Topnotch Supplement Pharmacology Handout PDF

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TABLE OF CONTENTS BASIC PRINCIPLES OF PHARMACOLOGY
TOPIC PAGE NUMBER
Basic Principles of Pharmacology 1 INTRODUCTION
Pharmacodynamics 4
Pharmacokinetics 6 DEFINITION OF TERMS
Drug Metabolism 7  DRUGS
Drug Evaluation and Regulation 8 o Any substance that brings about a change in biologic
Autonomic Pharmacology 9 function through its chemical actions
Cholinoreceptor-Activating and 11
Cholinesterase-Inhibiting Drugs  PHARMACODYNAMICS
Cholinoreceptor Blockers 12 o Actions of a drug on the body
Adrenergic Pharmacology 13  Receptor interaction
Sympatomimethics 14  Dose-response phenomena
Adrenoreceptor Blockers 15  Mechanisms of therapeutic and toxic
Treatment of Glaucoma 16 actions
Drugs for Hypertension 17
Drugs Used in the Treatment of Angina 19  PHARMACOKINETICS
Pectoris o Actions of the body on the drug
Drugs used in Heart Failure 21 o Concerned with:
Anti-Arrhythmic Drugs 22  Absorption
Diuretics 25  Distribution
Drugs used in the Treatment of 28  Metabolism
Hyperlipidemia  Elimination
Histamine, Serotonin, Ergot Alkaloids 30
Prostaglandins and Other Eicosanoids 31 MNEMONICS – Pharmacodynamics vs Pharmacokinetics
Bronchodilators & Other Drugs Used in 32 pharmacoDynaMics pharmacoKineTics
Asthma (Drug  Man) (Katawan  Tableta)
Agents Used in Anemia and Hematopoietic 33
Growth Factors NATURE OF DRUGS
Drugs Used in Coagulation Disorders 36  SIZE AND MOLECULAR WEIGHT
NSAIDS, Acetaminophen, DMARDS and 40 o Vary from MW 7 (lithium) to over MW 50,000
Drugs Used in Gout (alteplase, thrombolytic enzymes)
o Majority have MW 100 to 1000
Sedative-Hypnotic Drugs 44
o <100 – rarely sufficiently selective in their actions
Alcohols 46
o >1000 – poorly absorbed and and poorly ditributed
Antiseizure Drugs 48
General Anesthetics 49
REVIEW – Anticoagulants
Local Anesthetics 51
WARFARIN – small
Skeletal Muscle Relaxants 52
MOA: Inhibits Vit K-dependent factors synthesis
Drugs Used in Parkinsonism 54
Monitor: PT/INR (can cross the placenta)
Antiosychotic Agents and Lithium 55 Antidote: Vit K; FFP
Antidepressants 57
Opioid Analgesics and Antagonists 59 HEPARIN – large
Drugs of Abuse 60 MOA: Activates anti-thrombin III
Endocrine Pharmacology 62 Monitor: aPTT (cannot cross the placenta)
Antibiotic Agents 72 Antidote: Protamine Sulfate
Antifungal Agents 80
Antiviral Chemotherapy and Prophylaxis 81  DRUG-RECEPTOR BONDS
Antiprotozoal Drugs 83 o Arranged according to decreasing order of strength
Antihelminthic Drugs 85  Covalent bonds
Cancer Chemotherapy 86  Electrostatic bonds
Gastrointestinal Pharmacology 90  Ionic bonds
Toxicology 91  Hydrogen bonding
Management of the Poisoned Patient 95  van der Waals
 Hydrophobic bonding
o Strength of bond formed by drugs determine
reversibility of effects
 PRALIDOXIME (cannot reverse insecticide
poisoning if the bonds formed by the poison
have aged and become covalent)
MOVEMENT OF DRUGS IN THE BODY

 Drug molecules must travel from the site of administration
to the site of action
 Permeation
 Fick’s Law of Diffusion
 Water and Lipid solubility of Drugs
PERMEATION – is the movement of drug molecules into and within

biologic environments
o Aqueous diffusion
o Lipid diffusion
o Transport by special carriers
o Endocytosis, pinocytosis
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Aqueous Diffusion Dissocation of Weak Acids
 Passive movement of non-protein-bound drugs between
the blood and extravascular space through small water- HA ↔ A- + H+
filled pores (exceptions: Brain, Testes, Eye and Placenta) Protonated ↔ unprotonated + H+
 Affected by drug concentration and charge R – COOH ↔ R – COO- + H+
 Governed by Fick’s Law of Diffusion
 unprotonated (A-) form is more water-soluble and
Lipid Diffusion undergoes better clearance
 Movement of drugs through lipid memebranes (i.e. BBB,  protonated (HA) form is more lipid-soluble and more likely
Placenta) separating body compartment, and from the ECF to cross biological membranes
to the ICF
 Most important limiting factor for permeation Dissocation of Weak Bases
 Governed by Fick’s Law of Diffusion
 Very important for the diffusion of weak acids and weak BH ↔ B + H+
bases Protonated ↔ unprotonated + H+
R – NH3 ↔ R- NH2 + H+
Transport by Special Carriers
 Drugs that do not readily cross through membranes may be Weak Acids and Bases
Above pKa:
transported across barriers by mechanisms that carry
Unprotonated > protonated
similar endogenous substances
o Ions through Na/K pump
o Neurotransmitter through reuptake transporters At pH = pKa
o Metabolites such as glucose through GLUT Unprotonated = protonated
o Carriers for foreign molecules or xenobiotics
 NOT governed by Fick’s Law of Diffusion and is capacity-
limited Below pKa:
Protonated > unprotonated
Endocytosis
 Endocytosis: large drugs bind to receptors, are internalized
and released after vesicle breakdown (exocytosis is the
reverse process)
 Small polar drugs combine with special proteins to form
complexes which undergo endocytosis MNEMONIC – pKa
o Vitamin B12 bound to Intrinsic factor  UP & Above
o Iron bound to transferrin  Unprotonated > Protonated: Above pKa
FICK’S Law of Diffusion PRACTICE PROBLEMS:

1. Aspirin is a weak organic acid with a pKa of 3.5. What
 Predicts the rate of movement of molecules across a barrier
percentage of a given dose will be in the lipid soluble form
at a stomach pH of 2.5?
pH = pKa + log U/P

2.5 = 3.5 + log U/P
 Pharmacologic Implications:
2.5 – 3.5 = log U/P
o Absorption is faster in organs with large SA
-1 = log U/P
(intestinal > stomach)
10-1 = U/P
o Absorption is faster in organs with thinner
Unprotonated is 10-1 or 0.10 or 10%
membranes (lung > skin)
Protonated is 90%
WATER AND LIPID SOLUBILITY OF DRUGS
Since aspirin is a weak acid, the more lipid soluble form is
 Aqueous solubility is directly proportional to electrostatic
the protonated HA form. Hence, the final answer is 90%
charge (ionization, polarity)
o Ionized and polar drugs are more water-soluble
2. Atropine is a weak organic base with a pKa of 9.7. What
o Increased aqueous solubility = increased clearance
percentage of a given dose will be in the lipid soluble form
 Lipid solubility is inversely proportional to electrostatic at a pH of 7.7?
charge (ionization, polarity)
o Non-ionized and non-polar drugs are more lipid-
soluble
o Increase lipid solubility = increased capacity to
cross biological membranes
Weak Acids and Bases

 Many drugs are weak acids and weak bases
 Dissociate into ionized and non-ionized forms
 pH determines the fraction of drug molecules charged
(ionized) versus uncharged (non-ionized)
 predicted by Henderson-Hasselbach equation
 relationship between pH, pKa (dissociation constant) and
concentration of charged and uncharged forms Application of Henderson-Hasselbach Equation
 Excretion of a weak acid may be accelerated by alkalinizing
Henderson-Hasselbach Equation the urine with bicarbonate (HCO3-)
 Excretion of a weak base may be accelerated by acidifying
the urine with ammonium chloride (NH4Cl)
MNEMONICS – BICARBONATE and AMMONIUM CHLORIDE

Alkalinizing Agent = Basic = give Bicarbonate
Acidifying Agent = ACid = give Ammonium Chloride
DRUG ABSORPTION Rectal (Suppository) Route
 Partial avoidance of the first pass effect
Absorption  Useful for large amounts of drugs with unpleasant tastes and
 Transfer of a drug from its site of administration to the for patients who are vomiting
bloodstream
 Affected by 3 major factors: CORRELATIONS – Anatomy – Rectal Route
o Route of administration Why is there only partial bypass of the first-pass effect on rectal
o Blood flor administration?
o Concentration Review the VENOUS DRAINAGE OF THE RECTUM
 Superior Rectal vein: IMV PV (first-pass)
ROUTES OF ADMINISTRATION  Middle Rectal vein: IIV  IVC
 Inferior Rectal vein: IPV  IIV  IVC
Oral Route
 Offers maximum convenience Inhalational Route
 Most common route of drug administration  Offers delivery closest to the target in respiratory diseases
 Absorption is slow and less complete  Rapid absorption with minimal systemic effects
o Gastric contents  Convenient for drugs that are gases at room temperature
o First-pass effect (nitrous oxide, nitric oxide) or easily volatilized
 A significant amount of the drug is (anesthetics)
metabolized in the gut wall, portal
circulation and liver before it reaches the Topical Route
ssystemic circulation  Application to skin, mucous membranes of the eye, ear, nose,
throat, airway, or vagina for local effect
Intravenous Route  Absorption varies with the area of application and drug
 Instantaneous and complete absorption that bypasses first- formulation
pass effect (100% bioavailability) o Increasing ability to retard evaporation
 Potentially more dangerous:  (more evaporation) tinctures > wet
o High blood levels reached on rapid administration dressings > lotions > gels > aerosols >
o Inadvertent systemic introduction of bacteria powders > pastes > creams > foams >
through the IV line (line sepsis) ointments (less evaporation)
 Slowest route of drug administration
Intramuscular Route
 Absorption is faster and more complete than oral (higher KEY LEARNING POINTS – Topical Preparations
bioavailability) Describe the utility of dermatologic drug preparations for skin
o Bypasses first-pass effect inflammation:
 Large volumes may be delivered if drug is not too irritating  Acute inflammation = drying agents (tinctures, wet
(i.e. 5g of MgSO4) dressings, and lotions)
 Anticoagulant cannot be given by this route because they  Chronic inflammation = lubricating agents (creams,
may cause bleeding (hematomas) ointments)
KEY LEARNING POINTS – IM Injections to Buttocks Transdermal Route

Which quadrant of the buttocks is safest for IM drug  Application to the skin for systemic effect
administration?  Absorption occurs very slowly but bypasses the first-pass
effect
DRUG DISTRIBUTION
Distribution
 Drug reversibly leaves the bloodstream and enters the
target organ
 Depends upon 4 major factors:
o Size of the organ
o Blood flow
o Solubility
 Superolateral = safe o Binding
 Superomedial = gluteus medius gait
 Inferomedial = sciatic nerve SIZE OF THE ORGAN
 Determines concentration gradient between blood and the
Subcutaneous Route organ
 Slower absorption than intramuscular route o Skeletal muscles is very large organ
o NO blood vessels in the subcutaneous space  Large doses are required to actually
 Large volume doses are less feasible change the concentration gradient
 Bypasses the first-pass effect o The brain is a small and compact organ
 Anticoagulants do NOT cause hematomas when  Only a small amount of drugs is
administered via this route required to change concentration
gradients
Buccal and Sublingual Route
 Buccal: pouch between the gums and cheek BLOOD FLOW
 Sublingual: under the tongue  Important determinant of the rate of drug uptake
 Direct absorption into the systemic venous circulation  Well-perfused organs will achieve high tissue
bypassing the first-pass effect concentrations sooner than poorly perfused tissues
 Concentration of drugs with rapid elimination will not
CORRELATIONS – Anatomy – Sublingual Drugs significantly rise in poorly perfused tissues
Through which blood vessels do drugs administered SL pass before
reaching the heart?
Lingual vein  Internajugular vein  Brachiocephalic
(innominate) vein  Superior vena cava  Right atrium
SOLUBILITY MNEMONICS – Zero Order Kinetics
 Influences the concentration of the drug in the extracellular What drugs display zero-order elimination kinetics?
fluid surrounding blood vessels WHAT PET
 Most barriers in the body (BBB, placenta, glomerulus) are  Warfarin
lipid-barriers  Heparin
o Non-ionized, non-polar drugs are more lipid-  Aspirin
soluble and undergo more extensive distribution  Tolbutamide
 Phenytoin
BINDING  Ethanol
 Binding to macromolecules in the blood or tissue will tend  Theophylline
to increase the drug’s concentration in that compartment
o Acidic drugs are bound to albumin PRACTICE PROBLEM – Elimination Kinetics
o Basic drugs are bound to orosomucoid 1. Which drug displays first-order elimination? Zero-order
 Bound drugs CANNOT cross membranes and exert their elimination
effect 0h 1h 2h 3h 4h
 Only unbound drugs CAN cross membranes and exert their A 80mg 60mg 40mg 20mg 0mg
effect B 80mg 40mg 20mg 10mg 5mg
DRUG METABOLISM 2. Compute the remaining concentration of Drug A and B every

hour for 4 hours
Metabolism First-order elimination: Drug A t1/2 = 2h
 Drugs are chemically altered in the body Zero-order elimination: Drug B Rate = 50 mg/2h
 Drugs may undergo 3 metabolic fates: 0h 1h 2h 3h 4h
o Termination of drug action A 100mg
o Drug activation B 100mg
o Elimination without metabolism
TERMINATION OF DRUG ACTION

 Drugs are metabolized into biologically inactive derivatives
 Conversion to a metabolite is a form of elimination
DRUG ACTIVATION
 Prodrugs are metabolized in the body to become active
 Some drugs are metabolically active but still have active PHARMACODYNAMICS
metabolites
Receptors
ELIMINATION WITHOUT METABOLISM  Specific molecules in a biologic system with which drugs
 Some drugs are not modified by the body and continue to act interact to produce changes in the function of the system
until they are excreted  Must be selective in their ligand-binding characterstic
 Must be modified when they bind an agonist to bring about
DRUG ELIMINATION functional change
 Most are proteins
Elimination
 Elimination: termination of drug action Receptor Sites or Recognition Sites
 Excretion: release of drugs or their metabolites in the urine,  Specific binding region of the macromolecule
stool, bile, exhaled air, etc.  High and selective affinity for the drug molecule
 Duration of drug action is determined by:
o Dose administered Effectors
o Rate of elimination following the last dose  Translate the drug-receptor interaction into a change in
cellular activity
Elimination and Drug Metabolites  Some receptors are also effectors
 Elimination of parent molecule does not terminate the o A single molecule may incorporate both the drug
drug’s action for drugs with active metabolites binding site and the effector mechanism
 Excretion is the mode of elimination for drugs that are not  Tyrosine kinase receptor in insulin
metabolized receptor molecule
 Na/K channel in nicotinic Ach receptor
FIRST-ORDER ELIMINATION
 Rate of elimination is proportionate to the concentration Graded Dose-Response Relationships
o Concentration decreases exponentially over time  Dose-response curve
 Characteristic half-life elimination o Response of a particular receptor-effector system
o Concentration decreases by 50% for every half-life measured against increasing drug concentrations
 Most common type of elimination o Yields a sigmoid curve if plotted on a
semilogarithmic axis
ZERO-ORDER ELIMINATION  Efficacy (Emax) and Potency (EC50) are derived from this
 Rate of elimination is constant regardless of concentration curve
o Concentration decreases linearly over time
 Occurs when drugs have saturated their elimination Binding Affinity
mechanisms  Fraction of receptors bound by a drug plotted against the log
of the drug concentration
 Kd is the concentration required to bind 50% of the
receptors
o The smaller the Kd, the greater the affinity of a
drug for its receptor
Graded-Dose Response Curves Potency
 Denotes the amount of the drug needed to produce a given
effect
 Determined mainly by the affinity of the receptor for the
drug
 Measurement:
o In grade dose-response curves, it is the dose
required to produce 50% of the maximal effect
o In quantal dose-response curves, three potency
variables are measurable (ED50, TD50, LD50)
Definitios
Emax = maximal effect achievable with increasing concentration of
a drug
EC50 = concentration of the drug wherein half of the maximal
effect is achieved
Bmax = maximum percentage of receptors with increasing
concentration of a drug
Kd = concentration wherein 50% of receptors is occupied
Quantal Dose-Response Relationships

 Minimum dose require to produce a specified response is
determined in each member of a population
 Quantal dose-response curve Factors Affecting Dose Response Curves
o Fraction of the population that responds to each
dose against the log of the dose administered
 No attempt is made to determine maximal effect
Quantal-Dose Response Curves
Full Agonists
 Capable of fully activating the effector system when it binds
to the receptor
 High affinity for the activated receptor conformation
 Sufficiently high concentrations result in all the receptor
achieving the activated state
Partial Agonists
 Produce less than the full effect, even when it has saturated
the receptors
Therapeutic Index  In the presence of an agonist, a partial agonist acts as an
inhibitor
Antagonists
 Do not provoke a biological response by themselves upon
binding to a receptor
 Blocks or dampens drug response in the presence of an
agonist
 Classification:
Efficacy o Competitive (reversible)
 Maximal efficacy or Emax o Non-competitive (irreversible)
 Maximal effect an agonist can produce if the dose taken to o Physiologic
very high levels o Chemical
 Determined mainly by the nature of the receptor and its
associated effector system
 Measured with graded dose-response curves NOT with
quantal dose-response curves
 Partial agonists have lower maximal efficacy than full
agonists
Competitive or Reversible Antagonists Apparent Volume of Distribution
 Bind to receptors in a reversible way without activating the  Volume at which drug would need to be uniformly
effector system distributed to produce an observed blood concentration
 Shift DRCs to the RIGHT (increase ED50) but same maximal
effect is reached
 Effects overcome by adding more agonist  Purely pharmacokinetic parameter with no direct physical
 Examples: equivalent
o β-blockers (Propranolol)  Can be altered by liver and kidney disease
o β-agonists (Isoproterenol)
Volume of Distribution
Non-competitive or Irreversible Antagonists
 Causes DOWNWARD shift of the DRC Low Vd Distribute in blood
 No horizontal shift of DRC (ED50 unchanged) unless spare Medium Vd Distribute in extracellular
receptors are present space or body water
 Not overcome by adding more agonists High Vd Distribute in tissues
 Examples:
o Norepinephrine
o Phenoxybenzamine
Physiologic Antagonists
 Binds to a different receptor, producing an effect opposite to
that produced by the drug it is antagonizing
 Examples:
o Histamine & Epinephrine
o Propranolol & Thyroid hormone
Chemical Antagonists
 Interact directly with the drug being antagonized to remove
it or to prevent it from reaching its target
 Does not depend on interaction with agonist receptors
 Examples:
o Dimercaprol for lead poisoning
o Pralidoxime for organophosphate poisoning
Variations in Drug Response
Tachyphylaxis Clearance
 Responsiveness diminishes rapidly after administration of  Relates the rate of elimination to the plasma concentration
drug
 Frequent or continuous exposure to agonists often results in
short-term diminution of the receptor response
 Depends on the drug and the condition of the organs of
MNEMONICS – Tachyphylaxis elimination
What drugs display tachyphylaxis? o For a drug that is very effectively extracted by an
MEDical students Love to watch CNN in HD! organ, clearance is flow-limited
Metoclopramide  For drugs eliminated with first-order kinetics, clearance is a
Ephedrine constant proportion
Dobutamine  For drugs eliminated with zero-order kinetics, clearance is a
LSD constant amount
Calcitonin  Most important pharmacokinetic parameter to be
Nitroglycerin considered in defining a rational steady state during
Nicotine dosage regimen
Hydralazine
Desmopressin
Tolerance
 Continuous activation may lead to depletion of essential
substrates
 Reversed by repletion of missing substrates
 EXAMPLE: depletion of thiol cofactors in nitroglycerin
tolerance, reversible with administration of glutathione
Idiosyncratic Drug Response

 One that is infrequently observed in most patients
 EXAMPLES:
o Aplastic anemia with chloramphenicol
o Cataracts with allopurinol
PHARMACOKINETICS
Effective Drug Concentration Steady State
 Concentration of a adrug at the receptor site (target organ)  Condition in which the average total amount of drug in the
 Except for topically applied agents, the concentration at the body does not change over multiple dosing intervals
receptor site is usually proportional to the drug’s  Rate of drug input equals the rate of elimination
concentration in the plasma or whole blood at equilibrium  Reached in 4-5 half-lives of the drug
Half-life Therapeutic Window
 Safe range between the minimum therapeutic concentration
and the minimum toxic concentration of a drug
 Constant for drugs following first-order kinetics o Minimum effective concentration usually
 Disease, age, and other variables usually alter clearance of a determines the desired trough levels of a drug
drug much more then Vd given intermittently
 Half-life may not change despite a decreased cleareance if o Minimum toxic concentration determines the
the Vd decreases at the same time permissible peak plasma concentration
Bioavailability
 Fraction of the administered dose that reaches the systemic Adjustment of Dosage
circulation  Renal disease or reduced cardiac output often reduces the
 Drugs administered intravenously have 100% clearance of drugs that depend on renal function
bioavailability  Impairment of hepatic clearance occurs when liver blood
 Reduced by incomplete absorption, first-pass metabolism, flow is reduced
and pre-systemic redistribution o EXAMPLES: heart failure, severe cirrhosis, other
 Determined by computing the area under the plasma forms of liver failure
concentration curve (AUC)
Adjustment of Dosage in Renal Impairment
 If a drug is cleared partly by the kidney and partly by other

routes, apply the equation only to the part of the dose that is
eliminated by the kidney
Cockroft – Gault Equation

 To calculate the patient’s creatinine clearance, use the
Cockroft-Gualt equation
PRACTICE PROBLEM – Bioavailability

After oral administration of 500mg of Drug A, only 300mg were PRACTICE PROBLEM – Corrected Dosage
absorbed into the patient’s systemic circulation. What is its A drug is 50% cleared by the kidney and 50% by the liver. Its
bioavailability? normal dosage is 200 mg/dL. What is the corrected dosage in a
patient with a creatinine clearance of 20 mL/min
Dosage Regimen
 Plan for drug administration over a time period DRUG METABOLISM
 Results in the achievement of therapeutic levels of the drug
in the blood without exceeding the minimum toxic Drug Metabolism
concentration  All organs are exposed to foreign chemical compounds
 Based on knowledge of both the minimum therapeutic and (xenobiotics)
minimum toxic concentrations for the drug, as well as its  Metabolic pathways alter drug activity and their
clearance and Vd susceptibility to excretion
Maintenance Dose Phase 1 Reactions

 Equal to the rate of elimination at steady state  Convert the parent drug to a more polar (water-soluble) or
more reactive product by unmasking or inserting a polar
functional group
 EXAMPLES: oxidation, reduction, deamination, hydrolysis
 Vd is NOT involved in calculating MD
 Important to maintain concentration above minimum MNEMONICS – Phase I Reactions
therapeutic level: A HORDe of PHASE I REACTIONS
o Give large doses at long intervals Hydrolysis
o Smaller doses at more frequent intervals Oxidation
Reduction
Loading Dose Deamination
 If the therapeutic concentration must be achieved rapidly
and the volume of distributin is large Cytochrome P450 Enzymes
 Also called mixed-function oxidases
 High concentration in the smooth endoplasmic reticulum of
the liver
 Clearance is NOT involved in calculating LD
 Not highly selective in their substrates
 If the LD is very large, dose should be given slowly to prevent
 Of the drugs metabolized by phase I cytochrome P450s,
toxicity
approximately 75% are metabolized by just two:
o Due to excessively high plasma levels during the
o CYP3A4 or CYP2D6
distribution phase
Examples of Phase 1 Reactions Enzyme Induction
 Results from increased synthesis of cytochrome P450
enzymes and heme
 Several days are usually required to reach maximum
induction
 Most common strong inducers are carbamazepine,
phenobarbital, phenytoin, and rifampin
MNEMONIC – CYTOCHROME P450 INDUCERS

Ethel Booba takes Phen-phen and Refuses Greasy Carb Shakes!
Ethanol
Barbiturates
Phenytoin
Rifampicin
Griseofulvin
Carbamazepine
St. John’s Wort / Smoking
Enzyme Inhibition
 Most significant inhibitors are Amiodarone, Cimetidine,
Phase 2 Reactions Furanocoumarins present in grapefruit juice, azole
 Involve conjugation of subgroups to –OH, –NH2, and –SH antifungals, and the HIV protease inhibitor (Ritonavir)
functions on the drug molecule  Metabolism may be decreased by reduction in blood flow to
o Makes the drug more polar and less lipid-soluble metabolizing organ
than the original drug molecule o EXAMPLE: Propranolol reduces hepatic blood flow
o EXAMPLES: glucoronate, acetate, glutathione,
glycine, sulfate, and methyl group Suicide Inhibitors
 Phase II enzymes are NOT very selective  Metabolized to products that irreversibly inhibit the
 Drugs may undergo phase II metabolism before or after metabolizing enzyme
phase I o EXAMPLES: Ethinyl estradiol, Norethindrone,
Spironolactone, Secobarbital, Allopurinol,
Examples of Phase 2 Reactions Fluroxene, PTU
MNEMONICS – CYTOCHROME P450 INHIBITORS

Inhibitors Stop Cyber Kids from Eating GRApefruit OV!
Isoniazid
Sulfonamides
Cimetidine
Ketoconazole
Erythromycin
Grapefruit Juice
Ritonavir
Amiodarone
Sites of Drug Metabolism Quinidine
 LIVER Valproic acid
o Most important organ for drug metabolism _______________________________________________________________________________
 KIDNEYS
DRUG EVALUATION AND REGULATION
 TISSUE COMPARTMENTS
o Few drugs (eg, esters) are metabolized in many
Animal Testing
tissues (eg, liver, blood, intestinal wall) because of
 Required before human studies begin
the broad distribution of their enzymes
 Function of the proposed use and the urgency of the
Drug Biotransformation application
o Drug proposed for nonsystemic use requires less
 Most often due to genetic or drug-induced differences
extensive testing
 Gender is important for only a few drugs
o Anticancer drugs and drugs proposed for use in
o First-pass metabolism of alcohol (M>F)
AIDS require less evidence of safety
 Primary determinant of clearance
o Variations must be considered carefully when
Acute Toxicity
designing or modifying a dosage regimen
 Required for all new drugs
 Involve administration of single doses of the agent up to the
Genetic Factors
lethal level in at least 2 species (eg, 1 rodent and 1
 Drug-metabolizing systems differ among families or
nonrodent)
populations in genetically determined ways
 Recent advances in genomic techniques allow screening for
Subacute and Chronic Toxicity
a huge variety of polymorphisms (pharmacogenomics)
 Required for most agents, especially those intended for
chronic use
Examples in Pharmacogenomics
 Duration: 2 – 4 weeks (subacute) or 6 – 24 months (chronic),
 HYDROLYSIS OF ESTERS
in at least 2 species
Succinylcholine metabolism by pseudocholinesterase
 ACETYLATION OF AMINES
Pharmacologic Profile
Fast and slow acetylation of isoniazid, hydralazine
 Description of all the pharmacologic effects
and procainamide
o Effects on cardiovascular function,
 OXIDATION
gastrointestinal activity, respiration, renal
Debrisoquin, Sparteine, Phenformin,
function, and endocrine function, CNS
Dextromethorphan, Metoprolol, and
 Both graded and quantal dose-response data are gathered
Tricyclic antidepressants
Reproductive Toxicity Mutagenesis
 Involves the study of the fertility effects of the candidate  Induction of changes in the genetic material of animals of
drug and its teratogenic and mutagenic toxicity any age and therefore induction of heritable abnormalities
 FDA uses a 5-level descriptive scale to summarize o EXAMPLES: aflatoxin, cancer chemotherapeutic
information regarding the safety of drugs in pregnancy drugs, and other agents that bind to DNA
FDA Drug Categories Ames Test

