, Thromboembolism, Endometrial Hyperplasia
Other hormonal antagonists: Aromatase inhibitors, GnRH agonist and antagonists, androgen receptor antagonists (see Chapter 40)
DHFR, dihydrofolate reductase; EGF, epidermal growth factor; GnRH, gonadotropin-releasing hormone; VEGF, vascular endothelial growth factor.

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I. PRINCIPLES OF ONCOLOGY.
Cancer refers to a heterogeneous group of diseases caused by an impairment of the normal functioning of genes, which leads to genetic damage.
A. Characteristics of cancer cells.
1. Carcinogenesismechanism of how many cancers occur is thought to be a multistage,
multifactorial process that involves both genetic and environmental factors.
a. Initiation first step involves the exposure of normal cells to a carcinogen, producing genetic damage to a cell.
b. Promotionenvironment becomes altered to allow preferential growth of mutated cells over normal cells.
The mutated cells become cancerous.
c. ProgressionIncreased proliferation of cancer cells allows for invasion into local tissue andmetastasis.
2. Types of cancer. Tumors can be benign or malignant.
Benign tumors are generally slow growing, resemble normal cells, are localized, and are not harmful.
Malignant tumors oft en proliferate more rapidly, have an atypical appearance, invade and destroy surrounding tissues,
and are harmful if left untreated. Malignant cancers are further categorized by the location from where the tumor cells arise.
a. Solid tumors. Carcinomas are tumors of epithelial cells. These include specifi c tissue cancers (e.g., lung, colon, breast).
Sarcomas include tumors of connective tissue such as bone (e.g., osteosarcoma) or muscle (e.g., leiomyosarcoma).
b. Hematological malignancies. Lymphomas are tumors of the lymphatic system and include Hodgkin and non-Hodgkin lymphomas.
Leukemias are tumors of blood-forming elements & classified as acute or chronic and myeloid or lymphoid.
B. Incidence.The most common cancers are breast, prostate, and colorectal.
The leading cause of cancer death is lung cancer.
C. Cause. Many factors have been implicated in the origin of cancer. Some of these factors are as follows:
1. Viruses, including Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human papillomavirus (HPV)
2. Environmental and occupational exposures, such as ionizing and ultraviolet radiation and exposure to chemicals,
including vinyl chloride, benzene, and asbestos
3. Lifestyle factors, such as high-fat, low-fi ber diets and tobacco and ethanol use
4. Medications, including alkylating agents and immunosuppressants
5. Genetic factors, including inherited mutations, cancer-causing genes (oncogenes), and defective tumor-suppressor genes
D. Detection and diagnosis are critical for the appropriate treatment of cancer. Earlier detection may improve response to treatment.
1. Warning signs of cancer have been outlined by the American Cancer Society. General signs and symptoms of cancer may include
unexplained weight loss, fever, fatigue, pain, and skin changes. Signs and symptoms of specifi c types of cancer can include
changes in bowel habits or bladder bleeding or discharge, thickening or lump in the breast or other body part, indigestion
or diffi culty swallowing, a recent change in a wart or mole, other skin changes, or a nagging cough or hoarseness.
2. Guidelines for screening asymptomatic people for the presence of cancer have been established by the American Cancer Society,
the National Cancer Institute, and the U.S. Preventive Health Services Task Force, among others. Because many
cancers do not produce signs or symptoms until they have become large, the goal of screening is to detect
cancers early, when the disease may be more likely to be curable, thus potentially reducing cancer-related
mortality. Th e diff erent sets of guidelines vary slightly in their recommendations for age and frequency of
screening procedures.
3. Tumor markers are biochemical indicators of the presence of neoplastic proliferation detected in serum, plasma, or other body fl uids.
These tumor markers may be used initially as screening tests, to reveal further information aft er abnormal test results,
or to monitor the effi cacy of therapy. Elevated levels of these markers are not defi nitive for the presence of cancer
because levels can be elevated in other benign and malignant conditions, and false-positive results do occur. Examples of
some commonly used markers include the following:
a. Carcinoembryonic antigen (CEA) for colorectal cancer
b. -Fetoprotein (AFP) for hepatocellular carcinoma or hepatoblastoma
c. Prostate-specifi c antigen (PSA) for prostate cancer
4. Tumor biopsy. The defi nitive test for the presence of cancerous cells is a biopsy and pathological examination of the biopsy specimen.
Several types of procedures are used in the pathological analysis of tumors, including evaluating the morphological
features of the tissue and cells (via pathologic evaluation), looking for cell-surface markers (via fl ow cytometry), and
cytogenetic evaluation for specifi c chromosomal abnormalities (via fl uorescence in situ hybridization).
5. Imaging studies, such as radiograph, CT scans, MRI, and positron emission tomography (PET), may be used to aid in the diagnosis or
location of a tumor and to monitor response to treatment.
6. Other laboratory tests commonly used for cancer diagnosis include complete blood counts (CBCs) and blood chemistries.
A CBC measures the levels of the three basic blood cells—white cells, red cells, and platelets.
a. The CBC will oft en include an absolute neutrophil count (ANC), which measures the absolute number of neutrophils in a
person’s white blood count. Th e ANC is calculated by multiplying the white blood count (WBC) ( total neutrophils (segmented
neutrophils percent ) segmented bands percent) ANC. Segmented neutrophils are oft en listed as “polys” and segmented bands
are immature “polys.”

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II. CELL LIFE CYCLE is essential to the understanding of the activity of chemotherapy agents in the treatment of cancer
A. Phases of the cell cycle
1. M phase, or mitosis, is the phase in which the cell divides into two daughter cells.
2. G1 phase, or postmitotic gap, is when RNA and the proteins required for the specialized functions of the cell are synthesized
in preparation for DNA synthesis.
3. S phase is the phase in which DNA synthesis and replication occurs.
4. G2 phase, or the premitotic or postsynthetic gap, is the phase in which RNA and the enzymes topoisomerase I and II are produced
to prepare for duplication of the cell.
5. G0 phase, or resting phase, is the phase in which the cell is not committed to division.
Cells in this phase are generally not sensitive to chemotherapy. Some of these cells may reenter the actively
dividing cell cycle. In a process called recruitment, some chemotherapy regimens are designed to enhance this
reentry by killing a large number of actively dividing cells.

B. Cell growth kinetics. Several terms describe cell growth kinetics.

1. Cell growth fraction is the proportion of cells in the tumor dividing or preparing to divide.
As the tumor enlarges, the cell growth fraction decreases because a larger proportion of cells may not be able to obtain
adequate nutrients and blood supply for replication.
2. Cell cycle time is the average time for a cell that has just completed mitosis to grow and again divide and again pass through mitosis.
Cell cycle time is specifi c for each individual tumor.
3. Tumor doubling time is the time for the tumor to double in size. As the tumor gets larger, its doubling time gets longer because
it contains a smaller proportion of actively dividing cells owing to restrictions of space, nutrient availability, and blood
supply.
4. Th e gompertzian growth curve illustrates these cell growth concepts
C. Tumor cell burden is the number of tumor cells in the body.
1. Because a large number of cells is required to produce symptoms and be clinically detectable (approximately 109 cells),
the tumor may be in the plateau phase of the growth curve by the time it is discovered.
2. Th e cell kill hypothesis states that a certain percentage of tumor cells will be killed with each course of cancer chemotherapy.
a. As tumor cells are killed, cells in G0 may be recruited into G1, resulting in tumor regrowth.
b. Th us, repeated cycles of chemotherapy are required to achieve a complete response or remission.
c. Th e percentage of cells killed depends on the chemotherapy dose.
3. In theory, the tumor burden would never reach absolute zero because only a percentage of cells are killed with each cycle.
Less than 104 cells may depend on elimination by the host’s immune system.
D. Chemotherapeutic agents may be classifi ed according to their reliance on cell cycle kinetics for their cytotoxic effect.
Combinations of chemotherapy agents that are active in diff erent phases of the cell cycle may result in a greater cell kill.
A cell cycle classifi cation of some commonly used chemotherapeutic agents is given in II.D.1.a–d.
1. Phase-specifi c agents are most active against cells that are in a specifi c phase of the cell cycle.
These agents are most eff ective against tumors with a high growth fraction. Th eoretically, administering these agents as continuous intravenous
infusions or by multiple repeated doses may increase the likelihood of hitting the majority of cells in the specifi c phase at any one time. Th
erefore, these agents are also considered schedule-dependent agents.
Examples are as follows:
a. M phase: mitotic inhibitors (e.g., vinca alkaloids, taxanes)
b. G1 phase: asparaginase, prednisone
antineoplastic agnet prepration from E.coli containing the enzyme L-asparagine amidohydrolase
c. S phase: antimetabolites
d. G2 phase: bleomycin, etoposide
2. Phase-nonspecifi c agents are eff ective while cells are in the active cycle but do not require that the cell be in a particular phase.
These agents generally show more activity against slow-growing tumors. Th ey may be administered as single bolus doses because their activity is
independent of the cell cycle. Th ese drugs are also considered dose-dependent agents.
Examples are alkylating agents and antitumor antibiotics.
3. Cell cycle–nonspecifi c agents are eff ective in all phases, including G0.
Examples are carmustine and lomustine.
Radiation therapy is also considered cell cycle nonspecific.

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III. CHEMOTHERAPY
A. Objectives of chemotherapy
1. For cancers like leukemias and lymphomas, several phases of chemotherapy are necessary.
A cure may be sought with aggressive therapy for a prolonged period to eradicate all disease. For leukemias, this curative approach may
consist of the following components:
a. Remission induction: therapy given with the intent of maximizing cell kill.
b. Consolidation (also known as intensifi cation or post-remission therapy): therapy to eradicate any clinically undetectable disease
and to lower the tumor cell burden below 103, at which level host immunological defenses may keep the cells in control.
c. Maintenance: therapy given in lower doses with the aim of maintaining or prolonging a remission.
2. For solid tumors, one or more approaches to chemotherapy may be used when seeking a cure based on the known utility of chemotherapy in line
with other modalities, such as surgery or radiation.
a. Adjuvant chemotherapy is given aft er more defi nitive therapy, such as surgery,
to eliminate any remaining disease or undetected micrometastasis.
b. Neoadjuvant chemotherapy is given to decrease the tumor burden before defi nitive therapy, such as surgery or radiation.
4. Palliative therapy is usually given when complete eradication of the tumor is considered unlikely or the patient refuses aggressive therapy.
Palliative chemotherapy may be given to decrease the tumor size, control growth, and reduce symptoms.
5. Salvage chemotherapy is given as an attempt to get a patient into remission, aft er previous therapies have failed.

B. Chemotherapy dosing may be based on body weight, body surface area (BSA), or area under the concentration versus time curve (AUC).
BSA is most frequently used because it provides an accurate comparison of activity and toxicity across species, making it easier to translate
preclinical dosing into clinical trials and practice in humans. In addition, BSA correlates with cardiac output, which determines renal and
hepatic blood fl ow and thus aff ects drug elimination. In very young or very small patients (e.g., infants less than a year of age or less than 10
to 12 kg of body weight), the BSA is not a good measure for calculating the dose as it can overestimate the patient’s size and lead to
overdosing of chemotherapeutic agents, resulting in excessive toxicities. In this patient population, dosing chemotherapy based on body
weight (in kilograms) is oft en a more frequently employed technique.
C. Dosing adjustments may be required for kidney or liver dysfunction to prevent toxicity. For some agents, dose adjustments are also made based on
hematologic or non-hematologic toxicities. Very little is known about dosing chemotherapy in the obese population.
D. Combination chemotherapy is usually more eff ective than single-agent therapy.
1. When combining chemotherapy agents, factors to consider include
a. Antitumor activity
b. Diff erent mechanisms of action
c. Minimally overlapping toxicities
2. Th e reasons for administering combination chemotherapy include
a. Overcoming or preventing resistance
b. Cytotoxicity to resting and dividing cells
c. Biochemical enhancement of effect
d. Rescue of normal cells
3. Dosing and scheduling of combination regimens are important because they are designed to allow recovery of normal cells.
These regimens generally are given as short courses of therapy in cycles.
4. Acronyms oft en are used to designate chemotherapy regimens.
For example, CMF refers to a combination of cyclophosphamide, methotrexate, and fl uorouracil used in the treatment of breast cancer.
E. Administration
1. Routes of administration vary depending on the agent and the disease state.
Although intravenous (IV) administration is most commonly employed, oral administration of chemotherapy is becoming increasingly more
common.
2. Other administration techniques include oral, subcutaneous, intrathecal, intra-arterial, intraperitoneal, intravesical,
continuous IV infusion, bolus IV infusion, and hepatic artery infusion.
3. Drugs that may be given intrathecally include methotrexate, cytarabine, and hydrocortisone.
Drugs should not be administered by the intrathecal route without specifi c information supporting intrathecal administration.
Inadvertent administration of vinca alkaloids (e.g., vincristine) by the intrathecal route results in ascending paralysis and death.
Th e U.S. Food and Drug Administration (FDA) requires that specifi c wording alerting the provider to this error must be included on the packaging
of each dose of vincristine. Th ey also recommend that safety measures are employed in the preparation and delivery of vinca alkaloids.
4. Products with diff erent formulations, including liposomal or pegylated agents (e.g., liposomal doxorubicin, pegfi lgrastim),
are being used to decrease frequency of administration and/or reduce toxicities.
F. Response to chemotherapy is defined in several ways and does not always correlate with patient survival.
1. Complete response (CR) indicates disappearance of all clinical, gross, and microscopic disease.
2. PR indicates a greater than 50% reduction in tumor size, lasting a reasonable period. Some evidence of disease remains aft er therapy.
3. Response rate (RR) is defined as CR _ PR.
4. SD indicates tumor that neither grows nor shrinks signifi cantly (less than 25% change in size).
5. PD or no response aft er therapy is defi ned by a greater than 25% increase in tumor size or the appearance of new lesions.
G. Factors aff ecting response to chemotherapy
1. Tumor cell heterogeneity. Large tumors have completed multiple cell divisions, resulting in several mutations and genetically diverse cells.
2. Drug resistance. The Goldie-Coldman hypothesis states that genetic changes are associated with drug resistance,
and the probability of resistance increases as tumor size increases. The hypothesis assumes that at the time of diagnosis, most
tumors possess resistant clones. A well-studied mechanism of resistance involves the multidrug resistance (mdr) gene, which codes
for membrane-bound P-glycoprotein. P-glycoprotein serves as a channel through which cellular toxins (i.e., chemotherapeutic
agents) may be excreted from the cell.
3. Dose intensity is defined as a specifi c dose delivered over a specifi c period. Occasionally, the full dose cannot be given or a cycle is delayed owing
to complications or toxicities. Suboptimal doses have resulted in reduced response rates and survival.
Dose density involves shortening the usual interval between doses to maximize the drug eff ects on the tumor growth kinetics.
4. Patient-specifi c factors such as poor functional status, impaired organ function, or concomitant diseases may compromise
how a chemotherapy regimen is given and affect how the patient responds to treatment.

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IV. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

A. Alkylating agents were the first group of antineoplastic agents.
The prototype of this class is mechlorethamine, or nitrogen mustard, which was researched as a chemical warfare agent.
Alkylating agents cause cross-linking and abnormal base pairing of DNA strands, which inhibit replication of the DNA.
This mechanism is known as alkylation. These are phase-nonspecifi c agents.
B. Most of the antitumor antibiotics are obtained from organisms of the Streptomyces genus.
These agents may act by either alkylation (mitomycin) or intercalation.
Intercalation is the process by which the drug slides between DNA base pairs and inhibits DNA synthesis. These are phase- nonspecifi c agents.
C. Antimetabolites are structural analogs of naturally occurring substrates for biochemical reactions.
They inhibit DNA synthesis by acting as false substitutions in the production of nucleic acids.
These are S phase–specific agents. Unique features involving the use of antimetabolites are as follows:
1. Leucovorin rescue must be given following with high-dose methotrexate administration to rescue normal,
healthy cells from the cytotoxicity of methotrexate.
Leucovorin serves as a reduced folate (i.e., folinic acid) that enters the folic acid synthesis pathway downstream of the site of
effect of methotrexate. Timing and dosing of leucovorin is critical to ensure the maximal benefi t with the least risk of reversing
the cytotoxic eff ects of methotrexate.
2. Polymorphisms of thiopurine methyltransferase (TPMT) may produce excessive toxicity in patients receiving mercaptopurine.
Dose reductions may be necessary in some patients.
D. Mitotic inhibitors. The vinca alkaloids arrest cell division by preventing microtubule formation.
The taxanes promote microtubule assembly and stabilization, thus prohibiting cell division.
These are M phase–specifi c agents.
E. Topoisomerase inhibitors inhibit the enzymes topoisomerase I or II.
The topoisomerases are necessary for DNA replication and RNA transcription.
These are G2 phase–specifi c agents.
F. Enzymes. Asparaginase is an enzyme that causes the degradation of the amino acid asparagine to aspartic acid and ammonia.
Unlike normal cells, tumor cells lack the ability to synthesize asparagine.
This is a G1 phase–specifi c agent.
G. Protein tyrosine kinase inhibitors. These agents are also known as targeted agents because they affect specifi c receptors to induce cancer cell death.
1. Imatinib, dasatinib, and nilotinib are selective tyrosine kinase inhibitor that causes apoptosis or arrest of growth in cells
expressing the Bcr-Abl oncoprotein.
Bcr-Abl is the product of a specifi c chromosomal abnormality (Philadelphia chromosome), which is present in
virtually all patients with chronic myelogenous leukemia (CML).
2. Erlotinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase.
EGFR is a cell surface receptor that is overexpressed in certain solid tumors.
The binding of the EGFR receptor to its ligand activates tyrosine kinase, which then stimulates cell proliferation and growth of the tumor.
Erlotinib blocks the tyrosine kinase signaling cascade and inhibits cancer cell growth.
H. Various miscellaneous agents have a critical role in the treatment of specifi c cancers.
1. Retinoid derivatives
a. Tretinoin (all-trans-retinoic acid; ATRA) is a retinoic acid derivative that is used in the treatment of a specifi c type of
acute myelogenous leukemia, known as acute promyelocytic leukemia (APL), to help cells diff erentiate into functionally
mature cells.
b. Isotretinoin (13-cis-retinoic acid; 13-CRA) is a retinoic acid derivative that is used in the treatment of neuroblastoma,
a type of solid tumor seen in young children.
c. Bexarotene is a selective retinoid X receptor (RXR) ligand used for cutaneous T-cell lym phoma.
Activation of the retinoid receptors leads to regulation of gene expression and apoptosis.
2. Arsenic trioxide is an antineoplastic compound used in the treatment of APL that may induce selective apoptosis of APL cells.
3. Bortezomib is a proteosome inhibitor currently used in patients with multiple myeloma and under investigation
for the treatment of several other types of cancer.
a. Proteosomes are enzyme complexes that are responsible for degrading proteins that control the cell cycle.
b. Bortezomib is specifi c in that it interferes with the degradation of nuclear factor  (NF-). NF- is released
from its inhibitory partner protein and moves to the nucleus. When the inhibitory partner does not degrade because of the action of
bortezomib, NF- is prevented from transcribing the genes that promote cancer growth.
4. Th alidomide and lenalidomide are immunomodulatory agents with various mechanisms of action.
They work as angiogenesis inhibitors by interfering with the growth of new blood vessels needed for tumor growth and survival.
They inhibit the production of tumor necrosis factor  (TNF-) production, induce oxidative damage to DNA, and help stimulate
human T cells. They can be used as treatment for multiple myeloma in combination with dexamethasone.
I. Hormones are a class of heterogeneous compounds that have various eff ects on cells.
J. Biological response modifi ers alter or enhance the patient’s immune system to fi ght cancer or to lessen the side eff ects of the cancer treatment.
1. Cytokines are soluble factors secreted or released by cells that affect the activity of other cells and/or the secreting cell it self.
These agents generally act as regulatory or hematopoietic growth factors.
2. Monoclonal antibodies are recombinant antibodies designed to identify cancer-specifi c antigens,
bind to the antigens on the patient’s cancer cells, and allow the patient’s immune system to eliminate those cells.
a. Some monoclonal antibodies have been conjugated to radioisotopes (e.g., ibritumomab tiuxetan)
to help target cytotoxic therapy to the tumor cells.
b. Bevacizumab (Avastin) is a chimeric monoclonal antibody that targets and inhibits vascular endothelial growth factor (VEGF).
VEGF is an important regulator of the growth and survival of blood vessels, known as angiogenesis.
Bevacizumab works by inhibiting angiogenesis and, therefore, inhibiting the blood supply to the tumor.
c. Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to the HER2/neu (ErbB2) receptor.
This receptor is overexpressed in many patients with breast cancer.
Trastuzumab has several proposed mechanisms, including antibody-dependent cell-mediated cytotoxicity, downregulation of the
HER2/neu receptors resulting in disruption of downstream signaling, cell cycle arrest in the G1 phase, and suppression of angiogenesis.
3. Immunotoxins. Denileukin dift itox is a fusion protein composed of diphtheria toxin and interleukin 2 (IL-2).

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It is designed to direct the cytocidal action of diphtheria toxin to cells with the IL-2 receptor on their surface. This form of therapy is
able to bypass the need for a functioning immune system, which may be defective in many cancer patients.
4. Tumor vaccines. Sipuleucel-T (Provenge) is a therapeutic, patient-specifi c cancer vaccine.
It was the first therapeutic cancer vaccine to demonstrate a survival advantage in phase III clinical trials.

V. TOXICITIES OF CHEMOTHERAPY AGENTS

Chemotherapeutic agents are most toxic to rapidly proliferating cells, including mucous membranes, skin, hair, gastrointestinal (GI) tract, and bone
marrow.
A. Bone marrow suppression is the most common dose-limiting side effect of cancer therapy and may be one of the most life threatening.
1. Complications
a. Infections. White blood cells are most aff ected due to their short life span (6 to 12 hrs).
(1) A significant decrease in the white blood cell count, particularly a neutrophil count less than 500/mm3 (neutropenia),
predisposes the patient to development of serious infections.
(2) Th e usual signs and symptoms of infection may be absent, and fever may be the only indicator (febrile neutropenia).
(3) Colony-stimulating factors—for example, granulocyte colony-stimulating factor (GCSF) and
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
—may be used to stimulate neutrophil production and lessen the degree and duration of
neutropenia.
b. Bleeding. Platelets have an intermediate life span of 5 to 10 days. Decreased platelets (thrombocytopenia) can also occur from chemotherapy,
which can lead to bleeding and may require platelet transfusions.
c. Anemia and fatigue secondary to cancer chemotherapy may also occur.
It generally does not occur as quickly as other bone marrow toxicities because of the long life span of red blood cells (about 120 days).
Human recombinant erythropoietin (e.g., epoetin, darbepoetin) may be used to increase hemoglobin, decrease transfusion requirements,
and decrease fatigue. Recent data suggests that the risks (i.e., tumor progression and thrombosis) associated with the use of these agents
(erythropoietin-stimulating agents, or ESAs) in patients with cancer can outweigh their benefits.
2. The time course of myelosuppression varies with the chemotherapy regimen.
In general, the onset of myelosuppression is 7 to 10 days aft er the chemotherapy has been administered.
The lowest point of the counts, called the nadir, is usually reached in 10 to 14 days, though for some agents this can be much longer.
Recovery of counts usually occurs in 2 to 3 weeks.
3. The depth and duration of myelosuppression is related to the chemotherapy agents used and doses given.
a. Drugs that can cause severe myelosuppression include carmustine, cytarabine, daunorubicin, doxorubicin, and paclitaxel.
b. Some chemotherapy agents cause little or no myelosuppression. These include asparaginase, bleomycin, and vincristine.
c. Suffi cient count recovery is typically required before receiving subsequent chemotherapy cycles.
Requirements vary based on the treatment protocol and the agents to be administered. Some protocols include requirements such as an ANC
more than 1000/mm3 and platelets more than 100,000/mm3 prior to the administration of additional chemotherapy.
B. Dermatological toxicity
1. Alopecia is the loss of hair associated with chemotherapy. Not all agents cause alopecia, and hair loss may be partial or complete.
Chemotherapy agents that commonly cause alopecia include cyclophosphamide, doxorubicin, mechlorethamine, and paclitaxel.
2. Drugs associated with necrosis of tissue are called vesicants. Local tissue necrosis may result from extravasation
of vesicant chemotherapeutic agents outside the vein and into the subcutaneous tissue during administration.
a. Most vesicant extravasations produce immediate pain or burning. However, a delayed reaction may occur hours to weeks later.
Signifi cant tissue injury, including ulceration or necrosis, may require plastic surgery intervention.
b. Th e treatment of extravasations varies, depending on the vesicant.
Heat or cold packs and chemicals such as hyaluronidase or dexrazoxane (Totect) may be used.
c. Examples of vesicant agents include dactinomycin, daunorubicin, doxorubicin, idarubicin, mechlorethamine, mitomycin,
vinblastine, vincristine, and vinorelbine.
d. Some agents are classifi ed as irritants (e.g., etoposide) and can cause irritation but not necessarily necrosis when extravasated.
3. The EGFR inhibitors have been associated with a papulopustular, acneiform-like skin rash.
The development of this rash may be associated with a greater success in treating specifi c types of cancers.
4. Cancer chemotherapy can cause other skin changes such as dryness and photosensitivity. Examples are fl uorouracil and methotrexate.
C. GI toxicities are frequently experienced by patients receiving chemotherapy.
1. Nausea and vomiting are oft en among the most distressing toxicities from the patient’s perspective.
However, this side effect can generally be prevented or controlled with the use of currently available antiemetics.
a. Nausea and vomiting may be classified as acute, delayed, anticipatory, or breakthrough in nature.
Antiemetics should be used prophylactically to prevent the occurrence of nausea and vomiting, particularly with chemotherapeutic
agents that have a high emetogenic risk. Various clinical guidelines have been created to guide the use of antiemetics in patients receiving
chemotherapy.
b. Severe vomiting can result in dehydration, electrolyte imbalances, and esophageal tears and
may result in interruptions in therapy or therapy discontinuation.
d. Th e occurrence of nausea and vomiting is infl uenced by the emetogenicity of the chemotherapeutic agent or combination of agents,
the chemotherapeutic dose, the method of administration, and individual patient characteristics.
2. Stomatitis is a generalized infl ammation of the oral mucosa or other areas of the GI tract.
Because of the rapid turnover of epithelial cells in the GI tract, this is a common site of toxicity.
a. Signs and symptoms include erythema, pain, dryness of the mouth, burning or tingling of the lips, ulcerations, and bleeding.
b. Chemotherapy agents commonly associated with stomatitis include capecitabine, fl uorouracil, and methotrexate.
c. Time course. Stomatitis usually appears within a week aft er the off ending agent is administeredand resolves in 10 to 14 days.
d. Consequences of stomatitis include infection of the ulcerated areas, inability to eat, pain requiring opioid analgesics,
and subsequent decreases in chemotherapy doses.
e. Topical and local analgesics in the form of mouth rinses are commonly used and can help with mouth and throat pain.
3. Other GI toxicities include diarrhea (e.g., irinotecan, fl uorouracil), constipation (e.g., vincristine), anorexia, and taste changes.