Category Description  Standard in vitro test for mutagenicity
A Controlled studies in women fail to demonstrate a risk to the  Uses a special strain of Salmonella that naturally depends
fetus in the first trimester (and ther is no evidence of a risk in on specific nutrients
later trimesters), and the possibility of fetal harm appears
remote  Loss of this dependence signals a mutation
B Either animal reproduction studies have not demonstrated a
fetal risk but there are no controlled studies in pregnant Dominant Lethal Test
women, or animal reproduction studies have shown an  In vivo mutagenicity test carried out in mice
adverse effect (other than a decrease fertility) that was not  Male animals are exposed to the test substance before
confirmed in controlled studies in women in the first trimester mating
(and ther is no evidence of a risk in later trimesters)
 Abnormalities in the results fo the subsequent mating signal
C Either studies in animals have revealed adverse effects on the
a mutation in the male’s germ cells
fetus (teratogenic or emryocidal 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 Carcinogenesis
potential benefit justifies the potential risk to the fetus  Induction of malignant characteristics in cells
D There is positive evidence of human fetal risk, but the benefits  Difficult and expensive to study
from use in pregnant women may be acceptable despite the  High degree of correlation between mutagenicity in the
risk (eg, if the drug is needed in a life-threatening situation or Ames test and carcinogenicity in some animal tests
for a serious disease for which safer drugs cannot be used or
o EXAMPLES: coal tar, aflatoxin, nitrosamines,
are ineffective)
X Studies in animals or human beings have demonstrated fetal
urethane, vinyl chloride, polycyclic aromatic
abnormalities or ther is evidence of fetal risk based on human hydrocarbons in tobacco smoke
experience or both, and the risk of the use of the drug in Clinical Trial
pregnant women clearly outweighs any possible benefit. The  Requires approval by institutional committees that monitor
drug is contraindicated in women who are or may become the ethical (informed consent, patient safety) and scientific
pregnant aspects (study design, statistical power) of the proposed tests
Drugs and Pregnancy Investigational New Drug (IND)

Pregnant Pregnant  Includes all the preclinical data colleceted up to the time of
Class Human Animal Examples
submission and the detailed proposal for clinical trials
Studies Studies
A safe safe Folic acid, thyroid hormones
New Drug Application (NDA)
B no studies safe Zidovudine
safe unsafe  Constitutes the request for approval of general marketing of
C no studies unsafe Aspirin the new agent for prescription usa and includes all the
no studies no studies results of preclinical and clinical testing
D unsafe unsafe ACE inhibitors, Anticonvulsants
X unsafe unsafe Statins, OCPs, Clomiphene, PHASE 1 TRIAL
Misoprostol, High-dose vitamin A  Careful evaluation of the dose-response relationship and
pharmacokinetics among normal human volunteers (25-50)
Teratogenesis o EXCEPTION! In cancer and highly toxic agents
 Induction of developmental defects in the somatic tissues of (volunteer patients with target disease)
the fetus  Acute effects of the agent are studied over a broad range of
 Studied by treating pregnant female animals of at least 2 dosages
species at selected times during early pregnancy when
organogenesis is known to take place PHASE 2 TRIAL
o EXAMPLES: thalidomide, isotretinoin, valproic  Evaluation of a drug in a moderate number of patients (eg,
acid, ethanol, glucocorticoids, warfarin, 100-300) with the target disease
lithium, and androgens  Placebo or positive control durg is included in a sigle-blind
or double-blind design
COMMON TERATOGENS  Under carefully controlled conditions with close monitoring
TERATOGEN EFFECT
usually in hospital ward
ACE inhibitors Fetal renal damage
 Determine whether the agent has the desired efficacy at
Antiepileptic Drugs Neural tube defects
Phenytoin Fetal hydantoin syndrome
doses that are tolerated by sick patients
Oral hypoglycemic agents Neonatal hypoglycemia
Barbiturates Neonatal dependence PHASE 3 TRIAL
Diethylstilbestrol (DES) Vaginal clear cell adenocarcinoma  Large design involving many patients (1000-5000) and
Ethanol Fetal alcohol syndrome many clinicians
Lithium Ebstein’s anomaly  Include placebo and positive control in a double-blind
Isotretinoin Craniofacial malformations crossover design
Iodide Congenital hypothyroidism  Explore further the spectrum of beneficial actions of the new
Misoprostol Mobius sequence drug to compare it with older therapies, and to discover
Penicillamine Cutis laxa
toxicities
Thalidomide Phocomelia
Smoking Intrauterine growth restriction (IUGR)
 Large amounts of data are collected
Tetracycline Tooth discoloration  Usually very expensive
Streptomycin Ototoxicity
Methimazole Aplasia cutis congenita PHASE 4 TRIAL
Sulfonamides Kernicterus  Post-marketing surveillance phase
Fluoroquinolones Cartilage damage  Detects toxicities that occur very infrequently
Warfarin 1st trimester Chondrodysplasia  Findings reported early enough to prevent major
2nd trimester CNS malformations therapeutic disasters
3rd trimester Bleeding diatheses
Drug Patents
 Usually submitted around the time that a new drug enters
animal testing
 Right to market the drug without competition from other
firms for a period of 20 years
 After expiration of patent, any company may apply to the
FDA for permission to market a generic version of the same
drug
o Must demonstrate that their generic drug molecule
is bioequivalent
Bioequivalence
 Two related drugs are bioequivalent if they show
comparable bioavailability and similar times to achieve a
peak blood concentrations
 Used in determining safety and efficacy of generic drugs
ORGAN EFFECT
Sympathetic Parasympathetic
Pupils Mydriasis (α1) Miosis (M3)
Heart rate Tachycardia (β1) Bradycardia (M2)
Orphan Drug Heart contractility Increased (β1) Decreased (M2)
 Drug for a rare disease (one affecting fewer than 200,000 Blood vessels NO EFFECT
people) Skin, splanchnic Constriction (α1) NO EFFECT
 Often neglected because the sales of an effective agent for an Skeletal Dilation (β2, M3) NO EFFECT
uncommon ailment might not pay the costs of development Bronchi Dilation (β2) Contraction (M3)
GIT walls Relaxation (α2, β2) Contraction (M3)
GIT sphincters Contraction (α1) Relaxation (M3)
AUTONOMIC PHARMACOLOGY GIT secretions NO EFFECT Increased (M1, M3)
Bladder wall Relaxation (β2) Contraction (M3)
Autonomic Nervous System Bladder sphincter Contraction (α1) Relaxation (M3)
 Major involuntary, unconscious, automatic portion of the Uterus Contraction (α1) Contraction (M3)
nervous system Relaxation (β2)
 Major divisions: Penis Ejaculation (α) Erection (M)
o Parasympathetic ANS (PANS) Sweat glands ↑ sweating (α) NO EFFECT
o Sympathetic ANS (SANS) Liver Gluconeogenesis NO EFFECT
o Enteric nervous system (ENS) Glycogenolysis (α, β2)
 Consists of myenteric plexus (plexus of Fat cells Lipolysis (β3) NO EFFECT
Auerbach) and submucous plexus (plexus Kidnets ↑ renin (β1) NO EFFECT
of Meissner)
SANS PANS MNEMONIC – for Parasympathetic Nervous System

Thoracic (T1-T12) and CN III, VII, IX and X PLASMA!
Spinal Roots Lumbar (L1-L5) Sacral segments of Parasympathetic NS, Long preganglionic fiber, Acetylcholine,
of Origin segments of the spinal spinal cord Short postgalionic fibers, Acetylcholine
cord
Paraventral chains that Most are located in
Location of lie along the spinal the organs MNEMONIC – Point and Shoot!
Ganglia column, some along the innervated, more Point (Erection) = Parasympathetic NS
anterior aspects of the distant from the Shoot (Ejection) = Sympathetic NS
abdominal aorta spinal cord
Preganglionic Short Long
Fibers
Postganglionic Long Short
Fibers
CHOLINERGIC PHARMACOLOGY CHOLINORECEPTOR-ACTIVATING AND
CHOLINESTERASE-INHIBITING DRUGS
Acetycholine
 Primary transmitter in all autonomic ganglia and at the
synapses between parasympathetic postganglionic neurons
and their effector cells
 Primary transmitter at the somatic (voluntary) skeletal
muscle neuromuscular junction
DIRECT – ACTING CHOLINOMIMETICS, MUSCARINIC
BETANECHOL
Class Cholinomimetic (direct – acting, muscarinic)
MOA Activates muscarinic (M3) receptors
Uses Bladder and bowel atony (post-surgery or spinal cord
injury)
SE Cyclospasm, Diarrhea, Urinary urgency, Vasodilation,
Reflex tachycardia, Sweating
MNEMONICS – Betanechol
B = Betanechol = Bowel and Bladder Atony
PILOCARPINE
Class Cholinomimetic (direct – acting, muscarinic)
MOA Activates muscarinic (M3) receptors in ciliary muscle
(increasing aqueous humor outflow) and salivary
glands (increasing salivation)
STEP 1 – SYNTHESIS Uses Glaucome, Sjogren’s syndrome, Sicca syndrome
 ACh is synthesized from Acetyl CoA and choline by the SE Miosis, Blurring of vision (due to cyclospasm)
enzyme acetyltransferase (ChAT)
o Choline transport inhibited by HEMICHOLINIUM KEY LEARNING POINTS – Sjogren’s Syndrome!
What is Sjogren Syndrome?
STEP 2 – STORAGE Autoimmune disorder characterized by:
 ACh is actively transported (endocytosis) into vesicles for  XEROSTOMIA (dry mouth)
storage by vesicle-associated transport (VAT)  XEROPHTHALMIA (dry eys)
o Inhibited by VESAMICOL  RHEUMATOID ARTHRITIS
STEP 3 – RELEASE DIRECT – ACTING CHOLINOMIMETICS, NICOTINIC

 Entry of calcium triggers interaction among SNARE proteins
(VAMPs and SNAPs) NICOTINE
o BOTULINUM toxins alter synaptobrevins to SimD VARENICLINE
prevent release of ACh Class Cholinomimetic (direct – acting, nicotinic)
MOA Activates nicotinic ACh receptors (NN and NM)
STEP 4 – TERMINATION Uses Smoking Cessation
 Degradation of ACh into choline and acetate by SE Generalized ganglionic stimulation (hypertension,
acetylcholinesterase tachycardia, nausea, vomiting, diarrhea)
o Inhibited by INDIRECT-ACTING Notes Overdose leads to convulsions, paralysis and coma
CHOLINOMIMETICS (CARBAMATES,
ORGANOPHOSPHATES, and NEOSTIGMINE) Muscarinic Toxicity
 CNS stimulation
Cholinergic Drug Effects  EYE: miosis, spasm of accommodation
 Not very useful for systemic therapy because their effects  LUNGS: bronchoconstriction
are not sufficiently selective  GIT/GUT: excessive gastrointestinal and genitourinary
o PANS and SANS ganglia and somatic smooth muscle activity
neuromuscular junctions all may be blocked  Increased secretory activity (sweat glands, airway,
 Botulinum toxin is a very alrge molecule and diffuses very gastrointestinal tract, lacrimal glands)
slowly  Vasodilation
o Injection for relatively selective local effects
Mushroom Posoning
Cholinoreceptors
 Muscarine and similar alkaloids found in mushrooms
Receptor Location Mechanism Major functions
M1 Nerve endings Gq-coupled ↑ IP3, DAG cascade (Inocybe and Amanita muscaria)
M2 Heart, some nerve endings Gl-coupled ↓ cAMP, activates K+ o Responsible for the short-acting form of
channels mushroom poisoning (nausea, vomiting and
M3 Effector cells: smooth muscle, Gq-coupled ↑ IP3, DAG cascade diarrhea)
glands, endothelium
NN ANS ganglia Ion channel Depolarizes, evokes
action potential Nicotinic Toxicity
NM Neuromuscular end plate Ion channel Depolarizes, evokes  Ganglionic stimulation
action potential
 Blockade of neuromuscular end plate depolarization
o Leading to fasciculations and paralysis
 CNS toxicity: stimulation (convulsions) followed by CNS
depression
INDIRECT – ACTING CHOLINOMIMETICS MNEMONICS – ORGANOPHOSPHATE POISONING!
What are the signs and symptoms of organophosphate poisoning?
MOA of Indirect-Acting Cholinomimetics DUMBBELSS!
 Bind to cholinesterase and undergo prompt hydrolysis Diarrhea
o Alcohol portion released Urination
o Acidic portion retained and released slowly Miosis
 Prevents the binding and hydrolysis of Bronchospasm
endogenous acetylcholine
 Amplify acetylcholine effects wherever Bradycardia
ACh is released Excitation (skeletal muscle and CNS)
 No significant actions at uninnervated sites where ACh is Lacrimation
NOT normally released Sweating
Salivation
EDROPHONIUM
Class Cholinomimetic (indirect – acting) TREATMENT OF ORGANOPHOSPHATE POISONING
MOA Inhibits acetylcholinesterase. Amplifies endogenously
released acetylcholine ATROPINE
Uses Myasthenia gravis (diagnosis – Tensilon test), Class Cholinergic Antagonist (muscarinic)
Differentiation of cholinergic crisis and mysthenic crisis MOA Competitively blocks ALL muscarinic receptors
SE Miosis, Salivation, Nausea, Vomiting, Diarrhea, Uses Mydriatic, Cycloplegic, Antidote for
Bradychardia organophosphate poisoning (first choice),
Notes Very short-acting upon intravenous administration Bradycardia, Hypersalivation
SE Tachycardia, Mydriasis, Cycloplegia, Skin flushing,
NEOSTIGMINE Delirium, Hallucinations
SimD PYRIDOSTIGMINE, PHYSOSTIGMINE Notes No effect on the nicotinic signs of toxicity
Class Cholinomimetic (indirect – acting)
MOA Inhibits acetylcholinesterase. Amplifies endogenously PRALIDOXIME
released acetylcholine Class Cholinesterase Regenerator, Antidote
Uses Myasthenia gravis (treatment), Reversal of MOA Binds phosphorus of organophosphate. Breaks
nondepolarizing neuromuscular blockade, Ogilvie organophosphate bond with cholinesterase
syndrome, Glaucoma (physostigmine ONLY) Uses Antidote for organophosphate poisoning and nerve
SE Miosis, Salivation, Nausea, Vomiting, Diarrhea, gas poisoning (sarin, tabun)
Bradychardia SE Muscle weakness
Notes Muscarinic effects are blocked by ATROPINE Notes Must be administerd before 6–8 hours of
organophosphate bond with cholinesterase occurs
CORRELATIONS – Myasthenia Gravis!
What is myasthenia gravis? CHOLINOCEPTOR BLOCKERS
Autoimmune destruction of nicotinic ACh receptors,
characterized by:
 Fluctuating muscle
 Weakness
 Ocular symptoms
 Bulbar symptoms
 Proximal muscle weakness
Differentiate myasthenic crisis from cholinergic crisis.

MYASTHENIC CRISIS Atropine
 Acute worsening of symptoms due to infection, stress or  Prototype nonselective muscarinic blocker
UNDERmedication  Found in Atropa belladonna
 Tertiary amine that readily crosses membrane barriers
CHOLINERGIC CRISIS
 Excessive activation of cholinoceptors (skeletal muscle MNEMONICS – Cytoplegia and Mydriasis
weakness and parasympathetic signs) due to C = Cycloplegia = Ciliary muscle paralysis = loss of Accomodation
OVERmedication M = Mydriasis = Dilate (or you dilate your mouth when you say
mydriasis)
How does EDROPHONIUM differentiate myasthenic crisis from
cholinergic crisis? ATROPINE
 IMPROVES muscle strength in MYASTHENIC CRISIS SimD HOMATROPINE, CYCLOPENTOLATE, TROPICAMIDE
 WEAKENS muscle strength in CHOLINERGIC CRISIS Class Cholinergic antagonists (muscarinic)
MOA Competitively blocks ALL muscarinic receptors
RIVASTIGMINE Uses Mydriatic, Cycloplegic, Antidote for
SimD GALANTAMINE, DONEPEZIL, TACRINE organophosphate poisoning, (first choice),
Class Cholinomimetic (indirect – acting) Bradycardia, Hypersalivation
MOA Inhibits acetylcholinesterase. Amplifies endogenously SE Tachycardia, Mydriasis, Cycloplegia, Skin flushing,
released acetylcholine Delirium, Hallucinations
Uses ALZHEIMER’S DISEASE
SE Miosis, Salivation, Nausea, Vomiting, Diarrhea, BENZTROPINE
Bradychardia SimD BIPERIDEN, TRIHEXYPHENIDYL
Class Cholinergic antagonists (muscarinic)
MOA Competitively blocks ALL muscarinic receptors.
Restores neurotransmitter balance in the basal
ganglia
Uses PARKINSON’S DISEASE
SE Blurring of vision, Dry eyes, Constipation, Dry mouth,
Urinary retention
Notes Reduces tremors more than bradykinesia or rigidity
MNEMONICS – Muscarinic Antagonists for Parkinsonism MNEMONICS – Succinylcholine
Try to park your Benz, Beep here! Kapag nakapag-DEPOsit ka sa toilet, SUCCess yun!
TRIhexyphenidyl (DEPOlarizing = SUCCinylcholine
BENZtropine
BIPeriden
ADRENERGIC PHARMACOLOGY
IPRATROPIUM
SimD TIOTROPIUM NOREPINEPHRINE
Class Cholinergic anragonists (muscarinic)  Primary transmitter at the sympathetic post-ganglionic
MOA Blocks muscarinic receptors in bronchial smooth neuron-effector cell synapses in most tissues
muscle. Prevents vagal-stimulated bronchoconstriction. o EXCEPTIONS!
Uses ASTHMA, COPD  Eccrine sweat galnds
SE Dry mouth, Cough, Nasal dryness  Vasodilator sympathetic fibers in skeletal
Notes More effective and less toxic than beta-agonists in muscle
patients with COPD and Heart disease
MNEMONICS – Dopamine / Norepinephrine
KEY LEARNING POINTS – Ipratropium in COPD Dopamine vasoDILATES renal blood vessel while;
Why is ipratropium the preferred bronchodilator in patients with Norepinephrine vasoCONSTRICTS them
comorbid COPD and heart disease?
 Less likely to cause tachycardia; and
 Cardiac arrhythmias
SCOPOLAMINE
Class Cholinergic antagonists (muscarinic)
MOA Competitively blocks ALL muscarinic receptors.
Antagonizes histamine and serotonin
Uses MOTION SICKNESS
SE Drowsiness, Blurring of vision, Dry eyes, Constipation,
Dry mouth, Urinary retention
Notes Applied as a transdermal patch
Atropine Toxicity
 Atropine fever (hyperthermia)
 Atropine flush (cutaneous vasodilation)
 Decreased secretions
 Tachycardia
 Arrhythmias (intravenous conduction block)
 Constipation
 Blurred vision
 CNS toxicity
MNEMONICS – Atropine Toxicity

 HOT as a hare
STEP 1 – SYNTHESIS
 DRY as a bone
 Tyrosine is hydroxylated by tyrosine hydroxylase to DOPA
 RED as a beet
o Inhibited by METYROSINE
 BLIND as a bat
 MAD as a hatter  DOPA is decarboxylated to Dopamine
 Dopamine is hydroxylated to Norepinephrine
Contraindications to Muscarinic Blockers!
 Cautious use in infants STEP 2 – STORAGE
 Hyperthermia due to decreased sweating  Norepinephrine and dopamine are transported into vesicles
 Acute angle-closure glaucoma o Inactivated by monoamine oxidase in the
cytoplasm
 Benign prostatic hyperplasia
 MAOIs increase stores of Norepinephrine and Dopamine
Ganglion Blockers  Vesicular transport inhibited by RESERPINE
 Competitive pharmacologic antagonists at nicotinic
acetylcholine receptors STEP 3 – RELEASE
 First successful agents for the treatment of hypertension but  Entry of calcium triggers interaction among SNARE proteins
were abandoned (VAMPs and SNAPs)
 Adverse effects of ganglion blockade in hypertension are so o Inhibited by GUANETHIDINE
severe o Promoted by AMPHETAMINES and TYRAMINE
HEXAMETHONIUM STEP 4 – TERMINATION

SimD TRIMETHAPHAN  Diffusion and reuptake via NET and DAT in synaptic cleft
Class Cholinergic antagonists (nicotinic) o Inhibited by COCAINE and TCAs
MOA Completitively blocks NN nicotinic ACh receptors  Metabolized by MAO and COMT into metanephrine and VMA
Uses Hypertension (obsolete), Hypertensive emergencies o Inhibited by MAOIs and COMT INHIBITORS
SE POSTURAL HYPOTENSION, Dry mouth, Blurred vision,
Constipation, Sexual dysfunction
Neuromuscular Blockers
 Important for producing complete skeletal muscle
relaxation in surgery
 Classification:
o NONDEPOLARIZING – Tubocurarine,
Pancuronium, Atracurium, Vecuronium
o DEPOLARIZING – Succinylcholine
SITES OF AUTONOMIC DRUG ACTION Miscellaneous Adrenergic Effects
STEPS INHIBITORS  Beta – 3 (β3) Adrenergic Effects
CHOLINERGIC ADRENERGIC Tissue Actions
SYNTHESIS Hemicholinium Metyrosine fat cells Stimulates lipolysis
STORAGE Vesamicol Reserpine
RELEASE Botulinum Guanethidine  Dopamie – 1 (D1) Adrenergic Effects
TERMINATION Tissue Actions
Metabolism Neostigmine MAOIs, COMTIs Renal and other splanchnic Dilates (↓ resistance)
Reuptake NONE Cocaine, TCAs blood vessels
Drug Effects on Adrenergic Transmission  Dopamine – 2 (D2) Adrenergic Effects

 Used in treatment of several diseases (pheochromocytoma, Tissue Action
hypertension) Nerve terminals Inhibits adenylyl cyclase
o Block sympathetic but NOT parasympathetic
functions
 Other drugs promote catecholamine release SYMPATHOMIMETICS
o Predictably cause sympathomimetic effects
Adrenoceptors
Receptor Location G 2nd Major
Messenger Functions
Alpha1 (α1) Effector tissues ↑ IP3, DAG ↑ Ca2+, causes
Smooth muscle Gq contraction,
Glands secretion
Alpha2 (α2) Nerve endings Gi ↓ cAMP ↓ transmitter
Smooth muscle release, causes
contraction
Beta1 (β1) Cardiac muscle Gs ↑ cAMP ↑ heart rate,
JG apparatus force ↑ renin
release
Beta2 (β2) Smooth muscle Gs ↑ cAMP Relax smooth
Liver muscle, ↑
Heart glycogenolysis,
↑ HR, force
Beta3 (β3) Adipose cells Gs ↑ cAMP ↑ lipolysis
Dopamine (D1) Smooth muscle Gs ↑ cAMP Relax renal
vascular
smooth muscle
Alpha – 1 (α1) Adrenergic Effects MOA of Sympathomimetics

Tissue Actions  Direct activation of adrenoceptors
Most vascular smooth muscle Contracts (↑ vasacular resistance)  Indirect activation by increasing concentration of available
Pupillary dilator muscle Contracts (mydriasis) catecholamines in the synapse
Pilomotor smooth muscle Contracts (erects hair) o Release of stored catecholamines
Liver (in some species, eg, rat) Stimulates glycogenolysis o Inhibition of reuptake
Alpha – 2 (α2) Adrenergic Effects EPINEPHRINE

Tissue Actions Class Sympathomimetic (non-selective, direct-acting)
Adrenergic and Cholinergic Inhibits transmitter release MOA Activates α and β adrenergic receptors
nerve terminals α1:vasoconstriction, increases BP
Platelets Stimulates aggregation β1: increased HR, conduction and contractility
Some vascular smooth muscle Contracts β2: bronchodilation
Fat cells Inhibits lipolysis Uses Cardiac arrest, Anaphylaxis, Asthma, COPD, Hemostasis
Pancreatic B cells Inhibits insulin release SE Hypertension, Tachycardia, Ischemia, Hyperglycemia
Beta – 1 (β1) Adrenergic Effects NOREPINEPHRINE

Tissue Action Class Sympathomimetic (non-selective, direct-acting)
Heart Stimulates rate and force MOA Activates α and β adrenergic receptors
JG cells of kidney Stimulates renin release α1:vasoconstriction, increases BP
β1: increased HR, conduction and contractility
Beta – 2 (β2) Adrenergic Effects β2: bronchodilation
Tissue Action Uses Neurogenic shock, Cardiogenic shock (last resort)
Airways, uterine, and vascular Relaxes SE Extreme vasospasm, Tissue necrosis, Excessive blood
smooth muscle pressure increase, Arrhythmias, Infarction, Reflex
Liver (human) Stimulates glycogenolysis bradycardia
Pancreatic (B) cells Stimulates insulin release Notes Compensatory vagal reflexes tend to overcome the
Somatic motor neuron Causes tremor direct positive chronotropic effects
terminals (voluntary muscle)
Heart Stimulates rate and force DOPAMINE
Class Sympathomimetic (non-selective, direct-acting)
MNEMONIC – Beta Receptors MOA Activates α, β and D1 adrenergic receptors
You have 1 HEART and 2 LUNGS! α1:vasoconstriction, increases BP
β1 for the heart; β1: increased HR, conduction and contractility
β2 for the lungs D1: vasodilation in splanchnic and renal vessels
Uses Shock, Heart failure
SE Cardiovascular disturbance, Arrhythmias
Dose-Dependent Actions of Dopamine Selective Beta-2 (β2) Agonists
 LOW DOSE (1-5 mcg/kg/min)
o Vasodilation in the splanchnic and renal vascular ALBUTEROL/SALBUTAMOL
beds via D1 receptors SimD TERBUTALINE, RITODRINE
o Increased renal blood flow and urine output Class Sympathomimetic (beta-2 selective)
MOA Activates β2 receptors in bronchial smooth muscle.
 MEDIUM DOSE (5-15 mcg/kg/min) Causes bronchodilation.
o Increased renal blood flow, heart rate, cardiac Uses Acute asthma attacks (drug of choice), TOCOLYSIS for
contractility, and cardiac output via β1 receptors preterm labor (terbutaline and ritodrine)
SE Tachycardia, Tremors, Nervousness, Restlessness,
 HIGH DOSE (>15 mcg/kg/min) Arrhythmias when used excessively, Loss of
o Vasoconstriction and increased blood pressure via responsiveness (tolerance, tachyphylaxis)
α receptors Notes May precipitate arrhythmias in patients with concurrent
COPD and heart disease
ISOPROTERENOL
Class Sympathomimetic (beta non-selective) Clinical Applications of Sympathomimetics
MOA Non-selectively activates β adrenergic receptors Clinical Condition Desired Parameter Sympathomimetic of
β1: increased HR, conduction and contractility choice
β2: bronchodilation Acute heart failure Increased cardiac β1 & D1 agonists
Uses ASTHMA Septic shock output
SE Cardiovascular disturbance, Arrhythmias Hemostasis Vasoconstriction α1 agonists
Decongestion Temporary
Spinal shock maintenance of BP
Selective Alpha-1 (α1) Agonists Bronchospasm Bronchodilation β2 agonists
Premature labor Uterine smooth
PHENYLEPHRINE muscle relaxation
SimD PSEUDOEPHEDRINE Hypertension Decrease BP α2 agonists
Class Sympathomimetic (alpha-1 selective) Glaucoma
MOA Selectively activates α1 adrenergic receptors
α1: vasoconstriction, increase BP ADRENOCEPTOR BLOCKERS
Uses Decongestants, Mydriatic, Drug-induced hypotension,
Spinal shock
SE REBOUND NASAL CONGESTION, Hypertension, Stroke,
Myocardial Infarction
Notes Ocular administration causes mydriasis WITHOUT
CYCLOPLEGIA
Selective Alpha-2 (α2) Agonists
CLONIDINE
Class Sympathomimetic (alpha-2 selective)
MOA Activates α2 adrenergic receptors
α2: decreases central sympathetic outflow
Uses Hypertension, Cancer pain, Opioid withdrawal
SE Sedation, Rebound hypertension, Dry mouth Non-selective Alpha Blockers
Notes Taper use prior to discontinuation to avoid rebound
hypertension PHENOXYBENZAMINE
To treat rebound hypertension, administer Class Adrenergic antagonist (alpha non-selective)
PHENTOLAMINE MOA Irreversibly blocks α adrenergic receptors (α1 > α2)
Uses PHEOCHROMOCYTOMA (pre-surgical)
METHYLDOPA SE Orthostatic hypotension, Reflex tachycardia,
Class Sympathomimetic (alpha-2 selective) Gastrointestinal irritation
MOA Activates α2 adrenergic receptors Notes Forms covalent bond with α receptors (effects last for
α2: decreases central sympathetic outflow several days)
Uses PRE-ECLAMPSIA
SE Sedation, Hemoyltic anemia (positive Coomb’s test) PHETOLAMINE
Class Adrenergic antagonist (alpha non-selective)
APRACLONIDINE MOA Reversibly blocks α adrenergic receptors (α1 > α2)
SimD BRIMONIDINE Uses Pheochromocytoma (pre-surgical), Antidote to α1
Class Sympathomimetic (alpha-2 selective) agonist oerdose, REBOUND HYPERTENSION
MOA Activates α2 adrenergic receptors SE Orthostatic hypotension, Reflex tachycardia,
α2: decreases secretion of aqueous humor Gastrointestinal irritation
Uses GLAUCOMA
SE Blurring of vision, Dry mouth, Conjunctivitis Selective Alpha1 (α1) Blockers
Selective Beta-1 (β1) Agonists PRAZOSIN

SimD DOXAZOSIN, TERAZOSIN, TAMSULOSIN, SILODOSIN
DOBUTAMINE Class Adrenergic antagonist (alpha-1 selective)
Class Sympathomimetic (beta-1 selective) MOA Selectively blocks α1 adrenergic receptors
MOA Activates β1 adrenergic receptors Uses Benign prostatic hyperplasia, Hypertension
β1: increases HR and contractility SE First dose orthostatic hypotension, Reflex tachycardia
Uses Acute heart failure, Cardiogenic shock (less chance)
SE Tachycardia, Arrhythmias, Tachyphylaxis Notes Tamsulosin is most selective for prostatic smooth
Notes May also be used in cardiac stress testing muscle
KEY LEARNING POINTS – Alpha-1 Selectivity TREATMENT OF GLAUCOMA
What is the pharmacologic advantage of α1 selectivity?
 Relax tachycardia is less common and less severe Complex Organ Control: The Eye!
 Reciprocal control of the PUPIL
MNEMONICS – Isoproterenol o SANS (pupillary dilator muscle)
ISOproterenol is NOT a beta blocker! o PANS (pupillary constrictor)
It is a non-selective beta agonist.
I SOrry ka! Akala ko beta blocker ka!  CILIARY MUSCLE (controls accommodation)
o PANS (primary control of muscarinic receptors
Non-selective Beta Blockers o Insignificant contributions from the SANA
PROPRANOLOL  CILIARY EPITHELIUM

SimD PINDOLOL, TIMOLOL, LABETALOL, CARVEDILOL, o Important receptors with permissive effect on
NADOLOL aqueous humor secretion
Class Adrenergic antagonists (beta non-selective)
MOA Blocks β1 and β2 receptors. Blocks sympathetic effects
on heart and BP. Reduces renin release
Uses Angina prophylaxis, Hypertension, Arrhythmias,
Migraine, Performance anxiety, Hyperthyroidism
SE Bronchospasm, AV block, Heart failure, CNS sedation,
Erectile dysfunction
Notes Masks symptoms of hypoglycemia in diabetics
CARVEDILOL and LABETALOL has combined α and β
blockade (may be used in pheochromocytoma)
Beta-Blockers in Diabetic Patients

 Masking of premonitory symptoms of hypoglycemia from
insulin overdosage (tachycardia, tremor, anxiety)
 Impaired hepatic mobilization of glucose
Intrinsic Sympathomimetic Activity

 Parital agonist activity
 Advantage in treating patients with asthma because these
drugs are less likely to cause bronchospasm
 PINDOLOL , ACEBUTOLOL
MNEMONICS – Beta Blockers with ISA FLOW OF AQUEOUS HUMOR

ISA PA! Isa pa! Isa pang CHICKEN JOY! Ciliary body  Posterior chamber  Anterior chamber angle  Pupil
Intrinsic Sympathomimetic Activity = PINDOLOL, ACEBUTOLOL  Anterior chamber  Trabecular meshwork  Canal of Schlemm 
Uveoscleral veins
Local Anesthetic Activity
Treatment of Glaucoma
 Membrane-stabilizing activity
Drug Class Examples Mechanism
 Disadvantage when beta-blockers are used topically in the Beta blockers TIMOLOL Decreased secretion of
eye: Osmotic agents MANNITOL aqueous humor from the
o Decreases protective reflexes α2 – agonist APRACLONIDINE ciliary epithelium
o Increases the risk of corneal ulceration Carbonic anhydrase ACETAZOLAMIDE
 Absent from TIMOLOL and BETAXOLOL making them inhibitors DORZOLAMIDE
useful in Glaucoma! Cholinomimetics PILOCARPINE Ciliary muscle contraction,
PHYSOSTIGMINE opening of trabecular
MNEMONICS – Nadolol meshwork, increased
outflow
NADOLOL = NAsa DOLO = longest half life!
Prostaglandins LATANOPROST Increased outflow through
canal of Schlemm
Selective Beta-1 (β1) Blockers Non-selective EPINEPHRINE Increased outflow via
α – agonists uveoscleral veins
ATENOLOL
SimD BETAXOLOL, ESMOLOL, ACEBUTOLOL, METOPROLOL .
Class Adrenergic antagonists (beta-1 selective)
MOA Selectively blocks β1 receptors. Blocks sympathetic
effects on heart and BP
Uses Angina, Hypertension, Heart failure, Supraventricular
tachycardia (ESMOLOL ONLY)
SE Bronchospasm (less chance), AV block, Heart failure,
CNS sedation, Erectile dysfunction
Notes Masks symptoms of hypoglycemia in diabetics
ESMOLOL has shortest half-life
MNEMONICS – Esmolol
ESMOLOL = ESMOL (small) = shortest half-life!
DRUGS FOR HYPERTENSION SYMPATHOPLEGICS
CNS Sympathetic Outflow Blockers

(Centrally-Acting Agents)
1. CNS Sympathetic Outflow Blockers

KEY LEARNING POINTS – Target BP
What is the blood pressure goal in hypertensive patients with: CLONIDINE
 No comorbidities? < 140/90 Class Sympathetic Outflow Blocker
 Diabetes mellitus? < 130/80 MOA Activates α2 adrenergic receptors.
 Chronic kidney disease? < 130/80 α2: decreases central sympathetic outflow
Uses Hypertension, Cancer pain, Opioid withdrawal
SE Sedation, Rebound hypertension, Dry mouth
Notes Taper use prior to discontinuation to avoid rebound
hypertension
To treat rebound hypertension, administer
PHENTOLAMINE
METHYLDOPA
Class Sympathetic Outflow Blocker
MOA Activates α2 adrenergic receptors.
α2: decreases central sympathetic outflow
Uses PRE-ECLAMPSIA
SE Sedation, Hemolytic anemia (positive Coomb’s test)
2. Ganglion Blockers
HEXAMETHONIUM
SimD TRIMETHAPHAN
Class Ganglion Blocker
MOA Competitively blocks Nn nicotinic ACh receptors
DIURETICS
Uses Hypertension (obsolete), Hypertensive emergencies
SE POSTURAL HYPOTENSION, Dry mouth, Blurred vision,
HYDROCHLOROTHIAZIDE
Constipation, Sexual dysfunction
SimD CHLORTHALIDONE, INDAPAMIDE, METOLAZONE
Class Thiazide Diuretics
3. Nerve Terminal Blockers
MOA Inhibit Na/Cl transporter in distal convoluted tubule.
Cause moderate diuresis and reduced excretion of
RESERPINE
calcium
SimD GUANETHIDINE
Uses Hypertension (first line), Heart failure, Hypercalciuria,
Class Nerve Termina Blocker
Renal calcium stones, Nephrogenic diabetes insipidus
MOA Irreversibly blocks the vesicular monoamine
SE Hypokalemic metabolic alkalosis,
transporter (VMAT)
Dilutional hyponatremia, Potassium wasting,
Uses Hypertension (obsolete)
Hyperglycemia, Hyperlipidemia, Hyperuricemia,
Sulfa allergy SE Sedation, Severe psychiatric depression,
Suicidal ideation
FUROSEMIDE
SimD BUMETANIDE, TORSEMIDE, ETHACRYNIC ACID* 4. Adrenergic Blockers
(greatest diuretic effect)
Class Loop Diuretics PRAZOSIN
MOA Inhibit Na/K/2Cl transporter in thick ascending limb of SimD DOXAZOSIN, TERAZOSIN, TAMSULOSIN, SILODOSIN
loop of Henle. Cause powerful diuresis and increase Ca+ Class Adrenergic antagonists (alpha-1 selective)
excretion. MOA Selectively blocks α1 adrenergic receptors
Uses Heart failure, Pulmonary edema, Hypertension, Uses Benign prostatic hyperplasia, Hypertension
Hypercalcemia, Acute renal failure, Anion overdose SE FIRST DOSE Orthostatic hypotension,
SE Hypokalemic metabolic alkalosis, Potassium wasting, Reflex tachycardia (less chance)
Dehydration, Ototoxicity, Sulfa allergy, Hyperuricemia, Notes Tamsulosin is most effective for prostatic smooth
Hypomagnesemia, Nephritis, Hypocalcemia muscle!
PROPRANOLOL NIFEDIPINE
SimD PINDOLOL, TIMOLOL, LABETALOL, CARVEDILOL, SimD AMLODIPINE, FELODIPINE, NICARDIPINE,
NADOLOL NISOLDIPINE
Class Adrenergic antagonists (beta non-selective) Class Dihydropyridine Calcium channel Blockers
MOA Blocks β1 and β2 receptors. Blocks sympathetic effects MOA Block voltage-gated L-type calcium channels
on heart and BP. Reduces renin release (vascular > cardiac)
Uses Angina prophylaxis, Hypertension, Arrhythmias, Uses Angina, Hypertension
Migraine, Performance anxiety, Hyperthyroidism SE Constipation, Pretibial edema, Nausea, Flushing,
SE Bronchospasms, AV block, Heart failure, CNS sedation, Dizziness, Gingival hyperplase (less chance)
Erectile dysfunction, Asthma, DM
Notes Masks symptoms of hypoglycemia in diabetics. 3. Parenteral Vasodilators
LABETALOL has combined α and β blockade (may be
used in Pheochromocytoma) NITROPRUSSIDE
Class Vasodilator
KEY LEARNING POINTS – Pheochromocytoma MOA Relaxes venous and arteriolar smoth muscle. Decreases
What drugs are used to control blood pressure in both preload and afterload. Activate guanidyl cyclase.
pheochromocytoma? Increases cGMP release
 PHENOXYBENZAMINE (irreversible alpha selective) Uses Hypertensive emergency, Acute heart failure,
 PHENTOLAMINE (reversible) Cardiogenic shock, Controlled hypotension
 LABETALOL SE Hypotension, Headache, CYANIDE TOXICITY
CARDIOACTIVE DRUGS! FENOLDOPAM

Singh – Vaughan Williams Classification Class Dopamine agonist
 Class I – Rapid Sodium channel Blockers MOA Causes arteriolar vasodilation of the afferent and
 Class II – Beta receptor Blockers efferent arterioles. Increases renal blood flow.
 Class III – Potassium channel Blockers Uses Hypertensive emergency (2nd type of hypertension)
 Class IV – Calcium channel Blockers SE Hypotension, Hypokalemia
Notes Duration of action: 10 minutes
VASODILATORS
ANGIOTENSIN ANTAGONISTS
1. Older Oral Vasodilators
HYDRALAZINE
Class Vasodilator
MOA Alters intracellular Ca2+ metabolism.
Relaxes arteriolar smooth muscle, causing vasodilation.
Decreases afterload.
Uses Hypertension, Heart failure (in combination with
Isosorbide Dinitrate – ISDN), Pre-eclampsia
SE Edema, Reflex tachycardia, Myocardial ischemia, Drug-
induced lupus
Notes Combination treatment with ISDN for Heart failure is
more effective than ACE Inhibitors in Blacks!
MNEMONICS – Drug-induced Lupus!

What medications may cause drug-induced lupus?
It’s HIPP to have LUPUS!!!
 HYDRALAZINE
 ISONIAZID 1. ACE Inhibitors
 PROCAINAMIDE
 PENICILLAMINE CAPTOPRIL
SimD ENALAPRIL, BENAZEPRIL, FOSINOPRIL, LISINOPRIL,
MINOXIDIL QUINAPRIL, RAMIPRIL, TRANDOLAPRIL
Class Vasodilator Class Angiotensin Converting Enzyme (ACE) – Inhibitors
MOA Opens K+ channels in vascular smooth muscles, causing MOA Inhibits ACE and formation of Angiotensin II. Decreases
hyperpolarization, muscle relaxation and vasodilation aldosterone secretion.
Uses Hypertension, ALOPECIA Uses Hypertension, Heart failure, Post-myocardial infarction,
SE Edema, Reflex tachycardia, Angina, Pericarditis, Diabetic nephropathy
Pulmonary hypertension, HYPERTRICHOSIS SE Cough, Taste disturbance, Angioedema, Hypotension,
Teratogen, Hyperkalemia
KEY LEARNING POINTS – Hypertrichosis and Minoxidil Use Notes Slow ventricular remodeling and increases survival in
How does minoxidil cause excessive hair growth? heart failure
 Minoxidil stimulates hair follicles (telogen phase) to Delays progression of diabetic nephropathy!
differentiate into growth follicles (anagen phase) FIRST LINE DRUG FOR CHRONIC HEART FAILURE!!
2. Calcium Channel Blockers KEY LEARING POINTS – ACE-Inhibitors

Why are patients with diabetic nephropathy treated with ACE-
VERAPAMIL Inhibitors?
SimD DILTIAZEM  ACE inhibitors decrease albumin excretion and slow
Class Non-dihydropyridine Calcium channel Blocker progression from micro- to macroalbuminuria
MOA Block voltage-gated L-type calcium channels (renoprotective effect)
(cardiac > vascular)
Uses Angina, Hypertension, Supraventricular tachycardia,
Migraine
SE Constipation, Pretibial edema, Nausea, Flushing,
Dizziness, Gingival hyperplasia, Heart failure, AV block,
Sinus node depression
2. Angiotensin Receptor Blockers
LOSARTAN
SimD CANDESARTAN, VALSARTAN, IRBESARTAN,
EPROSARTAN, TELMISARTAN
Class Angiotensin Receptor Blockers (ARB)
MOA Blockes Angiotensin (AT1 receptors) in vascular smooth
muscle and adrenal cortex. Decreases aldosterone
secretion.
Uses Hypertension, Heart failure, Diabetic nephropathy
SE Hypotension, Teratogen, Hyperkalemia
Notes Slows ventricular remodeling and increases survival in
heart failure
Delays progression of diabetic nephropathy!
KEY LEARNING POINTS – Hyperkalemia

Why do patients taking Angiotensin antagonists (ACE-Is/ARBs) VASODILATORS
develop hyperkalemia?
 ACE-Is/ARBs reduce aldosterone levels and causes 1. Nitrates
potassium retention
AMYL NITRITE
3. Renin Antagonists Class Ultra short-acting Nitrate
MOA Releases nitric oxide (NO), increases cGMP (cyclic
ALISKIREN Guanosine Monophosphate) and relaxes smooth muscles,
Class Renin Antagonist especially vascular
MOA Inhibits renin. Prevents conversion of Angiotensinogen Uses CYANIDE POISONING
to Angiotensin I SE Reflext tachycardia, Orthostatic hypotension, Headache,
Uses HYPERTENSION METHEMOGLOBINEMIA
SE Headache, Diarrhea, Angioedema, Renal impairment
Notes Not used with ACE-Is/ARBs, may lead to hyperkalemia KEY LEARNING POINTS – Cyanide
Which portion of the electron transport chain is affectec by
Malignant Hypertension (> 210/150) Cyanide?
 Complex IV (cytochrome oxidase) of the Electron
 Accelerated form of severe hypertension associated with
Transport Chain
rising blood pressure and rapidly progressing end-organ
damage
What is the antidote for Cyanide poisoning?
 MANAGEMENT!
 Inhaled amyl nitrite + IV sodium nitrite + IV sodium
o Powerful vasodilators (nitroprusside,
thiosulfate
fenoldopam, or diazoxide) combined with
diuretics (furosemide) and beta blockers to lower
MONDAY DISEASE
BP to 140-160/90-110
 Due to occupational exposure to nitrates
 Alternating development of tolerance (during the work
DRUGS USED IN THE TREATMENT OF week) and loss of tolerance (over the weekend) every
ANGINA PECTORIS Monday!
Atherosclerotic Angina NITROGLYCERIN

 Angina of effort or “Classic Angina” SimD ISOSORBIDE DINITRATE, ISOSORBIDE MONONITRATE
 Associated with atheromatous plaques that partially occlude Class Short-acting Nitrate
1 or more coronary arteries MOA Releases Nitric oxide (NO), increases cGMP (cyclic
 Constitutes about 90% of angina cases Guanosine Monophosphate) and relaxes smooth muscles,
especially vascular
Vasospastic Angina Uses ANGINA, ACUTE CORONARY SYNDROME
 Rest angina, Variant angina, or “Prinzmetal’s Angina” SE Reflex tachycardia, Orthostatic hypotension, Headache,
 Responsible for less than 10% of cases TOLERANCE (transdermal)
 Involves reversible spasm of coronaries, usually at the site Notes Dangerous hypotension with PDE inhibitors
of an atherosclerotic plaque
 May deteriorate into unstable angina
Unstable Angina
 Unstable/crescendo angina / “Acute Coronary Syndrome”
 Increase frequency and severity of attacks that result form a
combination of atherosclerotic plaques, platelet aggregation
and vasospasms
 Immediate precursor of Myocardial infarction
Therapeutic Strategies in Angina

 Defect that causes anginal pain is inadequate coronary
oxygen delivery relative to the myocardial oxygen
requirement
 Can be corrected in 2 ways: KEY LEARNING POINTS – Nitrate-Induced Headache
o Increasing oxygen delivery Why do patients taking nitrates usually experience throbbing
o Reducing oxygen requirement headaches?
 Due to meningeal artery vasodilation!
2. Calcium Channel Blockers METABOLISM MODIFIERS
NIFEDIPINE TRIMETAZIDINE
SimD AMLODIPINE, FELODIPINE, NICARDIPINE, SimD VASTAREL
NISOLDIPINE Class Metabolism Modifier
Class Dihydropyridine Calcium channel Blockers MOA Impairs glucose utilization through Fatty acid
MOA Block voltage-gated L-type calcium channels metabolism.
(vascular > cardiac) Inhibit beta oxidation of Fatty acids by inhibiting 3-
Uses Angina, Hypertension ketoacyl thiolase which enhances glucose oxidation
SE Constipation, Pretibial edema, Nausea, Flushing, Notes FIRST CYTOPROTECTIVE ANTI-ISCHEMIC AGENT
Dizziness, Gingival hyperplasia (less chance)
VERAPAMIL DRUGS USED IN HEART FAILURE

SimD DILTIAZEM
Class Non-dihydropyridine Calcium channel Blocker Pathophysiology of Congestive Heart Failure
MOA Block voltage-gated L-type calcium channels  Fundamental physiologic defect is decrease in cardiac
(cardiac > vascular) output relative to the needs of the body
Uses Angina, Hypertension, Supraventricular tachycardia,  Frequently associated with chronic hypertension, valvular
Migraine disease, coronary artery disease, and cardiomyopathies
Dizziness, Gingival hyperplasia, Heart failure, AV block, Therapeutic Strategies for CHF
Sinus node depression  Removal of retained salt and water with diuretics
 Reduction of afterload and salt and water retention by
DILTIAZEM means of ACE Inhibitors
Class Non-dihydropyridine Calcium channel Blocker  Reduction of excessive sympathetic stimulation by means of
MOA Block voltage-gated L-type calcium channels beta-blockers
(cardiac > vascular)  Reduction of preload or afterload with vasodilators
Uses Angina, Hypertension, Supraventricular tachycardia,  Direct augmentation of depressed cardiac contractility with
Vasospasm, RAYNAUD’S PHENOMENON positive inotropic drugs
Dizziness, Heart failure, AV block, Sinus node depression Current Clinical Evidence for CHF
 ACUTE HEART FAILURE
KEY LEARNING POINTS – Calcium Channel Blockers o Should be treated with loop diuretics
Why is calcium-dependent neurotransmission or hormone release o If very severe, use prompt-acting positive
not affected by Calcium Channel Blockers? inotropes (beta-agonists or PDE inhibitors) and
 CCBs block L-type calcium channels ONLY! vasodilators
 Other functions use N-, P- and R-types
 CHRONIC HEART FAILURE
What drug can cause gingival hyperplasia? o Treated with diuretics (often loop +
NapaCa-Pangit ng gingiVa mo! spironolactone) plus an ACE Inhibitor; and if
 NIFEDIPINE tolerated, add a beta-blocker
 CYCLOSPORINE o DIGITALIS may be helpful if systolic dysfunction is
 PHENYTOIN prominent! (cardio/renal-protective)
 VERAPAMIL
KEY LEARNING POINTS – Heart Failure
CARDIAC DEPRESSANTS Which type of heart failure presents with:
 LEFT HEART FAILURE
1. Beta Blockers o Orthopnea
o Paroxysmal Nocturnal Dyspnea (PND)
PROPRANOLOL o Pulmonary congestion
SimD ATENOLOL, METOPROLOL, other beta-blockers
Class Beta Receptor Blocker  RIGHT HEART FAILURE
MOA Blocks sympathetic effects on heart and Blood Pressure. o Hepatomegaly
Reduces renin release o Edema
Uses Angina prophylaxis, Hypertension, Arrhythmias, o Engorged Neck Veins
Migraine, Performance anxiety
SE Excessive β blockade: Bronchospasms, AV block, Heart
failure, CNS sedation, Masks hypoglycemia in diabetic
patients, Erectile dysfunction
Effects of Drug Combinations

Nitrates BB or CCB Combined
Alone Alone Nitrate and
BB or CCB
Heart rate Reflex increase DECREASE DECREASE DIGOXIN
Arterial pressure Decrease DECREASE DECREASE Class Cardiac glycoside
End-diastolic DECREASE Increase DECREASE MOA Inhibits Na/K ATPase, Increases intracellular Ca,
pressure
increasing cardiac contractility
Contractility Reflex increase DECREASE No effect or
decrease Uses Heart failure, Nodal arrhythmias
Ejection time Reflex increase Increase No effect SE Narrow therapeutic index, Arrhythmias, Vomiting,
Net myocardial DECREASE DECREASE DECREASE Diarrhea, VISUAL CHANGES
O2 requirement Intxn Reduced clearance with Quinidine, Amiodarone,
Cyclosporine, Diltiazem, and Verapamil
Notes Arrhythmogenesisincreased by hypokalemia,
hypomagnesemia, and hypercalcemia
MNEMONICS – Narrow Therapeutic Index 6. Vasodilators
What drugs have narrow therapeutic index?  NITROPRUSSIDE or NITROGLYCERIN for acute severe
WALA na Cyang PaPa!! VasTeD na!!! failure with congestion
 Warfarin  Dramatically effective in CHF due to increased afterload (eg,
 Aminoglycosides continuing hypertension in an individual who has just had
 Lithium an infarct)
 Amphotericin B  HYDRALAZINE and ISOSORBIDE DINITRATE has been
 Carbamazepine shown to reduce mortality in African Americans
 Phenobarbital  Calcium channel blockers are of NO VALUE in CHF
 Phenytoin
 Vancomycin MNEMONICS – Survival in CHF
 Theophylline What drugs have been shown to improve survival in cases of heart
 Digoxin failure?
ABA!! Buhay ka pa!!
Digitalis Toxicity  ACE Inhibitors
 Increased by HYPOKALEMIA, HYPOMAGNESEMIA and  Beta-blockers
HYPERCALCEMIA (same as Thiazide)  Aldosterone Antagonists
o Loop diuretics and Thiazides may significantly
reduce serum potassium and precipitate digitalis
toxicity
o Digitalis-induced vomiting may deplete serum
magnesium and similarly facilitate toxicity
ANTI-ARRHYTHMIC DRUGS
Treatment of Digitalis Toxicity

 CORRECTION OF POTASSIUM/MAGNESIUM DEFICIENCY
 ANTI-ARRHYTHMIC DRUGS
o Drug of choice is: LIDOCAINE
o Electronic pacemaker may be required in severe
cases
 DIGOXIN ANTIBODIES
o Digoxin antibodies (Fab fragments; Digibind)
Arrhythmogenic Mechanisms
o May save patients who would otherwise die
 ABNORMAL AUTOMATICITY
o Pacemaker acitivity that originates anywhere
OTHER DRUGS FOR CONGESTIVE HEART FAILURE
other than in the sinoatrial node
 ABNORMAL CONDUCTION
1. Diuretics
o Conduction of an impulse that does not follow the
 First-line therapy for both systolic and diastolic failure! defined path or re-enters tissue previously excited
 FUROSEMIDE for immediate reduction of the pulmonary
congestion and severe edema associated with acute heart TORSADES DE POINTES
failure  Often induced by anti-arrhythmics and other drugs that
 SPIRONOLACTONE (aldosterone antagonists) and change the shape of action potential and prolong QT interval
EPLERENONE have significant long-term benefits and can  “All anti-arrhythmics are PRO-ARRHYTHMICS”
reduce mortality in chronic failure
2. Angiotensin Antagonists
 First-line drugs for Chronic Heart Failure!
 Reduce aldosterone secretion, salt and water retention, and
vascular resistance
 Decrease ventricular remodeling (cardiprotective)
 Reduce morbidity and mortality in chronic heart failure ECG Morphology
 ARBs have the same benefits as ACE-Inhibitors  Polymorphic ventricular tachycardia, often displaying
WAXING and WANING QRS AMPLITUDE
3. Beta1-Selective Sympathomimetics  Associated with Long QT Syndrome
 DOBUTAMINE (β1 – selective) and DOPAMINE are useful in o Heritable abnormal prolongation of the QT interval
Acute heart failure caused by mutations in the IK or INa channel
 NOT appropriate for chronic failure because of tolerance, proteins
lack of oral efficacy and significant arrhythmogenic effects.
Singh–Vaughan Williams Classification
4. Beta-Blockers  Based loosely on the channel or receptor affected:
 CARVEDILOL, LABETALOL, and METOPROLOL reduce o CLASS 1: Sodium channel Blockers
progression of chronic heart failure o CLASS 2: Beta-adrenoceptor Blockers
 Beta-blockers are NOT of value in acute failure and may be o CLASS 3: Potassium channel Blockers
detrimental if systolic dysfunction is marked o CLASS 4: Calcium channel Blockers
5. Phosphodiesterase Inhibitors CLASS 1 ANTI-ARRHYTHMICS