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D. Tumor lysis syndrome (TLS) may occur in hematological malignancies such as leukemia and lymphoma in which there is a high tumor cell burden or
rapidly growing tumors. Owing to the spontaneous lysis of cells from treatment with chemotherapy, cell lysis causes release of
intracellular products, including uric acid, potassium, and phosphate, which can lead to renal failure and cardiac arrhythmias.
This may be prevented by giving intravenous hydration, by alkalinizing the urine,
and by giving agents such as allopurinol or rasburicase (Elitek) to decrease uric acid.
E. Hypercalcemia may occur in patients with solid or hematologic malignancies and can oft en be the presenting sign of malignancy.
The major cause of hypercalcemia is increased osteoclastic boneresorption, which is generally caused by the release of parathyroid
hormone-related protein (PTHrP) by the tumor cells. Common presenting symptoms include mental status changes, fatigue and muscle
weakness, polyuria, polydipsia, nausea, and vomiting. Treatment includes aggressive hydration with normal saline; calciuric therapy,
which consists of calcitonin; and bisphosphonates such as pamidronate (Aredia) or zoledronic acid (Zometa).
F. Chills and fever may occur aft er the administration of some chemotherapy and biological agents.
This fever generally can be diff erentiated from fever owing to infection because of its temporal relationship to chemotherapy
administration. Th is reaction is commonly associated with bleomycin, cytarabine, monoclonal antibodies, and IL-2.
G. Pulmonary toxicity is generally irreversible and may be fatal.
1. Signs and symptoms are shortness of breath, nonproductive cough, and low-grade fever. In some cases,
the risk of pulmonary toxicity increases as the cumulative dose of the drug increases (e.g., bleomycin).
2. Chemotherapeutic agents associated with pulmonary toxicity include bleomycin, busulfan, carmustine, and mitomycin.
H. Cardiac toxicity may manifest as an acute or chronic problem.
1. Acute changes are generally transient electrocardiograph abnormalities that may not be clinically significant.
2. Chronic cardiac toxicity presents as irreversible, left -sided heart failure.
Risk factors include chest irradiation and high cumulative doses of cardiotoxic chemotherapy.
3. Chemotherapy agents that are associated with chronic cardiotoxicity include daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone.
Dexrazoxane is a cardioprotective agent that may be used with doxorubicin to help prevent or lessen its toxic eff ects to the heart.
I. Hypersensitivity reactions may occur with any chemotherapy agent. Life-threatening reactions, including anaphylaxis,
appear to be more common with asparaginase, carboplatin, cisplatin, etoposide, paclitaxel, and teniposide.
J. Neurotoxicity may occur with systemic or intrathecal chemotherapy.
1. Vincristine is associated with autonomic and peripheral neuropathies.
Patients may experience gait disturbances, numbness and tingling of hands and feet, and loss of deep-tendon refl exes.
Inadvertent intrathecal administration of vincristine results in fatal neurotoxicity.
2. Peripheral neuropathy and ototoxicity are common dose-limiting toxicities of cisplatin.
Sensory neuropathies, including tingling or numbing of the hands and feet, may be associated with capecitabine, oxaliplatin, and paclitaxel.
3. Cerebellar toxicity has been reported with high doses of cytarabine and it manifests initially as loss of eye–hand coordination
and may progress to coma.
4. Arachnoiditis has been associated with intrathecal administration of cytarabine and methotrexate.
5. Encephalopathy has been reported in patients receiving ifosfamide.
Patient-related risk factors have been identified with this adverse event and include high serum creatinine,
low serum albumin, and the presence of pelvic disease.
K. Hemorrhagic cystitis is a bladder toxicity that is seen most commonly aft er administration of cyclophosphamide and ifosfamide.
Acrolein, a metabolite of these agents, is thought to cause a chemical irritation of the bladder mucosa, resulting in bleeding.
Preventive measures include aggressive hydration with subsequent frequent urination, and the administration of the uroprotectant mesna.
Mesna acts by binding to acrolein and preventing it from contacting the bladder mucosa.
L. Renal toxicity may manifest by elevations in serum creatinine and blood urea nitrogen (BUN) as well as electrolyte abnormalities.
Nephrotoxicity is associated with cisplatin, ifosfamide, methotrexate, and streptozocin.
Intravenous hydration is used to protect the kidneys from the nephrotoxic eff ects of cisplatin.
Osmotic diuresis with mannitol may help reduce the incidence of cisplatin nephrotoxicity.
M. Hepatotoxicity may manifest as elevated liver function tests, jaundice, or hepatitis.
Asparaginase, cytarabine, mercaptopurine, and methotrexate are known to cause hepatic toxicity.
N. Secondary malignancies, such as solid tumors, lymphomas, and leukemias, may occur many years after chemotherapy or radiation.
Antineoplastic agents known to possess a high carcinogenic risk include cyclophosphamide, etoposide, melphalan, and mechlorethamine.
O. Chemotherapy may cause infertility, which may be temporary or permanent.
Cyclophosphamide, chlorambucil, mechlorethamine, melphalan, and procarbazine are associated with a signifi cant incidence of infertility in males
and females.

VI. OTHER THERAPEUTIC MODALITIES

A. Surgery may be diagnostic (biopsy, exploratory laparotomy, second look) or therapeutic (tumor debulking or removal).
Surgery is oft en combined with chemotherapy and/or radiation.
B. Radiation therapy involves high doses of ionizing radiation directed at the cancerous tissue.
Radiation may be combined with surgery and/or chemotherapy.
Adverse reactions vary based on the area of the body being irradiated and may include stomatitis, nausea and vomiting, diarrhea, and
myelosuppression. In patients who have received anthracyclines, radiation recall dermatitis may occur resulting in skin infl ammation in the area of
previously received radiation.
C. Hematopoietic stem cell transplantation involves intravenous infusion of stem cells from a compatible donor
to a recipient following high-dose chemotherapy. It is used for treatment of diseases involving the bone
marrow or immune system and to allow for administration of high-dose chemotherapy or radiation for tumors
resistant to standard doses. Stem cells can be obtained from bone marrow or peripheral blood.
1. In autologous transplants, stem cells are obtained from the patient, preserved, and later reinfused into the same patient.
Allogeneic transplants involve two separate individuals. Cells are obtained from a matched donor and then infused into a separate patient.
A syngeneic transplant occurs when both the donor and recipient are identical twins.
2. Transplant-related complications include hepatic veno-occlusive disease (VOD), acute and chronic graft versus host disease (GVHD),
infection, and pulmonary complications.

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Pain is an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage or described in terms of such damage.
is a subjective, individual experience that has physical, psychological, and social determinants. There is no objective measurement of pain.
Acute pain lasts 30 days longer than the usual healing process for that type of injury, and occurs aft er muscle strains and tissue injury, such as trauma or
surgery. Th e pain is usually self-limiting, decreasing with time as the injury heals. It is described as a linear process, with a beginning and an
end. Increased autonomic nervous system activity oft en accompanies acute pain, causing tachycardia, tachypnea, hypertension, diaphoresis,
and mydriasis. Increased anxiety also may occur.
Chronic pain is persistent or episodic pain of a duration or intensity that adversely aff ects the function or well-being of the patient and can persist aft er
the resolution of an injury. Some define it as lasting more than 6 months.
a. Chronic nonmalignant pain may be a complication of acute injury in which the healing process does not occur as expected or may be caused by a
disease such as a rheumatological disorder (e.g., osteoarthritis, rheumatoid arthritis, fibromyalgia).
b. The elderly are more likely to experience chronic pain because of the increased prevalence of degenerative disorders in this age group.
c. The pain is constant, does not improve with time, and is described as a cyclic process (vicious circle).
d. Compared to acute pain, there is no longer autonomic nervous system stimulation, so the patient may not appear to be in pain. Instead, the
patient may be depressed; suff er insomnia, weight loss, and sexual dysfunction; and may not be able to cope with the normal activities of daily
living, including family and job-related activities.
Chronic cancer pain occurs in 60% to 90% of patients with cancer. Its characteristics are similar to those of chronic nonmalignant pain. In addition to
depression, prominent characteristics are fear, anger, and agony. Th e cause of chronic cancer pain can be related to the tumor or
cancer therapy or can be idiosyncratic. Tumor causes of pain include bone metastasis, compression of nerve structures, occlusion of
blood vessels, obstruction of bowel, or infi ltration of soft tissue.
Breakthrough pain is the intermittent, transitory increase in pain that occurs at a greater intensity over baseline chronic pain. It may have temporal
characteristics, precipitating factors, and predictability.
Neuropathic pain is a result of an injury or malfunction of the nervous system. Excluding patients with a progressive peripheral neuropathy or neuropathic
pain associated with a cancer lesion, tissue damage is not ongoing. Neuropathic pain is described as aching, throbbing, burning,
shooting, stinging, and tenderness or sensitivity of the skin.
Migraine pain is characterized by a severe headache generally associated with nausea and light and sound sensitivity. Migraine is a common disorder with
a 1 year prevalence rate in Americans of approximately 13% ranging from 6% to 7% of men and 18% of women.

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Antiprotozoal Drugs

Indications: Malaria
Amebiasis
Toxoplasmosis
Pneumocystosis
Trypanosomiasis
Leishmaniasis.

DRUGS USED FOR THE TREATMENT OF MALARIA

Drug Uses Adverse Effects
Chloroquine (Aralen®) Prophylaxis and treatment in areas without resistant P GI distress, rash, headache; auditory dysfunction and
falciparum; treatment of P vivax and P ovale malaria retinal dysfunction (high dose)
Mefloquine Prophylaxis and treatment in areas with resistant P GI distress, rash, headache; cardiac conduction defects
falciparum and neurologic symptoms (high dose)
Quininea Treatment of multidrug-resistant malaria Cinchonism, hemolysis in G6PD deficiency, blackwater
fever
Primaquine Eradication of liver stages of P vivax and P ovale GI distress, methemoglobinemia, hemolysis in G6PD
deficiency
Antifolates Prophylaxis and treatment of multidrug-resistant P falciparum GI distress, renal dysfunction, hemolysis, folate deficiency
malaria
Atovaquone-proguanil Prophylaxis and treatment of multidrug-resistant P falciparum GI distress, headache, rash hemolysis, folate deficiency
(Malarone) malaria
Artesunate, Artemether Treatment of multidrug-resistant malaria GI distress
 In most cases quinine is used together with doxycycline or clindamycin, or an antifolate.
 Quinidine gluconate (IV) is used in severe infections or for patients unable to take oral quinine.
 Resistance to Chloroquine is the most prevalent among other antimalarials.
Because Mefloquine is structurally realted to Chloroquine, cross resistance is possible

DRUGS USED IN THE TREATMENT OF AMEBIASIS

Disease Form Drug(s) of Choice Alternative Drug(s)
Asymptomatic, Intestinal infection Diloxanide furoate Iodoquinol, paramomycin
Mild to moderate intestinal infection Metronidazole plus luminal agent (see Tinidazole, or tetracycline, or erythromycin plus luminal agent
above)
Severe intestinal infection Metronidazole or tinidazole plus luminal Tetracycline or emetine or dihydroemetine plus luminal agent
agent
Hepatic abscess and other Metronidazole or tinidazole plus luminal Emetine or dihydroemetine plus choroquine (for liver abscess)
extraintestinal disease agent plus luminal agent

DRUGS USED IN THE TREATMENT OF OTHER PROTOZOAL INFECTIONS

Drug Indications
Melarsoprol Mucocutaneous forms of trypanosomiasis and the CNS stage (African sleeping sickness)
Metronidazole Drug of choice for infections caused by Giardia lamblia and Trichomonas vaginalis
Nifurtimox Trypanosomiasis caused by T cruzi
Pentamidine Hemolymphatic stage of trypanosomiasis and for Pneumocystis jiroveci infections
Pyrimethamine plus clindamycin or sulfadiazine plus folinic Drug combinations used in treatment of toxoplasmosis
acid
Sodium stibogluconate Treatment of leishmaniasis (all stages)
Suramin Drug of choice for hemolymphatic stage of trypanosomiasis (T brucei gambiense, T
rhodesiense)
Trimethoprim-sulfamethoxazole Drug combination of choice in Pneumocystis jiroveci infections
Metronidazole (Flagyl®)  urine may become discolored
 avoid consumption of alcoholic beverages

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Antihelminthic

DRUGS FOR THE TREATMENT OF HELMINTIC INFECTIONS

Infecting Organism Drugs of Choice Alternative Drugs
Nematodes
Ascaris lumbricoides (roundworm) Albendazole or mebendazole or pyrantel Piperazine
pamoate
Necator americanus & Ancylostoma duodenale Pyrantel pamoate or
(hookworm) albendazole or mebendazole
Trichuris trichiura (whipworm) Albendazole or mebendazole Pyrantel pamoate
Strongyloides stercoralis (threadworm) Ivermectin Albendazole, ebendazole
Enterobius vermicularis (pinworm) Mebendazole or pyrantel pamoate Albendazole
Trichinella spiralis (trichinosis) Mebendazole (+/– corticosteroids) Albendazole
Cutaneous larva migrans Albendazole or ivermectin
Wuchereria bancrofti and Brugia malayi (filariasis) Diethylcarbamazine Ivermectin
Onchocerca volvulus (onchocerciasis) Ivermectin
Trematodes (flukes)
Schistosoma haematobium Praziquantel Metrifonate
Schistosoma mansoni Praziquantel Oxamniquine
Schistosoma japonicum Praziquantel
Paragonimus westermani Praziquantel
Fasciola hepatica (sheep liver fluke) Bithional or triclabendazole
Fasciolopsis buski (large intestinal fluke) Praziquantel or niclosamide
Cestodes (tapeworms)
Taenia saginata (beef tapeworm) Praziquantel or niclosamide Mebendazole
Taenia solium (pork tapeworm) Praziquantel or niclosamide
Cysticercosis (pork tapeworm larval stage) Albendazole Praziquantel
Diphylobothrium latum (fish tapeworm) Praziquantel or niclosamide
Echinococcus granulosus (hydatid disease) Albendazole

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th
HIGH-YIELD TERMS (Katzung 9 )

I. AUTONOMIC DRUGS

Autonomic Pharmacology
Adrenergic A nerve ending that releases norepinephrine as the primary transmitter; also, a synapse in which norepinephrine is the
primary transmitter
Adrenoceptor, adrenergic A receptor that binds, and is activated by, one of the catecholamine transmitters or hormones (norepinephrine,
receptor epinephrine, dopamine) and related drugs
Autonomic effector cells Cells or tissues that have adrenoceptors or cholinoceptors which, when activated, alter the function of those cells or
or tissues tissues, for example, smooth muscle, cardiac muscle, glands
Baroreceptor reflex The neuronal homeostatic mechanism that maintains a constant arterial blood pressure; the sensory limb originates in
the baroreceptors of the carotid sinus and aortic arch; efferent pathways run in parasympathetic and sympathetic nerves
Cholinergic A nerve ending that releases acetylcholine; also, a synapse in which the primary transmitter is acetylcholine
Cholinoceptor, A receptor that binds, and is activated by, acetylcholine and related drugs
cholinergic receptor
Dopaminergic A nerve ending that releases dopamine as the primary transmitter; also a synapse in which dopamine is the primary
transmitter
Homeostatic reflex A compensatory mechanism for maintaining a body function at a predetermined level, for example, the baroreceptor
reflex for blood pressure
Parasympathetic The part of the autonomic nervous system that originates in the cranial nerves and sacral part of the spinal cord; the
craniosacral autonomic system
Postsynaptic receptor A receptor located on the distal side of a synapse, for example, on a postganglionic neuron or an autonomic effector cell
Presynaptic receptor A receptor located on the nerve ending from which the transmitter is released into the synapse; modulates the release of
transmitter
Sympathetic The part of the autonomic nervous system that originates in the thoracic and lumbar parts of the spinal cord

Introductory Autonomic Drugs

Drug Comment
Acetylcholine Primary transmitter at cholinergic nerve endings (preganglionic ANS, postganglionic parasympathetic, postganglionic
sympathetic to thermoregulatory sweat glands, and somatic neuromuscular end plates)
Amphetamine Sympathomimetic drug that facilitates the release of catecholamines from adrenergic nerve endings
Botulinum toxin Bacterial toxin that enzymatically disables release of acetylcholine from cholinergic nerve endings
Cocaine Drug that impairs reuptake of catecholamine transmitters (norepinephrine, dopamine) by adrenergic nerve endings
Dopamine Important central nervous system (CNS) transmitter with some peripheral effects (renal vasodilation, cardiac stimulation)
Epinephrine Hormone released from adrenal medulla, neurotransmitter in CNS
Hemicholiniums Drugs that inhibit transport of choline into cholinergic nerve endings
Metanephrine Product of epinephrine and norepinephrine metabolism
Metyrosine Inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in norepinephrine synthesis
Norepinephrine Primary transmitter at most sympathetic postganglionic nerve endings; important CNS transmitter
Reserpine Drug that inhibits uptake of dopamine and norepinephrine into transmitter vesicles of adrenergic nerves
Tetrodotoxin, Toxins that block sodium channels and thereby limit transmission in all nerve fibers
saxitoxin
Vesamicol Drug that inhibits uptake of acetylcholine into its transmitter vesicles

Sympathetic Drugs
Adrenergic Agonist (Sympathomimetic)
Anorexiant A drug that decreases appetite (causes anorexia)
Catecholamine A dihydroxyphenylethylamine derivative (eg, norepinephrine, epinephrine), a relatively polar molecule that is readily
metabolized by catechol-O-methyltransferase
Decongestant An -agonist drug that reduces conjunctival, nasal, or oropharyngeal mucosal vasodilation by constricting blood vessels in
the submucosal tissue
Mydriatic A drug that causes dilation of the pupil; opposite of miotic
Phenylisopropylamine A derivative of phenylisopropylamine (eg, amphetamine, ephedrine). Unlike catecholamines, phenylisopropylamines
usually have oral activity, a long half-life, some CNS activity, and an indirect mode of action
Selective -agonist, Drugs that have relatively greater effects on  or  adrenoceptors; none are absolutely selective or specific
-agonist
Sympathomimetic A drug that mimics stimulation of the sympathetic autonomic nervous system
Reuptake inhibitor An indirect-acting drug that increases the activity of transmitters in the synapse by inhibiting their reuptake into the
presynaptic nerve ending. May act selectively on noradrenergic, serotonergic, or both types of nerve endings

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Adrenergic Antagonist (Sympatholytics)

Competitive blocker A surmountable antagonist (eg, phentolamine); one that can be overcome by increasing the dose of agonist
Epinephrine reversal Conversion of the pressor response to epinephrine (typical of large doses) to a blood pressure-lowering effect;
caused by  blockers
Intrinsic sympathomimetic Partial agonist action by adrenoceptor blockers; typical of several  blockers (eg, pindolol, acebutolol)
activity (ISA)
Irreversible blocker A nonsurmountable inhibitor, usually because of covalent bond formation (eg, phenoxybenzamine)
Membrane stabilizing activity Local anesthetic action; typical of several  blockers (eg, propranolol)
(MSA)
Orthostatic hypotension Hypotension that is most marked in the upright position; caused by venous pooling (typical of blockade) or
inadequate blood volume (caused by blood loss or excessive diuresis)
Partial agonist A drug (eg, pindolol) that produces a smaller maximal effect than a full agonist and therefore can inhibit the effect
of a full agonist
Pheochromocytoma A tumor consisting of cells that release varying amounts of norepinephrine and epinephrine into the circulation

Parasympathetic Drugs
Cholinergic Agonist (Parasympathomimetic)
Choline ester A cholinomimetic drug consisting of choline (an alcohol) esterified with an acidic substance, (eg, acetic or
carbamic acid); usually poorly lipid-soluble
Cholinergic crisis The clinical condition of excessive activation of cholinoceptors; it may include skeletal muscle weakness as well
as parasympathetic signs
Cholinomimetic alkaloid A drug with weakly basic properties (usually of plant origin) whose effects resemble those of acetylcholine;
usually lipid-soluble
Cyclospasm Marked contraction of the ciliary muscle; maximum accommodation for close vision
Direct-acting cholinomimetic A drug that binds and activates cholinoceptors; the effects mimic those of acetylcholine
Endothelium-derived relaxing A potent vasodilator substance, largely nitric oxide (NO), that is released from vascular endothelial cells
factor (EDRF)
Indirect-acting cholinomimetic A drug that amplifies the effects of endogenous acetylcholine by inhibiting acetylcholinesterase
Muscarinic agonist A cholinomimetic drug that binds muscarinic receptors and has primarily muscarine-like actions
Myasthenic crisis In patients with myasthenia, an acute worsening of symptoms; usually relieved by increasing cholinomimetic
treatment
Nicotinic agonist A cholinomimetic drug that binds nicotinic receptors and has primarily nicotine-like actions
Organophosphate An ester of phosphoric acid and an alcohol that inhibits cholinesterase
Organophosphate aging A process whereby the organophosphate, after binding to cholinesterase, is chemically modified and becomes
more firmly bound to the enzyme
Parasympathomimetic A drug whose effects resemble those of stimulating the parasympathetic nerves

Cholinergic Antagonists (Parasympatholytics)

Anticholinergic A drug that blocks muscarinic or nicotinic receptors, but commonly used to mean antimuscarinic
Antimuscarinic A drug that blocks muscarinic but not nicotinic receptors
Atropine fever Hyperthermia induced by antimuscarinic drugs; caused mainly by inhibition of sweating
Atropine flush Marked cutaneous vasodilation of the arms and upper torso and head by antimuscarinic drugs; mechanism unknown
Cholinesterase regenerator A chemical antagonist that binds the phosphorus of organophosphates and displaces acetylcholinesterase
Cycloplegia Paralysis of accommodation; inability to focus on close objects
Depolarizing blockade Flaccid skeletal muscle paralysis caused by persistent depolarization of the neuromuscular end plate
Miotic A drug that constricts the pupil
Mydriatic A drug that dilates the pupil
Nondepolarizing blockade Flaccid skeletal muscle paralysis caused by blockade of the nicotinic receptor and prevention of end plate
depolarization
Parasympatholytic, A drug that reduces the effects of parasympathetic nerve stimulation, usually by blockade of the muscarinic receptors
parasympathoplegic of autonomic effector tissues

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II. AUTOCOIDS

Autocoids
Acid-peptic disease Disease of the upper digestive tract caused by acid and pepsin; includes gastroesophageal reflux, erosions, and ulcers
Autacoids Endogenous substances with complex physiologic and pathophysiologic functions that have potent nonautonomic
pharmacologic effects when administered as drugs; commonly understood to include histamine, serotonin, prostaglandins, and
vasoactive peptides
Carcinoid A neoplasm of the gastrointestinal tract or bronchi that may secrete serotonin and a variety of peptides
Ergotism ("St. Disease caused by excess ingestion of ergot alkaloids; classically an epidemic caused by consumption of grain (eg, in bread) that
Anthony's fire") is contaminated by the ergot fungus
Gastrinoma A tumor that produces large amounts of gastrin; associated with hypersecretion of gastric acid and pepsin leading to ulceration
IgE-mediated An allergic response, for example, hay fever, angioedema, caused by interaction of an antigen with IgE antibodies on mast
immediate reaction cells; results in the release of histamine and other mediators of allergy

Oxytocic A drug that causes contraction of the uterus

Zollinger-Ellison Syndrome of hypersecretion of gastric acid and pepsin, often caused by gastrinoma; it is associated with severe acid-peptic
syndrome ulceration and diarrhea
Characteristics of serotonin syndrome and other hyperthermic syndromes
Syndrome Precipitating Drugs Clinical Presentation Therapya

Serotonin SSRIs, second-generation antidepressants, Hyperthermia, hyperreflexia, tremor, Sedation (benzodiazepines), paralysis,
syndrome MAOIs, linezolid, tramadol, meperidine, clonus, hypertension, hyperactive intubation and ventilation b; consider 5-
fentanyl, ondansetron, sumatriptan, bowel sounds, diarrhea, mydriasis, HT2 block with cyproheptadine or
MDMA, LSD, St. John's wort, ginseng agitation, coma; onset within hours chlorpromazine

Neuroleptic D2-blocking antipsychotics Hyperthermia, acute severe Diphenhydramine, (parenteral), cooling

malignant parkinsonism; hypertension normal or if temperature is very high, sedation
syndrome reduced bowel sounds, onset over 1–3 with benzodiazepines
days
Malignant Volatile anesthetics, succinylcholine Hyperthermia, muscle rigidity, Dantrolene, cooling
hyperthermia hypertension, tachycardia; onset within
minutes
a
Precipitating drugs should be discontinued immediately.
b
All first-line therapy is in bold font.
MAOIs, monoamine oxidase inhibitors; MDMA, methylenedioxy-methamphetamine (ecstasy); SSRIs, selective serotonin reuptake inhibitors.

Prostaglandins & Other Eicosanoids

Abortifacient A drug used to cause an abortion. Example: prostaglandin F2
Cyclooxygenase Enzyme that converts arachidonic acid to PGG and PGH, the precursors of the prostaglandins
Dysmenorrhea Painful uterine cramping caused by prostaglandins released during menstruation
Endoperoxide General term for prostaglandin precursors, for example, PGG, PGH
Great vessel transposition Congenital anomaly in which the pulmonary artery exits from the left ventricle and the aorta from the right ventricle.
Incompatible with life after birth unless a large patent ductus or ventricular septal defect is present
Lipoxygenase Enzyme that converts arachidonic acid to leukotriene precursors (HPETEs)
NSAID Nonsteroidal anti-inflammatory drug, for example, aspirin, ibuprofen, celecoxib. Inhibitor of cyclooxygenase
Oxytocic A substance that causes uterine contraction
Patent ductus arteriosus Persistence after birth of the fetal shunt between the pulmonary artery and the aorta
Phospholipase A2 Enzyme in the cell membrane that generates arachidonic acid from membrane lipid constituents
Slow-reacting substance of Material originally identified by bioassay from tissues of animals in anaphylactic shock; now recognized as a mixture of
anaphylaxis (SRS-A) leukotrienes, especially LTC4, and LTD4

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III. NSAIDS & related drugs

NSAIDS
Antipyretic A drug that reduces fever (eg, aspirin, NSAIDs, acetaminophen)
Cyclooxygenase (COX) The enzyme at the head of the enzymatic pathway for prostaglandin synthesis (Figure 36-2)
Cytotoxic drug Drugs that interfere with essential metabolic processes, especially DNA maintenance and replication and cell
division. Such drugs generally kill rapidly dividing cells and are used for cancer chemotherapy and
immunosuppression
Disease-modifying antirheumatic Diverse group of drugs that modify the inflammatory processes underlying rheumatoid arthritis; they have a slow
drugs (DMARDs) (weeks to months) onset of clinical effects
Nonsteroidal anti-inflammatory Inhibitors of cyclooxygenase; the term nonsteroidal differentiates them from steroid drugs that mediate anti-
drugs (NSAIDs) inflammatory effects through activation of glucocorticoid receptors (eg, cortisol; Chapter 39)
Reye's syndrome A rare syndrome of rapid liver degeneration and encephalitis in children treated with aspirin during a viral infection
Tumor necrosis factor- (TNF-) A cytokine that plays a central role in inflammation
Uricosuric agent A drug that increases the renal excretion of uric acid
Xanthine oxidase A key enzyme in the purine metabolism pathway that ends with the production of uric acid

Disease-Modifying Antirheumatic Drugs (DMARDs)

Drug Other Clinical Uses Toxicity When Used for Rheumatoid Arthritis
Abatacept Infection, exacerbation of COPD, hypersensitivity reactions
Anakinra Injection-site reaction, infection, neutropenia
Methotrexate Anticancer Nausea, mucosal ulcers, hematotoxicity, hepatotoxicity, teratogenicity
Hydroxychloroquine, Antimalarial Rash, gastrointestinal disturbance, myopathy, neuropathy, ocular toxicity
chloroquine
Sulfasalazine Inflammatory bowel disease Rash, gastrointestinal disturbance, dizziness, headache, leukopenia
Leflunomide Teratogen, hepatotoxicity, gastrointestinal disturbance, skin reactions
Cyclosporine Tissue transplantation Nephrotoxicity, hypertension, liver toxicity
Anti-TNF- drugs (infliximab, Inflammatory bowel disease, other Infection, lymphoma, hepatoxicity, hematologic effects, hypersensitivity
etanercept, adalimumab) rheumatic disorders reactions, cardiovascular toxicity
Rituximab Non-Hodgkin's lymphoma Infusion reaction, rash, infection, cardiac toxicity
Gold compounds Many adverse effects, including diarrhea, dermatitis, hematologic
abnormalities
Penicillamine Chelating agent Many adverse effects, including proteinuria, dermatitis, gastrointestinal
disturbance, hematologic abnormalities

IV. ANALGESICS

Opioid Analgesics & Antagonists

Opiate A drug derived from alkaloids of the opium poppy
Opioid The class of drugs that includes opiates, opiopeptins, and all synthetic and semisynthetic drugs that mimic the actions of
the opiates
Opioid peptides Endogenous peptides that act on opioid receptors
Opioid agonist A drug that activates some or all opioid receptor subtypes and does not block any
Partial agonist A drug that can activate an opioid receptor to effect a submaximal response
Opioid antagonist A drug that blocks some or all opioid receptor subtypes
Mixed agonist-antagonist A drug that activates some opioid receptor subtypes and blocks other opioid receptor subtypes

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V. DRUGS FOR COAGULATION DISORDERS

Activated partial thromboplastin Laboratory test used to monitor the anticoagulant effect of unfractionated heparin and direct thrombin inhibitors;
time (aPTT) test prolonged when drug effect is adequate
Antithrombin III An endogenous anticlotting protein that irreversibly inactivates thrombin and factor Xa. Its enzymatic action is
markedly accelerated by the heparins
Clotting cascade System of serine proteases and substrates in the blood that provides rapid generation of clotting factors in
response to blood vessel damage
Glycoprotein IIb/IIIa (GPIIb/IIIa) A protein complex on the surface of platelets. When activated, it aggregates platelets primarily by binding to fibrin.
Endogenous factors including thromboxane A2, ADP, and serotonin initiate a signaling cascade that activates
GPIIb/IIIa
Heparin-induced A hypercoagulable state plus thrombocytopenia that occurs in a small number of individuals treated with
thrombocytopenia (HIT) unfractionated heparin
LMW heparins Fractionated preparations of heparin of molecular weight 2000—6000. Unfractionated heparin has a molecular
weight range of 5000—30,000
Prothrombin time (PT) test Laboratory test used to monitor the anticoagulant effect of warfarin;
prolonged when drug effect is adequate

Properties of heparins and warfarin

Property Heparins Warfarin
Structure Large acidic polysaccharide polymers Small lipid-soluble molecule
Route of Parenteral Oral
administration
Site of action Blood Liver
Onset of action Rapid (minutes) Slow (days); limited by half-lives of preexisting normal factors
Mechanism of Activates antithrombin III, which proteolyzes coagulation Impairs post-translational modification of factors II, VII, IX
action factors including thrombin and factor Xa and X
Monitoring aPTT for unfractionated heparin but not LMW heparins Prothrombin time
Antidote Protamine for heparin; unfractionated protamine reversal Vitamin K1 , plasma, prothrombin complex concentrates
of LMW heparins is incomplete
Use Mostly acute, over days Chronic, over weeks to months
Use in pregnancy Yes No
aPTT, activated partial thromboplastin time; LMW, low molecular weight.

Agents Used in Anemias & Hematopoietic Growth Factors: Introduction

Cobalamin Vitamin B12
dTMP synthesis A set of biochemical reactions that produce deoxythymidylate (dTMP), an essential constituent of DNA synthesis. The cycle
depends on the conversion of dihydrofolate to tetrahydrofolate by dihydrofolate reductase
G-CSF Granulocyte colony-stimulating factor, a hematopoietic growth factor that regulates production and function of neutrophils
GM-CSF Granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor that regulates production of granulocytes
(basophils, eosinophils, and neutrophils), and other myeloid cells
Hemochromatosis A condition of chronic excess total body iron caused either by an inherited abnormality of iron absorption or by frequent
transfusions to treat certain types of hemolytic disorders (eg, thalassemia major)
Megaloblastic A deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally large. Results from either folate
anemia or vitamin B12 deficiency anemia
Microcytic anemia A deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally small. Often caused by iron
deficiency
Neutropenia An abnormally low number of neutrophils in the blood; patients with neutropenia are susceptible to serious infection
Pernicious anemia A form of megaloblastic anemia resulting from deficiency of intrinsic factor, a protein produced by gastric mucosal cells and
required for intestinal absorption of vitamin B12
Thrombocytopenia An abnormally low number of platelets in the blood; patients with thrombocytopenia are susceptible to hemorrhage

VI. DRUGS FOR LIPID DISORDERS

Lipoproteins Macromolecular complexes in the blood that transport lipids

Apolipoproteins Proteins on the surface of lipoproteins;
they play critical roles in the regulation of lipoprotein metabolism and uptake into cells
Low-density lipoprotein Cholesterol-rich lipoprotein whose regulated uptake by hepatocytes and other cells requires functional LDL receptors;
(LDL) an elevated LDL concentration is associated with atherosclerosis
High-density lipoprotein Cholesterol-rich lipoprotein that transports cholesterol from the tissues to the liver;
(HDL) a low concentration is associated with atherosclerosis
Very-low-density Triglyceride- and cholesterol-rich lipoprotein secreted by the liver that transports triglycerides to the periphery;
lipoprotein (VLDL) precursor of LDL
HMG-CoA reductase 3-Hydroxy-3-methylglutaryl-coenzyme A reductase;
the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis
Lipoprotein lipase (LPL) An enzyme found primarily on the surface of endothelial cells that releases free fatty acids from triglycerides in lipoproteins;
the free fatty acids are taken up into cells
Proliferator-activated Member of a family of nuclear transcription regulators that participate in the regulation of metabolic processes;
receptor-alpha (PPAR-) target of the fibrate drugs

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VII. CARDIOVASCULAR DRUGS

Anti-Hypertensives
Baroreceptor reflex Primary autonomic mechanism for blood pressure homeostasis;
involves sensory input from carotid sinus and aorta to the vasomotor center and output via the parasympathetic
and sympathetic motor nerves
Catecholamine reuptake pump Nerve terminal transporter responsible for recycling norepinephrine after release into the synapse
(norepinephrine transporter [NET])
Catecholamine vesicle pump Storage vesicle transporter that pumps amine from cytoplasm into vesicle
End-organ damage Vascular damage in heart, kidney, retina, or brain
Essential hypertension Hypertension of unknown etiology;
also called primary hypertension
False transmitter Substance, for example, octopamine, stored in vesicles and released into synaptic cleft but lacking the effect of
the true transmitter, for example, norepinephrine
Orthostatic hypotension Hypotension on assuming upright posture;
postural hypotension
Postganglionic neuron blocker Drug that blocks transmission by an action in the terminals of the postganglionic nerves
Rebound hypertension Elevated blood pressure (usually above pretreatment levels) resulting from loss of antihypertensive drug effect
Reflex tachycardia Tachycardia resulting from lowering of blood pressure; mediated by the baroreceptor reflex
Stepped care Progressive addition of drugs to a regimen, starting with one (usually a diuretic) and adding in stepwise fashion a
sympatholytic, an ACE inhibitor, and (sometimes) a vasodilator
Sympatholytic, sympathoplegic Drug that reduces

Diuretic Agents
Bicarbonate diuretic A diuretic that selectively increases sodium bicarbonate excretion. Example: a carbonic anhydrase inhibitor
Diluting segment A segment of the nephron that removes solute without water; the thick ascending limb and the distal convoluted
tubule are active salt-absorbing segments that are not permeable by water
Hyperchloremic metabolic A shift in body electrolyte and pH balance involving elevated chloride, diminished bicarbonate concentration, and
acidosis a decrease in pH in the blood. Typical result of bicarbonate diuresis
Hypokalemic metabolic A shift in body electrolyte balance and pH involving a decrease in serum potassium and an increase in blood pH.
alkalosis Typical result of loop and thiazide diuretic actions
Nephrogenic diabetes insipidus Loss of urine-concentrating ability in the kidney caused by lack of responsiveness to antidiuretic hormone (ADH is
normal or high)
Pituitary diabetes insipidus Loss of urine-concentrating ability in the kidney caused by lack of antidiuretic hormone (ADH is low or absent)
Potassium-sparing diuretic A diuretic that reduces the exchange of potassium for sodium in the collecting tubule; a drug that increases
sodium and reduces potassium excretion. Example: aldosterone antagonists.
Uricosuric diuretic A diuretic that increases uric acid excretion, usually by inhibiting uric acid reabsorption in the proximal tubule.
Example: ethacrynic acid

Drugs for Angina Pectoris

Angina of effort, classic angina, Angina pectoris (crushing, strangling chest pain) that is precipitated by exertion, that is, increased O2 demand that
atherosclerotic angina cannot be met because of relatively irreversible atherosclerotic obstruction of coronary arteries
Vasospastic angina, variant angina, Angina precipitated by reversible spasm of coronary vessels
Prinzmetal's angina
Coronary vasodilator Older, incorrect name for drugs useful in angina; drugs that relieve angina of effort do not usually act primarily
through coronary vasodilation; some potent coronary vasodilators are ineffective in angina
"Monday disease" Industrial disease caused by chronic exposure to vasodilating concentrations of organic nitrates in the workplace;
characterized by headache, dizziness, and tachycardia on return to work after 2 days absence
Nitrate tolerance, tachyphylaxis Loss of effect of a nitrate vasodilator when exposure is prolonged beyond 10–12 h
Unstable angina Rapidly progressing increase in frequency and severity of anginal attacks, especially pain at rest; an acute
coronary syndrome and often heralds imminent myocardial infarction
Preload Filling pressure of the heart, dependent on venous tone and blood volume; determines end-diastolic fiber length
and tension
Afterload Resistance to ejection of stroke volume; determined by arterial blood pressure and arterial stiffness; afterload
determines systolic fiber tension
Intramyocardial fiber tension Force exerted by myocardial fibers, especially ventricular fibers at any given time;
a primary determinant of O2 requirement
Double product The product of heart rate and systolic blood pressure; an estimate of cardiac work
Myocardial revascularization Mechanical intervention to improve O2 delivery to the myocardium by angioplasty or bypass grafting

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Drugs for Heart failure

Bigeminy An arrhythmia consisting of normal sinus beats coupled with ventricular extrasystoles, that is, "twinned" beats (Figure 13–4)
End-diastolic fiber The length of the ventricular fibers at the end of diastole; a determinant of the force of the following contraction
length
Heart failure A condition in which the cardiac output is insufficient for the needs of the body. Low-output failure may be due to decreased
stroke volume (systolic failure) or decreased filling (diastolic failure)
PDE inhibitor Phosphodiesterase inhibitor; a drug that inhibits one or more enzymes that degrade cAMP (and other cyclic nucleotides).
Examples: high concentrations of theophylline, inamrinone
Premature An abnormal beat arising from a cell below the AV node—often from a Purkinje fiber, sometimes from a ventricular fiber
ventricular beats
Sodium pump A transport molecule in the membranes of all vertebrate cells; responsible for the maintenance of normal low intracellular
(Na + /K + ATPase) sodium and high intracellular potassium concentrations; it uses ATP to pump these ions against their concentration gradients
Sodium-calcium A transport molecule in the membrane of many cells that pumps one calcium atom outward against its concentration gradient in
exchanger exchange for three sodium ions moving inward down their concentration gradient
Ventricular function The graph that relates cardiac output, stroke volume, etc, to filling pressure or end-diastolic fiber length; also known as the
curve Frank-Starling curve
Ventricular An arrhythmia consisting entirely or largely of beats originating below the AV node
tachycardia

Anti-Arrhythmic Drugs
Abnormal automaticity Pacemaker activity that originates anywhere other than in the sinoatrial node
Abnormal conduction Conduction of an impulse that does not follow the path defined in Figure 14–1 or reenters tissue previously excited
Atrial, ventricular Arrhythmias involving rapid reentry and chaotic movement of impulses through the tissue of the atria or ventricles.
fibrillation (AF, VF) Ventricular, but not atrial, fibrillation is fatal if not terminated within a few minutes
Group (class) 1, 2, 3, A method for classifying antiarrhythmic drugs, sometimes called the Singh-Vaughan Williams classification; based loosely on
and 4 drugs the channel or receptor affected
Reentrant arrhythmias Arrhythmias of abnormal conduction; they involve the repetitive movement of an impulse through tissue previously excited
by the same impulse
Effective refractory The time that must pass after the upstroke of a conducted impulse in a part of the heart before a new action potential can be
period propagated in that cell or tissue
Selective depression The ability of certain drugs to selectively depress areas of excitable membrane that are most susceptible, leaving other areas
relatively unaffected
Supraventricular A reentrant arrhythmia that travels through the AV node; it may also be conducted through atrial tissue as part of the
tachycardia (SVT) reentrant circuit
Ventricular tachycardia A very common arrhythmia, often associated with myocardial infarction; ventricular tachycardia may involve abnormal
(VT) automaticity or abnormal conduction, usually impairs cardiac output, and may deteriorate into ventricular fibrillation; for
these reasons it requires prompt management

VIII. DRUGS FOR THE RESPIRATORY SYSTEM

Drugs for the Respiratory System

Bronchial hyperreactivity Pathologic increase in the bronchoconstrictor response to antigens and irritants; caused by bronchial inflammation
IgE-mediated disease Disease caused by excessive or misdirected immune response mediated by IgE antibodies. Example: asthma
Mast cell degranulation Exocytosis of granules from mast cells with release of mediators of inflammation and bronchoconstriction
Phosphodiesterase (PDE) Family of enzymes that degrade cyclic nucleotides to nucleotides, for example, cAMP (active) to AMP (inactive);
various isoforms, some degrade cGMP to GMP
Tachyphylaxis Rapid loss of responsiveness to a stimulus (eg, a drug)

IX. DRUGS FOR GASTROINTESTINAL DISORDERS

DRUGS FOR GASTROINTESTINAL DISORDERS

Acid-peptic disease A group of disorders involving erosion or ulceration of the mucosal lining of the gastrointestinal tract; includes GERD,
gastric and duodenal ulcers, nonulcer dyspepsia, and stress-related gastritis
Antiemetic A drug that reduces nausea and vomiting
Gastroesophageal reflux Esophageal irritation or inflammation due to reflux of stomach acid; also known as heartburn
disease (GERD)
Gastroparesis Paralysis of the muscles of the stomach and possibly other parts of the gastrointestinal tract due to damage to
gastrointestinal nerves or muscle; common in advanced diabetes and advanced Parkinson disease
Inflammatory bowel disease Inflammatory disorder involving irritation and ulceration of the colon and rectum (ulcerative colitis) or the colon plus
(IBD) more proximal parts of the gastrointestinal tract (Crohn's disease)
Irritable bowel syndrome Disease of unknown origin characterized by episodes of abdominal discomfort and abnormal bowel function (diarrhea,
(IBS) constipation, or both)
Prokinetic A drug that promotes gastrointestinal motility
Proton pump The parietal cell H+/K+ ATPase that uses the energy of ATP to secrete protons into the stomach (Figure 59–1); final
common target of drugs that suppress acid secretion

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X. ENDOCRINE DRUGS

Hypothalamic & Pituitary Hormones

Acromegaly A syndrome of growth hormone (GH) excess in adults that is characterized by abnormal growth of tissues—particularly
connective tissue—metabolic abnormalities, and cardiac dysfunction
Central diabetes A syndrome of polyuria, polydipsia, and hypernatremia caused by inadequate production of vasopressin
insipidus
Gigantism A syndrome of GH excess in children and adolescents with open long bone epiphyses that results in excessive height
Gonadotropins The 2 anterior pituitary hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) that regulate reproduction in
males and females
Insulin-like growth A growth factor that is the primary mediator of GH effects
factor-1 (IGF-1)
Prolactinoma Pituitary tumor that secretes excessive amounts of prolactin and is associated with a syndrome of infertility and galactorrhea
Tocolytics Drug used to inhibit preterm labor (eg, the oxytocin receptor antagonist atosiban; magnesium sulfate; nifedipine; 2 agonists)

Corticosteroids
Addison's disease Partial or complete loss of adrenocortical function, including loss of glucocorticoid and mineralocorticoid function
Adrenal suppression A suppression of the ability of the adrenal cortex to produce corticosteroids. Most commonly is an iatrogenic effect of
prolonged exogenous glucocorticoid treatment
Cushing's syndrome A metabolic disorder caused by excess secretion of adrenocorticoid steroids, which is most commonly due to increased
amounts of ACTH
Glucocorticoid A substance, usually a steroid, that activates glucocorticoid receptors (eg, cortisol)
Mineralocorticoid A substance, usually a steroid, that activates mineralocorticoid receptors (eg, aldosterone)

Thyroid & Antithyroid Drugs

Goiter Enlargement of the thyroid gland
Graves' disease Autoimmune disorder that results in hyperthyroidism during the early phase and can progress to hypothyroidism if
there is destruction of the gland in later phases
Thyroglobulin A protein synthesized in the thyroid gland; its tyrosine residues are used to synthesize thyroid hormones
Thyroid-stimulating The anterior pituitary hormone that regulates thyroid gland growth, uptake of iodine and synthesis of thyroid hormone
hormone (TSH)
Thyroid storm Severe thyrotoxicosis
Thyrotoxicosis Medical syndrome caused by an excess of thyroid hormone (Table 38–1)
Thyroxine-binding globulin Protein synthesized in the liver that transports thyroid hormone in the blood
(TBG)

Gonadal Hormones & Inhibitors

5-Reductase The enzyme that converts testosterone to dihydrotestosterone (DHT); it is inhibited by finasteride, a drug used to
treat benign prostatic hyperplasia and prevent male-pattern hair loss in men
Anabolic steroid Androgen receptor agonists used for anabolic effects (eg, weight gain, increased muscle mass)
Breakthrough bleeding Vaginal bleeding that occurs outside of the period of regular menstrual bleeding
Combined oral contraceptive Hormonal contraceptive administered orally that contains an estrogen and a progestin
(COC or just OC)
Hirsutism A male pattern of body hair growth (face, chest, abdomen) in females that results from hyperandrogenism
HRT Hormone replacement therapy; refers to estrogen replacement for women who have lost ovarian function and
nearly always involves combination therapy with estrogen and a progestin
SERM Selective estrogen receptor modulator such as tamoxifen

Pancreatic Hormones, Antidiabetic Agents, & Glucagon

-Glucosidase An enzyme in the gastrointestinal tract that converts complex starches and oligosaccharides to monosaccharides;
inhibited by acarbose and miglitol
Beta (B) cells in the islets of Insulin-producing cells in the endocrine pancreas
Langerhans
Hypoglycemia Dangerously lowered serum glucose concentration; a toxic effect of high insulin concentrations and the
secretagogue class of oral antidiabetic drugs
Lactic acidosis Acidemia due to excess serum lactic acid; can result from excess production or decreased metabolism of lactic acid
Type 1 diabetes mellitus A form of chronic hyperglycemia caused by immunologic destruction of pancreatic beta cells
Type 2 diabetes mellitus A form of chronic hyperglycemia initially caused by resistance to insulin; often progresses to insulin deficiency

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XI. DRUGS FOR OSTEOPOROSIS

Drugs That Affect Bone Mineral Homeostasis

Hyperparathyroidism A condition of PTH excess characterized by hypercalcemia, bone pain, cognitive abnormalities, and renal stones. Primary
disease results from parathyroid gland dysfunction. Secondary disease most commonly results from chronic kidney disease
Osteoblast Bone cell that promotes bone formation
Osteoclast Bone cell that promotes bone resorption
Osteomalacia A condition of abnormal mineralization of adult bone secondary to nutritional deficiency of vitamin D or inherited defects in
the formation or action of active vitamin D metabolites
Osteoporosis Abnormal loss of bone with increased risk of fractures, spinal deformities, and loss of stature; remaining bone is histologically
normal
Paget's disease A bone disorder, of unknown origin, characterized by excessive bone destruction and disorganized repair. Complications
include skeletal deformity, musculoskeletal pain, kidney stones, and organ dysfunction secondary to pressure from bony
overgrowth
Rickets The same as osteomalacia, but it occurs in the growing skeleton
RANK ligand An osteoblast-derived growth factor that stimulates osteoclast activity and osteoclast precursor differentiation

Actions of PTH and active vitamin D metabolites on intestine, kidney, and bone.
Organ Parathyroid hormone (PTH) Active Vitamin D Metabolites
Intestine Indirectly increases calcium and phosphate absorption by Increased calcium and phosphate absorption
increasing vitamin D metabolites
Kidney Decreased calcium excretion, increased phosphate Increased resorption of calcium and phosphate but usually net
excretion increase in urinary calcium due to effects in GI tract and bone
Bone Calcium and phosphate resorption increased by continuous Direct effect is increased calcium and phosphate resorption;
high concentrations. Low intermittent doses increase bone indirect effect is promoting mineralization by increasing the
formation availability of calcium and phosphate
Net effect on Serum calcium increased, serum phosphate decreased Serum calcium and phosphate both increased
serum levels

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XII. CNS DRUGS

Sedative-Hypnotic Drugs
Sedation Reduction of anxiety
Addiction The state of response to a drug whereby the drug taker feels compelled to use the drug and suffers anxiety when separated from it
Anesthesia Loss of consciousness associated with absence of response to pain
Anxiolytic A drug that reduces anxiety, a sedative
Dependence The state of response to a drug whereby removal of the drug evokes unpleasant, possibly life-threatening symptoms, often the opposite
of the drug's effects
Hypnosis Induction of sleep
REM sleep Phase of sleep associated with rapid eye movements; most dreaming takes place during REM sleep
Sedation Reduction of anxiety
Tolerance Reduction in drug effect requiring an increase in dosage to maintain the same response

 Antidepressants
Amine hypothesis of mood The hypothesis that major depressive disorders result from a functional deficiency of norepinephrine or
serotonin at synapses in the CNS
MAO inhibitors (MAOIs) Drugs inhibiting monoamine oxidases that metabolize norepinephrine and serotonin MAO type A) and
dopamine (MAO type B)
Tricyclic antidepressants (TCAs) Structurally related drugs that block reuptake transporters of both norepinephrine (NE) and serotonin (5-
HT)
Selective serotonin reuptake inhibitors Drugs that selectively inhibit serotonin (5-HT) transporters with only modest effects on other
(SSRIs) neurotransmitters
Serotonin-norepinephrine reuptake Heterocyclic drugs that block NE and 5-HT transporters, but lack the alpha blocking, anticholinergic and
inhibitors (SNRIs) antihistaminic actions of TCAs
5-HT2 receptor antagonists Structurally related drugs that block this subgroup of serotonin receptors with only minor effects on amine
transporters
Heterocyclics Term used for antidepressants of varying chemical structures, the characteristics of which do not strictly
conform to any of the above designations

 Antiseizure Drugs
Seizures Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
Partial seizures, Consciousness preserved; manifested variously as convulsive jerking, paresthesias, psychic symptoms (altered sensory
simple perception, illusions, hallucinations, affect changes), and autonomic dysfunction
Partial seizures, Impaired consciousness that is preceded, accompanied, or followed by psychological symptoms
complex
Tonic-clonic seizures, Tonic phase (less than 1 min) involves abrupt loss of consciousness, muscle rigidity, and respiration arrest; clonic phase (2–3
generalized min) involves jerking of body muscles, with lip or tongue biting, and fecal and urinary incontinence; formerly called grand mal
Absence seizures, Impaired consciousness (often abrupt onset and brief), sometimes with automatisms, loss of postural tone, or enuresis; begin
generalized in childhood (formerly, petit mal) and usually cease by age 20 yrs
Myoclonic seizures Single or multiple myoclonic muscle jerks
Status epilepticus A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it is a life-threatening emergency

Drugs Used in Parkinsonism & Other Movement Disorders

Athetosis Involuntary slow writhing movements, especially severe in the hands; "mobile spasm"
Chorea Irregular, unpredictable, involuntary muscle jerks that impair voluntary activity
Dystonia Prolonged muscle contractions with twisting and repetitive movements or abnormal posture; may occur in the form of rhythmic
jerks
Huntingdon's An inherited adult-onset neurologic disease characterized by dementia and bizarre involuntary movements
disease
Parkinsonism A progressive neurologic disease characterized by shufflinq gait, stooped posture, resting tremor, speech impediments, movement
difficulties, and an eventual slowing of mental processes and dementia
Tics Sudden coordinated abnormal movements, usually repetitive, especially about the face and head
Tourette's A neurologic disease of unknown cause that presents with multiple tics associated with snorting, sniffing, and involuntary
syndrome vocalizations (often obscene)
Wilson's disease An inherited (autosomal recessive) disorder of copper accumulation in liver, brain, kidneys, and eyes; symptoms include jaundice,
vomiting, tremors, muscle weakness, stiff movements, liver failure, and dementia

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General Anesthetics
Balanced anesthesia Anesthesia produced by a mixture of drugs, often including both inhaled and intravenous agents
Inhalation anesthesia Anesthesia induced by inhalation of drug
Minimum alveolar anesthetic The alveolar concentration of an anesthetic that is required to prevent a response to a standardized painful
concentration (MAC) stimulus in 50% of patients
Analgesia A state of decreased awareness of pain, sometimes with amnesia
General anesthesia A state of unconsciousness, analgesia, and amnesia, with skeletal muscle relaxation and loss of reflexes

Stages of Anesthesia
Stage 1: Analgesia The patient has decreased awareness of pain, sometimes with amnesia. Consciousness may be
(Corticol) impaired but is not lost.
Stage 2: Disinhibition The patient appears to be delirious and excited. Amnesia occurs, reflexes are enhanced, and respiration
(Delirium-Excitement) is typically irregular; retching and incontinence may occur.
Stage 3: Surgical Anesthesia The patient is unconscious and has no pain reflexes; respiration is very regular, and blood pressure is
maintained.
Stage 4: Medullary Depression The patient develops severe respiratory and cardiovascular depression that requires mechanical and
pharmacologic support.