 Examples: INAMRINONE, MILRINONE  Have local anesthetic activity
 Mechanism of Action:  Acts on PHASE 0 of cardiac action potential
o Increase cAMP by inhibiting its breakdown by  Further subdivided based on their effects on AP duration
phosphodiesterase; o GROUP 1A drugs prolong the AP duration
o Increase intracellular Ca2+ o GROUP 1B drugs shorten the AP duration
o Vasodilation o GROUP 1C drugs have NO EFFECT on AP duration
 Should NOT be used in chronic failure because they increase
morbidity and mortality
MOA of CLASS 1 Anti-arrhythmics 2. Class 1B Anti-arrhythmics
 ALL group 1 drugs slow or block conduction in ischemic and
depolarized cells; and slow or abolish abnormal pacemakers MOA of GROUP 1B Anti-arrhythmics
 Most selective agents (GROUP 1B) have significant effects  REDUCES AP duration
on sodium channels in ischemic tissue, BUT negligible effects  Slows recovery of sodium channels from inactivation
on normal cells leading to prolonged ERP
 Use dependent or state dependent in their action!  Selectively affects ischemic or depolarized Purkinje and
o Selectively depress tissues that are frequently ventricular tissue
depolarizing o Because these agents have little effect on normal
o Selectively depresses tissues that are relatively cardiac cells, they have LITTLE EFFECT on the
depolarized during rest ECG
 AMIODARONE has class A1 activity
LIDOCAINE
KEY LEARNING POINTS – CLASS 1 Anti-arrhythmics SimD MEXILETINE, TOCAINIDE, PHENYTOIN
What are the effects of class 1 anti-arrhythmics on action potential Class Class 1B Anti-arrhythmics
duration? MOA Highly-selective use- and state-dependent INa block;
 CLASS 1A: prolongs AP duration Minimal effect in normal tissue; NO EFFECT on IK
 CLASS 1B: shortens AP duration Uses Drug of choice for Ventricular arrhythmias post-
 CLASS 1C: no effect on AP duration myocardial infarction; Digoxin-induced arrhythmias
SE CNS stimulation, Cardiovascular depression,
1. Class 1A Anti-arrhythmics Arrhythmias, Allergy, Seizure, AGRANULOCYTOSIS*
(Tocainide)
PROCAINAMIDE Notes Hyperkalemia exacerbates cardiac toxicity
Class Class 1A Anti-arrhythmic Lidocaine is the LEAST cardiotoxic among conventional
MOA Use- and State-dependent block INachannels; Some block anti-arrhythmias
of IK channels.
Slowed conduction velocity and pacemaker activity; MNEMONICS – Class 1B Anti-arrhythmics!
Prolonged action potential duration and refractory Class 1B:
period I Buy Mexican Taco’s from Lily
Uses Atrian and Ventricular arrhythmias, especially after  MEXILETINE
Myocardial Infarction  TOCAINIDE
SE Arrhythmias, Hypotension, Lupus-like syndrome  LIDOCAINE
Notes Hyperkalemia exacerbates cardiac toxicity;
Duration of action: 2-3 hours What are the drugs that can cause AGRANULOCYTOSIS?
AGRANULOCYTOSIS!! CCCAPPIT!
DISOPYRAMIDE  CLOZAPINE
Class Class 1A anti-arrhythmic  CO-TRIMOXAZOLE
MOA Use- and State-dependent block INachannels; Some block  COLCHICINE
of IK channels.  AMINOPYRINE
Slowed conduction velocity and pacemaker activity;  PHENYLBUTAZONE
Prolonged action potential duration and refractory  PROPYLTHIOURACIL (PTU)
period  INDOMETHACIN
Uses Atrial and Ventricular arrhythmias  TOCAINIDE
SE Arrhythmias, Hypotension, Marked anti-muscarinic
effects, Heart failure 3. Class 1C Anti-arrhythmics
Notes Hyperkalemia exacerbates cardiac toxicity
MOA of GROUP 1C Anti-arrhythmics
QUINIDINE  Powerful depressant of Sodium current
Class Class 1A anti-arrhythmic  Can markedly slow conduction velocity in atrial and
MOA Use- and State-dependent block INachannels; Some block ventricular cells
of IK channels.  ECG effects:
Slowed conduction velocity and pacemaker activity; o NO EFFECT on ventricular AP duration or the QT
Prolonged action potential duration and refractory interval
period o Increases the QRS duration (pro-arrhythmics)
Uses Atrial and Ventricular arrhythmias, MALARIA
SE Arrhythmias (torsades), Hypotension, CINCHONISM FLECAINIDE
(headache, vertigo, tinnitus), Cardiac depression, GI SimD PROPAFENONE, ENCAINIDE, MORICIZINE
upset, Autoimmune reactions (ITP) Class Class 1C anti-arrhythmic
Notes Hyperkalemia exacerbates cardiac toxicity. MOA Selective use- and state-dependent block INachannels;
Reduces clearance of digoxin! Slowed conduction velocity and pacemaker activity.
Uses REFRACTORY ARRHYTHMIAS
MNEMONICS – Class 1A Anti-arrhythmics! SE Increased arrhythmias (pro-arrhythmic effects), CNS
Class 1A: excitation
I Am the Queen who Proclaimed Diso’s pyramid!! Notes Hyperkalemia exacerbates cardiac toxicity,
 QUINIDINE contraindicated for post-MI arrhythmias
 PROCAINAMIDE
 DISOPYRAMIDE MNEMONICS – Class 1C Anti-arrhythmics!
Class 1C:
Treatment of Class A1 Overdose Chicken ay Pagain For Enrico!!
 SODIUM LACTATE to reverse drug-induced arrhythmias  PROPAFENONE
 PRESSOR SYMPATHOMIMETICS to reverse drug-induced  FLECAINIDE
hypotension, if indicated:  ENCAINIDE
Summary of the Clinical Uses of Class I Anti-arrhythmics DOFETILIDE
 Class 1A SimD IBUTILIDE
o All types of Arrhythmias Class Class 3 Anti-arrhythmics
o Arrhythmias in acute phase of Myocardial MOA Selective IK block; Prolonged action potential and QT
Infarction interval
o Procainamide and Amiodarone for __________________ Uses Treatment and prophylaxis of ATRIAL FIBRILLATION
 Class 1B SE Torsades de Pointes
o Acute ventricular arrhythmias, especially post-MI
o Atrial arrhythmias due to Digitalis SOTALOL
 Class 1C Class Class 3 Anti-arrhythmics
o Refractory arrhythmias MOA IK block and beta-adrenoceptor block
Uses Ventricular arrhythmias, Atrial fibrillation,
CLASS 2 ANTI-ARRHYTHMICS Supraventricular tachycardia
SE Dose-related torsade de pointes, Excessive beta-
MOA of CLASS 2 Anti-arrhythmics blockade (sinus bradycardia, asthma)
 Primarily cardiac beta-adrenoceptor blockade and
reduction in cAMP AMIODARONE
o Reduction of both sodium and calcium currents SimD DRONEDARONE
o Suppression of abnormal pacemakers Class Class 3 Anti-arrhythmics
 AV node is particulary sensitive to blockers MOA Strong IK block produces marked prolongation of action
o PR interval is usually prolonged potential and refractory period.
 Act on PHASE 4 Group 1 activity slows conduction velocity;
 SOTALOL and AMIODARONE also have group 2 effects Group 2 and 4 activity confer additional anti-
arrhythmic activity
PROPRANOLOL Uses REFRACTORY ARRHYTHMIAS, Used off-label in many
SimD METOPROLOL, TIMOLOL arrhythmias
Class Class 2 Anti-arrhythmics SE Microcrystalline deposits in cornea and skin, Thyroid
MOA Block off beta-receptors; Slowed pacemaker activity dysfunction (hyper- or hypo-), Paresthesias, Tremor,
Uses Post-MI prophylaxis against sudden death, Pulmonary fibrosis
Thyrotoxicosis Notes MOST EFFICACIOUS of all Anti-arrhythmic drugs
SE Bronchospasms, Cardiac depression, AV block,
Hypotension KEY LEARNING POINTS – Amiodarone Toxicity
Notes In CHF, reduces progression and decreases incidence of AMIODARONE TOXICITY
potentially fatal arrhythmias.  Pulmonary fibrosis
SOTALOL is a beta-blocker anti-arrhythmic that has  Paresthesias
Class 3 properties.  Tremors
 Thyroid dysfunction
ESMOLOL  Corneal deposits
Class Class 2 Anti-arrhythmics  Skin deposits
MOA Selectively block off beta-1 receptors,
Slowed pacemaker activity MNEMONICS – Class 3 Anti-arrhythmics
Uses Acute perioperative and thyrotoxic arrhythmias, AIDS!!
Supraventricular tachycardia  AMIODARONE
SE Bronchospasms, Cardiac depression, AV block,  IBUTILIDE
Hypotension  DOFETILIDE
 SOTALOL
KEY LEARNING POINTS – Beta Blockers!
What are the major subgroups of Beta blockers? CLASS 4 ANTI-ARRHYTHMICS
Non-selective PROPRANOLOL, MOA of CLASS 4 Anti-arrhythmics

TIMOLOL (Glaucoma)  Effective in arrhythmias that must traverse calcium-
Beta1-selective ACEBUTOLOL dependent cardiac tissue (eg, the AV Node)
ATENOLOL  Cause a state- and use-dependent selective depression of
BETAXOLOL calcium currents
ESMOLOL  AV conduction velocity is decreased and effective refractory
METOPROLOL period increased
Partial agonist PINDOLOL, ACEBUTOLOL  ECG morphology
Lacking local anesthetic effect TIMOLOL o PR interval is consistently INCREASED!
Low lipid solubility ATENOLOL
Shortest-acting ESMOLOL KEY LEARNING POINTS – Dihydropyridine CCBs
Longest-acting NADOLOL Why are dihydropyridine calcium channel blocker NOT useful as
Combined α and β blockade CARVEDILOL, LABETALOL anti-arrhythmics?
 Dihydropyridine CCBs evoke compensatory sympathetic
discharge which facilitates arrhythmias rather than
terminating them
CLASS 3 ANTI-ARRHYTHMICS  > vascular  vasodilator  ↑ HR response
MOA of CLASS 3 Anti-arrhythmics VERAPAMIL

 Act on PHASE 3 Class Non-dihydropyridine Calcium channel Blocker
 Hallmark is PROLONGATION of the AP Duration MOA Block voltage-gated L-type calcium channels
o Caused by blockade of IK potassium channels that (cardiac > vascular)
are responsible for the repolarization of the AP Uses Angina, Hypertension, Supraventricular tachycardia,
o Results in an increase in ERP and reduces the Migraine
ability of the heart to respond to rapid tachycardias SE Constipation, Pretibial edema, Nausea, Flushing,
 ECG Morphology Dizziness, Gingival hyperplasia, Heart failure, AV block,
o Increase in QT interval Sinus node depression
DILTIAZEM
Class Non-dihydropyridine Calcium channel Blocker
MOA Block voltage-gated L-type calcium channels
(cardiac > vascular)
Uses Angina, Hypertension, Supraventricular tachycardia,
Vasospasm, RAYNAUD’S PHENOMENON
Dizziness, Heart failure, AV block, Sinus node depression
Summary of the Effects of Anti-arrhythmics Drugs

Class Prototype Effects on AP Effects on
duration ECG
1A Procainamide PROLONGS PROLONGS PR interval,
PROLONGS QRS duration,
PROLONGS QT interval
1B Lidocaine SHORTENS NO EFFECT on normal cells
1C Flecainide NO EFFECT PROLONGS QRS duration
2 Propranolol NO EFFECT PROLONGS PR interval
3 Dofetilide PROLONGS PROLONGS QT interval
4 Verapamil NO EFFECT PROLONGS PR interval
MISCELLANEOUS ANTI-ARRHYTHMICS
ADENOSINE
CARBONIC ANHYDRASE INHIBITORS
Class Miscellaneous Anti-arrhythmic
MOA Increase in diastolic Ik of AV node that causes marked Proximal Convoluted Tubule
hyperpolarization and conduction block; Reduced ICa
 Carries out isosmotic reabsorption of amino acids, glucose,
Uses AV donal arrhythmias; Drug of Choice for and numerous cations
PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA o Major site for sodium chloride and sodium
SE Flushing, Hypotension, Transient chest pain, Dyspnea bicarbonate reabsorption (60-70%)
Notes Potent bronchoconstrictor!  Site of uric acid transport
 Site of action of carbonic anhydrase inhibitors
Potassium Ion
 MOA: Depresses ectopic pacemaker, including those caused
by digitalis toxicity
 When treating arrhythmias, serum potassium should be
measured and normalized if ABNORMAL
o Hypokalemia is associated with an increased
incidence of arrhythmias, especially in patients
receiving Digitalis
o Excessive Potassium levels depress conduction
and can cause re-entry arrhythmias
Magnesium Ion
 MOA: Poorly understood, possible increase in Na+/K+
ATPase activity
 Similar depressant effects as potassium on digitalis-induced
arrhythmias
 Effective in some cases of torsades de pointes
NON-PHARMACOLOGIC TREATMENT ACETAZOLAMIDE

 Electrical Methods SimD DORZOLAMIDE, BRINZOLAMIDE, METHAZOLAMIDE
o External Defibrillator DICHLORPHENAMIDE
o Implanted Defibrillator Class Carbonic Anhydrase Inhibitors
o Implanted pacemaker MOA Inhibits carbonic anhydrase in proximal tubule.
o Radiofrequency Ablation of Arrhythmogenics In Glaucoma, secretion of aqueous humor is reduced,
and in Mountain sickness, metabolic acidosis increases
respiration.
DIURETICS Uses Glaucoma, Mountain Sickness, Edema with alkalosis
SE Drowsiness, Paresthesia, Sulfa allergy, Renal calcium
stones, Potassium wasting, Hyperchloremic metabolic
acidosis, Hepatic encephalopathy in cirrhotic patients
MNEMONICS – Metabolic Acidosis

ACIDazolamide causes ACIDosis
LOOP DIURETICS
Thick Ascending Limb of the Loop of Henle

 Responsible for a significant percentage of sodium chloride
reabsorption via the Na+/K+/2Cl- transporter
 Site of calcium and magnesium reabsorption
 Site of action of loop diuretics
 Prostaglandins are important in maintaining glomerular
filtration
 NSAIDs decrease the efficacy of loop diuretics
HYDROCHLOROTHIAZIDE
SimD CHLORTHALIDONE, INDAPAMIDE, METOLAZONE
Class Thiazide Diuretics
MOA Inhibit Na/Cl transporter in distal convoluted tubule.
Causes moderate diuresis and reduced excretion of
calcium.
Uses Hypertension, Heart failure, Hypercalciuria, Renal
calcium stones, Nephrogenic diabetes insipidus
SE Hypokalemic metabolic alkalosis, Dilutional
hyponatremia, Potassium wasting, Hyperglycemia,
Hyperlipidemia, Hyperuricemia, Hypercalcemia, Sulfa
allergy
Notes Synergistic effect with loop diuretics.
Efficacy decreased by NSAIDs.
MNEMONICS – Thiazide Diuretics

HYPER GLUC!!
FUROSEMIDE  HyperGlycemia
SimD BUMETANIDE, TORSEMIDE,  HyperLipidemia
ETHACRYNIC ACID (Phenoxy- derivative)  HyperUricemia
Class Loop Diuretic  HyperCalcemia
MOA Inhibit Na/K/2Cl transporter in thick ascending limb of
loop of Henle. Causes powerful diuresis and increased POTASSIUM – SPARING DIURETICS
calcium excretion
Uses Heart failure, Pulmonary edema, Hypertension, Cortical Collecting Ducts
Hypercalcemia, Acute renal failure, ANION OVERDOSE  Last tubular site of sodium reabsorption
SE Hypokalemic metabolic alkalosis, Potassium wasting, o Responsible for reabsorption of 2-5% of the total
Dehydration, Ototoxicity, Sulfa allergy, Hyperuricemia, filtered Sodium
Hypocalcemia, Hypomagnesemia, Nephritis  Under the influence of ALDOSTERONE, reabsorption of
Notes Synergistic ototoxicity with aminoglycosides. sodium occurs via channels
Efficacy decreased by NSAIDs o Accompanied by an equivalent loss of potassium or
hydrogen ions
MNEMONICS – Loop Diuretic Toxicities  Primary site of Acidification of the Urine!
What are the adverse effects associated with loop diuretics?  Last site of Potassium excretion
OH DANG!! o Sites of action of the potassium-sparing diuretics
 Ototoxicity
 Hypokalemia SPIRONOLACTONE
 Dehydration SimD EPLERENONE
 Allergy to Sulfa
Class Potassium-sparing Diuretic (Aldosterone antagonists)
 Nephritis
MOA Steroid inhibitors of cytoplasmic aldosterone receptor
 Gout
in cortical collectind ducts. Reduces K+ excretion.
Uses Hyperaldosteronism, Hypertension, Heart failure,
THIAZIDE DIURETICS
Hypokalemia
SE Hyperkalemia, GYNECOMASTIA (spironolactone only),
Distal Convoluted Tubule
Impotence, Benign prostatic hyperplasia,
 Actively pumps sodium and chloride out of the lumen of the Hyperchloremic metabolic acidosis
nephron via the Na+/Cl- carrier
Notes Eplerenone reduces progression of DM nephropathy
 Site of action of thiazide diuretics and reduces mortality post-MI
 Responsible for approximately 5-8% of sodium
reabsorption AMILORIDE
 Calcium is also reabsorbed in this segment under the control SimD TRIAMTERENE
of PARATHYROID HORMONE (PTH)
Class Potassium-sparing Diuretic (Sodium blocker)
MOA Inhibit ENaC epithelial sodium channels in cortical
collecting duct, reduces Na+ reabsorption and K+
excretion
Uses HYPOKALEMIA
SE Hyperkalemia, Acute renal failure (with indomethacin),
Kidney stones, Metabolic acidosis
Notes Should never be given with potassium supplements!
MNEMONICS – Potassium-sparing Diuretics

The K+ STAEs (stays) with K-sparing diuretics!!
 SPIRONOLACTONE
 TRIAMTERENE
 AMILORIDE
 EPLERENONE
Which drugs can cause GYNECOMASTIA?

Some Drugs Create Awesome Knockers!
 SPIRONOLACTONE
 DIGOXIN
GYNECOMASTIA, IMPOTENCE, STERILITY!!  CIMETIDINE
 Ketoconazole  ALCOHOL
 Spironolactone  KETOCONAZOLE
 Cimetidine
OSMOTIC DIURETICS SUMMARY TABLE!
MOA of Osmotic Diuretics DRUG MOA/ Urinary Blood
 Remains in the lumen and “holds” water by virtue of its LOCATION Electryolytes pH
osmotic effect ACETAZOLAMIDE Inhibition of ↑Na, K Acidosis
 Reabsorption of water is also reduced in the descending carbonic ↓HCO3
limb of the loop of Henle and the collecting tubule anhydrase in
PCT
MANNITOL FUROSEMIDE Inhibition of ↑Na, K, Ca, Alkalosi
SimD GLYCERIN, ISOSORBIDE, UREA Na/K/Cl co- Mg, Cl s
Class Osmotic Diuretic transporter
MOA Osmotically retains water in tubule by reducing in Thick
reabsorption in proximal tubule, descending limb of ascending
Henle’s loop, and collecting ducts; limb of the
In the periphery, mannitol extracts water from cells loop of Henle
Uses RHABDOMYOLYSIS, Hemolysis, Increased intracranial HYDROCHLORO- Inhibition of ↑Na, K, Cl alkalosis
pressure, Acute glaucoma THIAZIDE NaCl co- ↓Ca
SE Transient volume expansion (hyponatremia, pulmonary transporter
edema; followed by hypernatremia), Headache, Nausea, in DCT
Vomiting, Diarrhea SPIRONOLACTONE Blocks Na ↓K+ acidosis
channels, ↑Na (small)
Blocks
ADH AGONISTS / ANTAGONISTS aldosterone
Medullat Collecting Duct in collecting
 Reabsorption of water occurs under the control of ANTI- tubules
DIURETIC HORMONE (ADH)
 Site of action of ADH agonists and antagonists DRUGS USED IN THE TREATMENT OF
HYPERLIPIDEMIAS
ANTIDIURETIC HORMONE
SimD DESMOPRESSIN
Class ADH Agonist
MOA Agonists at V1 and V2 ADH receptor. Activate insertion
of aquaporin water channels in collecting tubule.
Vasoconstriction
Uses Central diabetes insipidus, Nocturnal enuresis,
Hemophilia, von Willebrand’s disease Pathogenesis of Hyperlipoproteinemia
SE Hyponatremia, Hypertension  Premature atherosclerosis is strongly associated with
elevated concentrations of lipoproteins
o Elevated level of low-density lipoproteins (LDL)
CONIVAPTAN o Depressed level of high-density lipoproteins (HDL)
SimD TOLVAPTAN, LIXIVAPTAN, DEMECLOCYCLINE, o Hypertriglyceridemia
LITHIUM  Hyperchylomicronemia is associated with a high incidence
Class ADH Antagonist of acute pancreatitis
MOA Antagonist at V1a and V2 receptors
Uses SIADH, Hyponatremia Treatment Strategies: DIET!
SE Infusion site reactions, Hyperkalemia, Nephrogenic  Cholesterol and saturated fats are the primary dietary
diabetes insipidus, Renal failure (lithium, factors that contribute to elevated plasma lipoproteins
demeclocycline), Bone and teeth abnormalities  Dietary measures constitute the first method of
(demeclocycline) management
Notes CENTRAL PONTINE MYELINOLYSIS may occur with o May be sufficient to reduce lipoprotein levels to a
rapid correction of hyponatremia safe range
 ALCOHOL raises triglyceride and VLDL levels
o Should be avoided by patients with
QUICK MEMORY TIPS! hypertriglyceridemia!
Urine Na+: INCREASES (all diuretics); serum NaCl may decrease Treatment Strategies: DRUGS!
as a result!  Choice of drug is based on the lipid abnormality
 Drugs most effective at lowering LDL cholesterol
Urine K+: INCREASES (ALL, except K-sparing Diuretics); serum K+ o Statins, Resins, Ezetimibe, Niacin
may decrease as a result!  Drugs most effective at lowering triglyceride and VLDL and
raising HDL
Urine Ca2+: INCREASES (in loop diuretics); decrease serum Ca2+ o Niacin, Fibrates
DECREASES (in thiazide diuretics); increase serum Ca2+
Blood pH: DECREASES pH (acidemia)

 Furosemide
 Carbonic anhydrase inhibitors, decreases HCO3
reabsorption; prevents K+ secretion and H+ secretion
 K-sparing diuretics, aldosterone blockade
Blood pH: INCREASES pH (alkalemia)

 Both loop diuretics and thiazide diuretics
STATINS/HMG-COA REDUCTASE INHIBITORS CHOLESTEROL ABSORPTION BLOCKERS
MOA of Statins MOA of Ezetimibe