COLOR OF TANK
O2 Green
He Brown
Artificial air Brown-green
N Black
NO Blue

 Drugs of Abuse
Abstinence A term used to describe the signs and symptoms that occur on withdrawal of a drug in a dependent person
syndrome
Addiction Compulsive drug-using behavior in which the person uses the drug for personal satisfaction, often in the face of known risks to
health; formerly termed psychological dependence
Controlled A drug deemed to have abuse liability that is listed on governmental Schedules of Controlled Substances.a Such schedules categorize
substance illicit drugs, control prescribing practices, and mandate penalties for illegal possession, manufacture, and sale of listed drugs.
Controlled substance schedules are presumed to reflect current attitudes toward substance abuse; therefore, which drugs are
regulated depends on a social judgment
Dependence A state characterized by signs and symptoms, frequently the opposite of those caused by a drug, when it is withdrawn from chronic
use or when the dose is abruptly lowered; formerly termed physical or physiologic dependence
Designer drug A synthetic derivative of a drug, with slightly modified structure but no major change in pharmacodynamic action. Circumvention of
the Schedules of Controlled Drugs is a motivation for the illicit synthesis of designer drugs
Tolerance A decreased response to a drug, necessitating larger doses to achieve the same effect. This can result from increased disposition of
the drug (metabolic tolerance), an ability to compensate for the effects of a drug (behavioral tolerance), or changes in receptor or
effector systems involved in drug actions (functional tolerance)

Schedules of controlled drugs.a

Schedule Criteria Examples

I No medical use; high addiction potential Flunitrazepam, heroin, LSD, mescaline, PCP, MDA, MDMA, STP
II Medical use; high addiction potential Amphetamines, cocaine, methylphenidate, short acting
barbiturates, strong opioids
III Medical use; moderate abuse potential Anabolic steroids, barbiturates, dronabinol, ketamine
moderate opioid agonists
IV Medical use; low abuse potential Benzodiazepines, chloral hydrate, mild stimulants (eg, phentermine, sibutramine),
most hypnotics (eg, zaleplon, zolpidem), weak opioids

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XIII. CHEMOTHERAPEUTIC DRUGS

Cancer Chemotherapy
Cell cycle-nonspecific An anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in the
(CCNS) drug resting phase
Cell cycle-specific (CCS) drug An anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they
are in the G0 phase

Growth fraction The proportion of cells in a tumor population that are actively dividing
Myelosuppressant A drug that suppresses the formation of mature blood cells such as erythrocytes, leukocytes, and platelets. This effect
is also known as "bone marrow suppression"
Oncogene A mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in
noncancerous cells, causes them to behave like cancer cells

Selected examples of cancer chemotherapy.

Diagnosis Examples of Commonly-Used Anticancer Drugs
Acute lymphocytic leukemia in children Prednisone, vincristine, and asparaginase or an anthracycline, plus intrathecal methotrexate
Acute myelogenous leukemia in adults Cytarabine and idarubicin or daunorubicin
Breast carcinoma Cytotoxic agents, hormonal therapy with tamoxifen or an aromatase inhibitor (eg, anastrozole), trastuzumab
Chronic myelogenous leukemia Imatinib, newer tyrosine kinase inhibitors, interferon
Colon carcinoma Fluorouracil plus leucovorin plus oxaliplatin
Hodgkin's lymphoma ABVD regimen: doxorubicin (Adriamycin), bleomycin, vincristine, dacarbazine, and prednisone
Non-Hodgkin's lymphoma CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab
Ovarian carcinoma Paclitaxel and carboplatin
Pancreatic carcinoma Gemcitabine and erlotinib
Prostate carcinoma GnRH agonist (eg, leuprolide) or antagonist (eg, abarelix) and androgen receptor antagonist (eg, flutamide)
Lung carcinoma Carboplatin, paclitaxel, and bevacizumab
Testicular carcinoma PEB regimen: cisplatin (Platinol), etoposide, and bleomycin

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Immunopharmacology
Antigen-presenting cells Dendritic and Langerhans cells, macrophages, and B lymphocytes involved in the processing of proteins into cell surface
(APCs) forms recognizable by lymphoid cells
B cells Lymphoid cells derived from the bone marrow that mediate humoral immunity through the formation of antibodies
Clusters of differentiation Specific cell surface constituents identified by number (eg, CD4, CD8)
(CDs)
Cytokines Polypeptide modulators of cellular functions, including interferons, interleukins, and growth-stimulating factors
Immunophilins A family of cytoplasmic proteins that bind to the immunosuppressants cyclosporine, tacrolimus, and sirolimus and assist
these drugs in inhibiting T- and B-cell function
Major histocompatibility Cell surface molecules that bind antigen fragments and, when bound to antigen fragments, are recognized by helper T
complex (MHC) cells. MHC class I molecules are expressed by all cells, whereas MHC class II molecules are expressed by antigen-
presenting cells
Monoclonal antibody An antibody produced by a hybridoma clone that selectively binds to an antigen of biological or medical interest.
(MAb)
T cells Lymphoid cells derived from the thymus that mediate cellular immunity and can modify humoral immunity. The main
subclasses of T cells are CD4 (helper) cells and CD8 (cytotoxic) cells

Cytokines that modulate immune responses.

Cytokine Characteristic Properties
Interferon- (IFN-) Activates NK cells, antiviral, oncostatic
Interferon- (IFN-) Activates NK cells, antiviral, oncostatic
Interferon- (IFN-) Activates TH1, NK, cytotoxic T cells, and macrophages; antiviral, oncostatic
Interleukin-2 (IL-2) T-cell proliferation, activation of TH1, NK, and LAK cells

Interleukin-11 (IL-11) B-cell differentiation, megakaryocyte proliferation (see Chapter 33)

Tumor necrosis factor- (TNF-) Proinflammatory, macrophage activation, oncostatic
Tumor necrosis factor- (TNF-) Proinflammatory, chemotactic, oncostatic
Granulocyte colony-stimulating factor (G-CSF) Granulocyte production (see Chapter 33)
Granulocyte-macrophage colony-stimulating factor (GM-CSF) Granulocyte, monocyte, eosinophil production (see Chapter 33)

Drugs used as immunosuppressive agents

Drug Characteristics
Azathioprine Prodrug of the anticancer drug mercaptopurine, which interferes with purine nucleic acid metabolism used for rheumatic diseases
and organ transplantation (see Chapter 36)
Cyclophosphamide Anticancer alkylating agent used in organ transplantation and rheumatic diseases (see Chapters 36 and 54)
Leflunomide Inhibitor of dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis. Used in rheumatoid arthritis (see
Chapter 36)
Hydroxychloroquine Antimalarial drug with immunosuppressive activity used for rheumatoid arthritis and systemic lupus erythematosus (see Chapters
36 and 52)
Methotrexate Anticancer drug that inhibits dihydrofolate reductase used for rheumatoid arthritis and hematopoietic stem cell transplantation
(see Chapters 36 and 54)
Sulfasalazine Prodrug metabolized to sulfapyridine and 5-aminosalisylic acid (5-ASA). Used for rheumatoid arthritis and inflammatory bowel
disease (see Chapters 36 and 59)

Characteristics of selected monoclonal antibodies (MAbs) and immunoglobulin-based agents

MAb Characteristics and Clinical Uses
Abatacept Extracellular domain of cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) fused to human IgG Fc. Blocks T-cell activation by interfering
with the interaction of T-cell CD28 to APC CD 80/86 (Figure 55–2). Used for severe rheumatoid arthritis
Abciximab Antagonist of glycoprotein IIb1/IIIa receptor, preventing cross-linking reaction in platelet aggregation. Used post-angioplasty and in acute
coronary syndromes
Alefacept Fusion of a fragment of leukocyte-function-associated antigen-3 (LFA-3) to human IgG Fc region that prevents T-cell CD2 from binding to
APC LFA-3. Approved for psoriasis
Efalizumab MAb to CD-11a, the alpha subunit of T cell leukocyte-function-associated antigen-1 (LFA-1). Inhibits binding of LFA-1 to APC intercellular
adhesion molecule-1 (ICAM-1; Figure 55–2). Approved for psoriasis
Muromonab Antibody to the T3 (CD3) antigen on thymocytes. Used in acute renal allograft rejection
Omalizumab Anti-IgE MAb used to treat severe asthma (See Chapter 20)
Palivizumab Antibody to surface protein of respiratory syncytial virus (RSV). Used for prophylaxis and treatment of RSV infection
Rituximab Binds to the CD20 antigen on B lymphocytes and recruits immune effector functions to mediate lysis.
Used in B cell non-Hodgkin's lymphoma
Trastuzumab Binds to the HER-2 protein on the surface of tumor cells. Cytotoxic for breast tumors that overexpress HER-2 protein

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SPECIAL TOPIC

Dietary Supplements & Herbal Medications

= Common intended uses of some botanical or nutritional supplements
Botanical or Nutritional Supplement Common Intended Use
Echinacea Decrease duration and intensity of cold symptoms
Ephedra (ma huang) Treatment of respiratory ailments such as bronchitis and asthma, and as a CNS stimulant
Garlic For cholesterol lowering and atherosclerosis
Ginkgo Treatment of intermittent claudication, and cerebral insufficiency and dementia
Ginseng Improvement of physical and mental performance
Milk thistle Limitation of hepatic injury and as an antidote to Amanita mushroom poisoning
Saw palmetto Improvement in symptoms of benign prostatic hyperplasia
St. John's wort Treatment of mild to moderate depression
Coenzyme Q10 Improvement of ischemic heart disease and for Parkinson's disease
Glucosamine Reduction of pain associated with osteoarthritis
Melatonin Decrease jet lag symptoms and as a sleep aid

Alternative medicine Treatments that are not generally recognized by the medical community as standard or conventional medical approaches
Controlled clinical A clinical trial that compares a group of subjects who are receiving a treatment with a closely matched group of individuals who
trial are not receiving a treatment. Chapter 5 describes clinical trials in more detail
Herbal medication Plants or plant extracts that people use to improve their health
Nutritional A substance that is added to the diet to improve health and which usually contains dietary ingredients such as vitamins,
supplement minerals, amino acids, and enzymes
Placebo An inactive medication made to resemble the investigational formulation as much as possible

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TOXICOLOGY
Toxicology  is the branch of pharmacology that encompasses the
deleterious effects of chemicals on biologic systems.
 study of the effect mechanisms & treatment of poisons Branches of Toxicology:
science of poisons 1. Clinical Toxicology  aka Medical Toxicology
Paracelsus (16th century): “All drugs are poison,  deals w/ the diagnosis & treatment of poisoning
only the dose determine the effect.”  observation of the signs & symptoms
Poisons  Corpus delecti (body of evidence) of poisoning
 any agent that may cause serious damage/  focuses on the effects of substances in patients
disease/ injury/ death when applied or developed inside the caused by accidental poisonings or intentional
body overdoses of medications, drugs of abuse,
household products, or various other chemicals
Definitions 2. Experimental Toxicology  observation of toxic effects after
1. Clinical toxicology  Focuses on the effects of substances in patients administration to a biological system.
caused by accidental poisonings or intentional Parameters:
overdoses of medications, drugs of abuse, LD50  medial lethal dose
household products, or various other chemicals quantal dose response curve
2. Intoxication  Toxicity associated with any chemical substance 𝑇𝐷50
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 =
𝐸𝐷50
3. Poisoning  A clinical toxicity secondary to accidental exposure TLV/ TLC  Threshold Limit Value/
4. Overdose  An intentional exposure with the intent of Threshold Limit Concentration
causing self-injury or death maximum concentration safe for a drug
5. Toxicity  describes the degree to which a substance is poisonous or 3. Environment Toxicology  deals with the identification or removal of
can cause injury depends on a variety of factors: dose, the toxicants from the environment.
duration and route of exposure, shape and structure of the 4. Regulatory Toxicology  concern with the safety testing of products
chemical itself, and individual human factors. to provide information fro regulatory
6. Selective toxicity  means that a chemical will produce injury to one requirement & safety data sheet
kind of living matter without harming another form 5. Machanistic Toxicology  deals with the mechanism of
of life, even though the two may exist close action of the poisons
together. 6. Descriptive Toxicology  concerned with tosicity testing,
7. Sensitive Sub-Population  describes those persons who are more at which provides necessary information for
risk from illness due to exposure to safety evaluation & regulatory requirements
hazardous substances than the average, 7. Forensic Toxicology  concerned with the medico-legal aspects
healthy person. These persons usually of the harmful effects of chemical on humans
include the very young, the chronically ill, & animals
and the very old. It may also include 8. Chemical toxicology  is a scientific discipline involving the study of
pregnant women and women of structure and mechanism related to the toxic
childbearing age. Depending on the type of effects of chemical agents, and encompasses
contaminant, other factors(e.g., age, technology advances in research related to
weight, lifestyle, sex) could be used to chemical aspects of toxicology.
describe the population.
7. Harmful or adverse effects  are those that are damaging to either the Effects of Poisons:
survival or normal function of the 1. Local  effects can be seen at the site of application
individual. Ex: Phenol Corrosive
8. Hazard  likelihood that injury will occur in a given situation or setting 2. Remote  effects of poisons id distributed from point of entry
9. Risk  expected frequency of the occurrence of an undesirable effect Ex: Atropine  eyes  mydriasis
arising from exposure to a chemical or physical agent 3. Systemic  the effects of poison is distributed from the point of entry
10. Toxidromes  A group of signs, symptoms, and laboratory findings 5. Combination  Local + Remote
that suggest a specific ingestion Local + Systemic
11. Toxicokinetics vs. Toxicodynamics Ex: Phosphorus (St.Elmo’s Fire)
▪Toxicokinetics  describes the fate of toxic compound in the body. characteristics: Luminus Vomitus
The measurement of the time course of absorption, Garlic Odor
distribution, biotransformation, and excretion of can irritate
toxic compounds (sometimes referred to as metabolic disturbance
pharmacokinetics). Antidote: Copper Sulfate
▪Toxicodynamics  describesthe determination and quantification of Cantharidin
the sequence of events at the cellular and irritating active from dried blister better or
molecular levels catharides (Cantharides Vesicatoria)
12. Toxicogenetics vs. Toxicogenomics irritation
▪Toxicogenetics  describes consideration of stable and heritable metabolic disturbance
alterations in the genomethat are able to influence Death: 72 days
the relative susceptibility of anindividual (or group
of individuals) to the adverse health effectsthat
may result from exposure to an exogenous
material.
▪Toxicogenomics  describes analysis of gene-expression
changesinduced in a biologicalsystem by exposure
to a xenobiotic.

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Factors Affect Poisoning: General Assessment of a Poison Patient:

A. Poison Related A. Initial Assessment: Evaluate vital signs & support vital functions
1. Concentration  the higher the concentration, check in: A – Airways
the greater the toxic effect B – Breathing (ventilate, applied 100% O2)
2. Solubility  the higher the lipophilicity, the higher the toxication C – Circulation
3. Route of Administration  intravenous: 100% F D – Disability: Neurologic Status:
B. Patient Related Alertness
1. Age Verbal response
▪Pediatrics  is not yet fully developed which may cause the Pain Stimulus
accumulamation of drugs even when given at normal Unresponsiveness
doses. Exposure: Remove the patient then transfer to a
under developed Phase II Metabolism (Conjugation) safe area.
 developed Phase I Metabolism Remove the clothing to limit exposure.
1st day: Sulfation (Phase II)
2nd week: Reduction/ Redox (Phase I) B. Treatment of the depressed mental state
1st month: Acetylation (Phase II) 1. Adult – 500mL of 3% dextrose
2nd month Glucuronidation (Phase II) Children – 1mL/ kg
3rd month: Glycine/ Glutathione (Phase II) 2. Administer Vit.B (Thiamine) – 100mL IV push
▪Geriatrics  have slower metabolizing rates as compared to adults Wernickr Korsakoff Syndrome (Mental Retardation)
aged 20-40 3. Give Naloxone (0.4-2mg) to treat Opioid Poisoning
kidney function: excretion
liver function: metabolism C. Identify the patient & the poison
2. Habits Basic Info: Substance, Time Ingested, Amount, Signs & Symptoms
▪Smoking Cigarettes – Enzyme induction
▪Alcohol: Acute – Enzyme Inhibitor D. Decontamination
Chronic – Enzyme Inducer 1. Inhalational Exposure  one of the most dangerous
3. Tolerance  receptors becomes “Desensitize” Treatment: Rapid Removal from environment
 reduction physical response If necessary: 100% O2, assisted ventilation
  dose & frequency : causes an increase of toxic effect bronchodilation
▪Tachyphylaxis  rapid development of tolerance 2. Dermal Exposure
Ex: Nicotine, Nitrates, Morphine Treatment:
4. Idiosyncracy  genitically determined Remove contaminated materials from patient
Ex: Chloramphenicol – induced aplastic anemia wash with Slightly Cool Water
Hemolytic Anemia – G6PP deficiency – 100% F wash with Baking Soda
 Coomb’s Test a. HF – Ca Gluconate
 False (-): methyldopa b. Oxalic Acid – Ca Gluconate
Types of Poisoning: c. Phosphorus – Cu SO4 (blue vitriol)
1. Acute  promt & there is marked disturbances of function or death 3. Ocular Exposure – wash with Plain NSS irrigation for 15 minutes
within a short period of time
 amount in short period of time
Ex: Excessive Single Dose, use of a strong or true poison
2. Chronic  gradual & there is progressive deterioration of the
functioning of tissues
usually produced by taking small dose
for a protracted period of time
▪Commulative: toxic effects manifest
when a certain limit is reached
3. Combined: Acute + Chronic

Evidences of Poisoning:
1. Circumstantial  from the event & site of poisoning
not reliable/ no a strong evidence
2. Post Mortem  Corpus delecti
 gathered after an autopsy is performed
(examination of tissues, organs, body fluids after death)
 reliable evidence
3. Experimental Evidences  after observation of the signs/ symptoms
after administering to a living system
4. Chemical Evidence  is acquired by extracting body fluids from the
patient & tested w/ specific reagent or chemical
Ex: Phenol + FeCl3  (+) blue-violet
5. Symptomatic Evidence  comparison of the established signs/
symptoms w/ that of the patient

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General Antidotes  agents that counteracts the effect of poisons

1. Physiological Antidotes produce an effects as that of the poison
acting on different receptors
Ex: ▪Histamine  Epinephrine
(H1 receptor) (B2 receptor)
(bronchoconstriction) (bronchodilation)
▪INH Isonicotinichydrazide  Diazepam d. Whole Bowel Irrigation  cleaning of the bowel
▪Atropine  Physosttigmine by using PEG w/ Electrolyte
2. Chemical Antidotes  alter the chemical characteristics of the poison (Golytely®, Colyte®)
Ex: Cyanide (CN) + NaS2O4  SCN (H2O soluble)  is the most effective process for
3. Mechanical Antidote  is reliable evacuating the intestinal tract in
 prevent absorption of the poison (if the poisoned patients
poison has been ingested for less than 2 hrs. Dosage: 1-2 L/hr (PO or by NGT)
 suitable for cooperative & noncombatative Indication: Poorly adsorbed substances (Fe, Pb, Li)
patient SR preparation
a. Gastric Lavage: Body packers of illicit drugs
Use: Not alert or diminished gag reflex Late presentation
Patients who are seen early following SE: vomiting, abdominal bloating,
CI: 1. If the poison is corrosive or caustic fullness, flatulence, pruritus
2. Combatative Patient CI: prior, current or anticipated diarrhea
3, acid, alkali, or hydrocarbons/petroleum ingestion Volume depletion
b. Emesis  induce vomiting Significant gastrointestinal pathology/ dysfunction
▪Systemic Emetics  stimulate the vomiting center ileus, perforation, coloitis, toxic megacolo,
(chemoreceptor trigger zone) hemorrhage, & obstruction
Example: Apomorphine Uprotected or compromised airway
▪Local Emetics  cause irritation of the GIT Hemodynamic instability
Example: tickling the throat, syrup of Ipecac, tepid e. Precipitants  alter the poison by forming an insoluble by
water, saline solution forming an insoluble substance
Syrup of Ipecac: 4. Adsorbents  form physical complexes with poison preventing its
Age Dose (mL) absorption
6–9 5 Example: Activated Charcoal (burnt bread)
9 – 12 10 Universal Antidote: Activated Charcoal
1 – 12 15 Tannic Acid
> 12 yrs 30 Magnesium Oxide
CI: Ethanol, Iron, Lithium, Cyanide, Ethylene glycol, Lead, Mecury,
Intructions regarding Inducing vomiting as an initial Methanol, Organic Solvents, Potassium,
interventions of poisoning at home: Strong Acid, Strong Alkali
- For adults, use 2 tablespoonfuls of Ipecac Syrup 5. Extracorporeal Methods  for life-threatening types of poisons
followed by a glassful of water. (ex: poison in the blood)
-For children,less than 1 year-old but more than 6 a. Hemodialysis (filtration of blood)
months-old, a teaspoon of Ipecac Syrup may be while removing the person it can correct fluid &
used. electrolyte imbalance
- Extract of Ipecac should not be used in plase of ▪Requirements: Vd = <1 L/kg
Ipecac Syrup PB = <50%
- If Ipecac fails, time must not be wasted on trying to LMW = <600 Daltons
induce vomiting, & the patient must be ▪Indication: Ethylene Glycol, Methanol – more effective
immediately brought to the hospital Ethanol, Theophylline, Lithium, Salicylates,
CI: 1. Children <6 months of age Long-acting Barbiturates – less effective
2. With CNS depression or seizures ▪Drug Groups have high volumes of distribution which
3. Strong acid, alkali, or a sharp object ingestion makes Hemodialysis ineffective therapeutic option in
4. With compromised airway protective reflexes cases of Poisoning:
5. Ingestion of some types of hydrocarbons/ petroleum - Antipsychotics
can promote lung asphylaxis - Antidepressants
6. Ingestion of substances with an extremely rapid -Antimalarials
onset of action b. Peritonel Dialysis  There is no need for anticoagulant
7. With emesis following the ingestion  10-15% as affective as hemodialysis
c. Cathartics  induce evacuation of vowel c. Hemoperfussion  Passage of anticoagulant blood through a
Examples: Children – Castor Oil (Resinoleic Acid) column containing activated charcoal or
Irritant Laxatives resin particles.
Containing Magnesium only use for highly protein bound drugs
Containing Sulphates ▪Advantage: Faster than hemodialysis
Containing Biphosphate – “Fleet Enema” ▪Disadvantage: cannot correct fluid & electrolyte
Sodium Phosphate imbalance
Sodium Biphospahte ▪More Effective: Phenobarbital, Phenytoin,
Carbamazepine, Methotrexate,
Theophylline
▪Less Effective: Ethanol, Methanol

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6. Chelating Agent  contain electon-donating groups that react with Classification of Poisons
metals to form complexes Based on Specific Effects:
 used in heavy metal poisoning  Irritants  cause tissue necrosis on contact, caustic effects
 commulative poisoning Ex: Acid & Alkali
▪MOA: Coagulation of proteins (CHONS)  Neurotics  affect the CNS, Ex: Hallucinogens
by binding to Sulfhydryl (-SH) groups  Carcinogenics  stimulate growth of cancer cells
a. Dimercaprol (BAL- British AntiLewisite) Ex: Industrial Poisons
/ 2,3- dimercaptopropanolol  Asphyxiants  cause dyspnea, Ex: Methane Gas, Carbon Monoxide
 serves as the metal acceptor & prevents binding of  Lacrimators  stimulate flow of tears, Ex: Organophosphates
the –SH groups of enzymes to metals  Sternutators  cause excessive sneezing, Ex: Veratrine
 used in Hg, Pb, Au, Sb  Asthetics  produce muscular weakness, Ex: Neuromuscular Blockers
Intamuscular, needs an oil solvent (Peanut oil)  Narcotics  produce mental weakness/ depression,
CI: Fe, Cd, Se Ex: Sedative- Hypnotics
b. EDTA (Ethylene Diamine Tetraacetic Acid/
Calcium Disodium Edetate) Based on Origin:
only limited metals can be ▪ Natural
used for EDTA (higher affinity than Ca2+) Animal: also known as Zootoxin
used in Fe,Zn, Mg, Cd Plant: also known as Phytotoxins
c. Penicillamine (Cuprimine®) / --dimethylcysteine Microbials
hydrolytic produc of penicillin Minerals
PO; used in Cu, Pb, Hg ▪Synthetic
hydrolysis product of Penicillin
d. Deferoxamine/Deferoxime Based on Properties:
bonds with Fe  Ferroxamine Complex ▪ Chemical Composition
IV, IM, SC Inorganic
e. DMPS (2,3-dimercapto- 1- propanesulfonic Acid) Organic
f. DMSA (meso-2,3-dimercaptosuccinic Acid) ▪Volatility
g. DTPA (diethylenetriaminepentaacetic Acid, Calcim Salt) Volatile
h. DTC (Dithiocarbamte) -Hydrocyanic Acid: Prussic Acid
-Carbon Monoxide: Acetylene Gas; found as a byproduct of
incomplete combustion in automobile,
furnace, & in cigarettes
-alcohols/acetone/phenols/formaldehyde
Non-volatile
-alkaloids

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General Kinds of Poison:

A. Industrial & Household Poison 6. Hydrocarbon  mostly derived from petroleum distillates
1. Ethylene Glycol  used in Antifreeze Preparation ▪Petroleum distillates – “Kerosene”
 excreted by Kidney Signs & Symptoms: Lung Aspiration
 causes a drunken sate followed a day later by Treatment: Mineral oil  use to increase
severe high anion gap metabolic acidosis & acute the viscosity of toxicant
renal failure ▪Benzene – can cause megaloblastic leukemia; aplastic anemia
Signs & Symptoms:
▪ MOA: Dyspnea
CNS Depression  most important toxidrone of
acute exposure of Benzene
Bone Marrow Injury  most significant serious toxic
effect of chronic exposure to
▪Metabolites: Glycol Aldehyde, Glycolic acid, Glyoxylic acid Benzene
▪Toxic Metabolite: Oxalic acid, Formic Acid manifesting as aplastic
▪ Signs & Symptoms: Severe Metabolic Acidosis anemia, agranulocytosis, & a
CNS depression risk for the development of
Cardiopulmonary Depression Leukemia
Acute Renal Failure Treatment: Ventilatory Support + 100% O2
Seizure (treated w/ Diazepam) Mineral Oil  use to increase
▪Treatment: 1. Ethanol competes w/ alcohol dehydrogenase the viscosity of toxicant
2.Fomipazole  (-) alcohol dehydrogenase
3. Leucorin  Formic Acid  CO2
4. Hemodialysis + NaHCO3  Systemic Alkalizer 7. Nitrates & Nitrites
5. Ca gluconate  for Hypocalcemia a. Inorganic Nitrates – meat preservative
2. Methanol  “Wood Alcohol” ▪NaNO3 – “Chile Salt peter”
 denaturant, paint remover, solvent ▪KNO3 – “Salt peter”
▪MOA: Methanol  Formaldehyde  Formic Acid (Blindness) b. Organic Nitrates – for the treatment of Angina Pectoris
▪Metabolites: Formaldehyde, Formic Acid ▪Isosorbide Mononitrate (Imdur)
▪Signs & Symptoms: 1. Ocular Toxicity (visual disturbances) ▪Isosorbide Dinitrate (Isordil)
2. Metabolic Acidosis ▪Glyceryl Nitrates –
3. CNS Depression Organic Nitrates – vasodilator; Monday’s Disease
4. Seizure (treated w/ Diazepam) c. Inorganic Nitrites
▪Treatment: 1. Ethanol & Fomepizole  Tx of Met Hgb
 competes w/ alcohol dehydrogenase ▪Amyl ntrite
2. NaHCO3 – Systemic Circulation ▪NaNO2
3. Isopropyl Alcohol  “Crude Oil Alcohol” d. Organic Nitrites  antioxidant property
 70% alcohol MOA: Nitrates & Nitrites
 lead to ketosis (formation of Ketone Bodies) Signs & Symptoms: Light headedness, headache, nausea & vomiting,
metabolic Acidosis diarrhea, abdominal pain
▪Treatment: Hemodialysis + Gastric Lavage Treatment: Methylene Blue (1-2mg/kg)
4. Aldehydes: Low Dose= treatment
a. Formaldehyde  35-50% aldehyde High dose = can cause also MetHgb
 formalin, formol 8. Silica – “silicosis”
 embalming fluid Signs & Symptoms: Lung fibrosis, Bronchogenic CA
 Similar in presentation to methanol toxicity Treatment: “Alumina”
▪Signs & Symptoms: Local: Mucosal Irritation 9. Asbestos – “Asbestosis”
Systemic: CNS depression, Signs & Symptoms: Lung CA
Coma, Treatment: Decontamination
Metabolic Acidosis 10. Carbon Tetrachloride  used in non-flammable cleaning fluids &
▪Treatment: NH3 + NaHCO3 fire extinguisher
b. Aldehyde  responsible for “Hang-Over” Metabolites: Epoxide, Phosgene
 “Ethanal” ▪Phosgene – war weapon
▪Signs & Symptoms: CNS depression,  Poison gas
Metabolic Acidosis  hepatorenal toxin
▪Treatment: Hemodialysis, NaHCO3 Signs & Symptoms: Difficulty in breathing
Nausea & Vomiting
5. Ketones: Pulmonary Edema
Acetone (2-propanone)  primary ingredient in Skin lesions
fingernail polish remover, Treatment: Ventilatory support
airplane glue, 11. Household Poisons
varnish, & a. Bleaches – “NaOCl”
rubber cements Signs & Symptoms: Esophangeal Irritation
▪Signs & Symptoms: CNS depressionComa, Respiratory Dep. GI Discomfort
▪Treatment: Neutralization  Milk + H2O Treatment: Gastric Lavage
b. Oxalic Acid – metal cleaners & mat removers
Signs & Symptoms: Metabolic Acidosis, Seizure, Hypocalcemia
Treatment: Ca Gluconate  hypocalcemia

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B. Cosmetics: E. Poisons w/ Systemic Effects:

1. Deodorant 1. Hydrogen Fluoride (HF) – source: Fluorinated Water
a. Aluminum – “Shaver’s Disease” Signs & Symptoms: Hypocalcemia
 3rd most abundant element; most abundant metal Treatment: Ca Gluconate
used for healing burns & as abrasive in industries 2. Paraquat  agriculture: Weed Killer
has constipating & astringent effects  is known to accumulate slowly in the lungs by an active
b. Zinc  used in the galvanizing of iron & container for battery cells process & causes lung edema, alveolitis, & progressive
Deficiency: Parakeratosis (inflamed & scaly skin) pulmonary fibrosis days to weeks after an acute
Toxicity: Metal Fume Fever (muscle aches & fever) exposure
Treatment: Aspirin + Bed rest (recovery occurs after 12 days) Signs & Symptoms: Pulmonary edema,
2. Depilatories  for hair removal Pulmonary Fibrosis
 contains sulfides or thioglycolates Alveolitis
Signs & Symptoms: Local Irritation MOA: (-) inhibit superoxide dismutase
3. Permanganate  Strong Oxidizing Agent
C. Food Additives:  can cause Met Hgb
1. Chloramin T  in milk products 4. Phenol  “Carbolic Acid” : Joseph Lister
Signs & Symptoms: Transform in CN- MOA: Protein denaturation
Treatment: NaNO2 + NaS2O3 Signs & Symptoms:
2. Tartrazine  FD & C no. 5 (Tartrazine) Local: Mucosal/ Local Irritation, Redness of Skin, Corrosive
Signs & Symptoms: Anaphylaxis in allergic reaction Sytemic: Seizure, Coma, Liver damage, Kidney Damage
3. Monosodium Glutamate (MSG) Dx: Chemical Evidence= Phenol + FeCl2  Blue violet (+)
Signs & Symptoms: light headedness ( pressure in the head) Tx: Castor Oil (Resinoleic Acid: cathartic)
Tightness of the feet 5. Phosphorus  Luminous vomitus
Seizure  Garlic Odor
Treatment: Lessen MSG in foods Tx: CuSO4 (Blue Vitriol)
Types of Phosphorus
1. Red granular; non-toxic; matches
4. Saccharin & Aspartame  Artificial Sweeteners 2. Yellow/White toxic;can be seen in pyrotechniques & fireworks
Signs & Symptoms: diarrhea, Abdominal pain, Nausea, Pain 6. Picric Acid & Tannic Acid
▪Aspartame: Aspartic Acid Signs & Symptoms: Hepatic Injury
Methanol 7. Cyanide Sources: Prunus sp.
Phenylalanine  cause Phenylketonuria  Bitter Almond, Peach, Apricot,Cassava Peel, Lima
(lack of Phenylalanine Beans, wild black berry, plum, cherry laurel,
hydroxylase) mountain mahogany, Silver Cleaner
5. Naphthalene  Moth Balls, Coal Tar MOA: Inhibits Cytochrome Oxidase  O2 Consumption
Signs & Symptoms: Jaundice Signs & Symptoms: CNS & CV disturbances; Seizure;
Oliguria (low urine output) Respiratory Depression; Death;
Convulsion Odor of Bitter Almonds; Cherry Red Blood
Treatment: ASA Treatment: NaNO2 (IV)
Amyl Nitrite (Inhalation)
D. Acid & Alkali: Methylene Blue
▪Acids  causes Coagulative Necrosis Sodium thiosulfate (IV)
▪Alkali (Bases)  causes Liquefaction Necrosis Alternative: Dicobalt edentate (Kelocyanor®)
Treatment: Dilutional Therapy (large amount of water + milk) Hydroxocobalamin  Vitamin B12
Sp. Treatment for Alkali Poisoning: Vinegar; Fruit Juice 8. Carbon Monoxide  result from incomplete combustion
Sp. Treatment for Acid Poisoning (Ex: HCl): Antacid  secondary to smoking
-can be diluted w/ H2O except  most common cause of air pollution
w/ H2SO4 (highly exothermic) MOA: CO  Hg  Carboxyhemogloginemia  200x nonbinding
CI: Gastric Lavage capacity than Hg
Do not Neutralize Signs & Symptoms: Cherry red Color of the Blood
Emetic Hypoxia  anoxia  death
Cathartics Psychomotor Impairment  Headache 
Confusion  Tachycardia Coma
*The Brain & the heart are the most affected organs
*Forms Carboxyhemoglobin which ca not transport oxygen
*Smoking males have a higher Carboxyhemoglobin levels
Treatment: 100% O2; Hyperbaric O2  revives death tissue;
Artificial Air  80% helium + 20% Oxygen

Hyperbaric Oxygen Supplementation

 may be necessary intervention if no response is
seen w/ 100% Oxygen supplementation in cases
of poisoning w/ Carbon Monoxide & Cyanide

9. Hydrogen Sulfide  “Rotten-egg Odor”

MOA: Binds with Hemoglobin to form another abnormal form
of hemoglobin which is Sulfhemoglobinemia
Signs & Symptoms: Dyspnea (difficulty of breathing)
O2 COnsumption
Treatment: Hyperbaric O2

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F. Insecticide & Pesticides G. Heavy Metals

1. Organophosphates 1. Arsenic  Lewisite Metal
 Parathion, Malathion  for treatment of syphilis (Arsphenamine/Salvarsan/606)
MOA: Binds to Acetylcholine  manufacture of insecticides, glaswares
forming a stable phosphateester bond inactivation  result to hyperkeratosis & hyperpigmentation
of Ache   Ach (irreversible without treatment)  causes “black foot disease”
Signs & Symptoms: DUMBBELSS  proplasmic poison
Treatment: Atropine – inhibit Ach  choice of professional posoners
Pralidoxime – aid for the treatment MOA: Coagulation of protein by binding to SH groups
enzyme deactivation Signs & Symptoms: “Mee’s Line” (white line in the nails)
(Acetylcholinesterase) Abnormal Weigh gain, Watery Diarrhea
EdrophoniumTensilon® Milky/rosy complexion,Garlic odor of breath
Dx of Myasthenia Gravis Luminous vomitus, Alopecia
(Muscle weakness) Black line on gums/ bleeding gums
Delayed neurotoxicity associated w/ exposure to “Raindrop” pattern of Hyperpigmentation &
organophosphates characterized by polyneuropathy, paralysis, Hyperkeratosis
& axonal degeneration has been attributed to Inhibition of the Treatment: BAL/ Dimercaprol (+Penicillamine if severe)
Neuropathy target esterase 2. Cadmium  Itai-itai Disease (through consumption of cadmium-
2. Carbamate  not persistent toxicant contaminated rice in Japan)
 the clinical approach to management is similar to Sources: Anti-dandruff Shampoos,
organophosphate poisoning Smoke & stink bamboos, solder(metal alloys)
MOA: Reversibe binding to AChe Signs & Symptoms: Osteomalacia, Fractures.
Signs & Symptoms: DUMBBELSS Renal Abnormalities, Gait disturbances
Treatment: Atropine Treatment: EDTA (for acute ingestion)
Pralidoxime 3. Lead  “Plumbism” (Absorption of Lead via Respiratory Tract)
3. Rodenticides  agents to kill mice & rats  most ubiquitos of the toxic metals
a. Coumarin derivatives exposure may be through air,water or food sources
MOA: Inhibit Gamma decarboxylation of the Vitamin K Main target: Hematopoietic system & nervous system
dependent factors Factors predispose to increased Lead absorption:
Signs & Symptoms: Hemmorage/ Excessive Bleeding -Decreased Dietary Calcium
Parameters: INR (International Normalize Ratio) - Iron deficiency
𝑃𝑇 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 - Ingestion on an empty stomach
𝐼𝑁𝑅 =
𝑃𝑇 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 Pharmacokinetics:
Treatment: Vitamin K (Phytomendaione)
-Lead can cross the placenta & pose a potential hazard
Fresh Frozen Plasma
to the fetus
b. Heparin
-Yong children have greater degree of absorption of
MOA: Direct thrombin Inhibitor
ingested Lead than adults
Signs & Symptoms: Hemmorage/ Excessive Bleeding
-The major route of excretion of Lead is through Urine
Parameters: aPIT (activated Partial Thromboplastin Time)
 *Skeletal Muscle (Bone) –is the primary repository site of
Treatment: Protamine Sulfate
inorganic lead in the body of an
4. Chlorinated HC Pesticides
adult
 DDT; Chlordane Sources: Canned goods, Automobile exhaust, wine glasses,
 known to be Neurotoxin Old pipes, Cables, Paints
MOA: Inhibit the inactivation of Na channel MOA: Inhibits cytochrome, Inhibiys heme synthesis
Signs & Symptoms: Seizure, N/V (Nausea & Vomiting),  O2 Consumption 
Paresthesia, Respiratory Depression Signs & Symptoms: Pb encephalopathy
CNS Stimulation (primary toxidrome) Hemolytic Anemia
5. Botanical Insecticides: Abdomical Colic
- Nicotine Elevated Liver Enzymes
- Rotenone Pb palsy  wrist/foot drop
- Pyrethrum Milky vomitus
Black stools
Fanconi-like syndrome
( proteinuria- hematuria)
Treatment: Penicillamine, BAL, EDTA

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4. Mercury  aka. Quicksilver

 Messenger of the Gods
 Minimata Disease (mercury poisoning)
 through consumption of fish & shellfish
MOA: Coagulation of protein by binding to SH groups
Signs & Symptoms: Acrodinia ( photophobia, anorexia,
restlessness, stomatitis, oliguria,
severe diarrhea, pains in arms &
legs, pink palms & toes)
Gingivitis (hyperplasia)
Erethism (behavioral pattern characterized
by change in mood)
Treatment: Na Formaldehyde Sulfoximate (Antidote of Choice)
BAL (for high level of exposure)
Penicillamine (for low level of exposure)
Chelation w/ Unithiol may diminish nephrotoxicity
thay may result from acute exposure to
inorganic Mercury
Unithiol  Dimercaptopropanesulfonic acid
Three types of Mercury:
a. Elemental Mercury: Thermometer, Sphymomanometer
b. Inorganic Mercury: Hg2Cl2  Calomel
HgCl2  Corrosive Sublimate
c. Organic Mercury: Thimerosal–old(Methiolate®)
Benzalkonium Chloridenew(Methiolate®)
Methymercury  a highly toxic form of Hg causes Minimata dis.
5. Iron  for hemoglobin & myoglobin production
*Chronic excessive exposure to the metal can lead to
deposition in various organs & tissues causing the
development of conditions such as secondary DM,
restrictive cardiomyopathy, & hepatic failure;
Hemachromatosis
*Hemorrhagic gastroenteritis –is the most consistent
manifestation of acute
overdose of Iron in Children
cause of toxicity: Overingestion of OTC preparations
Lethal Dose: 200300mg/kg
Toxic Dose: >600mg/kg
Phases of toxicity:
I. nausea, vomiting, diarrhea, GI bleeding, hypotension
II. clinical improvement seen 624 hours postingestion
III. metabolic acidosis, renal & hepatic failure, sepsis,
pulmonary edema & death
Treatment: Deferoxamine/Deferoxime (Antidote of Choice)

6. Thallium
MOA: Binf to SH group
Signs & Symptoms: Gastroenteritis
Paresthesia (numbness)
Alopecia
Treatment: Prussian blue/ Ferric Ferrocyanide

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H. Drugs of Abuse
1. Opioids  from Papaver Somniferum (opium poppy) 4. Hallucinogens are substances that alter sensory processing in the
Natural: Opium, Morphine(pure agonist) brain, causing depersonalization, perceptual
Semi-Synthetic: Heroin (Diacetylmrphine) disturbances, & changes in thought processing
Codeine (Methylmorphine) a. LSD  Lysegic Acid Diethylamide
Synthetic: Methadone & Meperidine ergot derivatives
MOA: All bind to opioid receptors  Mu, Kappa, Delta MOA: Stimulates serotogenic receptors,
Signs & Symptoms: Triad: Coma Increase levels of 5-HT5
Miosis(pinpoint pupil) Signs & Symptoms: Increase suicidal tendency
Respiratoy depression Altered mental status
Meperidine: + Seizure Treatment: Benzodiazepine (for seizure)
Treatment: Naloxone (pure Antagonist), b. Mescaline  peyote cactus (Lophophora williamsii), “buttons”
Naltrexone, nalorphine, Nalmefen  related to Amphetamine
 competitive opioid antagonist but may precipitate  is one of the first phenylakylamine hallucinogen
withdrawal symptoms in an addict patient identifiesd
Activated Charcoal can limit further GI absorption c. Amphetamine derivatives
2. Amphetamine Ecstacy (MDMA, Methylenedioxymethamphetamine)
 -phenyllisopropylamine / -methylphenylethylamine ”E”,”adam”, “ XTC”
 alternative for ADHD  structurally relative to:
 Sympathomimetic agent -MDEA (3,4-methylenedioxyethamphetamine) – “eve”
 used in HPN, Arrhythmias, seizures, CNS stimulation -MDA (Methyldioxyamphetamine) –“Love drug”
MOA: Increases Dopamine Activity in the brain MOA: Acting like false neurotransmitters
Treatment: (act like catecholamines)
Seizures: Diazepan, Phenytoin Toxic dose: 50-150 mg
Psychosis/Agitation: Chlorpromazene, haloperidol, Diazepam Signs & Symptoms: Hypotension; Cardica arrest  Death
Hypertensive crisis: -blockers, -blockers Treatment: Force Diurestic (NH4Cl- acidifier)
Arrhythmias: Propanolo, Lidocaine Labetalol, Nitroprusside, Nifedipine for HPN
3. Sedatives & Hypnotics Methamphetamine  more substantial than amphetamine
a. Benzodiazepines  +alcohol fatal CNS & respiratory depression crystal form
MOA: potentiate neurotransmitters – GABA (inhibitory) ”Crack”, “Speed”, “Yaba”, “Go”, “Ice”,
Signs & Symptoms: Drowsiness, Ataxia, Confusion “Siopao”, “Ubas”, “Batak”, “Bato-Bato”,
Treatment: Flumazenil (Mazicon®) “Poor Man’s Cocaine”
reverses benzodiazepine effect in the CNS Ephedrine  Ma huang
b. Barbiturrates  enzyme Inducer Khat  “quat”, “qat”
used in induction of anesthesia & for seizures from Catha edulis shrub
Signs & Symptoms: -Cathinone active ingredient in fresh leaves of Khat
Mild: Slurred Speech  (benzylketamphetamine)
Ataxia -Cathine active ingredient when cathinoneis degraded as
Altered mental status the leaves age, which explains why dried Khat is
Severe: Comatose with absence of deep tendon reflexes, neither popular nor widely distributed.
Cheyne-Stokes (irregular) respiration -Methcathinone  methyl derivatives of cathinone
Treatment: Force Alkaline dieresis (NaHCO3)  chemicall synthesized from Ephedrine
Hemodialysis  aka “Ephedrone”
c. Chloral hydrate  Mickey Finn®  Street names: “Cat”, “Jeff”
invivo via alcohol dehydrogenase Trichloroethanol 5. Phencyclidine (PCP) poisoning  aka “Angel Dust”, snort, super grass
”Knock-out drops”, similar to barbiturates  similar to a dissociative anesthetic,
Treatment: Supportive Ketamine
Signs & Symptoms: Nystagmus (difficult to rotate your eyeballs)
Decrease consciousness
Acute brain syndrome (disorientation,
psychosis, coma)
Treatment: Benzodiazepine, Diazepam (for seizure)
Ntroprusside (for HPN)
6. Dimethyltryptamine (DMT)  a short acting hallucinogen found in
the seeds of Piptadenia peregrine.
7. Marijuana  Cannabis sativum
 aka Mary Jane, Hash-ish, Hash-oil, Weeds
 used a antiemetic for patient undergoing chemotherapy
A.I.: -9-tetrahydrocannabinol (THC)
8. Cocaine  Erythroxylon coca,
“crack”
“freebase” (purified)
MOA: Increase Dopamine activity
Treatment:
Seizures: Benzodiazepine
Psychosis: Neuroleptics
HPN: Labetalol

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9. Alcohol (Ethanol)  CNS depressant

 grain alcohol, neutral spirit
 responsible for major medical
& socio-economic problems
Acute Alcoholism (Enzyme Inhibitor)
Chronic Alcoholism (Enzyme Inducer)
Metabolites: Acetaldehyde, Acetic Acid
Signs & Symptoms: CNS depression, Acid-base Imbalance,
Metabolic Acidosis, Impaired Thermal
Regulation, Hypoglycemia
Treatment:
Thiamine (prevention of Wernicke-Korsakoff Syndrome)
Disulfiram (Antabuse®, used to stop alcohol addiction
Fomepizole
10. Nicotine  Enzyme Inducer
 active ingredient of tobacco for the addictive effect
Lethal Dose
Child: 1.5 – 2 mg/kg
Adult: 40 – 6- mg
Minimum fatal dose of Nicotine: 40 mg = 2 sticks ofCigar.
Acute Nicotine Toxicity: Hypertension
Cardiac Arrythmia
Management:
-Anticonvulsant (involves Benzodiazepine)
-Epinephrine & Neostigmine are both avoided
Treatment: Activated Charcoal
Gastric Lavage
Mecamylamine (Inversine®)
11. Strychnine  abused by athletes before
Scientific Name: Strychnos nux vomica
Signs & Symptoms: Rigor mortis,
Convulsion
Treatment: Diazepam
Phenobarbital
Neuromuscular Blockers
Skeletal Muscle Relxant
12. Volatile Substances
a. Toluene  Methy benzene
 “Glue Sniffers”
b. Nitrous Oxide  Anesthetic
 “laughing gas”
 may cause diffusional hypoxia
 Hysterical laughing
 blue container in hospital
Treatment: Ventilation Support, 100% oxygen

Drugs can be used to treat Heroin Addicts:

1. Methadone  reduce the craving of heroin
2. Naltrexone  blocks the effect of heroin
3. Levo--acetyl methodol (LAAM)  synthetic opioid, block the
effect of heroin for up to 72
hours w/ minimal side effects
when taken orally.
4. Buprenone  also used as a treatment of heroin addiction since
it does not produce the same level of physical
dependence as other opioids.

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I. Clinical Toxicology
1. Salicylates
Signs & Symptoms:
Mild: Tinnitus
Severe: Lethargy, Convulsions, coma, Metabolic Acidosis 9. Methyxanthines
Treatment: Theophylline
Urine Alkalinization with NaHCO3 Signs & Symptoms: Seizures, Cardiac Dysrhythmias
Vitamin K1/ fresh frozen plasma (for bleeding) Treatment: Ipecac Syrup, Activated Charcoal, WBI,
Hemodialysis or Hemoperfusion (100mg/dL) Hemoperfusion & Hemodialysis; consider -
2. Paracetamol / Acetaminophen blockers for manifestations
*Above 150-200 mg/L  minimum serum Acetaminohen level
(indicate a high risk for liver injury) 10. Lithium  DOC for mania & bipolar disorders
MOA: Depletion of Glutathione causing Hepatic necrosis Signs & Symptoms:
due to its toxic metabolite, NAPQI Mild: polyuria, blurred vision, weakness, slurred speech,
Phases of toxicity: Ataxia, tremor & myoclonic jerks
I. anorexia, diaphoresis Severe: delirium, coma, seizures & hyperthermia
II. asymptomatic Treatment: Ipecac Syrup, NA polysterene sulfonate,
III. abdominal pain, hepatic failure, coma, death WBI (SR products), hemodialysis (rebound effects)
Treatment: N-Acetylcystein (NAC, mucolytic) –PO 11. Tricyclic Antidepressants (TCAs)
-acts as a precursor for glutathione Signs & Symptoms: Anticholinergic signs & symptoms
3. Warfarin Cardiopulmonary toxicity
MOA: Inhibition of Vitmain K-related clotting factors (II, VII, IX) CNS manifestations
Principal Manifestation: Bleeding Treatment:
Treatment: Vitamin K Physostigmine: DOC for Anticholinergic signs & symptoms
4. Heparin NaHCO3: DOC for Cardiopulmonary toxicity
Principal Manifestation: Bleeding Phenytoin &/or Benzodiazepine: DOC for CNS manifestations
Treatment: Protamine Sulfate (acts as the base to neutralize 12. Isoniazid (INH)
heparin activity) Signs & Symptoms: Peripheral Neuropathy; Hepatitis
1mg Protamine = 100IU Heparin Management:
5. Chloramphenicol -Pyridoxine is given at a dose of 1mg per mg of Isoniazid
Gray Baby Syndrome: GI disturbance, vomiting, anorexia, -Activated Charcoal can limit further absorption of the
abdominal distention, diarrhea, drug form in the GIT
hypothermia, hypotension, & cyanosis - Benzodiazepine are used to control seizures
Treatment: Charcoal Hemoperfusion Treatment: Vitamin B6
6. Vancomycin  Red Man or Red Neck Syndrome 13. Beta-Blockers
Prevention: Prolonging the infusion to 1-2 hours Signs & Symptoms:
or increasing the dosing interval Hypotension, Bradycardia, AV block
7. Digoxin Bronchospasm (non-cardioselective agents)
Signs & Symptoms: Treatment: Glucagon
Mild: Nausea, vomiting, anorexia, confucion Epinephrine (w/ caution)
Severe: Cardiac dysrhythmias 14. Calcium-Channel Blockers
Treatment: Principal Manifestation: Hypotension
Lidocaine or Phenytoin Treatment: Calcium Chloride IVP
Digoxin-specific Fab antibodies (DIgibind) Glucagon
Potassium Chloride 15. Potassium
8. Muscle Relaxants Signs & Symptoms: Cardiac Irritability ; Dysrhythmia;
Succinylcholine & Tubocurarine Peripheral Weakness
Malignant Hyperthermia: Succinylcholine Treatment:
Histamine Release (Anaphylactic shock): Tubocurarine ▪Calcium Chloride (antagonize the cardiac effects of
Treatment: hyperkalemia)
Ephinephrine (DOC for Anaphylactic shock) ▪NaHCO3, Glucose, Insulin ( for intracellular shift of K
Dantrolene (DOC for Malignant hyperthermia) ▪Cation exchange resin: SPS,Sodium polystyrene Sulfonate
Neostigmine/ Pyridostigmine (exchange K with Na)
▪Hemodialysis: Last Measure

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TABLES OF TOXICOLOGY

 Detection of Poisons (Evidence of Poisoning –Chemical)