 Inhibition of hepatic cholesterol synthesis contributes a  Converted in the liver to the active glucuronide form
small amount to drug effect  Inhibits NPC1L1 transporter (a specific transport process
 Greater cholesterol-lowering effect derived from the in jejunal enterocyte) that mediates gastrointestinal uptake
compensatory response of the liver of cholesterol and phytosterols
o Increased number of high-affinity LDL receptors,  Prevents absorption of dietary cholesterol and cholesterol
which clear LDL and VLDL remnants from the that is excreted in bile
blood o Reduces cholesterol in tightly regulated hepatic
 Direct anti-atherosclerotic effects pool
 Prevent bone loss o Compensatory increase in the synthesis of high-
affinity LDL receptors increases the removal of
SIMVASTATIN LDL
SimD ATORVASTATIN, ROSUVASTATIN, FLUVASTATIN,
PRAVASTATIN, LOVASTATIN, PITAVASTATIN EZETIMIBE
Class Reversible competitive inhibitor of HMG-COA reductase Class Sterol Absorption Blocker
MOA Inhibits rate-limiting enzyme in cholesterol MOA Selective inhibitor of the NPC1L1 transporter,
biosynthesis. Increased hepatic cholesterol uptake. decreasing intestinal absorption of cholesterol and
Increased high-affinity LDL receptors. Decreased LDL other phytosterols
levels. Uses Hypercholesterolemia (high LDL), Phytosterolemia
Uses Hypercholesterolemia (high LDL), Acute coronary SE HEPATOTOXICITY (increased with statin use), Myositis
syndromes, Ischemic stroke Notes Synergistic LDL-lowering effect with statins
SE Hepatotoxicity, Myopathy, Rhabdomyolysis,
Gastrointestinal distress, Teratogen SITOSTEROL
Notes Increased risk of Myopathy and Rhabdomyolysis Class Sterol Absorption Blocker
when used with FIBRATE. MOA Cholesterol analog, takes the place of dietary and biliary
Given before bedtime because cholesterol synthesis cholesterol, decreasing intestinal absorption of
predominantly occurs at night cholesterol and other phytosterols
Uses Hypercholesterolemia (high LDL), Phytosterolemia
KEY LEARNING POINTS – Statins in Coronary Artery Disease! SE Gastrointestinal upset, bloating, IMPOTENCE (rare),
Why are statins used in the management of coronary artery Coronary events
disease?
 For the stabilization of atherosclerotic plaques NIACIN
For which biochemical pathway are the following rate-limiting MOA of Niacin
enzymes:  Multiple mechanisms of actions in various tissues
 HMG-CoA Synthase? KETOGENESIS o Inhibits lipolysis by hormone sensitive lipase
 HMG-CoA Reductase? CHOLESTEROL BIOSYNTHESIS o In the liver, niacin reduces VLDL synthesis
o In adipose tissue, niacin reduces hormone-
BILE ACID – BINDING RESINS (BARs) sensitive lipase activity, decreases plasma fatty
acids and triglyceride levels
MOA of Resins o In capillary endothelial cells, niacin causes
 Over 90% of bile acids are reabsorbed and returned to the increased clearance of VLDL by lipoprotein lipase
liver for reuse (enterohepatic circulation) o Niacin reduces the catabolic rate for HDL
 Resins bind bile acids and prevent their intestinal o Decreases circulating fibrinogen and increases tPA
absorption activity
o Divert hepatic cholesterol to synthesis of new bile  Net effect on lipid profile
acids o Most effective agent for increasing HDL levels
o Reduce amount of cholesterol in a tightly regulated o Reduces LDL cholesterol, triglycerides, and VLDL
pool
o Compensatory increase in high-affinity LDL NIACIN
receptors increases LDL removal Class Vitamin, Anti-hyperlipidemic drug
 Modest reduction in LDL cholesterol but have little effect on MOA Decreases VLDL synthesis and LDL cholesterol
HDL or Triglycerides concentrations. Increases HDL cholesterol
Uses Hypercholesterolemia (low HDL, high HDL/VLDL)
CHOLESTYRAMINE SE Flushing, Pruritus, Rashes, Acanthosis nigricans,
SimD COLESEVELAM, COLESTIPOL Gastrointestinal irritation, Hepatotoxicity (mild),
Class Bile acid-binding Resins Hyperuricemia, Impaired glucose tolerance,
MOA Binds bile acids, preventing their reabsorption and Arrhythmias, Amblyopia
increasing cholesterol utilization for replacement. Notes ASPIRIN pre-treatment reduces flushing.
Modestly lowers LDL levels.
Uses Hypercholesterolemia (high LDL), Pruritus in Avoid in patients with peptic ulcer disease. Potentiates
Cholestasis, Digitalis toxicity effects of anti-hypertensives (vasodilators, ganglion
SE Constipation, BLOATING, Gritty taste, Steatorrhea, Gall blockers)
stones (rare), Malabsorption (vitamin K)
Notes Increases TGs and VLDL in patients with high TGs MNEMONICS – Cutaneous Flushing
What are the drugs that cause flushing?
Treat constipation with fiber supplements/psyllium V–A–N–C
 Vancomycin
Avoid in patients with diverticulitis!  Adenosine
 Niacin
KEY LEARNING POINTS – Bile Acids  Calcium-channel Blockers
90% of bile is reabsorbed in the DISTAL ILEUM!!
“slap cheek” – Parvovirus B19
FIBRATES DISADVANTAGEOUS ANTI-HYPERLIPIDEMIC COMBINATIONS!
COMBINATION DISADVANTAGE
MOA of Fibrates Fibrate + Resin Increased risk of cholelithiasis
 Ligands for the peroxisome proliferator-activated receptor- Statin + Resin Impaired statin absorption
alpha (PPAR-α) protein Statin + Fibrate Increased risk of myopathy and
o Increased synthesis by adipose tissue of rhabdomyolysis
lipoprotein lipase
 Enhances clearance of triglycerides CORRELATIONS – Biochemistry – Lipoproteins
 In the liver, fibrates stimulate fatty acid oxidation Which anti-hyperlipidemic drugs are indicated for the inherited
o Limits supply of triglycerides and decreases VLDL lipoproteinemias?
synthesis Condition Cause Lipid 10 Tx 20 Tx
 Decreases expression of apoC-III Profile
I Primary Deficiency ↑ CM Low-fat Niacin
o Impedes the clearance of VLDL hyperchylomicronemia in LPL ↑ TGs diet Fibrate
o Increases the expression of apoA-I and apoA-II, or ApoC-II
which in turn increases HDL levels IIA Familial Defect in ↑ LDL Statin Niacin
hypercholesterolemia LDL N. VLDL Ezetimibe
 Little or no effect on LDL concentrations receptors
↑ VLDL Statin Niacin
Fibrate
GEMFIBROZIL Familial combined Over-
↑ LDL Statin Niacin
IIB production
SimD FENOFIBRATE, BEZAFIBRATE hypercholesterolemia of VLDL Ezetimibe
Class Fibric Acid Derivative ↑ VLDL Statin Niacin
↑LDL Ezetimibe
MOA Activates PPAR-α and increases expression of III Familial dysbeta- Deficiency ↑VLDL Fibrate Statin
lipoprotein lipase and apolipoproteins (apoA-I and lipoproteinemia in ApoE remnant Niacin
apoA-II). Lowers triglycerides. Increases HDL ↑ CM
Uses Drug of choice for HYPERTRIGLYCERIDEMIA, IV Familial Decreased ↑ TGs Fibrate
hypertriglyceridemia clearance ↑ VLDL Niacin
Hypercholesterolemia (low HDL, high LDL), Fat of VLDL
↓/N. LDL
redistribution syndrome V Familial combined Decreased ↑ TGs Fibrate
hypertriglyceridemia clearance ↑ CM Niacin
SE Nausea, Rashes, Leukopenia, Hemoconcentration, of VLDL
↑ VLDL
Increased risk of cholesterol gallstones ↓/N. LDL
Notes Increased risk of myopathy and rhabdomyolysis when
used with STATINS!
Avoided in patients with hepatic or renal dysfunction.

HISTAMINE, SEROTONIN AND
THE ERGOT ALKALOIDS
MNEMONICS – Fibrates
FULL: Fibrates Upregulate Lipoprotein Lipase!!
Combination Therapy
 All patients with hyperlipidemia are treated first with
dietary modification
 Certain drug combinations provide advantages whereas
others present specific challenges
SYNERGISTIC ANTI-HYPERLIPIDEMIC COMBINATIONS!

Synergistic CLINICAL USE
Combinations
Niacin + Statin Familial hypercholesterolemia
Statin + Ezetimibe Familial hypercholesterolemia
Niacin + Resin Familial combined hypercholesterolemia
Statin + Fibrate Familial combined hypercholesterolemia
STILL STILL
HIGH HIGH
Diet and
High LDL STATIN EZETIMIBE
Excercise
Diet and FIBRATE

High VLDL STATIN
Excercise
Diet and NIACIN

High TAG FIBRATE
Excercise
Diet and
Low HDL STATIN AUTACOIDS
Excercise
 Endogenous molecules with powerful pharmacologic effects
that do not fall into traditional autonomic groups
High LDL Diet and EZETIMIBE  HISTAMINE and SEROTONIN are the most important
STATIN
High VLDL Excercise or NIACIN amine autacoids
High LDL, STATIN +

Diet and
HIGH TGs, NIACIN +
Excercise
Low HDL FIBRATE
HISTAMINERGIC AGENTS SEROTONERGIC AGENTS
HISTAMINE SEROTONIN (5-Hydroxytryptamine or 5-HT)

 Formed from the amino acid HISTIDINE  Produced from the amino acid TRYPTOPHAN
 Metabolized by the enzyme monoamine oxidase and  Metabolized by monoamine oxidase
diamine oxidase  Excess production in the body is detected by 5-
 Excess production detected by measurement of IMIDAZOLE HYDROXYINDOLE ACETIC ACID (5-HIAA) in the Urine
ACETIC ACID in the Urine  Physiologic roles:
 Important pathophysiologic roles: o Neurotransmitter in CNS and enteric nervous
o Seasonal rhinitis (hay fever), Urticaria, and system
Angioedema o Local hormone that modulates gastrointestinal
o Control of acid secretion in the stomach activity
Triple Response (WHEAL, FLUSH and FLARE)
 Classic demonstration of histamine effect Serotonin Receptors and Effects
o Redness Type Distribution Mechanism Prototype Effects
Antagonists
o Swelling
5-HT1D Brain Gi; ↓ cAMP --- Synaptic inhibition
o Itch and Pain Vasoconstriction
 Mediated mainly by H1 and H2 receptors 5-HT2 Smooth muscle, Gq; ↑ IP3, Ketanserin CNS excitation,
 Involves a small red spot at the center of an intradermal Platelets DAG Smooth muscle
contraction or
injection of histamine surrounded by a red edematous relaxation,
wheal vasodilation,
diarrhea, broncho-
constriction
Histamine Receptors and Effects 5-HT3 Area postrema Ligand- Ondansetron Vomiting
Type Distribution Mechanism Prototype Effects
(CNS), sensory gated Ion
Antagonists
and enteric channel
Pain and itching, nerves
Smooth Gq; ↑ IP3, Diphenhydramine bronchoconstriction,
H1 muscle DAG vasodilation, local
5-HT4 Pre-synaptic Gs; ↑ cAMP Tegaserod Intestinal motility
nerve terminals (partial
edema in enteric agonist)
H2 Stomach, Gs; ↑ cAMP Cimetidine Gastric acid nervous system
Heart, Mast secretion, cardiac
cells stimulation
H3 Nerve Gi; ↓ cAMP Clobenpropit Modulation of other SUMATRIPTAN
endings, CNS NTs SimD ALMOTRIPTAN, ELETRIPTAN, FROVATRIPTAN,
H4 Leukocytes Gi; ↓ cAMP --- Leukocyte
NARATRIPTAN, RIZATRIPTAN, ZOLMITRIPTAN
chemotaxis
Class 5-HT1D/1B-receptor Agonists
DIPHENHYDRAMINE MOA 5-HT1D/1B agonists. Causes vasoconstriction. Modulates
SimD CHLORPHENIRAMINE, CYCLIZINE, MECLIZINE, neurotransmitter release.
PROMETHAZINE Uses Drug of choice for MIGRAINE, Cluster headache
Class H1-receptor Antagonists (first generation) SE Paresthesias, Diziness, Chest pain, Coronary vasospasm,
MOA Competitive pharmacologic block of peripheral and CNS can exacerbate Hypertension
H1 receptors plus α- and M-receptor block.
“Anti-motion Sickness Effect” ONDANSETRON
Uses Hay fever, Angioedema, Motion sickness, Insomnia, SimD GRANISETRON, DOLASETRON, PALONOSETRON,
Dystonia ALOSETRON
SE DROWSINESS, Blurred vision, Dry mouth, Urinary Class 5-HT3-receptor Antagonists
retention, Anorexia, Orthostatic hypotension, anti- MOA Pharmacologic antagonists. Blocks chemoreceptor
cholinergic effect trigger zone and enteric nervous system 5-HT3
receptors.
CETIRIZINE Uses Chemotherapy and post-operative vomiting, Irritable
SimD LORATADINE, FEXOFENADINE, DESLORATADINE, bowel disease (alosetron only)
TERFENADINE, ASTEMIZOLE, LEVOCETIRIZINE SE Diarrhea, Headache, QRS and QT prolongation
Class H1-receptor Antagonists (second generation) (dolasetron only), Constipation (alosetron only)
MOA Competitive pharmacologic block of peripheral H1
receptors. No autonomic or anti-motion sickness effects ERGOT ALKALOIDS
Uses Hay fever, Angioedema, Urticaria
SE NONE ERGOT ALKALOIDS
Notes Fatal arrhythmias from interaction between  Complex molecules produced by a fungus found in wet or
azoles/erythromycin and terfenadine/astemizole spoiled grain
o Responsible for the epidemics of “St. Anthony’s
CIMETIDINE fire” (ergotism) described during the Middle Ages
SimD RANITIDINE, FAMOTIDINE, NIZATIDINE  Most are partial agonists at α-adrenoceptors and 5-HT
receptors
Class H2-receptor Antagonists
 Classification
MOA Competitive pharmacologic block of H2 receptors.
o VASOSELECTIVE
Reduction of gastric acid secretion
o UTEROSELECTIVE
Uses Peptic ulcer disease, Zollinger-Ellison Syndrome,
Gastro-esophageal reflux
ERGOTAMINE
SE CYP450 inhibitor and anti-androgen effects like
SimD DIHYDROERGOTAMINE, METHYSERGIDE
gynecomastia (cimetidine only)
Class 5-HT2-receptor Antagonists (vasoselective)
MOA Mixed partial agonist effects at 5-HT2 and α-
adrenoceptors. Causes marked smooth muscle
contraction but blocks α-agonist vasoconstriction
Uses MIGRAINE, Cluster headache
SE Gastrointestinal upset, Vasospasm, Gangrene, Uterine
spasm, Retroperitoneal fibrosis (methysergide only)
Notes Antidote is NITROPRUSSIDE
ERGONOVINE Effects of Important Eicosanoids
SimD METHYLERGONOVINE Eicosanoids G-Protein Effects
Class 5-HT2-receptor Antagonists (uteroselective) LTB4 Gq Leukocyte chemotaxis
MOA Mixed partial agonist effects at 5-HT2 and α- LTC4 Gq Bronchoconstriction, slow-reacting
LTD4 Gq , G i substance of anaphylaxis
adrenoceptors. Causes marked smooth muscle
PGE1 Gs , G q Vascular smooth muscle relaxation,
contraction but blocks α-agonist vasoconstriction
Protective effects on gastric mucosa,
Uses POST-PARTUM BLEEDING, Migraine Maintains PDA (patent ductus arteriosus)
SE Gastrointestinal upset, Uterine spasms, Abortion PGE2 Gs , G q Vascular smooth muscle relaxation,
Increases uterine tone,
Maintains PDA (patent ductus arteriosus)
PGI2 Gs Vascular smooth muscle relaxation
PROSTAGLANDINS AND OTHER EICOSANOIDS (peripheral, pulmonary, coronary)
PGF2α Gq Increases uterine tone, decreases IOP
(intraocular pressure)
TXA2 Gq Platelet aggregation
MISOPROSTOL
SimD GEMEPROST
Class Prostaglandin E1 Analog
MOA Activates EP receptors. Causes increased HCO3 and
mucus secretion in stomach. Uterine contraction.
Uses Peptic Ulcer Disease, Prevention of NSAIDs-induced
gastric mucosal injury, abortifacient
SE Abdominal pain, Diarrhea, Uterine cramping,
Miscarriage, Teratogenic effect (Moebius sequence)
EICOSANOIDS ALPROSTADIL
 Important group of endogenous fatty acid derivatives that Class Prostaglandin E1 Analog
are produced from arachidonic acid MOA Activates EP receptors, Causes vascular smooth muscle
 Major families of eicosanoids include: relaxation and vasodilation
o Straight-chain derivatives (leukotrienes) Uses Maintenance of Patent Ductus Arteriosus (PDA), Erectile
o Cyclic derivatives (prostacyclin, prostaglandins, dysfunction
and thromboxane) SE Apnea, Hypotension, Arrhythmia, PRIAPISM, light-
 20 carbon atoms, 4 double bonds headedness
MNEMONICS – Alprostadil
Prostaglandin E1 (Alprostadil)
E1 (iwan) mong bukas ang Ductus!!
Maintains patency (open) of Ductus arteriosus
DINOPROSTONE
SimD SULPROSTONE
Class Prostaglandin E2 Analog
MOA Low concentrations contract, Higher concentrations
relax uterine and cervical smooth muscle
Uses INDUCTION OF LABOR (cervical opening),
Abortifacient
SE Cramping, Fetal trauma
CARBOPROST
SimD BIMATOPROST, TRAVOPROST, UNOPROSTONE
Class Prostaglandin E2α Analog
KEY LEARNING PONTS – Biochemistry MOA Activates FP receptors.
Uses Control of post-partum hemorrhage, Abortifacient
Thromboxane (Tetraeicosanoic acid) – for Platelet aggregation SE Vomiting, Diarrhea, Transient bronchoconstriction
Cyclooxygenase 1  produces Prostaglandin (mucus)  GI EPOPROSTENOL

Class BERAPROST, ILOPROST, TREPROSTINIL
Cyclooxygenase 2  produces Prostacyclin (pulmonary MOA Prostaglandin I2 Analog
circulation); mediates pain and inflammation Uses Activates IP receptors. Causes vasodilation, Reduces
platelet aggregation
Cyclooxygenase Isoforms SE PULMONARY HYPERTENSION, Reduces platelet
 CYCLOOXYGENASE-1 (COX-1) aggregation in dialysis machines
o Found in many tissues Notes Hypotension, Flushin, Headache
o Important for a variety of normal physiologic
processes LATANOPROST
o “Cyloprotective cyclooxygenase” SimD BIMATOPROST, TRAVOPROST, UNOPROSTONE
Class Prostaglandin F2α Analog
 CYCLOOXYGENASE-2 (COX-2) MOA Activates FP receptors. Increases outflow of aqueous
o Found primarily in inflammatory cells humor, reduces intraocular pressure
o Major role in tissue injury (eg, inflammation) Uses Drug of choice for GLAUCOMA
o Synthesis of prostacyclin in the vascular SE Alters color of the iris, causing permanent eye color
endothelium and of prostaglandins important in change
renal functions
BRONCHODILATORS AND OTHER DRUGS USED IN SALMETEROL

SimD FORMOTEROL, CLENETEROL, BAMBUTEROL
ASTHMA
Class Beta-2-selective Agonist (long-acting)
MOA Activates Beta-2 receptors in bronchial smooth muscle.
ASTHMA
Causes bronchodilation. Potentiation of corticosteroid
 Characterized by airway inflammation and episodic,
action.
reversible bronchospasm
Uses Asthma prophylaxis (not for acute relief)
 Major risk factor of asthma: INFECTION
Arrhythmias when used excessively, Loss of
responsiveness (tolerance, tachyphylaxis)
Notes Increase asthma mortality when used alone; May
precipitate arrhythmias
IPRATROPIUM
SimD TIOROPIUM
Class Muscarinic receptor Antagonist
MOA Blocks muscarinic receptors in bronchial smooth
muscle. Prevents vagal-stimulated bronchoconstriction.
Uses Asthma, COPD
Pathophysiology of Asthma SE Dry mouth
 Bronchoconstriction caused by release of several mediators Notes More effective and less toxic than beta-agonists in
from IgE-sensitized mast cells patients with COPD
 Chemotactic mediators attract inflammatory cells to the
airways, leading to chronic inflammation THEOPHYLLINE
 Results in marked bronchial hyper-reactivity, partially SimD AMINOPHYLLINE, PENTOXIFYLLINE
mediated by vagal reflexes Class Methylxanthine
MOA Phosphodiesterase inhibition. Adenosine receptor
Strategies of Asthma Therapy antagonists. Causes bronchodilation
 Acute Attacks of Bronchospasms (relievers) Uses ASTHMA (prophylactic against nocturnal attacks)
o Use bronchodilators or relievers Intermittent claudication (pentoxifylline only)
o Short-acting beta agonists SE Insomnia, Tremors, Anorexia, Seizures, Arrhythmias
o Muscarinic antagonists Notes Antidote in overdosage is BETA BLOCKERS!
o Methylxanthines Higher clearance in adolescents and smokers.
o Intravenous corticosteroids Narrow therapeutic window.
 Long-term prevention and prophylaxis (controllers)
o Use anti-inflammatory drugs or controllers CROMOLYN
o Corticosteroids SimD NEDOCROMIL, LODOXAMIDE
o Long-acting beta agonists Class Mast cell Stabilizers
o Mast cell stabilizers MOA Prevents calcium influx and stabilizes mast cells,
o Anti-IgE antibodies preventing degranulation and release of histamine,
o Leukotriene antagonists leukotrienes and other mediators.
Uses ASTHMA PROPHYLAXIS, Allergies (ophthalmic,
nasopharyngeal, gastrointestinal)
SE Cough, Airway irritation
Notes NO BRONCHODILATOR ACTION!
FLUTICASONE
SimD BECLOMETHASONE, BUDESONIDE, CICLESONIDE,
FLUNISOLIDE, MOMETASONE, TRIAMCINOLONE
Class Corticosteroid
MOA Inhibitor of Phospholipase A2. Reduces expression of
cyclooxygenase
Uses ASTHMA PROPHYLAXIS (drug of choice for
immunosuppression) , COPD, Allergic rhinitis
SE Oropharyngeal candidiasis, Minimal systemic steroid
toxicity (eg, adrenal suppression), Mild growth
retardation
Notes IV HYDROCORTISONE is used in the treatment of
severe refractory asthma (status asthmaticus).
CICLESONIDE has lowest systemic steroid toxicity.
ALBUTEROL / SALBUTAMOL KEY LEARNING POINTS – Anti-Platelet Aggregation

SimD LEVALBUTEROL, TERBUTALINE, METAPROTERENOL,  PGI2 – Prostacyclin
PIRBUTEROL, PROCATEROL, FENOTEROL  cAMP
Class Beta-2-selective Agonists (short-acting)  PGE1
MOA Activates Beta-2 receptors in bronchial smooth muscle.
Causes bronchodilation.
Uses ACUTE ASTHMA ATTACKS (drug of choice)
Arrhythmias when used excessively, Loss of
responsiveness (tolerance, tachyphylaxis)
Notes May precipitate arrhythmias in patient with concurrent
COPD and Heart disease
AGENTS USED IN ANEMIAS & HEMATOPOIETIC

GROWTH FACTORS
HEMOCHROMATOSIS
 State of chronic iron overload that damages the organs that
store excess iron (heart, liver, pancreas)
 TRIAD:
o Cirrhosis, DM, Skin pigmentation
 OCCURRENCE:
o Persons with an inherited abnormality of iron
absorption
o Persons who receive frequent transfusion for
treatment of hemolytic disorders (eg, thalassemia
major)
 TREATMENT:
o Phlebotomy
o Chronic administration of DEFEROXAMINE or
DEFERASIROX
DEFEROXAMINE
SimD DEFERASIROX
Class Heavy metal Chelator
MOA Chelates excess iron
Uses Acute iron poisoning, Hemochromatosis NOT
adequately treated by phlebotomy Pharmacodynamics of Vitamin B12
SE Hypotension, ARDs, Neurotoxicity, Increased  Essential in 2 reactions
susceptibility to infections o Conversion of methylmalonyl-coenzyme A (CoA)
to succinyl-CoA
Role of Vitamin B12 (Cobalamin) o Conversion of homocysteine to methionine
 Cobalt-containing molecule  Linked to folic acid metabolism and synthesis of
 Cofactor in the transfer of 1-carbon units, a step necessary deoxythymidylate (dTMP), a precursor required for DNA
for the synthesis of DNA synthesis
 Deficiency of either vitamin B12 or B9 (folic acid) usually
manifests as megaloblastic anemia
 Vitamin B12 deficiency and NOT folic acid deficiency
causes Neurologic defects!
Question: What are the neurologic defects of vitamin B12

deficiency? Vitamin B12 Deficiency
 Folates accumulate as N5methyltetrahydrofolate
Answer:  Supply of tetrahydrofolate is depleted
 Ataxic Gait – Spinocerebellar tract  Production of red blood cells slows
 Impaired position  Administration of folic acid to patients with vitamin B12
 Vibratory sense spasticity deficiency helps refill the tetrahydrofolate pool and partially
or fully corrects the anemia
 Exogenous folic acid does not correct the neurologic defects
Pharmacokinetics of Vitamin B12 (Cobalamin) of vitamin B12 deficiency
 Produced ONLY by Bacteria
 Absorbed in the Distal Ileum in the presence of intrinsic CYANOCOBALAMIN
factor SimD HYDROXOCOBALAMIN
 Plasma transport is accomplished by binding to Class Hematopoietic Growth Factor
transcobalamin II MOA Cofactor required for essential enzymatic reactions that
 Stored in the LIVER in large amounts (5-year supply) form tetrahydrofolate, convert homocysteine to
 2 available forms: methionine, and metabolize methylmalonyl-CoA
o Cyanocobalamin and Hydroxocobalamin Uses Vitamin B12 deficiency, Megaloblastic anemia
(pernicious anemia, gatric resection)
SE NO significant toxicity
OPRELVEKIN (IL-11)
SimD THROMBOPOIETIN
Class Megakaryocyte Growth Factor
MOA Recombinant form of an endogenous cytokine; Activates
IL-11 receptors
Uses Secondary prevention of thrombocytopenia in patients
undergoing cytotoxic chemotherapy for non-myeloid
cancers
SE Fatigue, Headache, Dizziness, Anemia, Fluid
accumulation in the lungs, Transient atrial arrhythmias
DRUGS USED IN COAGULATION DISORDERS
Mechanisms of Hemostasis:
1. Vasoconstriction
2. Platelet plug formation
3. Formation of clot via blood coagulation
4. Fibrous organization
Pharmacokinetics of Vitamin B9 (Folic Acid)

 Readily absorbed by the gastrointestinal tract (Jejunum)
 Only modest amounts are stored in the body
 Decrease in dietary intake within 1-6 months is followed by
megaloblastic anemia
FOLIC ACID
SimD FOLACIN (PTEROYLGLUTAMIC ACID), FOLINIC ACID
Class Hematopoietic Growth Factor
MOA Precursor of an essential donor of methyl groups used
for synthesis of amino acids, purines, and
deoxynucleotide.
Uses Megaloblastic anemia, Prevention of Neural Tube
Defects (spina bifida), Prevention of Coronary Artery
Disease 1st STEP: VASOCONSTRICTION
SE NO significant toxicity  Local autacoid factors from traumatized tissues and
platelets
Recombinant Hematopoietic Growth Factors o Thromboxane A2 (TXA2): platelet activator and
 Glycoprotein hormones that regulate the differentiation and powerful vasoconstrictor
maturation of stem cells within the bone marrow o Endothelium: a potent endothelium derived
 Approved for treatment of patients with blood cell vasoconstrictor
deficiencies  Local myogenic spasm
 Nervous reflexes
EPOETIN ALFA
SimD DARBEPOETIN ALFA, 2nd STEP: PLATELET PLUG FORMATION (Primary Hemostasis)
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA  Exposed subendothelial collagen is highly thrmbogenic
Class Hematopoietic Growth Factor  Platelet adhesion
MOA Agonist of erythropoietin receptors expressed by red o Mediated by Gp IIb,IIIa and vWF (essential for
cell progenitors binding subendothelial collagen to platelets) by
Uses Anemia associated with chronic renal failure, HIV GpIb receptor in the platelet surface
infection, Cancer, and Prematurity  Platelet release reaction
SE Hypertension, Thrombosis, Pure red cell aplasia o Adenosine diphosphate (ADP): platelet
Notes Hemoglobin levels should be maintained < 12 g/dL aggregation
Performance-enhancing drug in athletes o Thromboxane A2 (TXA2): platelet activator and
(prohibited use) powerful vasoconstrictor
o Serotonin: platelet aggregation and
(G-CSF) vasoconstriction
SimD SARGRAMOSTIM (GM-CSF), PEGFILGRASTIM  Platelet aggregation  Platelet plug
Class Myeloid Growth Factors
MOA Binds receptors on myeloid progenitors and stimulates 3rd STEP: FORMATION OF CLOT VIA COAGULATION
cell maturation and proliferation.  2 Coagulation Pathways:
Accelerates neutrophil recovery and reduces incidence o INTRINSIC PATHWAY: PTT
of infection  Factor V, VIII, IX, X, XI, XII, Prothrombin,
Uses Neutropenia associated with Chemotherapy, Fibrinogen
Myelodysplasia, and aplastic anemia. o EXTRINSIC PATHWAY: PT
Mobilization of peripheral blood cells in preparation for  Factor V, VII, X, Prothrombin, Fibrinogen
hematopoietic stem cell transplantation  Net result of coagulation pathways: PROTHROMBIN
SE Bone pain (arthralgia), Fever, Edema ACTIVATOR (rate-limiting factor causing blood
coagulation)
4th STEP: FIBROUS ORGANIZATION

 Fibrin mesh stabilize your platelet plug
Glycoprotein Function
Ia Adhesion to collagen ANTI-PLATELET DRUG
Ib Binds vWF  Arterial thrombosis is the most common cause of acute
Def: Bernard-Soullier Syndrome (giant platelets) Myocardial Infarction (MI), ischemic stroke, and limb
IIb-IIIa Binds fibrinogen & vWF gangrene
Def: Glanzmann’s Thrombasthenia  Predominance of platelets in arterial thrombi
IV Binds Thrombospondin
V Binds Thrombin
IX Associated with Ib complex Plaque Disruption
KEY LEARNING POINTS – Phases of Platelet Reaction

Tissue Factor Collagen vWF
1. Platelet adhesion
 Platelets stick to a foreign surface NOT familiar to them
 Initiated by exposure to subendothelial collagen
 Dependent on: vWF & Gp Ib Platelet Adhesion and Secretion
2. Platelet activation COX-1