Tests Poison Detected Notes
AAS Heavy Metals
Beilstein Chlorine  Green flame
Benzoldt Gunning Acetone  Indigotine
Bromine Water Aniline  Flesh-colored  (tribromoaniline)
Brown Ring Nitrite & Nitrate  + FeSO4 + H2SO4  brown ring at the interfere
Lieben’s Iodoform Methanol (vs Ethanol)  Yellow  (iododform, CHI3)
Marquis’ Common drugs of abuse  Dark purple/black (Ecstacy)
 Orange to brown (Amphetamine & Methamphetamine)
 Purple/black (Propoxyphene)
 Pink to purple (Heroin & Opiates)
 Red (Aspirin)
Marsh Arsenic  Mirror-like 
 Soluble in NaOCl
Reinsch Heavy Metals  Purple black (Sb)
 Dull black (As)
 Shiny black (Bi)
 Silvery (Hg)
 needs confirmation via AAS
Rodillon/ Millon Phenol  Light to dark red color (mercurous phenate or nitrate phenate)
Modified Duquenois Marijuana  Red color (THC) on TLC
Nessler (Mercuric KI) Chloroform (vs Chloral hydrate)  Yellow  (Iodoform)
Nylander Bismuth  White  (bismuth subnitrate)
Phenylisocyanide Nitrobenzene  + chloroform  aniline & phenylisocyanide (irritable odor detected)
Picrate Test Prussic Acid  Yellow to brick red 
Schonbien – Pagenstecher Prussic Acid  Deep blue (guaiac paper)
KI Hg  Orange , excess dissolves   orange solution (Valser’s Reagent)
Scherer P  Black 
Mitscherlich P  Phosphorescence
Schwartz’s Resorcinol Chloroform  Yellowish red color with yellowish green fluorescence
Tollen’s Reducing substances  Mirror-like  (elemental Ag)
Xanthogenate CS2  Release of H2S

 Evidence of Poisoning –Symptomatic Evidences

Odor of Breath Substance/s Skin DIscoloration Substance/s
Shoe Polish Nitrobenzene Boiled lobster appearance Boric Acid
Fruity Odor Ethanol Bleaching White Phenol
Garlic Arsenic, Brown Black Sulfuric Acid,
Phosphorus, Iodine,
Malathion, Silver Nitrate
Thallium Deep Brown Bromine
Mouse Urine Coniine Ash Gray Mercuric Chloride,
Stale Tobacco Nicotine Physostigmine
Bitter almonds Cyanide Blue Silver Salts
Sweet, penetrating odor Acetone, Yellow Picric Acic,
Chloroform Nitric Acid
Pearlike Chloral Hydrate Pale bonds on fingernails Arsenic
Rotten Egg Hydrogen sulfide Bluish gray Silver Salts
Mothballs Naphthalene
Wintergreen Methylsalicylate

Vomitus Substance/s Respiratory Changes Substance/s Blood Changes Substance/s

Blue-green Copper Violent Sneezing Veratrine Blood Coagulability Heparins,
Ground coffee Sulfuric Acid Irritation Sulfur Dioxide Coumarins,
Luminous vomit Phosphorous, Dyspnea Carbon Monoxide Benzene
Arsenic General Respiratory Opium, Cherry Red Blood Carbon Monoxide,
Yellow green Chromium Depression Barbiturates, Cyanide
Benzodiazepine, Dark Red Blood Nicotine
Cyanide Chocolate Blood Aniline,
Nitrites,
Nitro derivatives

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Visual
Bowel Changes Substance/s Urinary Changes Substance/s Substance/s
Disturbances
Black Charcoal, Dark Yellow Picric Acid Purple Vision Digitalis,
Bismuth, Yellow brown Aloe, Marijuana
Iron, Senna Blurred Vision Anticholinergics
Lead, Odor of Violets Turpentine Partial / Total Methanol,
Magnesium Dioxide, Green Blue Phenols & derivatives, Blindness Formic Acid
Silver Nitrate Methylene Blue Solanine
Clay-like Alcohol, Wine or red brown Caffeine, Optic Neuritis Ethambutol
Barium Benzene, Blood Shot eyes Marijuana
White Aluminum hydroxide Rifampicin,
Blue Boric Acid, Lead,
Methylene Blue, Mercury,
Iodine Carbon Tetrachloride
Green Indomethacin,
Iron,
Cupric sulfate
Red (also vomit) Hemolytic Substances

Other Changes
alopecia Arsenic
Tinnitus Salicylates,
Discoloration of Gums Substance/s
Quinine
Blue line gum Bismuth
Ototoxicity Aminoglycosides,
Lead
Loop Diuretics
Black line gum Mercury
Xerostomia Anticholinergics
Arsenic
Bloody Sputum Cadmium
Muscular twitching, Barium
Loss of voice
Loose teeth Mercury,
Lead,
Phosphorous
Bleeding Gums Arsenic,
Mercury
Lock Jaw Strychnine
Blister formation Cantharidin

 Metabolites
Parent Compounds Metabolites Parent Compounds Metabolites
Parathion Paraoxon Diazepam Desmethyldiazepam/ Oxazepam
Imipramine Desipramine Digitoxin Digoxin
Malathion Malaoxon Quinidine 3-hydroxyquinidine
Methamphetamine P-hydroxyl amphetamine Theophylline Caffeine
Paracetamol N-acetyl-para-quinoneimine Acetonitrile Cyanide
DIquat/Paraquat Free redicals/ reactive O2 species Aromatic HC Epoxides
Ethylene Glycol Oxalic Acid Ethanol Acetaldehyde
Aspirin Salicylic Acid Isopropyl Alcohol Acetone
Allopurinol Alloxanthine Methylene Chloride Carbon Monoxide
Amitriptyline Nortryptiline Methanol Formaldehyde & formic Acid
Chloramphenicol Glycolic acid metabolite Naphthalene Epoxide
Codeine Morphine Chloral Hydrate Trichloroethanol
Cortison Cortisol Prednisone Prenisolone
Acetohexamide Hydroxyhexamide Benzyl Alcohol Benzoic Acid/ Hippuric Acid
Phenylbutazone Oxyphenylbutazone Meperidine Normepiridine
Primidone Phenobarbital

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Classification of Poisons
Based on Origin
▪Natural
Animal: aka Zootoxins
Poison Source/s Notes
Latrotoxin Black widow spider/ Hourglass spider  Produces cholinergic signs & symptoms, flushed sweating face
(Latrodectus mactans) contorted in a painful grimace w/ conjunctivitis, restlessness & HPN
 Treatment: Calcium Gluconate, Antivenom
5-Hydroxytryptamine Scorpion (Centuroides scupturatus)  Neurutoxin
 Treatment: Barbiturate & IV antivenom
Bee venom Hymenoptera (bee, wasps, ants)  Red Ants (Formic Acid)
 Anaphylactic Shock
 Treatment: Diphenhydramine & Steroids
Hyaluronidase Snakes  First Aid: Suction & tourniquet, incision (w/in 20 minutes to remove
20%)
 Treatment: Antivenom
Tetrodotoxin Amphibians (toads, newts,  Treatment: Barbiturates, DiazepamConvulsion), Ca Gluconate,
frogs(bufotoxin)), buffer fishes Propanolol
Cantharidin Blister fly/ Spanish fly  Local irritants, Aphrodisiac
Clupeotoxin Oysters, Sardines (venerupin),  Sharp metallic taste, Abdominal pain, vomiting & Diarrhea
Anchovies
Scromboid toxin Tuna (saurine)  Confused w/ MSG reactions
Mackerel (Gemblid)  May be caused by dolphins (non-scromboid)
Ciguatoxin Fish organs (liver)  Most common poison from ingested fish
–edible organs of fish

Plant: aka Phytotoxins

Poison Source/s Poison Source/s
Abrin Jequirity bean Cicutoxin Water hemlock
Aconitine Aconite, Monkshood Colchicine Autumn crocus
Atropine Deadly nightshade Convalllarin Lily of the Valley
Digitalis glycosides Foxglove Coniine Poison Hemlock
Quinine Bitter bark Phenanthridine alkaloids Dalfodil, Jonquil
Nicotine Tobacco Pdophyllotoxin American mandrake, Mayapple
Amygdalin Prunus sp. (Cherry apple) Oxalic Acid & Anthraquinones Rhubarb, Boston Ivy
Ricin Castor bean Oxalic Acid Carambola/ Star druit
Sanguinarine Bloodroot Santonine Santonica
Taxines Japanese yew Solanine Black Nigthshade, Rotten potato
Arecoline Betel nut Veratrine False hellebore, Corn Lily
Brucine Nux vomica Physostigmine Calabar bean
Picrotoxin Fish berries Phalloidine Death Angel
Myristicin Nutmeg Manihotoxin Cassava
Muscarine Amanita Uroshiol Poison Ivy
Sapotoxin Saponin Containing

Mushroom Toxins
Group Mushroom Toxin Notes
I Amanitotoxins,  Hepatotoxin
Cyclopeptides  Treatment: Thioctic Acid, Dextrose, Penicillin (Interference w/ albumin binding), Vitamin K,
Dexamethasone
IA Orellanine,  Nephrotoxins
Orrelline  Treatment: Charcoal Hemoperfussion
II Muscimol,  Hallucinogens, Anticholinergic signs & symptoms
Ibotenic Acid  Treatment: Physostigmine
III Gyrometrin  Hepatotoxin
 Hydrolyzes to form monomethylhydrazine used as rocket fuel
 Produced by a poisonous mushroom, Gyrometra esculenta
IV Muscarine  Parasympathetic Overstimulation
 Treatment: Atropine
V Coprine  Disulfiram Reactions
 Treatment: IV NSS
 , Dopamie or NE for hypotension
VI Psitocin,  Hallucinogens
Psitocybin  Treatment: Diazepam

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Microbial Toxins
Poison Source/s Notes
Saxitoxin Dinoflagellates  Red tide poisoning, paralytic shellfish poisoning (PSP)
Aflatoxin Aspergillus flavus  Found in improperly dried peanuts
 Carcinogenic
Ptomaine Bacterial decay  Spoiled food
Tyrotoxin Bacterial decay  Expired milk & dairy products
Ergot Claviceps purpurea  Ergotism, convulsion & gangrene (St. Anthony’s Fire)
Exotoxin Mostly form Gram (+)  Proteinaceous, high virulence, small lethal dose
Botulinum Toxin C. botulinum  Spoiled canned foods
 Neuromuscular poison
Tetanospasmin C. tetani  Causes tetany
Cytotoxin C. perfringens  Gas gangrene
Enterotoxin Staphylococcus aureus  Most common cause of food poisoning
 Causes TSS (Toxic Shock Syndrome – mostly in menstruating women)
Diphteria Cytotoxin Corynebacterium diptheriae  Protein synthesis inhibitor in nerves, heart & kidney cells
C. Entertoxin Vibrio cholerae  Causes rice watery stool
E. Enterotoxin E. coli  Traveller’s diarrhea (ETEC)
 Causes rise watery stool
Endotoxin Mostly form Gram ()  Lipoidal, low toxicity, high dose to become lethal
Typhoid Salmonella typhosa  Causes typhoid fever
Proteus Proteus species  Causes UTI (treated w/ Ciprofloxacin)

Mineral Toxins
Poison Other Name Notes
HCl Muriatic acid  Found in bathroom disinfectants
 Causes Whitish Burns
Acids/Acidic H2SO4 Oil of Vitreol  Causes brown-black burns, ground coffee vomitus
HNO3 Aqua fortis  Causes yellow burns
Phenol Carbolic Acid  Causes (bleaching) whitish burns
NaOH Lye  Found in detergents
Sosa  Forms hard soap
Base
KOH Caustic Potash  Found in detergents
 Forms a soft salt
NaOCl Dakin’s Solution  Bleaching agent
Salts  Deodorizing agent
Lead Chromate  Used as yellow food color (Icing)

▪Synthetic
Poison Notes Poison Notes
Aluminum Chlorohydrate  Found in deodorants H2S (Hydrogen Sulfide)  Sewer gas, stink damp
Eosin  Found in lipsticks  Found in petroleum refineries, tanneries,
Methanol  “Wood Alcohol” mines, & rayon factories
 Denaturant, pain solvent, varnish  Causes “gas eye” for workers in tunnels
 Causes blindness Aniline  “Blue oil”
Formaldehyde  “Formalin”  Found in crayons
 Found in embalming fluid  Tx: Methylene Blue
Isopropyl Alcohol  “Crude oil alcohol” Ethylene Oxide  Anti-freeze liquid
 Ingredient of rubbing alcohol  Used in aeronautics
 Very toxic (120mL limit) Chloral Hydrate  “knock-out drops”
Phencyclidine  “angel dust”  Sedative
 Psychedelic Saponated Cresol  Lysol
Asbestos  Used as a fire retardant Chloramine-T  Found in milk
 Used In fire proof clothing of firemen  H20 purifier, mouthwash
 Causes silicosis & lung cancer  Converted to cyanide derivatives
 Cyanosis, respiratory failure, collapse
 Tx: Sodium nitrite. Sodium thiosulfate
CCl4  Carbon Tetrachloride
 Ingredient of non-flammable cleaning CS2 (Carbon disulfide)  Used in textile industry
fluids & fire-extinguishers  Causes red blood cells Hemolysis
 Most hepatotoxic among the Aliphatic  Tx: Amyl nitrite, Sodium nitrite
halides
Naphthalene  “moth balls”
 Toilet bowl deodorant Acetone  Found in nail polish removers & model air
 Obtained from coal tar plane glues or cements
Picric Acid  “trinitrophenol” Nitrobenzene  Essence of mirbane
 Colorant in textile industries  Found in shoe polish
LSD  Morning glory
 Obtained from ergot
 Psychedelic

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Classification of Poisons
Based on Properties
▪Chemical composition
Inorganic
Pb  Causes plumbism Mg  Natural calcium channel blocker
 Sources: canned goods, automobile exhaust  Second most abundant intracellular fluid cation
 (as tetraethyl lead), wine glass, old pipes, cables, paints  Possesses cathartic action & anti-convulsive properties
Au  Source: Gold salts used as anti-inflammatory agents & for Li  Metal used as heat exchanger in air conditioners
lupus eryhtomatosus  Salts are used for mania
Cr  Glucose tolerance factor Ag  Causes argyria
 Found in brown sugar & butter  Found in indelible inks
 Toxicity resembles Diabetes Mellitus  Protein precipitant
 human carcinogen & induces lung cancers among exposed
workers
Co  Used in the manufacture of permanent magnet & in beer Zr  Used as an ingredient of deodorant & antiperspirant
 Metal found in Cyanocobalamin  Causes granulomas
Os  Densest metal Fe  Hematinic
 Used in the preparation of slides for electron microscopy  Toxicity due to overdose of preparation
Mn  Used as a co-factor in enzymatic reactions Sn  Found in canned milk & other canned products
As  Lewis metal Al  Causes Shaver’s Disease
 Used in the manufacture of insecticide (Paris Green, Fowler’s,  Third most abundant element on earth;
Donovan’s Solution)  Most abundant metal
 Metal present in Salvasan  Constipating effects
 Possesses Anti-leukemic Properties (as trioxide salt)  Used as abrasive in industries
 Protoplasmic poison  Used for the healing of burns
Cd  Metal responsible for Itai-itai poisoning Zn  Used in galvanizing iron & as container in battery cells
 Found in anti-dandruff shampoos &  Deficiency causes Paraketosis
 smoke/ stink bombs, solder  “Metal Fume” fever
Be  Most toxic metal B  Used in the vulcanizing of rubber
 Found in Fluorescent & neon lamps  Increases thermal coefficient of expansion of glass
Hg  “quicksilver” Ni  Found in pansy jewelry
 Causes Minimata Disease  Produced in fossil fuel combustion
 Hydrargyrism  Causes contactdermatits
 Found in Thermometers, in cosmetic (calomel), merthiolate  Most powerful inorganic carcinogen
Ga  Used in the manufacture of arc lamps W  Used in the manufacture of lamps & ball points of pens
I  Causes Iodism Cu  Causes Wilson’s Disease
 Sources: Over ingestion of Iodized salt  Used in Water Purification
 Cause Hepatolenticular Degeneration
Br  Dark brownish volatile liquid w/ a suffocating odor Sb  Found in tartar emetic & brown mixture
 Causes Brominism  Protoplasmic poison
Ce  Used as catalyst in resin forming materials Mo  Used in bacterial fixation of atmospheric nitrogen
Bi  “Beautiful meadow” Ba  Found in depilatories & green colored fireworks
 Used in the silvering of mirrors  Causes Baritosis (muscular twitching & hoarseness)
F  Fluorosis in children P  “Lucifer’s jaw”, “St.Elmos’s Fire”
 Found in drinking water supplies & in toothpaste  Found in matches & firecrackers
 Used as a rat & roach poison  Used as a rat & roach poison
Cl  Tear gas Th  Most toxic metal
 Used in water disifection  Used as a rat, roach, & ant poison

Organic
Potassium Bromate  Dough improver
 Found in cold wave neutralizers
 Hbr (irritating acid)
 Vomiting, collapse
 Tx: Sodium Thiosulfate
Tartrazine  Food colorant
MSG  Monosodium Glutamate
 Causes Chinese Restaurant syndrome
Monomethyl Hydrazine  Produced by a poisonous mushroom, Gyrometra esculenta
Tannic Acid  Carcinogen foud in iced tea
Nitrite  Food preservative / colorant
BHA/BHT  Butylated Hydroxyanisole (BHA)
 Butylated Hydroxytoluene (BHT)
 Carcinogenic antioxidant
Saccharin  Artificial sweetener
Aspartame  Artificial sweetener
Boric Acid  Used in astringent preparation
 Causes the “boiled lobster” apparatus

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Poisons and Antidotes

Hydrocarbons
Food Poisoning Kerosene Mineral oil
Botulism ABE Botulinus Antitoxin
Nitrites Methylene blue
Sulfite Epinephrine
Corrosives
Ammonia Formaldehyde
Medicinal Poisons
Bromine Sodium Chloride,
Amphetamine Chlorpromazine
Ammonium Chloride
Atropine + Diphenoxylate Naloxone,
Oxalic Acid Calcium Gluconate
(Lomotil®) Naltrexone,
Nalorphine Sodium Phosphate Fluoride Calcium Gluconate
Benzodiazepines Flumazenil
Beta-Blockers Glucagon Metallic Poisons
Bromides Sodium Chloride Antimony Poisoning Dimercaprol [British Anti-Lewisites (BAL)]
Calcium Channel Blockers Glucagon or Calcium Chloride Arsenic Dimercaptosuccinic acid ( DMSA),
Digitalis Potassium Chloride Dimercaprol and Penicillamine
Digoxin Digoxin-specific Fab antibodies Beryllium Ethylenediaminetetraacetic Acid (EDTA)
(DIgibind) Bismuth Dimercaprol [British Anti-Lewisites (BAL)]
Heparin Protamin Sulfate Cadmium Ethylenediaminetetraacetic Acid (EDTA)
Iron Deferoxime / Deferoxamine Chromium Ethylenediaminetetraacetic Acid (EDTA),
Isoniazid Pyridoxine Dimercaprol [British Anti-Lewisites (BAL)]
Magnesium Sulfate Calcium Gluconate Copper Dimercaprol [British Anti-Lewisites (BAL)],
Neuromuscular Blocker Edrophonium Chloride, Penicillamine
Neostigmine, Gold Poisoning Dimercaprol [British Anti-Lewisites (BAL)]
Pyridostigmine Lead EDTA,
Opiates Naloxone, BAL,
Naltrexone, DMSA,
Nalorphine Penicillamine,
Paracetamol N-Acetylcysteine (NAC) Succimer
(Acetaminophen) Manganese Ethylenediaminetetraacetic Acid (EDTA)
Phenobarbital Sodium Bicarbonate Mercury Sodium Formaldehyde sulfoxylate,
Salicylates Sodium Bicarbonate BAL,
DMSA,
Tricyclic Antidepressants Physostigmine
Penicillamine
Warfarin Vitamin K (Phytomenadione)
Nickel Ethylenediaminetetraacetic Acid (EDTA),
Dimercaprol [British Anti-Lewisites (BAL)]
Agricultural Poisons Phosphorous Cupric Sulfate
Aniline Methylene Blue Selenium Ethylenediaminetetraacetic Acid (EDTA)
Barium Magnesium Sulfate, Titanium Prussian blue or Ferric Ferrocyanide
Benzodiazepines Tungsten Dimercaprol [British Anti-Lewisites (BAL)]
Carbamate insecticides Atropine Zinc Ethylenediaminetetraacetic Acid (EDTA),
Dichlorodiphenyltrichloroethane Barbiturates Dimercaprol [British Anti-Lewisites (BAL)]
(DDT)
Hydrocarbon insecticides Physostigmine Alkaloids
Nitrobenzene Methylene Blue Atropine Physostigmine
Nitrogen Compounds Caffeine Esmolol
Organophosphates Atropine Ergot and Tolazoline
Pralidoxime derivatives Sodium Nitoprusside
Paraquat Bentonite, Nicotine Diazepam
Fuller's Earth, Sodium Quinidine Sodium Bicarbonate
Sulfate Strychnine Diazepam,
Parathion Pralidoxime Neuromuscular blockers,
Barbiturates
Alcohols and Glycols Atropine
Ethanol Disulfuram Theophylline Esmolol
Ethylene Ethanol,
glycol Fomepizole, Antiseptic
Folic Acid Bleaching Agents Sodium Thiosulfate
Methanol Ethanol, Cationic Detergents Ordinary Soap
Fomepizole, Chlormine-T Sodium nitrite
Morphine, Sodium Thiosulfate
Folic Acid Iodine Starch Solution and
Sodium Thiosulfate
Aldehyde Phenol Castor oil
Formaldehyde Ammonia, Silver Salts Sodium Chloride,
Sodium Bicarbonate Na Thiosulfate,
K Ferricyanide

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Cosmetics
Bromates Sodium thiosufate

Animals and Plants Hazards

Black Widow Spider Antivenom
Ibotenic Acid Physostigmine
Monomethylhydrazine Pyridoxine
Methylene Blue
Muscarine Atropine
Muscimol Physostigmine
Mushrooms Penicillin
Rattle Snake bite Antivenom,
Suction
Tourniquet
Scorpion Antiserum Cyanides,
Sulfides
Carbon Monoxide
Carbon Monoxid 100% O2 or
Hyperbaric O2
Cyanide Amyl Nitrite,
Na Nitrite,
Na Thiosulfate,
Hydroxocobalamie,
100% O2 or
Hyperbaric O2
Sulfides Amyl Nitrite
Sodium Nitrite

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OTHERS

Biologic Warfare Agents:

Bacteria
Anthrax  Caused by Bacillus Anthracis
 Gram () spore forming bacillus found in soil
Plague  Caused by yersinia Pestis
 Gram(+) bacillus
Tularemia  Zoonotic disease spread by bloodsucking
arthropods or by direct contact w/ infected
animal material
 Occur in humans in ulceroglandular or
typhoidal forms
Brucellosis  Caused by Brucellae (Brucella mellitensis,
abortus, suis, & canis)
Q fever  Self-limited febrile, zoonotic disease
Virus
Smallpox  Caused by variola virus, a large DNA
orthopoxvirus
Viral  RIbavirin is the mainstray of therapy
Hemorrhagic
Fevers
Toxin
Staphyloccal  Caused by Staphylococcus aureus, which is
Enterotoxins recognized as a superantigen because of its
profound activation of the immune system
upon-exposure even to minute quantities
Trichothecene  Are low-molecular-weight
Mycotoxins (250-500 daltons)
 Nonvolatile compounds produced by
filamentous fungi (molds) of various genera,
 Including:
Fusarium
Myrothecium
Trichoderma
Stachybotrys

Types of Pesticides
Algicides  Algae
Biocides  Microorganisms
Fungicides  Fungi (blights, molds, mildew, rusts)
Fumigants  Pest in building or soil
Herbicides  Weeds
Insecticides  Insects & other arthropods
Miticides/ Ascarides  Mites/ ascaris
Molluscicides  Snails& slugs
Nematicides  Nematodes (worm-like organisms)
Ovicides  Eggs of insects & mites
Pheromones  Disrupt the mating behavior of insects
Rodenticides  Mice & other rodents
Defoliants  Cause leaves or other foliage to drop from
plants
Dessicants  Promote drying in living tissue

Toxicity of a Specific Herbal Preparations in

Central Nervous System:
Absinthe Found in wormwood (Artemisia absinthium)
Chronic absinthe use causes absinthism whish is
characterized by psychosis, hallucinations,
intellectual, deterioration & seizures.
Ephedra Contains alkaloid, ephedrine, & in some species,
pseuephedrine
Arecoline Found in Betel Nut (Arecha catechu)
May cause exacerbation of bronchospasm in
asthmatic patients chewing betel nut.

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Essential oils  Are a class of aromatic hydrocarbons extracted

through steam distillation or sold pressed from
leaves, flowers, bark, wood, fruit, or peel of a single
parent plant
Absinthe  An emerald green liqueur that is made from the
extract of the wormwood plant.
Camphor  Belongs to terpene family & cause Central Nervous
System toxicity
 Is extracted from an evergreen tree in the Laurel
family, Cinnamon camphora.
Clove  Contains Eugenol, a phenol
Eucalyptus  Contain up to 70% of eucalyptol, a monocyclic
terpene compound w/ an ether bridge between
carbons 1 & 8
Nutmeg  Has been used as abortifacient & abused as a
hallucinogen
 Extracted from the fruit of the evergreen tree
Myristica fragrans
Pennyroyal  Menthe pulegium
Pine oil  Form the wood of pine trees
Wintergreen  Gautheria procumbenz, a fragrant ground cover
plant
 Relieve symptoms of rheumatism

Classification of Poison
(Categorized by Greek Physician Dioscoride in his Materia Medica
by their origin)
Animal Poison  Referred to the venom from poisonous animals
 Includes the venom of snakes, toads, salamanders,
jellyfish, stingrays, sea hares
Vegetable Poison  Notorious Poisonous Plants include:
Aconitum specie: aconite, monkshood
Conium maculatum: Poison hemlock
Hyoscyamus niger: henbane
Madragora Officinarum: mandrake
Papaver somniferum: opium poppy
Veretrum album: Hellebore
 Hemlock  employed in the execution of socrates
Mineral poisons  Consider the metals:
 Antimony, arsenic, lead, mearcury
Gases

Examples of Air Pollutants:

Carbon Monoxide  Combines readily w/ hemoglobin (Hb) to form
carboxyhemoglobin (COHb), thus preventing the
transfer of oxygen to tissues
Sulfur Oxide  Common component of polluted air
Nitrogen Oxide  NO, a gas found in photochemical smog, is also
pulmonary irritant & is known to lead to
pulmonary edema & hemorrhagic
Ozone  Or highly irritating & oxidizing gas that s formed
by photochemical action by UV light on nitrogen
dioxide in smog
Tropospheric  Occurs from 0 to 10 miles above the earth’s
Ozone surface
 Is harmful (bad ozone)
Stratospheric  Located about 30 miles above the earth’s surface
Ozone  Responsible for filtering out incoming UV
radiation & thus is beneficial
 Good Ozone
Lead  One of the most familiar of the particulates in air
pollutant

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Agricultural Chemicals (Pesticides)

Pyrithrin  Compounds present in flowers of the
chrysanthemum, Pyrethrum cineraefolium
Rotenone  Compound or the active ingredient found in
Derris plant species (D. elliptic & lonchocarpus
spp.)
 Used by Chinese & by south American natives as
fish poison
Paris Green  Mixture of copper & arsenic
Bordeux  Combination of lime & copper sulfate
Mixture
Petroleum oils  Control scale insects & red spider mites
DDT  Chlorinated Hydrocarbons insecticides
Red Squill  From the bulbs of red squill, Urginea (Scilla)
maritime, for controlling rodents
Atrazine  Triazine herbicides

Algal Toxins
Amnestic Caused by domoic acid
Shellfish Produced by Pseudonitzschia diatoms
Poisoning (ASP) Main contaminations: mussels, clams, crabs
Paralytic Caused bu Saxitoxin
Shellfish Produce by Alexandrium dinoflagellates
poisoning (PSP) Main contaminations: mussels, clams, crabs, fish
Neurotoxic Caused by brevetoxin
Shellfish Produced by dinoflagellate Karenia brevis
Poisoning (NSP) Aka Gymnodium breves
Caused by a re-tide producer
Not fatal to humans (last only several days)
Known to kill fish, invertebrates, seabirds, &
marine animals
Main contantaminations: oysters, clams, filter
feeder
Diarrheic Caused by okadaic acid
Shellfish Produced by Dynophysis dinoflagellates
Poisoning (DSP) Main Contaminations: mussels, clams, bivalves o
the cold & warm temperature
Ciguatera Fish Caused by CIguatoxin
poisoning (CFP) Produced by dinoflagellates including
Ganbierdiscus, Prorocentrium & Ostreopsis
Cyanobacterial Caused by biotoxins & cytotoxins, including
(Blue-Green anatoxin, microcystin, & nodularin produced by
Bacteria) Toxins cyanobacteria,including Anabaena,
Aphanizomenon, Nodularia, Oscillatoria &
Microcystis
Main contaminations: Eutrophic fresh water
rivers,lakes & streams
Ambush Were believed to produce toxin that has been
Predator implicated in several large fish kills & is suspect in
(Pfiestweria causing adverse human health effects. (toxins are
Piscicida & Toxic not yet identidfied
Pfiesteria Produced by dinoflagellates including, Pfiesteria
Complex) Toxin piscicida, Pfiesteria shumwayae

Lung Toxicants (Examples)

Monocrotaline Found in the leaves & seeds of the plant Crotalaria
spectabilis, has been the most extensively studied
of the pyrrolizidine alkaloid
Ipomeanol One of the best known examples of a toxic
compounds being activated in the lung
Naturally occurring furn is produced by the mold
Fusarium solani that infects sweet potatoes
Paraquat Reduced by cytochrome P45 redectase & NADPH

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Animals Toxins
Snake venom Toxins that are cardiotoxic or neurotoxic
Accentuated by phospholipases, peptidases,
proteases, & other enzymes present in venoms.
These enzymes may affect the blood clotting
mechanism & damage blood vessels.
Puffer fish (Sphaeroides spp.) produces Tetradotoxin (TTX)
Bites & Stings of (bees, ants, wasps, & hornets)
Hymenoptera Result fatal anaphylactic reaction
The venom & defensive secretions of insects
contain:
Formic acid, Benzoquinone & other quinines,
terpenes such as citronellal

Some component of Bee Venom:

Compound Effect
Biogenic Amine
Histamine Pain, vasodilation, increased capillary
permeability
Peptides
Apamine CNS effect
Malittin Hemolytic, serotonin release, cardiotoxic
Mast cell degranulating Histamine release from mast cells
peptides
Enzymes
Phospholipase A Increased spreading & penetration of
tissue
Hyaluronidase

Microbial Toxins
 Is usually reserved by microbiologist for toxic substances produced
by microorganisms that are of high molecular weight & have
antigenic properties
 Are toxic compounds produced by bacteria that do not fit these
criteria are referred to simply as poison.
 Includes: Tetanus Toxin. Botulinum Toxin, Diphtheria Toxin
Bacillus thuringiensis  used as insectides due to a toxin

Mycotoxins  toxin from fungus

▪Aflatoxin are product species of the genus Aspergillus,
particularly A. flavus, a common fungus found as contaminant
of grain, maize, peanuts
 first implicated in poultry disease such as Turkey-X disease
Aflatoxin B1  most toxic of the aflatoxins
 must be activated enzymatically to exert its
carcinogenic effect
▪Tricothecenes  are alarge class of sesquiterpenoid fungal metabolites
produced particularly by membes of the genera
Fusarium & Tricoderma
Abakabi disease  in Japan
Stachybotrytoxicosis  in USSR
Avermectin for the control f insecticides & nematode
▪Ergot  found in Claviceps pupurea

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Reactive Metabolites (Example of Activating Reactions)

1. Parathion  is one of the several organophosphorus insecticides
2. Vinyl Chloride  is a second example of suicide inhibitors
3. Methanol  is not responsible for the toxic effects but is rapidly
metabolized in human by alcohol dehydrogenase to
formaldehyde which is subsexquently metabolized by
aldehyde dehydrogenase to form the highly toxic formic
acid
Reports: One-third have severe visual loss or blindness
One-third of the exposed population recovered w/ no ill effects
One-third have died
4. Aflatoxin B1  is one of the mycotoxins produced by Aspergillus flavus
& A. parasiticus
 is a well-known hepatotoxicant & hepatocarcinogen
Formation of Aflatoxin B1 Dihydrodiol by liver Microsomes
Source of Microsomes Dihydrodiol Formation
Rat 0.7
057 mouse 1.3
Guinea Pig 2.0
Phenobarbital-induced rat 3.3
Chicken 4.8
Mg formed/mg microsomal protein/ 30 min
5. Carbon Tetrachloride  cause fatty acid accumulation & hepatic
necrosis
6. Acetylaminofluorine  is correlated w/ the ability of the organism to
sequentially produce the N-hydroxylated
metabolite followed by the sulfate ester
 carcine
7. Benzopyrene  one of the most prevalent polycyclic aromatic
hydrocarbons found in cigarette smoke
8. Acetaminophen
9. Cyacasin  from Cycad Nut

Common Polycyclic Aromatic Hydrocarbons

 Pyrene
 Boznopyrene/ Benzo(A)pyrene
 Methyldolanthrene
 Benzopyrene/ Benzo (e)pyrene
 Dibenz(a.h)anthracene
 Diben (a.h)acridine

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A. Modes of Toxic Action includes the consideration, at the fundamental

level of organ, cell and molecular function, of all events leading to toxicity in vivo: uptake, distribution, metabolism, mode of action,
and excretion.
 used to describe an important molecular
event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of
organophosphorus and carbamate insecticides.
Important aspects include the following:
1. Biochemical and molecular toxicology  consider events at the
biochemical and molecular levels, including enzymes that metabolize xenobiotics, generation of reactive intermediates, interaction of
xenobiotics or their metabolites with macromolecules, gene expression in metabolism and modes of action, and signaling pathways in toxic
action.
2. Behavioral toxicology  deals with the effects of toxicants on
animal and human behavior, which is the final integrated expression of nervous function in the intact animal. This involves both the peripheral
and central nervous systems, as well as effects mediated by other organ systems, such as the endocrine glands.
3. Nutritional toxicology  deals with the effects of diet on the
expression of toxicity and with the mechanisms of these effects.
4. Carcinogenes is includes the chemical, biochemical, and molecular
events that lead to the large number of effects on cell growth collectively known as cancer.
5. Teratogenesis  includes the chemical, biochemical, and molecular
events that lead to deleterious effects on development.
6. Mutagenesis  is concerned with toxic effects on the genetic
material and the inheritance of these effects.
7. Organ toxicity  considers effects at the level of organ function
(neurotoxicity, hepatotoxicity, nephrotoxicity, etc.).

B. Measurement of Toxicants and Toxicity  deal primarily wit

analytical chemistry, bioassay, and applied mathematics; they are designed to provide the methodology to answer certain critically
important questions:
Is the substance likely to be toxic?
What is its chemical identify?
How much of it is present?
How can we assay its toxic effect, and what is the minimum level at which this toxic effect can be detected?
A number of important fields are included:
1. Analytical toxicology  is a branch of analytical chemistry
concerned with the identification and assay of toxic chemicals and their metabolites in biological and environmental materials.
2. Toxicity testing  involves the use of living systems to estimate
toxic effects. It covers the gamut from short-term tests for genotoxicity such as the Ames test and cell culture techniques to the use of intact
animals for a variety of tests from acute toxicity to lifetime chronic toxicity
3. Toxicologic pathology  is the branch of pathology that deals with
the effects of toxic agents manifested as changes in subcellular, cellular, tissue, or organ morphology.
4. Structure-activity studies  are concerned with the relationship
between the chemical and physical properties of a chemical and toxicity and, particularly, the use of such relationships as predictors of toxicity.
5. Biomathematics and statistics  relate to many areas of toxicology.
They deal with data analysis, the determination of significance, and the formulation of risk estimates and predictive models.
6. Epidemiology as it applies to toxicology, is of great importance as it
deals with the relationship between chemical exposure and human disease in actual populations rather than in experimental settings.

C. Applied Toxicology  includes the various aspects of toxicology as they

apply in the field or the development of new methodology or new selective toxicants for early application in the field setting.
1. Clinical toxicology  is the diagnosis and treatment
of human poisoning.
2. Veterinary toxicology  is the diagnosis and treatment of poisoning
in animals other than humans, particularly livestock and companion animals, but not excluding feral species. Other important concerns of
veterinary toxicology are the possible transmission of toxins to the human population in meat, fish, milk, and other foodstuffs and the care and
ethical treatment of experimental animals.
3. Forensic toxicology  concerns the medicolegal aspects,
including detection of poisons in clinical and other samples.
4. Environmental toxicology  is concerned with the movement of
toxicants and their metabolites and degradation products in the environment and in food chains and with the effect of such contaminants on
individuals and, especially, populations.
5. Industrial toxicology  is a specific area of environmental
toxicology that deals with the work environment and constitutes a significant part of industrial hygiene.

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D. Chemical Use Classes  includes the toxicology aspects of the

development of new chemicals for commercial use. In some of these use classes, toxicity, at least to some organisms, is a desirable trait; in others, it is
an undesirable side effect. Use classes are not composed entirely of synthetic chemicals; many natural products are isolated and used for commercial
and other purposes and must be subjected to the same toxicity testing as that required for synthetic chemicals.
Examples of such natural products include the insecticide, pyrethrin, the clinical drug, digitalis, and the drug of abuse, cocaine.
1. Agricultural chemicals  include many compounds,
such as insecticides, herbicides, fungicides, and rodenticides, in which toxicity to the target organism is a desired quality whereas toxicity to
“nontarget species” is to be avoided.
2. Clinical drugs  are properly the province of
pharmaceutical chemistry and pharmacology.
3. Drugs of abuse  are chemicals taken for psychological or other
effects and may cause dependence and toxicity. Many of these are illegal, but some are of clinical significance when used correctly.
4. Food additives  are of concern to toxicologists only when they are
toxic or being tested for possible toxicity.
5. Industrial chemicals  are so numerous that testing them for
toxicity or controlling exposure to those known to be toxic is a large area of toxicological activity.
6. Naturally occurring substances  include many phytotoxins,
mycotoxins, and minerals, all occurring in the environment.
7. Combustion products  are not properly a use class but are a large
and important class of toxicants, generated primarily from fuels and other industrial chemicals.

E. Regulatory Toxicology  concerned with the formulation of laws,

and regulations authorized by laws, are intended to minimize the effect of toxic chemicals on human health and the environment.
1. Legal aspects  are the formulation of laws and regulations and their
enforcement. In the United States, enforcement falls under such government agencies as the Environmental Protection Agency (EPA), the Food
and Drug Administration (FDA), and the Occupational Safety and Health Administration (OSHA).
2. Risk assessment  is the definition of risks, potential risks,
and the risk-benefit equations necessary for the regulation of toxic substances. Risk assessment is logically followed by risk communication and
risk management.
F. Others
1. Product Developent Toxicology  includes service & preclinical
toxicology for product development
2. Reproductive Toxicology  screening & identification of reproductive

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th
HIGH YIELD TERMS (Katzung 9 Edition)

Environmental and Occupational Toxicology

Bioaccumulation The increasing concentration of a substance in the environment as the result of environmental persistence
and physical properties (eg, lipid solubility) that leads to accumulation in biologic tissues
Endocrine disruptors Chemicals in the environment that have estrogen-like or antiandrogen activity or disrupt thyroid function.
There is concern that exposure to endocrine disruptors may increase reproductive cancers, impair fertility,
and have teratogenic effects
Environmental toxicology The area of toxicology that deals with the effects of agents found in the environment; regulated by the
Environmental Protection Agency (EPA) in the United States
Occupational toxicology The area of toxicology that deals with the toxic effects of chemicals found in the workplace; regulated by the
Occupational Safety and Health Administration (OSHA) in the United States
Threshold limit value The amount of exposure to a given agent that is deemed safe for a stated time period. It is higher for shorter
periods than for longer periods

Heavy Metals
Chelating agent A molecule with 2 or more electronegative groups that can form stable coordinate complexes with multivalent cationic
metal atoms
Erethism Syndrome resulting from mercury poisoning characterized by insomnia, memory loss, excitability, and delirium
Pica The ingestion of nonfood substances; in the present context, pica refers to ingestion of lead-based paint fragments by
small children
Plumbism A range of toxic syndromes due to chronic lead poisoning that may vary as a function of blood or tissue levels and patient
age

Important characteristics of the toxicology of arsenic, iron, lead, and mercury.

Metal Form Route of Target Organs Treatmenta
Entering Absorption for Toxicity
Body
Lead Inorganic Gastrointestinal, Hematopoietic Dimercaprol,
lead oxides respiratory, skin system, CNS, EDTA,
and salts (minor) kidneys succimer,
Tetraethyl Skin (major), CNS unithiol
lead gastrointestinal Seizure
control,
supportive
Arsenic Inorganic All mucous Capillaries, Dimercaprol,
arsenic surfaces gastrointestinal unithiol,
salts tract, succimer,
hematopoietic penicillamine
system
Arsine gas Inhalation Erythrocytes Supportive
Mercury Elemental Inhalation CNS, kidneys Succimer,
Inorganic Gastrointestinal Kidneys, unithiol
salts gastrointestinal Succimer,
tract unithiol,
penicillamine,
dimercaprol
Organic Gastrointestinal CNS Supportive
mercurials
Iron Ferrous Gastrointestinal Gastrointestinal, Deferoxamine
sulfate CNS, blood
a
In all cases, removal of the person from the source of toxicity is the first
requirement of management.

Management of the Poisoned Patient

ABCDs Mnemonic for the supportive initial treatment of all poisoned patients that stands for Airway, Breathing, Circulation, and
Dextrose or Decontamination
Anion gap The difference between the serum concentrations of the major cations (Na+/K+) and (HCO– 3/CI –); an increased anion gap
indicates the presence of extra anions and is most commonly caused by metabolic acidosis

Antidote A substance that counteracts the effect of a poison

Osmolar gap The difference between the measured serum osmolality and the osmolality that is calculated from serum concentrations of
sodium, glucose, and BUN; an increased osmolar gap is associated with poisoning due to ethanol and other alcohols

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Toxic features of selected agents.

Agent Toxic Features
Acetaminophen Mild anorexia, nausea, vomiting, delayed jaundice, hepatic and renal failure
Botulism Dysphagia, dysarthria, ptosis, ophthalmoplegia, muscle weakness; incubation period 12–36 h
Carbon monoxide Coma, metabolic acidosis, retinal hemorrhages
Cyanide Bitter almond odor, seizures, coma, abnormal ECG
Ethylene glycol Renal failure, crystals in urine, increased anion and osmolar gap, initial CNS excitation; eye
examination normal
Iron Bloody diarrhea, coma, radiopaque material in gut (seen on x-ray), high leukocyte count,
hyperglycemia
Lead Abdominal pain, hypertension, seizures, muscle weakness, metallic taste, anorexia,
encephalopathy, delayed motor neuropathy, changes in renal and reproductive function
Lysergic acid (LSD) Hallucinations, dilated pupils, hypertension
Mercury Acute renal failure, tremor, salivation, gingivitis, colitis, erethism (fits of crying, irrational
behavior), nephrotic syndrome
Methanol Rapid Respiration, Visual Symptoms (Blindness w/ an initial “snowstorm-like” visual disturbances,
Osmolar Gap, Severe Metabolic Acidosis, COma
Mushrooms (Amanitaphalloides type) Severe nausea and vomiting 8 h after ingestion; delayed hepatic and renal failure
Phencyclidine (PCP) Coma with eyes open, horizontal and vertical nystagmus

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Important antidotes
Antidote Poison(s)
Acetylcysteine Acetaminophen; best given within 8–10 h of
overdose
Atropine Cholinesterase inhibitors
Bicarbonate, Membrane-depressant cardiotoxic drugs (eg,
sodium quinidine, tricyclic antidepressants)
Calcium Fluoride; calcium channel blockers
Deferoxamine Iron salts
Digoxin antibodies Digoxin and related cardiac glycoside
Esmolol Caffeine, theophylline, sympathomimetics
Ethanol Methanol, ethylene glycol
Flumazenil Benzodiazepines, zolpidem
Fomepizole Methanol, ethylene glycol
Glucagon Beta adrenoceptor blockers
Glucose Hypoglycemics
Hydroxocobalamin Cyanide
Naloxone Opioid analgesics
Oxygen Carbon monoxide
Physostigmine "Suggested" for muscarinic receptor blockers,
NOT tricyclics
Pralidoxime Organophosphate cholinesterase inhibitors

Toxicity Rating Human Lethal Toxic Dosages:

2 5,000 -50,000 mg/kg body weight
3 500 -5000 mg/kg body weight
4 50 -500 mg/kg body weight
5 5-50 mg/kg body weight
6 Not more than 5 mg/kg body weight

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Methanol & Metformin  lactic acidosis, can cause a high onion

gap metabolic acidosis.

Polychlornated Biphenyl (PCBs)  cause Yusho Disease in Japan,

documented in 1960s

Methylene Blue  manage complication of exposure to Nitrogen

Oxides & Nitrobenzene

Royal Jelly can cause Anaphylaxis & Bronchospasm

Ginkgo Biloba  should be cautioned w/ patient receiving
anticoagulant therapy & patient w/ history of
seizure.
Ginseng (Panax Ginseng)  can increase risk of bleeding & may
also exacerbate hypertension

Ingestion  most common mode of exposure to poison

Initially manage w/ Administration of MILK:

-Hypochlorite (acaustic alkali)
-Corrosive Acids
-Fluoride Poisoning

Complication of Physostigmine Therapy to mage Poisoning w/

Antimuscarinics:
-Cholinergic Crisis
-Seizure
-Asystole

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ADVERSE DRUG REACTIONS

Adverse Drug Reactions  “one which is noxious and unintended, and

which occurs at doses normally used in man for Factors affecting ADR’s
the prophylaxis, diagnosis, or therapy of 1. Age: Pediatrics/ Geriatrics
disease, or for the modification of physiological ▪ Pediatrics  underdeveloped Phase II metabolism
function.” WHO ▪Geriatrics  kidney; liver function

2. Gender: Females are more ADR than males

Adverse Drug Events  “Any untoward medical occurrence in a patient or Rationale:  fat deposits
clinical investigation subject administered a
pharmaceutical product and which does not 3. Error in self medication of prescribed drug: Geriatrics
have to have a casual relationship with this
treatment.” FDA 4. Exaggeration of expected pharmacologic effect
Examples: Ex: Antihypertensive – excessive hypotension
Antihistamine (H1) – 1st generation
▪ADR  expected/ establish  sedation 5. Race:
▪ADE  isolated access  SJS ▪Fast Acetylators: N-acetyl transferase
▪Slow Acetylators: N-acetyl transferase
ADE can be: Ex: INH/ Isoniazid
a. ADE occurring in the courses of the use of the drug in professional/ CI: fast development of resistance toward INH
practice Ethambutol
b. ADE occurring in Drug overdose whether accidental or intentional
c. ADE occurring in Drug Abuse 6. Concomminant administration of drugs w/ synergistic effect
d. ADE occurring in Drug withdrawal Ex: ASA + Warfarin = hemorrhage
e. ADE occurring in significant function of expected pharmacologic
activity 7. Concomminant Illness: “Polypharmacy”

8. Vias
▪Alcohol: Acute: Inhibitor
Chronic: Inducer
▪Cigarette Tobacco: Inducer

9. Cytotoxic Reactions (Blood Transfusion Reactions)

Ex: Hepatic necrosis associated w/ the overdose acetaminophen
Antidote: N-acetycysteine

10. Immunologic reactions

▪Quinidine – induce Thrombocytopenia
▪Hydralazine – induce SLE

11. Genetically determined enzyme deficiency

▪Primaquine – induce Hemolytic Anemia, due to G6PP deficiency

12. Idiosyncratic reaction

▪Chloramphenicol – induce Aplastic Anemia

13. Dose of the Drug

14. Duration of treatment

15. Intrinsic toxic effect of the drug

narrow Therapeutic toxicity

Drug Classes cause the greatest incidences of ADR’s:

- Antibiotics
- Analgesics (Narcotics)
- Cardiovascular Drugs
- Anticonvulsnats
-Sedatives
- Anticoagulants
- Psychotherapeutics

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Types of ADR B. Type B (Bizaare)

A. Type A (Augmented)  uncommon
 common  unpredictable
 predictable  not dose-related/ dose-dependent
 dose-related/ dose-dependent  have no relation to the pharmacological action of the drug
 clearance-dependent Subtypes:
Subtypes: 1.Idiosyncratic Reactions  genetically-determined reactions
1. Extension Effects aka “Excessive Action” ▪Corrective Measures: Withdraw the medication
 related/ associated to MOA/pharmacological Treat symptomatically
activity of the drug Avoid future exposure
unwanted effects of drug overdose ▪Example: Chloramphenicol  Induce Aplastic Anemia
▪Corrective Measures: Decrease the dose/ frequency Antipsychotic Agents  Malignant hyperthermia
Titrate the drug to its immiscible G6PD + Antimalarials/ Sulfonamides
effective dose  Hemolytic Anemia
▪Example: Oral sulfonylureas  Excessive hypoglycemia Carbamazepine, Phenytoin, Soldonamides
Cardiac glyscoside  Arrhythmia  Steven-Johnson Syndrome
Albuterol  Tachycardia 2. Hypersensitivity Reactions  unusual susceptibility
AntiHPN  Excessive hypotension  immune response to environmental
Antibiotics  Diarrhea antigens resulting in symptomatic
CNS Depressants  Sedation reactions upon secondary exposure to
Anticoagulant  Bleeding the same antigen, more commonly
Overdosage  results from drug levels above the referred to as allergen.
therapeutic levels ▪Corrective Measures: Withdraw the medication
2. Side Effects  unwanted effects w/c occurs in normal doses & usually Institute supportive measure
related or unrelated to the MOA. Avoid future exposure
 harmful or beneficial ▪Example: Herxheimer reaction (Beta-lactam antibiotic)
▪Example: Antihistamine (1st gen): Sedation Acute intermittent porphyrra (Barbiturates)
insomnia; antianxiety Psychosis, Neuropathy, Autonomic Instability
Menoxidil (arteriolar vasodilator) Types of Hypersensitivity Reactions:
for alopecia/ MPB Type I (Immediate or Anaphylactic Immune Response)
hair growth (hypertrichosis): Type II (Cytotoxic Reactions)
shampoo (2%) Type III (Immune Complex Hypersensitivity)
Opiates (decrease motility): constipation Type IV (Cell-mediated or Delayed Type)
Nitroglycerin (vasodilation): headache
Ace inhibitor (-pril, inh. bradykinin): cough Types of Hypersensitivity Reactions:
Type I (Immediate or Anaphylactic Immune Response)
 most common category of allergic reaction
 occurs after antigen (e.g. pollen) binds onto IgE found on
the surfaces of mast cells
re-exposure to the same allergen  cross linking of the
cell-bound IgE  degranulation (release of histamines,
leukotrienes & prostaglandins)
Examples: Anaphylaxis (Penicillin)
Hay fever
Asthma
Urticaria (hives)
Type II (Cytotoxic Reactions)
initiated by antibody (IgG/ IgM) directed against antigens
found on the cell membrane of a given target cell (e.g.
leukocytes, erythrocytes)  complement mediated lysis
 Examples: Hemolytic Anemia (Methyldopa)
Aplastic Anemia (Chloramphenicol)
Blood Transfusion reactions
Granulocytopenia
Thrombocytopenia
Type III (Immune Complex Hypersensitivity)
 tissue deposition of antigen-antibody complexes w/
complement activation & tissue damage
 Examples: Blood dyscrasias or serum sickness
Arthus Reaction
SLE ( Hydralazine, Phenyotin, INH,
Procainamide)
Type IV (Cell-mediated or Delayed Type)
 T-lymphocytes sensitized by an antigen release
lymphokines after subsequent contact with the same
antigen
 lymphokines induce inflammation & activate
macrophages
 Examples: Tuberculin Skin Test
Contact dermatitis (Poison Ivy)

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C. Type C (Continuous) D. Type D (Delayed)

 uncommon Subtypes:
 dose- & time- related 1. Carcinogenicity  ability of any substance to cause or induce cancer
 associated with the cumulative dose of the drug ▪Corrective Measures: Monitor the patient
Subtypes: Inform the physician/ medical team
1. Drug Addiction  condition where a person takes a drug ▪Example: Polycyclic/ aromatic Hydrocarbons
compulsively, despite potential harm to Urethanes
themselves, or their desire to stop. Nitrosamines
▪Example: Marijuana Azo dyes
Opiates Alkylating agents (Bisulfan, Ethionine)
2. Drug Dependence  unwanted condition resulting to tolerance & Antineoplastic Agents
physical dependence/ psychic crowing Heterocyclic amines
 compulsion to take the drug repeatedly & Aflatoxin
experiences unpleasant symptoms if Carcinogenesis  unrestrained proliferation of somatic cells
discontinued 2. Teratogenicity  ability of any substance to cause congenital
▪Corrective Measures: Withdraw the medication under malformations or birth defects
medical supervision ▪Corrective Measures: Avoid exposure during first trimester
Psychotherapy of pregnancy
▪Example: Nicotine Avoid exposure to women in child-
Codeine bearing age
Caffeine ▪Example: Thalidomide (phocomelia)
Opioid Retinol & derivatives- Isotretinoin (powerful
Benzodiazepines teratogen)
Physical Dependence  occurs when a drug has been used Carbamazepine & Valproic Acid ( neural tube
habitually & the body has become accustomed defects)
to its effects. The person must then continue to Diethystilbestrol (increased risk of developing
use the drug in order to feel normal, or its vaginal adenocarcinoma after
absence will trigger the symptoms of puberty)
withdrawal. Phenytoin (fetal hydantoin syndrome)
Psychological Dependence  occurs when a drug has been used Streptomycin (8th nerve damage)
habitually & the mind has become emotionally Tetracyclines (discoloration & defects of teeth &
reliant on its effects either to elicit pleasure or altered bone growth)
relive pain, & dose not feel capable of Teratogenesis  abnormal deformities in the fetus
functioning without it. 3. Mutagenesis  permanent change of Germ cell
▪Corrective Measures: Avoid exposure to children & adults
of child-bearing age
3. Drug Tolerance  reduce pharmacologic response due to ▪Example: Aflatoxin
“desensitization” of receptors. Benzopyrene
 reduced effect w/ repeated use of drug; need for Caffeine
higher doses to produce the same effect. Cyclamates
▪Corrective Measures: Increase the dose/ frequency Nitrites
Change the medication LSD
▪Example: Atropine
Histamine
Alcohol
Barbiturates
Nitrates
Nicotine

Drug Resistance  a decrease in responsiveness of the invading

microorganism (e.g. micro-organism, neoplasm,
or pests) to Chemotherapeutic agents.