 Simultaneous events
 Morphologic changes and functional changes in platelets TXA2 ADP
 Activated by Thromboxan A2
3. Platelet secretion
 Alpha granules Thrombin Platelet Recruitment and Activation
 PF 4
 Beta-thromboglobulin
 Thrombospondin SCH530348
GP IIb/IIIa Activation
 Platelet-derived Growth Factor (PDGF) E5555
 “permeability factor”
 vWF
 Fibrinogen Platelet Aggregation
 Fator V
 Fibronectin KEY LEARNING POINTS – Antiplatelet Drugs!
 Dense granules 1. COX inhibitors
 Magnesium  Aspirin
 Phosphate
 Calcium 2. ADP antagonists (Thienopyridines)
 ADP & ATP  Ticlopidine
 Serotonin / 5-Hydroxytryptamine  Clopidogrel
 Epinephrine  Prasugrel
 Cangrelor
4. Platelet aggregation  Ticagrelor
 Other platelets are stimulated by ADP to undergo shape
change (disk  spherical  pseudopods) exposing the Gp 3. Gp IIb/IIIa inhibitors
IIb-IIIa complex  Abciximab
 Fibrinogen binding links platelets = first & reversible  Eptifibatide
 After release reaction, is irreversible aggregation  Tirofiban
4. Thrombin inhibitors
 Dabigatran
 Ximelagatran
 Vorapaxar
5. Anticoagulants
6. Phosphodiesterase inhibitors
 Dipyridamole
 Cilostazol
ASPIRIN (ACETYLSALICYLIC ACID, ASA) CLOPIDOGREL
SimD SALSALATE, SODIUM SALICYLATE SimD TICLOPIDINE, PRASUGEL
Class Anti-Platelet Dug, Anti-inflammatory Drug Class Anti-platelet Drugs (Thienopyridine)
Anti-pyretic, Analgesic MOA Irreversibly inhibits binding of ADP to platelet
MOA Non-selective, irreversible COX 1 & 2 inhibitor. Reduces receptors, reducing platelet aggregation
platelet production of thromboxane A2, a potent Uses Prevention and treatment of Arterial Thrombosis
stimulator of platelet aggregation. (stroke, transient ischemic attack/TIA, unstable angina),
Uses Prevention of arterial thrombosis (MI, TIA, CVD), Prevention of restenosis after PCI, Acute coronary
Inflammatory disorders (rheumatic fever, KAWASAKI syndromes
DISEASE, juvenile rheumatoid arthritis) SE Bleeding, Nausea, Dyspepsia, Hematologic (neutropenia,
SE Gastrointestinal toxicity, Nephrotoxicity, Tinnitus, leukopenia, thrombotic thrombocytopenic purpura)
Hypersensitivity, Hyperventilation, HAGMA Notes GI & Hematologic SE are more common with Ticlopidine
Notes Toxic dose (150 mg/kg), Lethal dose (500 mg/kg) Additive effects with Aspirin!
Uncoupler of oxidative phosphorylation associated with
REYE’S SYNDROME in children DIPYRIDAMOLE
SimD CILOSTAZOL
KEY LEARNING POINTS – Aspirin Toxicity Class Anti-platelet Drug
How many 500 mg Aspirin tablets must be ingested to produce MOA Inhibits phosphodiesterase III and increases cAMP in
toxicity? Death? platelets and blood vessels. Inhibits platelet aggregation
and causes vasodilation.
TOXIC DOSE = 150 mg/kg Uses Prevention of thromboembolic complications of cardiac
150mg/kg x 70 kg/500mg/tab = 21 tabs valve replacement, Secondary prevention of ischemic
stroke (with aspirin), Intermittent claudication
LETHAL DOSE = 500 mg/kg (cilostazol only)
500 mg/kg x 70 kg/500mg/tab = 70 tabs SE Headache (because it is a vasodilator), Palpitations
Notes Dipyridamole, by itself, has a little or no benefit.
What is the triad of Aspirin hypersensitivity? Cilostazol is contraindicated in Heart Failure!
SAMTER TRIAD
1. Asthma ANTICOAGULANTS
2. Aspirin sensitivity  Mainly for the prevention and treatment of venous
3. Nasal polyps thrombosis (pulmonary embolism, deep vein thrombosis)
 Drugs which inhibit the formation of fibrin clots
 2 major types of anticoagulants:
Aspirin Intoxication o Indirect thrombin inhibitors:
 Increased respiratory drive leads to hyperventilation and  HEPARIN
respiratory alkalosis  ENOXAPARIN (LMWH)
 Uncoupling of Oxidative Phosphorylation leads to  LEPIRUDIN
increased anaerobic metabolism via lactic acidosis and high- o Direct thrombin Inhibitors:
anion gap metabolic acidosis (HAGMA)  COUMARIN Derivatives (warfarin)
KEY LEARNING POINTS – Aspirin Intoxication Comparison of Heparin and Warfarin

What is the expected acid-base abnormality in salicylate Property HEPARIN WARFARIN
poisoning? Structure Large acidic Small lipid-soluble
 RESPIRATORY ALKALOSIS with HAGMA polysaccharide molecule
Route Parenteral Oral
What is the difference between the presentation of aspirin Site of Action Blood Liver
intoxication in children and adults? Onset Rapid (minutes) Slow (days)
 ADULTS: mixed acid-base disorder (Respiratory MOA Impairs post-translational
Alkalosis with HAGMA) Activates Anti-thrombin III modification of factors II,
 CHILDREN: pure acid-base disorder (HAGMA) VII, IX, and X (vitamin K-
dependent)
Monitoring PTT PT
What is the difference between an inhibitor and an uncoupler of Antidote Protamine Vitamin K, FFP
oxidative phosphorylation? Use Mostly acute, over days Chronic, over weeks to
 INHIBITORS: completely halt ETC months
 UNCOUPLERS: dissipate proton gradient without Pregnancy Yes No
interrupting ETC
MNEMONICS – PT/PTT
ABCIXIMAB What laboratory test will you request to assess the extrinsic and
SimD EPTIFIBATIDE, TIROFIBAN intrinsic coagulation pathways?
Class Anti-platelet Drugs
MOA Inhibits platelet aggregation by interfering with Gp PiTT = PTT for INTRINSIC PATHWAY! (heparin)
IIb/IIIa binding to fibrinogen and other ligands PeT = PT for EXTRINSIC PATHWAY!(warfarin)
Uses Used during percutaneous coronary intervention (PCI)
to prevent thrombosis, Adjunct to thrombolysis, Acute HEPARIN = drug of choice for anticoagulation during pregnancy!
coronary syndromes (unstable angina, NSTEMI)
SE Bleeding, Thrombocytopenia HEPARIN
Notes Prevents vessel restenosis, reinfarction and death Class Anticoagulant (indirect thrombin inhibitor)
MOA Activates anti-thrombin III (inactivates thrombin or
factor IIa, Factor IXa & Factor Xa by forming stable
complexes with them)
Uses Deep venous thrombosis, Pulmonary embolism,
Myocardial infarction, Unstable angina, Adjuvant to
percutaneous coronary intervention (PCI) and
thrombolytics, Atrial fibrillation
SE Bleeding, Heparin-induced thrombocytopenia,
Osteoporosis with chronice use
Notes Monitor with aPTT! Antidote: PROTAMINE SULFATE
KEY LEARNING POINTS – anticoagulant Overlap
In patients requiring anticoagulation, why is an overlap between
heparin and warfarin usually done?
 Warfarin’s effect require elimination of preformed
clotting factors (8 – 60 hours)
 To bypass the initial prothrombotic effect of warfarin
(skin necrosis)
WARFARIN
Drug Interactions of Warfarin

 Cytochrome P450-inducers increase clearance and reduce
the anticoagulant effect of a given dose
 Cytochrome P450-inhibitors recude clearance and increase
the anticoagulant effect of a given dose
MNEMONICS – P450 INDUCERS AND INHIBITORS
CYTOCHROME P450 INDUCERS

Ethel Booba takes Phen-Phen and Refuses Greasy Carb Shakes!!
 Ethanol
 Barbiturates
 Phenytoin
ENOXAPARIN  Rifampicin
SimD DALTEPARIN, TINZAPARIN, DANAPAROID,  Griseofulvin
FONDAPARINUX  Carbamazepine
Class Anticoagulant (indirect thrombin inhibitor)  St. John’s Wort / Smoking
MOA Binds and potentiates effect of antithrombin III on factor
Xa (more selective). Less effect on thrombin CYTOCHROME P450 INHIBITORS
Uses Deep venous thrombosis, Pulmonary embolism, Inhibtors Stop Cyber Kids Eating GRApefruit Q!!
Myocardial infarction, Unstable angina, Adjuvant to  Isoniazid
percutaneous coronary intervention (PCI) and  Sulfonamides
thrombolytics, Atrial fibrillation  Cimetidine
SE Bleeding, Less risk of thrombocytopenia  Ketoconazole
Notes Does NOT require aPTT monitoring.  Erythromycin
Protamine sulfate is only partially effective in reversing  Grapefruit juice
effects  Ritonavir
 Amiodarone
LEPIRUDIN  Quinidine
SimD DESIRUDIN, BIVALIRUDIN, ARGATROBAN
Class Anticoagulant (direct thrombin inhibitor)
MOA Binds to thrombin’s active site and inhibits its enzymatic PROTAMINE SULFATE
action Class Antidote
Uses Anticoagulation in patients with heparin-induced MOA Chemical agonist of Heparin. Reverses excessive
thrombocytopenia (HIT), Percutaneous coronary anticlotting activity of unfractionated heparin
angioplasty (with aspirin) Uses Heparin overdosage
SE Bleeding, Effect-prolonging antibodies, Anaphylactic SE Hypotension, Bradycardia, Flushing, Hypersensitivity,
reactions Dyspnea
Notes Monitor effect with aPTT. Notes Partially reverses effects of LMWHs (low-molecular
No reversal agent exist! weight heparins)
Used with caution for patients with renal insufficiency
FIBRINOLYTIC DRUGS:
WARFARIN  Mainly for the treatment of acute myocardial infraction,
SimD DICUMAROL ischemic stroke and massive pulmonary embolism
Class Anticoagulant
MOA Inhibits vitamin K epoxide reductase (responsible for
γ-carboxylation of the vitamin K-dependent clotting
factors – factors II, VII, IX, X, Protein C & Protein S)
Uses CHRONIC ANTICOAGULATION (DVT, Atrial fibrillation,
valve replacement) EXCEPT in Pregnancy!!
SE Bleeding, Warfarin-induced skin necrosis (for patients
with Protein C/S deficiency), Teratogen (bone defects,
hemorrhage)
Notes Monitor effects with PT
Antidote is VITAMIN K (slow) or FFP (fast)
Narrow therapeutic window
Active ingredient in most Rat Poisons!
NSAIDs, ACETAMINOPHEN, DMARDS AND DRUGS

USED IN GOUT
Inflammation
 Complex response to cell injury that primarily occurs in the
vascularized connective tissue and often involves the
immune response
 Mediators of inflammation, function to eliminate the cause
ALTEPLASE of cell injury and clear away debris, in preparation for tissue
SimD ANISTREPLASE, RETEPLASE, STREPTOKINASE, repair
TENECTEPLASE, UROKINASE  Causes pain and tissue damage
Class Thrombolytics
MOA Tissue plasminogen activator analog. Converts ANTI-INFLAMMATORY DRUGS
plasminogen to plasmin, which degrades the fibrin and
fibrinogen, causing thrombolysis. 1. Non-Steroidal Anti-Inflammatory Drugs
Uses Acute myocardial infarction, Ischemic stroke,
Pulmonary embolism Classification of NSAIDs
SE Bleeding, Cerebral hemorrhage, Reperfusion,  SALICYLATES
Arrhythmias o Aspirin (attach to platelets – 7 days)
Notes Loss of effectiveness (on 2nd use) and allergic reactions  NON-SELECTIVE NSAIDs
may be observed with streptokinase. o Ibuprofen
Antidote is AMINOCAPROIC ACID o Indomethacin
o Ketorolac
Contraindications to Thrombolysis o Piroxicam
 History of cerebrovascular hemorrhage at any time  COX-2 SELECTIVE NSAIDS
 Non-hemorrhagic stroke or other cerebrovascular event o Celecoxib
within the past year o Etoricoxib
 Marked hypertension (>180/110 mmHg) at any time o Parecoxib
during the acute presentation
 Suspicion of AORTIC DISSECTION Common NSAIDs Toxicities
 Active internal bleeding (excluding menses)  CNS: Headache, Tinnitus Dizziness
 CVS: Hypertension, Edema, Heart Failure
AMINOCAPROIC ACID  GIT: Abdominal pain, Dysplasia, Nausea, Vomiting, Ulcers,
SimD TRANEXAMIC ACID Bleeding
Class Antiplasmin Drug (procoagulant)  HEMATOLOGIC: Thrombocytopenia, Neutropenia, Aplastic
MOA Competitively inhibits plasminogen activation anemia
Uses Prevention and treatment of acute bleeding episodes in  HEPATIC: Abnormal liver function tests, Liver failure
patients with high risk of bleeding (hemophilia,  PULMONARY: Asthma
intracranial aneurysms, menstrual, obstetrics,  RASHES: all types, Pruritus
thrombolytics, post-operative)  RENAL: Renal insufficiency, Renal failure, Hyperkalemia,
SE Thrombosis, Hypotension, Myopathy, Diarrhea Proteinuria
Notes Contraindicated in Disseminated Intravascular
Coagulation (DIC) and Genitourinary bleeding ASPIRIN (ACETYLSALICYLIC ACID, ASA)
SimD SALSALATE, SODIUM SALICYLATE
VITAMIN K1 (PHYTONADIONE) Class Anti-Platelet Dug, NSAIDs (salicylate)
SimD VITAMIN K2 (MENAQUINONE) MOA Non-selective, irreversible COX 1 & 2 inhibitor.
VITAMIN K3 (MENADIONE) Reduces platelet production of thromboxane A2, a
Class Endogenous Vitamin, Antidote potent stimulator of platelet aggregation.
MOA Increases supply of reduced vitamin K, which is required Uses Prevention of arterial thrombosis (MI, TIA, CVD),
for synthesis of functional vitamin K-dependent clotting Inflammatory disorders (rheumatic fever, KAWASAKI
and anti-clotting factors DISEASE, juvenile rheumatoid arthritis)
Uses Vitamin K deficiency, Antidote to Warfarin, Prevention SE Gastrointestinal toxicity, Nephrotoxicity, Tinnitus,
of hemorrhagic diatheses in newborns Hypersensitivity, Hyperventilation, HAGMA,
SE Severe infusion reaction when administered too fast Hyperuricemia
(dyspnea, chest and back pain) Notes Uncoupler of oxidative phosphorylation associated with
Notes Vitamin K3 (menadione) shoulde NEVER be used in REYE’S SYNDROME in children
therapeutics (ineffective)
Prevents uric acid excretion (don’t use in gout)!!
DESMOPRESSIN
Dosage Ranges of Aspirin
Class ADH Agonist
 LOW RANGE (< 300 mg/dL)
MOA Vasopressin V2 receptor Agonist
o Effective in reducing platelet aggregation
Uses Hemophilia A, von Willebrand’s Disease, Central
o Follow first-order elimination kinetics
Diabetes insipidus
 INTERMEDIATE DOSES (300 – 2400 mg/dL)
SE Headaches, Flushing, Nausea, Hyponatremia, Seizures
o Anti-pyretic and analgesic effects
Notes Increases the Factor VIII activity of patients with mild
 HIGH DOSES (2400 – 4000 mg/dL)
Hemophilia A or von Willebrands Disease
o Anti-inflammatory effects
o Follows zero-order elimination kinetics
Aspirin Overdose 2. Disease-Modifying Anti-Rheumatic Drugs (DMARDS)
 DOSAGE:
o Toxic dose: 150 mg/kg (21 aspirin 500 mg tabs) RHEUMATOID ARTHRITIS
o Lethal dose: 30g (60 aspirin 500 mg tabs)  Chronic inflammatory disease of unknown etiology marked
 CLINICAL PRESENTATION by a symmetric, peripheral polyarthritis
o HAGMA  It is the most common form of chronic inflammatory
o Dehydration arthritis
o Hyperthermia
o Collapse Disease-Modifying Anti-Rheumatic Drugs (DMARDs)
o Coma  Heterogenous group of agents with anti-inflammatory
 TREATMENT actions used in several connective tissue diseases
o No specific antidote  Cause slowing or even reversal of joint damage
o Supportive management  May take 6 weeks to 6 months for their benefits to become
o Activated charcoal / gastric lavage apparent
o Alkalinize the urine with BICARBONATE
METHOTREXATE
IBUPROFEN Class Disease-Modifying Anti-Rheumatic Drug,
SimD DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, Cancer Chemotherapeutic Drug
FLURBIPROFEN, KETOPROFEN, MELOXICAM, MOA Inhibits AICAR transformylase
NABUMETONE, NAPROXEN, OXAPROZIN, PIROXICAM, (phosphoribosylaminoimidazolecarboxamide
SULINDAC, TOLMETIN, MEFENAMIC ACID formyltransferase) and Thymidylate synthase, with
Class NSAIDs (non-selective) secondary effects on polymorphonuclear chemotaxis
MOA Non-selective reversible COX-1 & COX-2 inhibitor. Uses Rheumatoid arthritis, SLE, Juvenile rheumatic
Inhibits prostaglandin synthesis. (idiopathic) arthritis/JRA, Psoriatic arthritis, Ankylosing
Uses Analgesia (musculoskeletal, headache, dysmenorrhea), spondylitis, Polymyositis , Dermatomyositis, Wegener’s
Antipyretic, Anti-inflammatory granulomatosis, Giant cell arteritis, Vasculitis
SE Gastrointestinal bleeding (less than aspirin), SE Nausea, Mucosal ulcers, Hepatotoxicity,
Nephrotoxicity Hypersensitivity, Pseudolymphomatous reaction
Notes Long-term use reduces the risk of colon cancer. Notes DMARDs of first choice to treat Rheumatoid
Arthritis!
Misoprostol prevents NSAIDs-induced gastritis! Rescue agent is LEUCOVERIN (Folinic acid)
Meloxicam & Piroxicam: COX-2 > COX-1
INFLIXIMAB
KETOROLAC SimD ADALIMUMAB, ETANERCEPT
Class NSAIDs (non-seletive) Class Disease-Modifying Anti-Rheumatic Drug
MOA Non-selective reversible COX-1 & COX-2 inhibitor. MOA Binds to TNF-α and prevents it from activating TNF-α
Inhibits prostaglandin synthesis. receptor
Uses Post-surgical analgesic control (moderate to severe, Uses CHRON’S DISEASE, Rheumatoid arthritis, Other
short-term) rheumatic diseases
SE High risk for gastrointestinal toxicity and SE Bacterial infections (URTIs), Reactivation of Latent
nephrotoxicity, Allergic reactions Tuberculosis, Lymphoma, Demyelination, Reactivation
Notes ONLY INTRAVENOUS NSAID. of hepatitis B, Autoantibody formation (ANA, Anti-
Used generally restricted to 72 hours ONLY! dsDNA), Infusion reactions
Notes Synergistic effects with Methotrexate
INDOMETHACIN
Class NSAIDs (non-selective) AZATHIOPRINE
MOA Non-selective reversible COX-1 & COX-2 inhibitor. Class Disease-Modifying Anti-Rheumatic Drug
Inhibits prostaglandin synthesis. MOA Forms 6-Thioguanine, suppressing inosinic acid
Uses Anti-inflammatory (gout, arthritis, ankylosing synthesis, B-cell and T-cell function, Immunoglobulin
spondylitis), CLOSURE OF PATENT DUCTUS production, and Interleukin 2 secretion
ARTERIOSUS! Uses Rheumatoid arthritis, Psoriatic arthritis, Reactive
SE Gastrointestinal toxicity, Pancreatitis, Nephrotoxicity, arthritis, Polymyositis, SLE, Behcet’s disease
Serious Hematologic reactions (aplastic anemia, SE Bone marrow suppression, Increased risk of infections,
thrombocytopenia) Increased incidence of lymphoma, Fever, Rash,
Hepatotoxicity, Allergic reactions
CELECOXIB Notes Cannot give Allopurinol with Azathioprine (allopurinol
SimD ETORICOXIB, PARECOXIB, ROFECOXIB, VALDECOXIB reduces xanthine oxidase catabolism of purine analogs,
Class NSAIDs (COX-2 selective) increasing 6-thioguanine nucleotides, leading to severe
MOA Selective COX-2 inhibitor. Inhibits prostaglandin leukopenia)
synthesis.
Uses Analgesia, Antipyretic, Anti-inflammatory CHLOROQUINE
SE Gastrointestinal bleeding (reduced risk), SimD HYDROXYCHLOROQUINE
Nephrotoxicity, Myocardial infarction and stroke Class Disease-Modifying Anti-Rheumatic Drug
(rofecoxib and valdecoxib only) Anti-malarial Drug
Notes COX-2 produces prostacyclin! MOA Suppression of T-lymphocyte responses to mitogens,
Celecoxib is anti-aggregant Decreased leukocyte chemotaxis, Stabilization of
lysosomal enzymes, Inhibition of DNA and RNA
synthesis, Trapping of free radicals
Uses Rheumatoid arthritis, SLE, Sjogren’s Syndrome,
MALARIA
SE Ocular toxicity, Dyspepsia, Nausea, Vomiting, Abdominal
pain, Rashes, Nightmares
Notes Safe for pregnant women!
CYCLOPHOSPHAMIDE Stages of Paracetamol Overdose
Class Disease-Modifying Anti-Rheumatic Drug, Stage Time Period Manifestations
Cancer Chemotherapeutic Drug I 0.5 to 24 hours Nausea, vomiting, diaphoresis, pallor,
MOA Forms phosphoramide mustard, which cross-links DNA lethargy, malaise
to prevent cell replication. II 24 to 72 hours Elevated liver enzymes, oliguria, azotemia,
increased PT, hyperbilirubinemia
Suppresses T-cell and B-cell function
II 72 to 96 hours Jaundice, hepatic encephalopathy, bleeding
Uses Rheumatoid arthritis, SLE, Vasculitis, Wegener’s diatheses, acute tubular necrosis, HAGMA,
granulomatosis, Severe rheumatic diseases coma, death
SE HEMORRHAGIC CYSTITIS IV 4 days to 2 weeks Recovery
Notes Rescue agent is MESNA!
Paracetamol Overdose
CYCLOSPORINE  DOSAGE:
Class Disease-Modifying Anti-Rheumatic Drug o Toxic Dose: 150 mg/kg (21 Paracetamol 500 mg
MOA Inhibits interleukin-1 and interleukin-2 receptor tabs)
production and secondarily inhibits macrophage T-cell o Lethal Dose: 15g (30 Paracetamol 500 mg tabs)
interaction and T-cell responsiveness  TREATMENT:
Uses Rheumatoid arthritis, SLE, Polymyositis, o Antidote: N-ACETYLCYSTEINE
Dermatomyositis, Wegener’s granulomatosis, Juvenile o Supportive management
rheumatoid arthritis, Tissue transplantation o Gastric decontamination with activated charcoal
SE Nephrotoxicity, Hypertension, Hyperkalemia,
Hepatotoxicity, Gingival hyperplasia, Hirsutism DRUGS FOR THE TREATMENT OF GOUT
MYCOPHENOLATE MOFETIL GOUT

Class Disease-Modifying Anti-Rheumatic Drug  Increased serum concentrations of uric acid
MOA Active product (mycophenolic acid) inhibits inosine  Acute attacks involve joint inflammation initiated by
monophosphate dehydrogenase (important enzyme in precipitation of uric acid crystals
the guanine nucleotide synthesis) and inhibits T-cell
lymphocyte proliferation Treatment Strategies for Gout
Uses SLE nephritis, Vasculitis, Wegener’s granulomatosis,  Reducing inflammation during acute attacks
Rheumatoid arthritis  Accelerating renal excretion of uric acid uricosuric drugs
SE Gastrointestinal disturbances, Headache, Hypertension,  Reducing the conversion of purines to uric acid by xanthine
Reversible myelosuppression (neutropenia) oxidase
SULFASALAZINE COLCHICINE
Class Disease-Modifying Anti-Rheumatic Drug Class Anti-gout Drug (microtubule assembly inhibitor)
MOA Active metabolite (sulfapyridine) inhibits the release of MOA Inhibits microtubule assembly, Decreases macrophage
inflammatory cytokines migration and phagocytosis
Uses Rheumatoid arthritis, Inflammatory bowel disease, JRA, Uses Gout, Familial mediterranean fever
Ankylosing spondylitis SE Diarrhea, Nausea, Vomiting, Abdominal pain, Hepatic
SE Nausea, Vomiting, Headache, Rash, Hemolytic anemia, necrosis, Acute renal failure, Disseminated intravascular
Methemoglobinemia, Neutropenia, Thrombocytopenia, coagulation, Seizures, Hair loss, Bone marrow
Pulmonary toxicity, Autoantibody formation (anti- depression (aplastic anemia), Peripheral neuritis,
dsDNA), Reversible infertility in men Myopathy
PARACETAMOL NSAIDs in Gout

 In addition to inhibiting prostaglandin synthase,
PARACETAMOL (ACETAMINOPHEN) indomethacin and other NSAIDs also inhibit urate crystal
SimD PHENACETIN phagocytosis
Class Analgesics (COX-3 inhibitor)  Aspirin is NOT used due to its renal retention of uric acid at
MOA Selectively inhibits COX-3. Weak COX-1 and COX-2 low doses
inhibitor. Inhibits prostaglandin synthesis (weak  Indomethacin is commonly used in the initial treatment of
prostaglandin inhibitor). gout as the replacement for colchicine
Uses Analgesia (mild), Antipyretic
SE Hepatotoxicity, Renal papillary necrosis and interstitial PROBENECID
nephritis (phenacetin only), Methemoglobinemia, SimD SULFINPYRAZONE
Hemolytic anemia Class Anti-gout Drug (uricosuric agent)
Notes Increased hepatotoxicity with alcohol use. MOA Compete with uric acid for reabsorption in the proximal
Preferred anti-pyretic in children (DOES NOT cause tubules, Increases uric acid excretion
REYE’s SYNDROME) Uses GOUT
Antidote is N-ACETYLCYSTEINE SE Gastrointestinal irritation, Rashes, Nephrotic syndrome
(probenecid only), Aplastic anemia
Mechanism of Paracetamol Overdose Notes May precipitate acute gout during early phase of drug
 Oxidation to a cytotoxic intermediate calle N-acetyl-p- action (prevent by co-administering with colchicine or
benzoquinoneimine (NAPQ1) by phase I cytochrome P450 indomethacin).
enzymes (CYP2E1) Inhibit secretion of other weak acids (eg, penicillin,
 Occurs if substrates for phase II conjugation reactions methotrexate)
(acetate and glucuronide) are lacking
 Centrilobular region (zone III) is preferentially involved
because it is the are of greatest concentration of CYP2E1
 Antidote is N-ACETYLCYSTEINE (NAC), a sulfhydryl donor
ALLOPURINOL SEDATIVE-HYPNOTIC DRUGS
Class Anti-gout Drug (xanthine oxidase inhibitor)
MOA Active metabolite (alloxanthine) irreversibly inhibits
Xanthine oxidase and lowers production of uric acid
Uses 1st line treatment of chronic gout! Tumor lysis
syndrome
SE Gastrointestinal upset, Rash, Peripheral neuritis,
Vasculitis, Bone marrow dysfunction, Aplastic anemia,
CATARACTS
Notes Inhibit metabolism of mercaptopurine and
azathioprine.
Withheld for 1 – 2 weeks after an acute episode of gouty
arthritis (co-administered with colchicine or
indomethacin to avoid an acute attack) DEFINITION OF TERMS
 SEDATIVES (ANXIOLYTICS)
FEBUXOSTAT o Drugs that reduce anxiety and exert a calming
Class Anti-gout Drug (xanthine oxidase inhibitor) effect
MOA Non-purine reversible inhibitor of xanthine oxidase o Degree of CNS depression should be the minimum
(more selective than allopurinol). Lowers production of consistent with therapeutic efficacy
uric acid  HYPNOTICS
Uses Chronic gout, Tumor lysis syndrome, Allopurinol o Drugs that produce drowsiness and encourage the
intolerance onset and maintenance of a state of sleep
SE Liver function abnormalities, Headache, o Involve more pronounced CNS depression than
Gastrointestinal upset sedation
Notes Withheld for 1 – 2 weeks after an acute episode of gouty
arthritis (co-administered with colchicine or
indomethacin to avoid an acute attack)
MNEMONICS – GABA receptor effects