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E. Type E (End of Use) F. Type F (Failure of Efficacy)

 uncommon  unexpected failure of efficacy
 withdrawal symptoms:  common
 Anxiety  Rhinrrhea  dose-related
 Irritability  Nausea & vomiting  may result from:
 Insomnia  GI cramping a. Use of Counterfeit drugs
 Chills  Diarrhea b. Use of substandard drugs
 Diaphoresis  Piloerection c. Use of placebo
 Salivation d. Antimicrobial resistance (drug resistance)
 generally occur shortly after stopping the drug  insensitivity of the pathogen to an antimicrobial agent
 Examples: Opiate withdrawal ▪Corrective Measures: Test the sensibility of the pathogen to
Rebound insomnia & excitation (Benzodiazepine) a certain antibiotic
Rebound hypertension (Clonidine) Avoid combination,
Rebound decongestant (Nasal decongestant) Like: Bactericidal + Bacteriostatic
Adreanl crisis (Addison’s disease) (steroids) = antagonism
▪Example: Antibacterial: Penicillin
Withdrawal  noxious or unintended response occurring when a Antimalarial: Chloroquine
drug is discontinued Antineoplastic: 5-Fluorouracil, Methotrexate
e. Patient’s non-compliance
f. Wrong route of administration
g. Drug instability
h. Drug-drug interactions

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DRUG INTERACTIONS
Drug Interactions  any adverse response after administration of a drug or B. Alteration in Distributions
another substances that can modify the patient’s a. Displacement from Protein Binding Sites
response. Albumin  for acidic drugs
-glycoprotein/globulin  for basic drugs
Two components: Examples: Aspirin(90-955 PB) + Warfarin
1. Precipitant drug  the drug or any substances (food, herb, chemical) (Warfarin will be displaced –free drug)
that may cause the interaction. Valproic Acid + Phenytoin (Gingival hyperplasia)
2. Object drug  the dug or any substances that is affected in the -(Phenytoin will be displaced)
interaction Warfarin + Phenylbutazone (Hemorrhage)
Glibenclamide + Phenylbutazone (Hypoglycemia)
Drug Interactions can be of the following: OHA + ASA (Hypoglycemia)
 Drug – drug Bilirubin + Salicylates (Kernicterus)
 Herb – drug b. Tissue & Cellular Interaction
 Food – drug Examples: Digoxin + Quinidine
 Chemical – drug arrhythmia
 Laboratory Test – drug C. Alteration in Metabolism
a. Hepatic Clearance
Classifications of Drug Interactions: CYP450 Enzyme System
I. Pharmacokinetic Interactions 1. CYP304 – oxidation (inh. by grapefruit)
Pharmacokinetics  occur if the absorption, distribution, metabolism, & 2. CYP206
excretion of the drug is affected by another drug, 3. CYP2C9
food or chemical. 4. CYP2E1
A. Alteration in Absorption 5. CYP1A2 (inh. by Cigarette smoking)
a. Complexation/ Chelation Enzyme Inhibitors Enzyme Inducers
▪Tetracycline + Metal-containing drugs “sickfaces.com” “GP PARKS”
(decreased Tetracycline Absorption)  Sodium valproate  Griseofulvin
▪Fluoroquinolones + Metal-containing drugs  Isoniazid  Phenobarbital
(decreased Fluoroquinolones Absorption)  CImetidine  Phenytoin
▪Cholestyramine + Digoxin  Ketoconazole  Alcohol (chronic)
(decreased Digoxin Absorption)  Fluconazole  Rifampicin
▪Cholestyramine + Warfarin  Alcohol (Acute)  Carbamazepine
(decreased Warfarin Absorption)  Ciprofloxacine  Sulfonlurea
▪Penicillamine + Metal-containing drugs  Erythromycin
(decreased Penicillamine Absorption)  Sulfanamide Herbs: St. John’s wort
▪Sucralfate + Levothyroxine  Chloramphenicol
(decreased Thyroxine Absorption)  Omeprazole
b. Adsorption  Metronidazole
▪Adsorbent + Any drug (decreased Drug Absorption)
Example of Adsorbents: Cholestripamine  Herbs:
Kaolin  Grape fruit
Acarbose  Valencia oranges
c. Increased GI motility
▪Cathartic + Any drug (decreased Drug Absorption) b. Non-hepatic Clearance
Example: Laxatives; Cathartics MAO
d. Decreased GI motility Example: Serotonin syndrome
Example: Anticholinergics (Hyosine N-butylbromide) SSRI + MAO-I
e. Increased Gastric Emptying  SSRI   serotonin
▪Atropine + Antacid (increased Antacid Absorption)  MAO-I   serotonin
▪Atropine + Amphetamine (decreased Amphetamine Absorption) SSRI – Example: Fluoxetine (Prozac®)
f. Decreased Gastric Emptying D. Alteration of Excretion
▪Nicotine + Antacid (decreased drug A) Renal Clearance
g. Alteration of pH of the stomach a. Glomerular Filtration rate + Renal blood flow
▪Antacid + Bisacodyl Ex: Methylxanthines (diuretic)
(premature liberation of Bisacodyl) b. Active tubular Secretions
▪Antacid + Ketoconazole Ex: Probenicid + Penicillin (a good combination)
(decreased Ketoconazole Absorption) (decreased renal Excretion of Penicillin)
Probenecid + Indomethacin
▪Antacid + Salicylates
(decreased renal Excretion of Endomethacin)
(decreased Salicylates Absorption) NSAIDs + Lithium salts
Examples: Antacids, H2RA, PPI (decreased renal Excretion of Lithium)
h. Alteration of GI microbial flora NSAIDs + Methotrxate
▪Antibiotics + Digoxin (increased Digoxin Absorption) (decreased renal excretion of Methotrexate)
Quinidine + Digoxin
Examples: Antibiotics (decreased renal & non-renal Excretion of Digoxin)
i. Interruption of Enterohepatic circulation Corticosteroids + ASA
▪Antibiotics + OCP (decreased OCP Absorption) (Increased renal Excretion of ASA)
j. Inhibition of metabolism in intestinal cells c. Tubular Reabsorption & Urine pH
Example: MaO-I (Tranylcypromine & Phenelzine) Ex: Poisoning Acidic drugs: ASA; Phenobarbital
k. Drug Bioavailability in other site of absorption Antidote: NaHCO3 urine alkalinizer
Example: Epinephrine + Lidocaine Basic drugs: Amphetamine; Ephedrine
(which is a good interaction since Epinephrine is Antidote: NH4Cl urine acidifier
vasoconstrictor)

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II. Pharmacodynamic Interactions F. Herb – drug Interaction

Pharmacodynamic  occur when the P’dynamic effect is affected by a Effect
drug, food, or chemical Black Cohosh + Antihypertensive - Increased effect of
A. Similar pharmacologic effects Antihypertensive (Hypotension)
Additive Effect Coenzyme Q10 + Warfarin -Bad combination
a. CNS depressants –increased sedation (same structure w/ Vit K) -Vitamin K antagonism
▪Alcohol + Barbiturates (Increased INR & risk of bleed)
▪Alcohol + Antihistamines (1st gen) Dong Quai + -blockers -Increased level of beta blockers
▪Alcohol + Chloral hydrate (Increased hypotension)
b. Anticholinergics Dong Quai + Benzodiazepines -Increased Benzodiazepine
▪Atropine + Hyoscine (excessive anticholinergic effect) levels (increased drowsiness &
c. Prolong QI interval CNS depression)
▪Digoxin + Quinidine (Arrhythmia) Echinacea + Immunosuppressant -Decreased Immunosuppression
d. Others: Monoclonal Antibodies
▪Alcohol + Chlorpropamide (Increased hypoglycemic effects) Ephedrine (Ma Huang) + -blockers -Sympathomimetic Effect
▪Flecainide + Verapamil (increased negative inotropic & (hypertension)
chronotropic effects) Ephedrine (Ma Huang) + MAOIs -Increased & prolonged
B. Antagonistic Effect sympathomimetic effect
Example: Epinephrine + Beta-blockers (Hypertensive crisis)
(tachy) (brady) Ephedrine + Corticosteroids -Decreased corticosteroid levels
C. Increased Sensitivity (decrease steroid effectiveness)
Example: Thiazide diuretics + Digoxin
Evening Primrose Oil + Antiplatelets -Both are antiplatelets
(hypokalemia) ( toxic effect)
-Decreased platelet aggregation
D. Intrinsic opposite effect at different target system
(Increased risk of bleed)
Example: Naloxone + Opioid Analgesics
Evening Primrose Oil + Phenothiazines -Reduced seizure threshold
E. Starting/ Stopping a therapy will affect the metabolism of a drug
(Seizures)
Example: Smoking Cessation
Ginkgo biloba + Warfarin/Heparin -Both have blood thinning
increased the concentration of the substrate drugs
effect, cause excessive bleeding
of CYP1A2
-Increased inhibition of Platelet
Clozapine + Haloperidol
Aggregation
Pharmacological Drug Interactions
(Increased risk of Bleeding)
1. Addition - 1+1=2 Ginseng + MAOI -Increased GABA metabolism &
response is equal to the combined effects of the individual increased dopamine levels
drugs (mania symptoms)
Bactericidal +Bactericidal Kava-Kava + Acetaminophen -Increased potential for hepatic
Example: Trimethoprim & Sulfamethoxazole inhibit different steps in Kava-Kava + Azole Antifungals toxicity (elevated LFT, hepatic
synthesis of folic acid, resulting Kava-Kava + Statins failure)
in the suppression of
Kava-Kava + Barbiturates -Increased GABA receptor
bactericidal growth
binding affinity (Increased
2. Synergism - 1+1>2 or 1+1=3 drowsiness, CNS depression)
response is greater than the combined effects of the
Kava-Kava + Levodopa -Dopamine blockade
individual drugs
(decreased effectiveness of
Bacteriostatic+Bacteriostatic Levodopa)
Example: Penicillin & Gentamicin
Soy + Levothyroxine -Decreased levels of
are synergistic in their antipseudomonal activities
Levothyroxine (hypothyroid
Bactericidal +Bactericidal symptoms)
Example: Trimethoprim & Sulfamethoxazole
St. John’s Wort + Irinotecan -Reduced levels of active
3. Potentiation - 1+0=2 Irinotecan metabolite for
a drug with no inherent activity will enhance the effect of chemotherapy
another drug (decreased myelosuppression)
e.g,  lactam antibiotic +  lactamse inh. St. John’s Wort + Digoxin Decreased concentration of
Example: Digoxin in Blood
Amoxicillin + Clavulanic Acid (Increased Amoxicillin Antibiotic Effect) Valerian + Sedatives -Increased CNS depression
Ampicillin + Sulbactam (Increased Ampicillin Antibiotic Effect) (drowsiness & sedation)
Pipercillin + Tazobactam (Increased Pipercillin Antibiotic Effect) Valerian + Benzodiazepines -Displaced Benzodiazepine but
Levodopa + Carbidopa (Increased Levodopa’s Effect) additive CNS depression
4. Antagonism - 1+1=0 (possible increase drowsiness)
 drug inhibits the effect of the other Ginger/ garlic/fever few + Warfarin -Both have blood thinning
Phenoxybenzamine +Catcholamines (management of effect, cause excessive bleeding
pheochromocytoma) -Directly inhibiting platelets &
Warfarin +Vitamin K (antidote for warfarin toxicity) causing increased risk of
Heparin + Protamine SO4 (Antidote for Heparin toxicity) bleeding
Opioids + Naloxone (Antidote for Opioid toxicity) Wheat grass + Warfarin -Antagonistic effect
Atropine + Neostigmine (antidote for Atropine toxicity) (Vit.K) (pro-coagulant) -Inadequate anticoagulation &
Benzodiazepine + Flumazenil (antidote for Benzodiazepine Toxicity) therapeutic Failure
Procaine + Sulfonamides (antagonism of Sulfonamide’s Antibacterial
activity) Garlic  is used w/ caution in patients who are
Bactericidal + Bacteriostatic -diabetic
Example: Penicillin + Erythromycin -pregnant
-w/ peptic ulcer

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G. Food-Drug Interaction III. Pharmacogenetics

a. Food can increase, decrease/ not affected at all drug absorption A. Polymorphism
Increased Absorption by Food Decreased Absorption by Food  more than abnormal “ALLELE” that can affect drug metabolism
D P GAMMIT PAPA NIA CEE QT race-dependent
Dicumarol Penicillamine
Propoxyphene Alendronate B. Single Nucleotide Polymorphism
Griseofulvin Penicillin  a single “ALLELE” can affect drug metabolism
Acarbose Aspirin ▪Metabolizers:
Metoprolol NSAID (ex: Naproxen) 1. Poor Metabolizers
Morphine Isoniazid 2. Intermediate Metabolizers
Itraconazole Acetaminophen 3. Normal Metabolizers4. Extensive Metabolizers
Theophilline Captopirl 5. Ultra-rapid Metabolizers
Erythromycin stearate
Ethanol C. Pregnancy Category
Quinolones Category Human Animals Risk
Tetracyclines A Yes Yes No
Metronidazole  not affected by food B No Yes No
Doxycycline & Minocycline  are affected only to a lesser extent C No Yes Yes
Griseofulvin & Theophylline  increased by high fat containing D Yes Yes But the benefit
foods outweighs the risk
b. Food can affect the absorption of drugs in modified-release form X Yes Yes But the risk
Ex: Enteric coated + Orange Juice/ Apple Juice outweighs the
c. Food can antagonize or stimulate the effect of another drug benefits
Ex: -Spinach/ broccoli + Warfarin (Antagonism)
other green leafy vegetables ADX – has been tested in Human & Animal
-CNS Depressants + Caffeine (Antagonism) B – only in Animal
-Tetracycline + Dairy Products (chelation causing decreased C – has been tested in Animal & has higher risk
Tetracycline absorption) D – BR (benefit outweighs the risk)
-MAOI + Tyramine-rich Foods (decreased metabolism of X – RB (risk outweighs the benefits)
Norepinephrine, causing
hypertensive crisis)
D. Classification of the Clinical Significance:
Tyramine-rich Foods: redwine, cheese,
Established  supported by well-proven clinical studies
beer, chicken liver
-INH + Histamine-rich foods
Probable  very likely but might not be well proven
Histamine-rich Foods: cheese, tropical fishes, tuna by clinical studies
Flushing reaction w/ headache difficulty of breathing Suspected  may occur but some data are lacking
(might be available)
-Bisacodyl + Milk (alteration of pH, causing premature liberation Possible  could occur but limited data are available
of Bisacodyl) Unlikely  doubtful
-ASA + Caffeine (alteration of pH, causing increase ASA  no good evidence of an altered clinical
absorption) effect is available
H.Chemical-Drug Interaction
a. Smoking cigarettes/ tobacco E. Management of Drug Interaction
induce CYP1A2 a. Review the Patient Profile
b.Alcohol: Acute – Enzyme Inhibitor b. Avoid complex/ contamination therapy
Chronic – Enzyme Inducer c. Advice the patient regarding the timing of administration
I.Laboratory Test-Drug Interaction
a. Penicillin, Chloramphenicol, Vitamin C, INH, Streptomycin
glucose in Urine (Benedict’s Test) Pharmaceutical Interactions
false (+) result is caused by a chemical or physical incompatibility when
b. Chlordiazepoxide two or more drugs are mixed together
Thyroid Function Test (I131)
false () result Classification of Drug Interactions:
c. Rifampicin(red-orange), Vit B2 (intense yellow), 1. Probable  very likely but might not be proven clinically
Chloroquine (brown) 2. Suspected  might occur & some data might be available
urinalysis 3. Established  supported by well-proven clinical studies
change in color 4. Possible  could occur; limited data are available
5. unlikely  doubtful; no good evidence of an altered clinical
effect is available

Homergic  is a term used to describe drugs that elicit the same

quality of effect & are mutually interactive, regardless
of whether there is anything in common between the
separate response systems
Homodynamic  when two homergic drugs can be agonists of the
same receptors so that the entire response system
is common to both & such drugs.
Heterergic  when two drug do not cause responses of the same
quality

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INCOMPATIBILITIES
Incompatibility 2. Chemical Incompatibilities
problem which could arise during the compounding reaction in which a visible change is not necessary observed
or dispensing of a prescription not visible
render the product unusable/ nonfunctional/
not suitable for administration
a. Oxidation (LEORA) Autoxidation/
arises during, before or after drug administration loss of electrons Self-oxidation
interaction of two or more substances reducing agent  is a type of oxidation
Dehydrogenation that occurs when
Forms:
Increase in oxidation state solutions are exposed
1. Physical Incompatibilities Triggered by oxygen, light, metals
o Incomplete Solution to atmospheric oxygen
Manifests as change in color
 is a complex reaction
o Precipitation Ex: Ascorbic Acid – Brown
that proceeds via a
o Liquefaction of Solid Ingredient Epinephrine – Pink
o Vaporization (Liquid to Gas) free-radical
b. Reduction (GEROA)
o Polymorphism gain electrons
mechanism
o Loss of Water Oxidizing agent  is an autocatalytic
2. Chemical Incompatibilities Hydrogenation reaction which cause a
o Oxidation (LEORA) Decrease in oxidation state chain reaction
o Reduction (GEROA) Ex: Tollen’s Test: AgNO3  Ag (ppt)
o Precipitation c. Precipitation
o Hydrolysis salting out process
o Photolysis/ Photo-Oxidation two or more drugs interacting to from a new substance
o Racemization Ex: Ca (OH)2 + CO2  CaCO3 + H2O
o Gelatination d. Hydrolysis
o Cementation involving water as solvent
o Complexation most common type of incompatibility
o pH incompatibilities most common mechanism of drug degradation
o Explosive Mixtures Ex: ASA acetic + salicylic acid
o Evolution of Gas Susceptible groups: Lactam (Penicillin, Caphalosporins)
o Solvolysis Esters (Cocaine, Physostigmine, Aspirin,
3. Therapeutic Incompatibilities Tetracaine, Procaine, Methyldopa)
1. Physical Incompatibilities Amides (Dibucaine)
physical or chemical interaction between two or more Imines (Diazepam)
ingredients that leads to a visibly recognizable change e. Photolysis/ Photo-Oxidation
easy to correct & predictable degradation by light
a. Incomplete Solution manifests as change in color
insolubility: Suspension Ex: Nifedipine, Nitroprusside, Riboflavin, Phenothiazines,
immiscibility: Emulsion Adraimycin, Cisplatin, Amphoterecin B
Ex: Gum & alcohol, Management: Place drug in an Amber bottle & Flint bottle.
Pectin & alcohol, f. Racemization
action or process of changing from an optically active compound
Resin & water,
into a racemic compound or an optically inactive mixture
Oil & water optically active  optically inactive
b. Precipitation Example: Volatile oils
salting out process racemic mixture: equal amounts of dextro (+) & levo (-) isomers
solute which is originally dissolved in solvent is thrown out of g. Gelatination
solution gel or gel formation
no new product is produced Ex: Acacia + Ferric Salts
Ex: Aromatic water & salt, h. Cementation
Spirits & salt solution, cake formation
camphor solution & water Ex: Acacia + Bismuth salts
c. Liquefaction of Solid Ingredient i. Complexation
Efflorescence  release of water of crystallization j. pH incompatibilities
(citric acid, atropine SO4, FeSO4, Alum) Ex: -Aminophylline + Erythromycin (bad combination)
Hygroscopicity  absorbs moisture but does not dissolve Aminophylline  requires alkaline medium
(silica gel) Erythromycin  decompose in an alkaline medium
Deliquescence  absorbs moisture & dissolves (NaCl) -Phenytoin + 5% Dextrose (bad combination)
Eutexia  lowering of melting point Phenytoin  decomposed in acidic medium
5% Dextrose  acidic
(menthol, phenol, thymol, camphor)
k. Explosive Mixtures
d. Vaporization (Liquid to Gas)
reducing agent (RA) + oxidizing agent (OA)
or volatilization
Ex: sugar + KMnO4
liberation of the active ingredient
Glycerin + KMnO4
Ex: Nitroglycerin
l. Evolution of Gas
e. Polymorphism
 effervescence
existence of one or more crystalline &/or amorphous form
Ex: Effervescent tablet (contains NaHCO3
Ex: Aspirin, Theobroma Cacao, Chloramphenicol, Sulfanilamide
&tartaric or citric acid)
f. Loss of Water
p-aminosalicylic acid (PAS)
liquid dosage forms:
m. Solvolysis  interaction of drug with solvent other than water
▪Emulsion (phase inversion in o/w emulsion)
▪Suspension & solutions (increased potency)

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2. Therapeutic Incompatibilities
undesirable pharmacological interaction between two or
more ingredients that leads to:
potentiation of the therapeutic effect of the ingredients
destruction of the effectiveness of one or more of the
ingredients
occurrence of a toxic manifestation within the patient
Ex: Penicillin (B’ricidal) + Tetracycline (B’static)
cause antagonism

Factors Affecting Incompatibilities

1. pH
2. time of dilution
3. duration of solution
4. order of mixing
5. temperature

Management of Incompatibilities
1. Avoid contamination.
2. Lessen the time of Content.
3. Mixed thoroughly

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COMMON DRUG INTERACTIONS

Drug or Drug Drugs involved Comment Drug or Drug Drugs involved Comment
Group Group
Alcohol Sedative-hypnotics, Additive CNS NSAIDs Anticoagulant Increased bleeding tendency
Opioid analgesics depression, sedation, because of reduced platelet
TCAs, ataxia, increased risk of aggragation
Antihistamines accident Ace Inhibitors Decreased antihypertensive
efficacy of ACE inhibitors
Aminoglycosides Loop diuretics Enhanced Ototoxicity Loop diuretics, Reduced diuretic efficacy
Antacids Iron Supplements Decreased gut Thiazides
FLuoroquinolones absorption, due either Phenytoin Doxycycline, Increased metabolism due to
Ketoconazole to reaction with the Methadone, enzyme induction; decreased
Tetracyclines drug affected or to Quinidine, efficacy
reduced gut acidity Steroids,
Antihistamine Antimuscarinics, Additive effects with Verapamil
(H1-blockers) Sedatives the drug involved
Antimuscarinic Drug absorbed from Slowed onset of effect Quinidine Digoxin Increased Digoxin levels due to
Drugs the small because stomach decrease clearance;
intestines emptying is delayed displacement may play a role
Barbiturates, Azoles, Increased clearance of Rifampin Azole Antifungals, Decreased effeicacy of these
especially CCBs, the affected drugs due Corticosteoids, drugs due to induction of
Phenobarbital Propanolol, to enzyme induction, Methadone, hepatic P450 isozymes
Quinidine, possibly leading to Theophylline,
Steroids, decrease in drug Tolbutamide
Warfarin, effectiveness Salicylates Corticosteroids Additive toxicity to gastric
& many other drugs mucosa
metabolized in
the liver
Beta-blockers Insulin Masking of symptoms Heparin Increased bleeding tendency
of hypoglycemia Warfarin
Prazocin Increased “first-dose”
syncope Methotrexate Decreased clearance causing
Bile acid-binding Acetaminophen, Reduce absorption of greater Methotrexate toxicity
resin Digitalis, the affected drug Sulfinpyrazone Decreased uricosuric effect
Thiazides,
SSRIs MAOIs, Serotonin syndrome:
Thyroxines
Meperidine, hypertension, tachycardia,
Carbamazepine Doxycycline, Reduced effect because TCAs muscle rigidity, hyperthermia,
Estrogen. of induction of seizures
Haloperidol, metabolism
Thiazides Digitalis Increased risk of digitalis
Theophylline,
toxicity because thiazides
Warfarin
diminish potassium stores
Cimetidine Benzodiazepines, Increased effect due to
Lidocaines, inhibition of hepatic Lithium Increased plasma levels of
Phenytoin, metabolism Lithium due to decreased total
Quinidine, body water
Theophylline, Warfarin Cimetidine, Increased anticoagulant effect
Warfarin Erythromycin, via inhibition of warfarin
Disulfiram, Ethanol Increased hangover Lovastatin, metabolism
Metronidazole, effect of ethanol, Metronidazole
Certain because aldehyde Anabolic steroids, Increased anticoagulant effects
Cephalosporin dehydrogenase is Aspirin, via Pharmacodynamic
blocked. NSAIDs, mechanism
Erythromycin Cisapride, Risk of toxicity due to Quinidine,
Quinidine, inhibition of Thyroxine
Sildenafil, metabolism of these
Theophylline drugs
Barbiturates, Decreased anticoagulant
Ketoconazole Benzodiazepines, Risk of toxicity due to Carbamazepine, effects due to increased
& other azoles Cesapride, inhibition of Phenytoin, clearance of warfarin via
Cyclosporine, metabolism of these Rifampin induction of hepatic P450
Fluoxetine, drugs isozymes
Lovastatin,
Omeprazole,
Quinidine,
Tolbutamide,
Warfarin
MAO inhibitors Catecholamines Increased NE in the
releasers sympathetic nerve
(Amphetamine, endings released by the
Ephedrine) interacting drugs
Tyramine-rich food Hypertensive crisis

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Downloaded by Ana R (hanahmrafael@gmail.com)