 BENZODIAZEPINES: frequency of opening
 BARBITURATES: duration of opening
Major Inhibitory Neurotransmitters:

 GABA  nervous system
 GLYCINE  spinal cord
Major Excitatory Neurotransmitters:

 GLUTAMIC ACID
 ASPARTIC ACID
 N-methyl-D-aspartate (NMDA)
BENZODIAZEPINES Benzodiazepine Overdose
 DOSAGE:
MIDAZOLAM o Toxic dose is 1000x the therapeutic dose
SimD BROTIZOLAM, TRIAZOLAM, OXAZEPAM, ETIZOLAM  CLINICAL PRESENTATION:
Class Benzodiazepine (short-acting) o Slurred speech
MOA Binds GABA-A receptor subunits to increase frequency o Ataxia
of chloride channel opening; o Altered (decreased) mental status
Membrane hyperpolarization o Respiratory depression
Uses Acute anxiety, Panic attacks, Anesthesia, Induction, Pre-  TREATMENT:
operative sedation o Antidote: FLUMAZENIL (a BZ receptor antagonist)
SE ANTEROGRADE AMNESIA, Decreased psychomotor o Activated charcoal is useless
skills, Unwanted daytime sedation, Tolerance,
Dependence liability, Rebound insomnia/anxiety FLUMAZENIL
Notes Additive CNS depression with Ethanol Class Antidote (benzodiazepine antagonist)
MOA Antagonist at benzodiazepine sites on GABA-A receptor
LORAZEPAM Uses Benzodiazepine overdose
SimD ALPRAZOLAM, ESTAZOLAM, CLONAZEPAM, SE Agitation, Confusion, Precipitates, BENZODIAZEPINE
LORMETAZEPAM, NITRAZEPAM, TEMAZEPAM WITHDRAWAL SYNDROME
Class Benzodiazepine (intermediate-acting) Notes Seizures and arrhythmias may occur when administered
MOA Binds GABA-A receptor subunits to increase frequency in patient who took both TCAs and Benzodiazepines.
of chloride channel opening; Available in IV!
Membrane hyperpolarization
Uses Anxiety disorders, Insomnia, Skeletal muscle relaxation, BARBITURATES
Seizure disorders, Tranquilizer
SE ANTEROGRADE AMNESIA, Decreased psychomotor THIOPENTAL
skills, Unwanted daytime sedation, Respiratory SimD METHOHEXITAL, THIAMYLAL
depression, Tolerance, Dependence liability Class Barbiturate (ultra-short acting)
Notes Additive CNS depression with Ethanol MOA Binds GABA-A receptor sites (distinct from
benzodiazepines); Increase duration of chloride channel
KET LEARNING POINTS – Sleep Disturbance from BZDs opening.
What abnormal sleep pattern results from the use of Uses Anesthesia induction, Increased ICP
benzodiazepines? SE Extension of CNS depressant actions, Tolerance,
Dependence liability (greater than benzodiazepines),
 Decreased REM sleep ACUTE INTERMITTENT PORPHYRIA
 Longer non-REM (stage 2) Notes Additive to CNS depression with Ethanol.
 Retrograde increase REM sleep in benzodiazepine Potent inducer of CYP450 enzymes
withdrawal
MNEMONICS – Thiopental
TAYOpental = TAYO agad (shortest-acting)!!
DIAZEPAM
SimD CHLORAZEPATE, CHLORDIAZEPOXIDE, FLURAZEPAM, PENTOBARBITAL
QUAZEPAM, FLUNITRAZEPAM SimD SECOBARBITAL, AMOBARBITAL, BUTALBITAL,
Class Benzodiazepine (long-acting) BUTABARBITAL, TALBUTAL, APROBARBITAL
MOA Binds GABA-A receptor subunits to increase frequency Class Barbiturate (short- and intermediate-acting)
of chloride channel opening; MOA Binds GABA-A receptor sites (distinct from
Membrane hyperpolarization benzodiazepines); Increase duration of chloride channel
Uses Anxiety disorders, Insomnia, Skeletal muscle relaxation, opening.
Seizure disorders, Tranquilizer, Uses Insomnia, Pre-operative sedation
ALCOHOL WITHDRWAL! SE Extension of CNS depressant actions, Tolerance,
SE ANTEROGRADE AMNESIA, Decreased psychomotor Dependence liability (greater than benzodiazepines),
skills, Unwanted daytime sedation, Respiratory ACUTE INTERMITTENT PORPHYRIA
depression, Tolerance, Dependence liability Notes Additive to CNS depression with Ethanol.
Notes Additive CNS depression with Ethanol Potent inducer of CYP450 enzymes
FLUNITRAZEPAM (Rohypnol) is used to a date-rape PHENOBARBITAL

drug!! (colorless, tasteless) SimD MEPHOBARBITAL, PRIMIDONE
Class Barbiturate (long-acting)
MNEMONICS – Chlordiazepoxide MOA Binds GABA-A receptor sites (distinct from
Which benzodiazepine has the longest half-life? benzodiazepines); Increase duration of chloride channel
opening.
CHLORDIAZEPOXIDE has the longest half-life (36-200 hours) Uses Insomnia, Seizure disorders, Status epilepticus,
and the longest spelling (many letters) Hyperbilirubinemias (Gilbert’s syndrome and
kernicterus)
Which drugs are considered date-rape drugs? SE Extension of CNS depressant actions, Tolerance,
 ALCOHOL (most common) Dependence liability (greater than benzodiazepines),
 FLUNITRAZEPAM (rohypnol) ACUTE INTERMITTENT PORPHYRIA
 GAMMA-HYDROXYBUTYRATE Notes Additive to CNS depression with Ethanol.
Potent inducer of CYP450 enzymes
Clinical Uses of Benzodiazepines
Clinical Use Preffered Benzodiazepine
Anticonvulsant maintenance CLONAZEPAM MNEMONICS – Biochemistry – Porphyria
Status epilepticus LORAZEPAM, DIAZEPAM What enzyme is deficient in Acute Intermittent Porphyria?
Skeletal muscle relaxation DIAZEPAM  HYDROXYMETHYLBILANE SYNTHASE
(eg, cerebral palsy)
Panic disorders, Phobias ALPRAZOLAM, CLONAZEPAM
Insomnia ESTAZOLAM, FLURAZEPAM, TRIAZOLAM
What is the most catastrophic symptom of sedative-hypnotic
Anesthesia induction MIDAZOLAM, DIAZEPAM withdrawal?
Bipolar disorder CLONAZEPAM  REBOUND SUICIDE
Alcohol withdrawal CHLORDIAZEPOXIDE, DIAZEPAM
MISCELLANEOUS (NEWER) HYPNOTICS ALCOHOL DEHYDROGENASE
 Cytosolic, NAD+-dependent enzyme
ZOLPIDEM  Found mainly in the LIVER and GUT
SimD ZALEPLON, ESZOPICLONE  Accounts for the metabolism of low to moderate doses of
Class Imidazopyridine ethanol
MOA Bind selectively to a subgroup of GABA-A receptors,  Because of the limited supply of the co-enzyme NAD+, the
acting like benzodiazepines to enhance membrane reaction has zero-order kinetics
hyperpolarization o Fixed capacity for ethanol metabolism of 7-10 g/h
Uses INSOMNIA ONLY!  Gastrointestinal metabolism of ethanol is lower in women
SE Modest day-after psychomotor depression, Few than in men
amnestic effects, Tolerance, Dependence liability (less
than benzodiazepines) KEY LEARNING POINTS!
Notes Effects reversed with FLUMAZENIL! Why is there Lactic acidosis and Hypoglycemia?
Lack anti-convulsant, anti-anxiety and muscle relaxant  Increased metabolism  inc. NADH:NAD+ ratio  diverts
effects pyruvate to lactate & OAA to malate
 AFTERMATH: inhibits gluconeogenesis and stimulates
MNEMONICS – Zolpidem FA synthesis
zZzzZZzzzZZzzzZZz (sleep)  CONSEQUENCE: hypoglycemia and hepatic fatty change
Zolpidem, Zaleplon = SLEEP DISORDERS (hepatocellular steatosis)
 Overproduction of lactate  acidosis
BUSPIRONE  Depletion of OAA shuts down the TCA cycle, shunts
Class Anxiolytic Drug acetyl-CoA into ketone production
MOA Partial agonist at 5-HT1A and possibly D2 receptors  Breakdown of excess malate increases NADPH and thus
Uses GENERALIZED ANXIETY DISORDER FA synthesis
SE Non-specific chest pain, Tachycardia, Palpitations,
Diziness, Nervousness, Tinnitus, Gastrointestinal
distress, Paresthesias, Dose-dependent pupillary
constriction
Notes No anticonvulsant
No muscle relaxant properties
Minimal CNS depressant effects
Minimal abuse liability
Minimal tolerance and withdrawal
MNEMONICS – Buspirone
Microsomal Ethanol Oxidizing System (MEOS)
Buspirone for Busy People (Always Anxious)
 Responsible for ethanol metabolism at blood levels higher
BuSPirone like your BenzodiaSePine!!
than 100 mg/dL
 Chronic ethanol consumption
Pineal Gland (no BBB)  ↑ age = calcifications occur & ↓ melatonin
o Induces cytochrome P450 enzymes synthesis and
MEOS activity (CYP2E1 – high affinity to ethanol)
o Development of tolerance to ethanol
ALCOHOLS  Acetaldehyde is rapidly metabolized to acetate by aldehyde
dehydrogenase
o Inhibited by disulfiram, metronidazole, oral
hypoglycemics, and some cephalosporins
o Genetic deficiency of aldehyde dehydrogenase in
Asians
Acute Effects of Ethanol

 CNS EFFECTS:
o Sedation, loss of inhibition, impaired judgment,
slurred speech, ataxia
 EFFECTS ON OTHER ORGAN SYSTEMS:
o Slight cardiac depression, vasodilation,
hypothermia, uterine muscle relaxation
Blood Alcohol Concentration (BAC)

BAC (mg/dL) Effects
50 – 100 Sedation, Subjective “high”, Slower reaction times
60 – 80 Impairment of driving ability (DUI)
100 – 200 Impaired motor functions, Slurred speech, Ataxia
200 – 300 Emesis, Stupor
300 – 400 Coma
> 500 Respiratory depression, Death
Chronic Effects of Ethanol

 TOLERANCE AND DEPENDENCE
o Result of CNS adaptation and increased ethanol
metabolism
o Cross-tolerance to benzodiazepines and
barbiturates
o Marked psychological and physical dependence
 LIVER DISEASE
o Most common complication of chronic alcohol
abuse
o Reduced gluconeogenesis leads to hypoglycemia
o Progressive loss of liver function (reversible fatty MNEMONICS – Delirium Tremens
liver to irreversible hepatitis, cirrhosis, and liver H – A – D 48!!
failure)  Hallucinations
o Increased severity in females and those with  Autonomic instability
hepatitis B and C  Delirium
 GASTROINTESTINAL SYSTEM 48 – 72 hours post-discontinuation
o Irritation, inflammation, bleeding and scarring of
gut wall ALCOHOL WITHDRAWAL SYNDROME
o Absorption defects and exacerbation of nutritional  TREATMENT
deficiencies o Correction of electrolyte imbalance
o Increased risk of PANCREATITIS! o Administration of thiamine
 CENTRAL NERVOUS SYSTEM o Administration of a sedative hypnotics
o Peripheral neuropathy is the most common  Substituting a long-acting sedative-
neurologic abnormality in chronic alcoholics hypnotic drug for alcohol and then
o WERNICKE-KORSAKOFF SYNDROME (ataxia, gradually reducing (“tapering”) the dose
confusion, paralysis of the extraocular muscles) of the long-acting drug
 Drug of choice is long-acting
MNEMONICS – Wernicke-Korsakoff Syndrome BENZODIAZEPINE (eg, diazepam,
Weird ACO = Wernicke-Korsakoff Syndrome chlordiazepoxide)
 Ataxia  Short-acting benzodiazepine with less
 Confusion complex metabolism (eg, lorazepam) is
 Ophthalmoplegia preferred in patients with compromised
What changes in the brain are seen in Wernicke-Korsakoff liver function
Syndrome?
 Hemorrhagic necrosis of the mammillary bodies Treatment of Alcoholism
(recollecive memory)  Opioid receptor antagonists (NALTREXONE)
o Decrease CNS effects of endogenous opioid
 ENDOCRINE SYSTEM peptides
o Gynecomastia, Testicular atrophy and Salt  NMDA receptor antagonists (ACAMPROSATE)
retention due to altered steroid metabolism in the  DISULFIRAM inhibits aldehyde dehydrogenase
cirrhotic liver o Acetaldehyde accumulation leads to nausea,
 CARDIOVASCULAR SYSTEM headache, flushing, and hypotension
o Increased incidence of hypertension, anemia and o (+) punishemnt
dilated cardiomyopathy
o Binge drinking can cause arrhythmias MNEMONICS – Disulfiram Reaction
o Ingestion of modest quantities of ethanol (10-15 What drug can cause disulfiram reaction?
g/day) raises HDL levels and may protect against Clara took the Pre-Medical Test in the PM!!
CAD  CHLORPROPAMIDE
 FETAL ALCOHOL SYNDROME  CEFOPERAZONE (3rd)
o Mental retardation (most common)  CEFOMANDOLE (2nd)
o Growth deficiencies  CEFOTETAN (2nd)
o Microcephaly  PROCARBAZINE (anti-neoplastic drug, Hodgkin’s
o Characteristic underdevelopment of midface Lymphoma)
region  METRONIDAZOLE
o Associated with heavy consumption of alcohol
during the first trimester of pregnancy METHANOL
 NEOPLASIA  SOURCES:
o Increased incidence of neoplastic diseases in GIT o Wood alcohol
o Small increase in the risk of breast cancer o Windshield cleaners
 IMMUNE SYSTEM o “Canned heat”
o Enhances inflammation in the liver and pancreas o Commercial solvents
o Inhibits immune function in other tissues o Photocopier toner
o Heavy use predisposes to infectious pneumonia  CLINICAL MANIFESTATIONS:
o Treatment of Acute and Chronic Alcoholism  Visual dysfunction, Gastrointestinal distress, Shortness of
 EXCESSIVE CNS DEPRESSION breath, Loss of consciousness, Coma
o Maintenance of vital signs  Accumulation of formaldehyde and formic acid causes
o Prevention of aspiration after vomiting severe acidosis, Retinal damage, and Blindness
o Intravenous dextrose
o Thiamine administration to protect against Treatment of Methanol Poisoning
Wernicke-Korsakoff syndrome  ETHANOL
o Correction of electrolyte imbalance o Retards formation of formaldehyde
o Acts as preferred substrate for alcohol
dehydrogenase
o Competitively inhibits the oxidation of methanol
 FOMEPIZOLE
o Inhibitor of alcohol dehydrogenase
 ETHYLENE GLYCOL  STATUS EPILEPTICUS
o SOURCES o Series of seizures (usually tonic-clonic) without
 Industrial exposure (by inhalation or skin recovery of consciousness between attacks
absorption) o Life-threatening emergency
 Self-administration (eg, by drinking
antifreeze products) Antiseizure Drug Na+ Ca2+ K+ GABA Glutamate Others
o CLINICAL MANIFESTATION Phenytoin •
Carbamazepine • •
 Severe acidosis and renal damage Valproic acid • • • NMDA
 Due to accumulation of oxalic acid Phenobarbital • • •
Oxcarbazepine • • •
Treatment of Ethylene Glycol Poisoning Clonazepam •
Diazepam •
 ETHANOL Ethosuximide •
o Competes for oxidation by alcohol dehydrogenase Gabapentin • • •
 FOMEPIZOLE Pregabalin • • •
o Slows or prevents formation of oxalic acid Vigabatrin •
Tiagabine •
Lamotrigine • • •
Levetiracetam • • •
Topiramate • • • • Carbonic anhydrase
Felbamate • NMDA
Zonisamide • • Carbonic anhydrase
TRADITIONAL ANTISEIZURE DRUGS
PHENYTOIN
SimD FOSYPHENYTOIN, MEPHENYTOIN, ETHOTOIN
Class Anticonvulsant Drugs (hydantoin)
MOA Blocks voltage-gated Na channels
Uses Drug of choice for Generalized tonic-clonic seizures
ANTI-SEIZURE DRUGS and Partial seizures! Status epilepticus, Arrhythmias
(group 1B action)
SE Nystagmus, Diplopia, Sedation, Gingival hyperplasia,
Hirsutism, Anemias, Peripheral neuropathy,
Osteoporosis, Teratogen (fetal hydantoin syndrome)
Notes Potent inducer of CYP450 enzymes.
Follows zero-order kinetics at high doses
FETAL HYDANTOIN SYNDROME

 Upturned nose
 Mild midfacial hypoplasia
 Long upper lip with thin vermillion border
 Lower distal digital hypoplasia
SEIZURES CARBAMAZEPINE
 Finite episodes of brain dysfunction resulting from Class Anticonvulsant Drug (tricyclic)
abnormal discharge of cerebral neurons MOA Blocks voltage-gated Na channels and decrease
 Classification based on seizure characteristics: glutamate release
o Simple or Complex Uses Drug of choice for Generalized tonic-clonic seizures,
o Partial, Generalized, or Partial with secondary Partial seizures and Trigeminal neuralgia! Bipolar
generalization disorders
SE Diplopia, Cognitive dysfunction, Drowsiness, Ataxia,
Types of Seizures Blood dyscrasias, Stevens-Johnson syndrome,
 SIMPLE PARTIAL SEIZURES Teratogenic potential
o Consciousness is preserved Notes Potent inducer of CYP450 enzymes
o Manifested variously as convulsive jerking,
paresthesias, psychic symptoms (altered sensory VALPROIC ACID
perception, illusions, hallucinations, affect SimD SODIUM VALPROATE
changes) and autonomic dysfunction Class Anticonvulsant drug (branched-chain fatty acids)
 COMPLEX PARTIAL SEIZURES MOA Blocks high-frequency firing of neurons modifies amino
o Impaired consciousness acid metabolism
o Preceded, accompanied, or followed by Uses Generalized tonic-clonic seizures, Partial seizures,
psychological symptoms Myoclonic seizures, Bipolar disorders (acute mania)
 GENERALIZED TONIC-CLONIC SEIZURES (GRAND MAL) SE Drowsiness, Nausea, Tremor, Alopecia, Weight gain,
o Tonic phase (less than 1 min) involves abrupt loss Hepatotoxicity (infants), Teratogen (neural tube defect,
of consciousness, muscle rigidity and respiration SPINA BIFIDA)
arrest Notes Inhibitor of CYP450 enzymes
o Clonic phase (2-3 min) involves jerking of body
muscles, with lip or tongue biting, and fecal and
KEY LEARNING POINTS – Valproic Acid
urinary incontinence
Valproate ate the Folate! (spina bifida)
 ABSENCE SEIZURES (PETIT MAL)
o Impaired consciousness (often abrupt onset and
brief)
o Automatisms; loss of postural tone, or enuresis
o Begin in childhood and usually cease by age 20 yrs
 MYOCLONIC SEIZURES
o Sudden, brief, shock-like contractions of
musculature (myoclonic jerks)
PHENOBARBITAL TOPIRAMATE
SimD PRIMIDONE Class Anticonvulsant Drug (monosaccharide derivative)
Class Anticonvulsant Drug (barbiturates) MOA Multiple actions on synaptic function, probably via
MOA Bind to GABA-A receptor sites (distinct from actions of phosphorylation (Na, Ca, GABA, AMPA-
benzodiazepines); Increases duration of chloride glutamate, carbonic anhydrase)
channel opening Uses Generalized tonic-clonic seizures, Absence seizures,
Uses Generalized tonic-clonic seizures, Partial seizures, Partial seizures, LENNOX-GASTAUT SYNDROME,
Status epilepticus, Insomnia, Hyperbilirubinemia WEST SYNDROME, Migraine
SE Extension of CNS depressant actions, Tolerance, SE Drowsiness, Dizziness, Ataxia, Psychomotor slowing,
Dependence liability (greater than benzodiazepines), Memory impairment, Paresthesias, Weight loss, Acute
Acute intermittent Porphyria myopia, Glaucoma, Urolithiasis
Notes Potent inducer of CYP450 enzymes. Notes Antiseizure drug with most number of mechanism of
Preferred antiseizure drug in children and pregnant action!
women!
Clinical Uses of Antiseizure Drugs
ETHOSUXIMIDE Seizure Type Drugs of Choice Alternative Drugs
SimD PHENSUXIMIDE, METHSUXIMIDE Generalized VALPROIC ACID Phenobarbital,
Class Anticonvulsant Drug (cyclic ureide) tonic-clonic PHENYTOIN Lamotrigine,
Seizures CARBAMAZEPINE Topiramate
MOA Decrease Ca2+ currents (T-type) in thalamus Partial Seizures CARBAMAZEPINE Felbamate,
Uses Drug of choice for ABSENCE SEIZURES LAMOTRIGINE Phenobarbital,
SE Gastrointestinal distress, Lethargy, Headache, PHENYTOIN Topiramate,
Behavioral changes Valproic acid
Absence Seizures ETHOSUXIMIDE Lamotrigine,
DIAZEPAM VALPROIC ACID Levetiracetam,
Zonisamide,
SimD Anticonvulsant Drug (benzodiazepine)
Clonazepam
Class Binds GABA-A receptor subunits to increase frequency Myoclonic and VALPROIC ACID Clonazepam,
of chloride channel opening; Membrane Atypical Absence (not in pregnancy) Levetiracetam,
hyperpolarization Syndromes Topiramate,
MOA STATUS EPILEPTICUS Zonisamide,
Uses Anterograde amnesia, Decreased psychomotor skills, Felbamate
Unwanted daytime sedation, Respiratory depression, Status Epilepticus LORAZEPAM
Tolerance, Dependence liability DIAZEPAM
PHENYTOIN
PHENOBARBITAL
CLONAZEPAM
Class Anticonvulsant Drug (benzodiazepine) Other Clinical Uses of Antiseizure Drugs!
MOA Binds GABA-A receptor subunits to increase frequency  BIPOLAR AFFECTIVE DISORDERS
of chloride channel opening; Membrane o Valproic acid (first-line for mania)
hyperpolarization o Carbamazepine
Uses Absence seizures, Myoclonic seizures, Infantile spasms o Lamotrigine
SE Anterograde amnesia, Decreased psychomotor skills,  TRIGEMINAL NEURALGIA
Unwanted daytime sedation, Respiratory depression, o Carbamazepine (drug of choice)
Tolerance, Dependence liability o Oxcarbazepine
 NEUROPATHIC PAIN (POSTHERPETIC NEURALGIA)
GABAPENTIN o Gabapentin
SimD PREGABALIN o Pregabalin
Class Anticonvulsant Drug (GABA derivative)  MIGRAINE
MOA Blocks Ca2+ cahnnels. Increases GABA release. Inhibits o Gabapentin
neuranl discharge from seizure foci. o Phenytoin
Uses Partial seizures, Neurpathic pain (postherpetic o Topiramate
neuralgia), Migraine
SE Dizziness, Sedation, Ataxia, Nystagmus, Tremor
GENERAL ANESTHETICS
LAMOTRIGINE
Class Anticonvulsant Drug (phenyltriazine)
GENERAL ANESTHESIA
MOA Blocks Na and Ca channels, decreases glutamate
 State characterized by unconsciousness, analgesia, amnesia,
Uses Generalized tonic-clonic seizures, Partial seizures, skeletal muscle relaxations, and loss of reflexes
Myoclonic seizures, Absence seizures, Bipolar disorders
 General anesthetics are CNS depressants with actions that
SE Diziness, Ataxia, Nausea, Rash, Stevens-Johnson can be induced and terminated more rapidly than those of
Syndrome conventional sedative-hypnotics
LEVETIRACETAM
Class Anticonvulsant Drug (piracetam)
MOA Selectively binds synaptic vesicular protein SV2A.
Modifies synaptic release of glutamate and GABA.
Uses Generalized tonic-clonic seizures, Partial seizures,
Juvenille myoclonic epilepsy
SE Dizziness, Sedation, Weakness, Irritability,
Hallucinations, Psychosis
Notes Drug interactions are minimal; Levetiracetam is NOT
metabolized by cytochrome P450!
Stages of Anesthesia NITROUS OXIDE
STAGE NAME EVENTS Class General Anesthetic (inhalational)
1 Analgesia  Decreased awareness of pain, MOA Facilitate GABA-mediated inhibition; Block brain NMDA
sometimes with amnesia and ACh-N receptors
 Consciousness is impaired,
NOT loss
Uses Anesthesias for minor surgery and dental procedures,
2 Disinhibition  Patient is delirious or excited Balanced anesthesia for major surgery
 Amnesia occurs, reflexes are SE Megaloblastic anemia on prolonged exposure,
enhanced, and respiration is EUPHORIA (laughing gas)
typically irregular Notes Lowest potency (highest MAC) and least cardiotoxicity
 Retching and incontinence among inhalational anesthetics
may occur Additive to CNS depression with many agents, especially
3 Surgical Anesthesia  Patient is unconscious opioids and sedative-hypnotics
 No pain reflexes, regular
respiration, and maintained
blood pressure DESFLURANE
4 Medullary Depression  Severe respiratory and Class General Anesthetic (inhalational)
cardiovascular depression MOA Facilitate GABA-mediated inhibition; Block brain NMDA
that requires mechanical and and ACh-N receptors
pharmacologic support Uses General Anesthesia
SE Bronchospasm (pulmonary irritant), Peripheral
INHALATIONAL ANESTHETICS vasodilation
Notes Contraindicated in Asthmatic patients!
INHALATIONAL ANESTHETICS Additive to CNS depression with many agents, especially
 Include Nitrous oxide, Halothane, Desflurane, Enflurane, opioids and sedative-hypnotics
Isoflurane, Sevoflurane, and Methoxyflurane
 Partial pressire of “tension” is a measure of concentration of SEVOFLURANE
inhaled anesthetics Class General Anesthetic (inhalational)
o Standard pressure of the total inhaled mixture is MOA Facilitate GABA-mediated inhibition; Block brain NMDA
atmospheric pressure (760 mmHg at sea level) and ACh-N receptors
o 50% nitrous oxide in the inhaled air would have a Uses General Anesthesia
partial pressure of 380 mmHf SE Peripheral vasodilation, Renal insufficiency
Notes Additive to CNS depression with many agents, especially
Minimum Alveolar Anesthetic Concentration (MAC)
opioids and sedative-hypnotics
 Best measure of potency of inhaled anesthetics
 Defined as the alveolar concentration required to eliminate ISOFLURANE
the response to a standardized painful stimulus in 50% of
Class General Anesthetic (inhalational)
patients
MOA Facilitate GABA-mediated inhibition; Block brain NMDA
 When several anesthetic agents are used simultaneously,
and ACh-N receptors
their MAC values are additive
Uses General Anesthesia
SE Catecholamine-induced arrhythmias, Peripheral
Properties of Inhaled Anesthetics
Anesthetic Partition MAC Metabolism Comments
vasodilation
Coefficient Notes Cardiotoxic – can cause CORONARY STEAL SYNDROME
Nitrous oxide 0.47 >100 None Incomplete anesthetic; Additive to CNS depression with many agents, especially
rapid onset and recovery
Desflurane 0.42 6–7 < 0.05 % Low volatility; poor
induction agent
(pungent); rapid recovery ENFLURANE
Sevoflurane 0.69 2.0 2–5% Rapid onset and recovery; Class General Anesthetic (inhalational)
(fluoride) unstable in soda-lime
Isoflurane 1.40 1.40 < 2% Medium rate of onset and MOA Facilitate GABA-mediated inhibition; Block brain NMDA
recovery and ACh-N receptors
Enflurane 1.80 1.7 8% Medium rate of onset and Uses General Anesthesia
recovery
SE Spike-and-wave activity, Muscle twitching, Breath-
Halothane 2.30 0.75 > 40% Medium rate of onset and
recovery holding, Myocardial depression, Renal insufficiency
Methoxy- 12 0.16 >70% Very slow onset and Notes Can cause seizures!
flurane (fluoride) recovery Additive to CNS depression with many agents, especially
Effects of Inhaled Anesthetics
 CNS EFFECTS HALOTHANE
o Decrease brain metabolic rate Class General Anesthetic (inhalational)
o Reduce vascular resistance, increase cerebral MOA Facilitate GABA-mediated inhibition; Block brain NMDA
blood flow and increase intracranial pressure and ACh-N receptors
 CARDIOVASCULAR EFFECTS Uses General Anesthesia
o Decrease arterial blood pressure moderately SE Catecholamine-induced arrhythmias, Myocardial
o Decrease blood flow to the liver and kidneys depression, Post-operative hepatitis
 RESPIRATORY EFFECTS Notes Additive to CNS depression with many agents, especially
o Increased rate of respiration opioids and sedative-hypnotics
o Dose-dependent decrease in tidal volume and
minute ventilation, leading to increase in arterial METHOXYFLURANE
CO2 tension
Class General Anesthetic (inhalational)
o Decrease ventilator response to hypoxia even at
MOA Facilitate GABA-mediated inhibition; Block brain NMDA
subanesthetic concentrations (eg, during
and ACh-N receptors
recovery)
Uses General Anesthesia
o Most inhaled anesthetics are bronchodilators
SE Renal insufficiency
KEY LEARNING POINTS! Notes Highest potency and lowest MAC among inhalational
Fick’s Law = anesthetic moves ACROSS a concentration gradient anesthetics (very slow onset and recovery).
Additive to CNS depression with many agents, especially
↑MAC = ↓ potency of the drug opioids and sedative-hypnotics
INTRAVENOUS ANESTHETICS TRIVIA – Death of Michael Jackson!
MICHAEL JACKSON (1958 – 2009)
THIOPENTAL Immediate COD: acute propofol intoxication!
SimD METHOHEXITAL, THIAMYLAL Contributory factors: drug interactions (lorazepam, midazolam,
Class General Anesthetic (intravenous) diazepam)
Barbiturate (ultrashort-acting)
MOA Binds to GABA-A receptor sites (distinct from LOCAL ANESTHETICS
benzodiazepines); Increases duration of chloride
channel opening LOCAL ANESTHETICS
Uses Anesthesia induction, Increased ICP  Results when sensory transmission from a local area of the
SE Extension of CNS depressant actions, Tolerance, body to the CNS is blocked
Dependence liability (greater than benzodiazepines),  Local anesthetics can be administered locally by injection or
Acute intermittent porphyria topical application to the target area
Notes Additive to CNS depression with Ethanol.
Potent inducer of CYP450 enzymes.
MIDAZOLAM
SimD BROTIZOLAM, TRIAZOLAM, OXAZEPAM, ETIZOLAM
Class General Anesthetic (intravenous)
Benzodiazepine (short-acting)
MOA Binds GABA-A receptor subunits to increase frequency
of chloride channel opening; Membrane
hyperpolarization MNEMONICS – Local Anesthetics
Uses Acute anxiety, Panic attacks, Anesthesia induction, How will you distinguish whether local anesthetics are esters or
Preoperative sedation amides?
SE Anterograde amnesia, Decreased psychomotor skills, ESTERS have only 1 “I” in their names!
Unwanted daytime sedation, Dependence liability, Post-  Tetracaine, Procaine, Benzocaine
operative respiratory depression AMIDES have 2 “I’s” in their names!
Notes Additive to CNS depression with Ethanol.  Bupivacaine, Ropivacaine, Lidocaine
Antidote is FLUMAZENIL!
MNEMONICS – Half-life of Local Anesthetics
KETAMINE Which local anesthetics have the shortest and longest half-lives?
Class General Anesthetic (intravenous) A PRO finisihes the race fastest!
MOA Blocks excitation by glutamate at NMDA receptors  PROCAINE = shortest half-life (1-2 mins)
Uses DISSOCIATIVE ANESTHESIA (analgesia, amnesia, and At the END of the long ROPe!
catatonia but with retained consciousness); patients are  ROPIVACAINE =longest half-life (4.2 hours)
awake but anesthesized!
SE Cardiovascular stimulation, Hypertension, Increased MOA of Local Anesthetics
ICP, Emergence delirium  Block voltage-dependent Na+ channels, reducing influx of
Notes Reduce emergence delirium by pretreatment with Na+, thereby preventing depolarization
benzodiazepines!  Most are weak bases that undergo dissociation
o More lipid-soluble (non-ionized, uncharged) form
ETOMIDATE reaches effective intracellular concentrations
Class General Anesthetic (intravenous) more rapidly
MOA Modulates GABA-A receptors containing β3 subunits o Once inside the axon, the ionized (charged) form of
Uses General anesthesia (specially in patients with limited the drug is the more effective blocking entity
cardiac or respiratory reserve)
SE Pain on injection, Myoclonus, Post-operative nausea and KEY LEARNING POINTS – Abscesses
vomiting, Adrenocortical suppression Why should you NOT inject local anesthetics into an abscess during
Notes Minimal effects on cardiovascular and respiratory incision and drainage?
functions. Preferred for pediatric patients!  It WONT work due to acidic environment
No analgesic properties!  Low pKa = charged form will predominate
 Will not be able to cross the membrane and exert its
FENTANYL action
SimD MORPHINE, ALFENTANIL, REMIFENTANIL
MOA of Local Anesthetics
Class General Anesthetic (intravenous)
Opioid Analgesic  Blockade of Na+ channels is both state-dependent and use-
dependent
MOA Interact with μ, δ, and κ receptors for endogenous
o State-dependent: activated > inactivated > resting
opioid peptides
o Use-dependent: rapidly firing fibers are usually
Uses General anesthesia
blocked before slowly firing fibers
SE Respiratory depression, Chest wall rigidity,
 Relationship of local anesthesia with electrolytes
Constipation
o Hyperkalemia enhances local anesthetic activity
Notes Antidote is NALOXONE!
o Hypercalcemia antagonizes local anesthetic
Neuroleptanesthesia achieved by combining fentanyl,
activity (main goal: block depolarization)
droperidol, and nitrous oxide
Toxicity of Local Anesthetics
PROPOFOL
 CNS EFFECTS
SimD FOSPROPOFOL o Lighe-headedness or sedation, restlessness,
Class General Anesthetic (intravenous) nystagmus, generalized tonic-clonic seizures,
MOA Potentiates GABA-A receptors, Blocks Na channels respiratory and cardiovascular depression
Uses General anesthesia, Prolonged sedation  CARDIOVASCULAR EFFECTS
SE Bradycardia, Hypotension, Pain at injection site, o All local anesthetics are vasodilators EXCEPT!
Anterograde amnesia, Dystonia, Priapism COCAINE (prevents reuptake of norepinephrine)
Notes Called “milk of amnesia”!! o Use with caution in patients with pre-exisiting
Used during bronchoscopy/endoscopy cardiovascular disease because they may develop
Additive effects with sedative-hypnotic drugs heart block and arrhythmias
ESTER LOCAL ANESTHETICS PRILOCAINE
Class Local Anesthetics (amide)
PROCAINE MOA Blockade of Na channels slows, then prevents axon
SimD NOVOCAINE potential propagation
Class Local Anesthetics (ester) Uses Local anesthesia, Dental anesthesia
MOA Blockade of Na channels slows, then prevents axon SE Light-headedness, Sedation, Restlessness, Nystagmus,
potential propagation Seizures, Respiratory and cardiovascular depression,
Uses Local anesthesia, Extravasation complications from METHEMOGLOBINEMIA
venipuncture, Inadvertent intra-arterial injections Notes Administer methylene blue if patient develops
SE Light-headedness, Sedation, Restlessness, Nystagmus, methemoglobinemia
Seizures, Respiratory and cardiovascular depression,
Antibody formation BUPIVACAINE
Notes Shortest half-life among local anesthetics Class Local Anesthetics (amide)
MOA Blockade of Na channels slows, then prevents axon
BENZOCAINE potential propagation
SimD BUTAMBEN Uses Local anesthesia, Epidural anesthesia, Intrathecal
Class Local Anesthetics (ester) anesthesia
MOA Blockade of Na channels slows, then prevents axon SE Light-headedness, Sedation, Restlessness, Nystagmus,
potential propagation Seizures, Respiratory and cardiovascular depression,
Uses Local anesthesia, Topical anesthesia (Oral spray) Severe cardiovascular toxicity, Hypotension,
SE Light-headedness, Sedation, Restlessness, Nystagmus, Arrhythmias (idioventricular rhythm – 240 bpm)
Seizures, Respiratory and cardiovascular depression, Notes Use with caution in pregnant women!
Skin irritation, Antibody formation Contraindicated in intravenous regional anesthesia.
Notes Use cautiously when treating sunburns or large areas of Treat cardiotoxicity with INTRALIPID (fat emulsion
skin! used in Total Parenteral Nutrition)
COCAINE ROPIVACAINE
Class Local Anesthetics (ester), Class Local Anesthetics (amide)
Drugs of Abuse MOA Blockade of Na channels slows, then prevents axon
MOA Blockade of Na channels slows, then prevents axon potential propagation
potential propagation Uses Local anesthesia, Epidural anesthesia
Uses Local anesthesia, Topical anesthesia SE Light-headedness, Sedation, Restlessness, Nystagmus,
SE Light-headedness, Sedation, Restlessness, Nystagmus, Seizures, Respiratory and cardiovascular depression,
Seizures, Respiratory and cardiovascular depression, Cardiotoxicity
Antibody formation, Abuse liability, Severe Notes Longest half-life among local anesthetics
hypertension, Cerebral hemorrhage, Cardiac Contraindicated in intravenous regional anesthesia.
arrhythmias, Myocardial infarction Treat cardiotoxicity with INTRALIPID (fat emulsion
used in Total Parenteral Nutrition)
TETRACAINE
Class Local Anesthetics (ester)
MOA Blockade of Na channels slows, then prevents axon SKELETAL MUSCLE RELAXANTS
potential propagation
Uses Local anesthesia, Spinal anesthesia, Epidural SKELETAL MUSCLE RELAXANTS
anesthesia, Topical ophthalmic anesthesia  Neuromuscular blocking drugs are used to produce muscle
SE Light-headedness, Sedation, Restlessness, Nystagmus, paralysis to facilitate surgery or assisted ventilation
Seizures, Respiratory and cardiovascular depression,  Spasmolytic drugs are used to reduce abnormally elevated
Antibody formation tone caused by neurologic or muscle end plate disease
AMIDE LOCAL ANESTHETICS
LIDOCAINE
Class Local Anesthetics (amide)
MOA Blockade of Na channels slows, then prevents axon
potential propagation
Uses Local anesthesia, Anti-arrhythmic (group 1B
activity); Used post-MI and for digitalis toxicity
SE Light-headedness, Sedation, Restlessness, Nystagmus,
Seizures, Respiratory and cardiovascular depression
KEY LEARNING POINTS – Toxic Dose of Lidocaine

What is the toxic dose of LIDOCAINE? Types of Neuromuscular Blockade
 Toxic dose = 5mg/kg  DEPOLARIZING BLOCKADE
 For any drug or solution, 1% = 10mg/mL o Neuromuscular paralysis that results from
For a 70kg patient: persistent depolarization of the end plate (eg, by
 70kg x 5 mg/kg = 350 mg toxic dose succinylcholine)
 If 1% solution is used: 350 mg/10mg/mL = 35 mL
 NON-DEPOLARIZING OR STABILIZING BLOCKADE
o Neuromuscular paralysis that results from
pharmacologic antagonism at the acetylcholine
receptor of the end plate (eg, by tubocurarine)
VECURONIUM
Class Non-depolarizing Neuromuscular Blocker
(intermediate-acting)
MOA Competitive antagonists at skeletal muscle nicotinic
acetylcholine receptors
Uses Skeletal muscle relaxation during intubation and
General anesthesia
SE Respiratory paralysis, Apnea
Notes Reverse effects with NEOSTIGMINE!
Undergoes HOFFMANN Elimination in bile.
Muscle relaxation is potentiated by inhaled anesthetics,
aminoglycosides and quinidine
ROCURONIUM
(intermediate-acting)
NON-DEPOLARIZING NEUROMUSCULAR BLOCKERS MOA Competitive antagonists at skeletal muscle nicotinic
acetylcholine receptors
MOA of Non-Depolarizing Neuromuscular Blockers Uses Skeletal muscle relaxation during intubation and
 Surmountable blockers that prevent the action of ACh at the General anesthesia
skeletal muscle end-plate SE Respiratory paralysis, Apnea, Hypersensitivity
 Effects reversed by cholinesterase inhibitors Notes Reverse effects with NEOSTIGMINE!
 Larger muscles are more resistant to neuromuscular SUGAMMADEX is a novel reversal agent for Rocuronium
blockade, but recover more rapidly
 ROCURONIUM has the most rapid onset time (60-120 sec) PANCURONIUM
 Diaphragm is resistant to blockage Class Non-depolarizing Neuromuscular Blocker
(long-acting)
TUBOCURARINE MOA Competitive antagonists at skeletal muscle nicotinic
Class Non-depolarizing Neuromuscular Blocker acetylcholine receptors. Moderate block on cardiac
(long-acting) muscarinic receptors.
MOA Competitive antagonists at skeletal muscle nicotinic Uses Skeletal muscle relaxation during intubation and
acetylcholine receptors General anesthesia, Euthanasia, Lethal injection,
Uses Skeletal muscle relaxation during intubation and STRYCHNINE POISONING!
General anesthesia SE Respiratory paralysis, Apnea, Tachycardia,
SE Respiratory paralysis, Apnea, Ganglion block Hypertension, Recurarization
(hypotension), Histamine release (moderate), Notes Reverse effects with NEOSTIGMINE!
Recurarization (part of the drug, hides in fat tissue)
Notes Relatively contraindicated in myocardial ischemia APPLICATIONS – Lethal injections
Reverse effects with NEOSTIGMINE! What are the drugs used in lethal injections?
 THIOPENTAL (5g)
 PANCURONIUM (100mg)
MIVACURIUM  POTASSIUM CHLORIDE (100 mEq)
(short-acting) DEPOLARIZING NEUROMUSCULAR BLOCKERS
MOA Competitive antagonists at skeletal muscle nicotinic
acetylcholine receptors Phases of Depolarizing Blockade
Uses Skeletal muscle relaxation during intubation and  PHASE I (DEPOLARIZATION)
General anesthesia o Membrane depolarizes with initial electric
SE Respiratory paralysis, Apnea, Histamine release discharge
(moderate) o Transient fasciculations followed by flaccid
Notes Reverse effects with NEOSTIGMINE! paralysis
Metabolized by pseudocholinesterase.  PHASE II (DESENSITIZATION)
o Membrane repolarizes BUT receptor is
ATRACURIUM desensitized to the effects of acetylcholine
SimD CISATRACURIUM
Class Non-depolarizing Neuromuscular Blocker SUCCINYLCHOLINE
(intermediate-acting) Class Depolarizing Neuromuscular Blocker
MOA Competitive antagonists at skeletal muscle nicotinic MOA Agonist at ACh-N receptors causing initial twitch then
acetylcholine receptors persistent depolarization
Uses Skeletal muscle relaxation during intubation and Uses Skeletal muscle relaxation during intubation and
General anesthesia general anesthesia
SE Respiratory paralysis, Apnea, Seizures, Histamine SE Muscle pain, Hyperkalemia, Increased intragastric
release, Bronchospasms pressure (aspiration), Increased intraocular pressure,
Notes Reverse effects with NEOSTIGMINE! Malignant hyperthermia
Undergoes HOFFMANN Elimination (rapid Notes Metabolized by pseudocholinesterase
spontaneous breakdown)
Less adverse effects with Cisatracurium! MALIGNANT HYPERTHERMIA
 Rare interaction of succinylcholine (and possibly
tubocurarine) with inhaled anesthetics (halothane)
 Potentially life-threatening condition characterized by
massive calcium release from the sarcoplasmic reticulum of
skeletal muscles
 Early sign: contraction of the jaw muscles (TRISMUS)
 Treated by rapidly cooling the patient and by administration
of DANTROLENE (prevents the release of Ca2+ from the
sarcoplasmic reticulum)
DRUGS USED IN PARKINSONISM Parkinsonian Phenomena

 ON – OFF PHENOMENA
o Alternating periods of improved mobility and
akinesia, occurring over a few hours to days
during treatment
 WEARING – OFF PHENOMENA

o Deterioration of drug effect in between medication
doses
o Due to progressive destruction of nigrostriatal
PARKINSON’S DISEASE neurons that occurs with disease progression
 Also known as Paralysis agitans
 Neurodegenerative disease caused by degeneration of BROMOCRIPTINE
dopaminergic neurons in the substantia nigra (loss of 60% SimD PERGOLIDE
of dopamine-producing neurons) Class Anti-parkinsonism Drug (dopamine agonist)
 Progressive neurologic diseases characterized by shuffling MOA Partial agonist at dopamine D2 receptors in the brain
gait, stoop posture, resting tremor, speech impediments, Uses Parkinson’s disease, Levodopa intolerance,
movement difficulties and an eventual slowing of mental Hyperprolactinemia
processes and dementia SE Anorexia, Nausea, Vomiting, Dyskinesias, Postural
hypotension, Behavioral changes, Erythromelalgia,
MNEMONICS – Parkinson’s Disease Pulmonary fibrosis
What are the primary signs of Parkinson’s Disease?
PARKINSON’S DISEASE! It’s a TRAP!! PRAMIPEXOLE
 Tremor SimD ROPINIROLE
 Rigidity Class Anti-parkinsonism Drug (dopamine agonist)
 Akinesia MOA Partial agonist at dopamine D3 receptors in the brain
 Postural instability Uses Parkinson’s disease, Restless Legs Syndrome
SE Anorexia, Nausea, Vomiting, Dyskinesias, Postural
Drug-Induced Parkinsonism hypotension, Behavioral changes, COMPULSIVE
 Occurrence of reversible Parkinsonian symptoms in patients GAMBLING, Hypersexuality, Over-eating,
taking the following drugs: Uncontrollable tendency to fall asleep
o Anti-psychotic drugs: (typical anti-psychotics) Notes Contraindicated in patients with active peptic ulcer
o Reserpine disease, psychotic illness, or recent myocardial
o MPTP (methylphenyltetrahydropyridine) infarction
APOMORPHINE
Class Anti-parkinsonism Drug (dopamine agonist)
MOA Partial agonist at dopamine D3 receptors in the brain.
Antagonist at 5-HT and alpha receptors.
Uses Off-periods of Parkinson’s disease, Alcoholism, Opiate
addiction, Erectile dysfunction, Alzheimer’s disease
SE Severe nausea, Dyskinesias, Hypotension, Drowsiness,
Sweating
Notes Premedicate with TRIMETHOBENZAMIDE to prevent
severe nausea
SELEGILINE
SimD RASAGILINE
Class Anti-parkinsonism Drug (MAO Type B inhibitor)
MOA Selective inhibitor of monoamine oxidase type B, leading
to decreased degradation of dopamine.
Increases response to levodopa/carbidopa.
Uses Parkinson’s disease
SE Insomnia, Mood changes, Dyskinesias, Gastrointestinal
distress, Hypotension
Notes Combination with meperidine causes agitation,
delirium, and death (fatal reaction)
Serotonin Syndrome occurs when used with SSRIs
LEVODOPA – CARBIDOPA
Class Anti-parkinsonism Drug (dopamine precursor) ENTACAPONE
MOA Levodopa is a dopamine precursor. Carbidopa inhibits SimD TOLCAPONE
peripheral metabolism via dopa decarboxylase. Class Anti-parkinsonism Drug (COMT inhibitor)
Uses PARKINSON’S DISEASE (primary drug) MOA Blocks L-dopa metabolism by inhibiting catechol-O-
SE Gastrointestinal upset (emesis), Dyskinesia methyltransferase in periphery (both) and CNS
(choreoathetosis), Behavioral changes, On-Off (tolcapone). Prolongs response to levodopa.
phenomena, Wearing-off phenomena, Postural Uses Parkinson’s disease (wearing-off phenomena)
hypotension SE Dyskinesias, Gastrointestinal distress, Postural
Notes Contraindicated in patients with history of PSYCHOSIS! hypotension, Sleep disturbance, Orange urine,
Hypertensive crisis occurs when used with monoamine Hepatotoxicity (tolcapone only), Neuroleptic
oxidase inhibitors malignant syndrome, Rhabdomyolysis
KEY LEARNING POINTS!

Parkinson’s Disease = doPamine Decrease
Alzheimer’s Disease = Acetylcholine Decrease
Dopaine CANNOT cross the BBB!
AMANTADINE Potency of Typical Antipsychotics
Class Anti-parkinsonism Drug (anti-viral)  LOW POTENCY
MOA Potentiate dopaminergic function by influencing the o Fewer extrapyramidal effects but more H1, α1, and
synthesis, release, or reuptake of dopamine. muscarinic blocking effects
Antagonizes the effects of adenosine at adenosine A 2A o EXAMPLES: chlorpromazine, thioridazine,
receptors mesoridazine
Uses Parkinson’s disease, Influenza  HIGH POTENCY
SE Behavioral changes (acute toxic psychosis), LIVEDO o More extrapyramidal effects and less H1, α1, and
RETICULARIS (swelling of medium-sized blood vessel muscarinic blocking effects
in lower extremeties), Gastrointestinal disturbances, o EXAMPLES: haloperidol, fluphenazine, droperidol
Urinary retention, Postural hypotension, Peripheral
edema Dopamine Hypotheis
Notes May improve bradykinesia, rigidity and tremor  Schizophrenia is caused by a relative excess dopamine in
specific neuronal tracts in the brain
MNEMONICS – Livedo Reticularis! o Many antipsychotic drugs block brain dopamine
What drugs can cause livedo reticularis? receptors (especially D2 receptors)
A man reads FHM and GQ!! o Dopamine agonist drugs (eg, amphetamine,
 Amantadine levodopa) exacerbate schizophrenia
 Hydroxyurea – chronic myelogenous leukemia o Increased density of dopamine receptors has been
 Minocycline detected in certain brain regions
 Gemcitabine – chemotherapeutic agent  Not fully satisfactory because antipsychotic drugs are only
 Quinidine partly effective in most patients
BENZTROPINE Dopamine Receptors

SimD BIPERIDEN, TRIHEXYPHENIDYL, ORPHENADRINE  Five different dopamine receptors (D1-D5)
Class Anti-parkinsonism Drug (anti-cholinergic)  D2 receptors in caudate putamen, nucleus accumbens
MOA Decreases the excitatory actions of cholinergic neurons (ventral tegmental area), cerebral cortex and hypothalamus
on cells in the striatum by blocking muscarinic o Target of action of older anti-psychotics
receptors. o Strong correlation between blockade of D2
Uses Parkinson’s disease, Extrapyramidal symptoms caused receptors and extrapyramidal dysfunction
by anti-psychotics
SE Drowsiness, Inattention, Confusion, Delusions, Dopaminergic Tracts
Hallucinations, Atropine-like effects  MESOCORTICAL – MESOLIMBIC
Notes Improve tremor and rigidity, with ittle effect on o Regulating mentation and mood
bradykinesia.  NIGROSTRIATAL
Exacerbate tardive dyskinesias that result from o Extrapyramidal function
prolonged use of anti-psychotic drugs  TUBERO-INFUNDIBULAR
o Control of prolactin release
 MEDULLARY-PERIVENTRICULAR
ANTIPSYCHOTIC AGENTS AND LITHIUM o Eating behavior
 INCERTOHYPOTHALAMIC
o Anticipatory motivational phase of copulatory
behavior
Treatment of Schizophrenia
 All antipsychotics reduce some of the positive symptoms of
schizophrenia
 Clozapine is effective in some schizophrenic patients
resistant to treatment with other antipsychotic drugs
 None of the typical antipsychotics has much effect on
negative symptoms of schizophrenia
 Atypical drugs are reported to improve some of the negative
symptoms of schizophrenia
Classification of Anti-psychotics Toxicities of Antipsychotics

 TYPICAL (CLASSICAL) ANTIPSYCHOTICS (first general Type Manifestations Mechanism
anesthesia with greater extrapyramidal symptoms) Autonomic Loss of accommodation, dry Muscarinic
o PHENOTHIAZINES Nervous System mouth, difficulty urinating, cholinoceptor
 Chlorpromazine constipation blockade
Orthostatic hypotension, Α-adrenoceptor
 Thioridazine
impotence, failure to blockade
 fluphenazine ejaculate
o THIOXANTHENES Central Nervous Parkinson’s syndrome, Dopamine-receptor
 thiothixene System akathisia, dystonias blockade
o BUTYROPHENONES Tardive dyskinesia Supersensitivity of
 Haloperidol (uncontrollable movement of dopamine receptors
 ATYPICAL ANTIPSYCHOTICS (metabolic side effects: muscles of the foot)
obesity, DM, agranulocytosis) Toxic-confusional state Muscarinic blockade
o HETEROCYCLICS Endocrine Amenorrhea-galactorrhea, Dopamine-receptor
 Clozapine System infertility, impotence blockade resulting in
hyperprolactinemia
 Loxapine
Other Weight gain Possible combined H1
 Olanzapine and 5-HT2 blockade
 Risperidone
 Quetiapine
KEY LEARNING POINTS!
 Ziprasidone
 Schizophrenia – increase in dopamine!
 Aripiprazole
 EPS – drug-induced parkinsonism (bind tightly to
dopamine-2 receptors)!
 2nd General anesthesia – binds tightly to serotonin
Neuroleptic-Induced Movement Disorders OLANZAPINE
Disorder Timing Characteristics Treatment Class Atypical anti-psychotic
Acute 4hrs – 4 dys Retrocollis, Diphenhydramine MOA Block of 5-HT2 receptors >> D2 receptors
Dystonia Opisthotonos, Uses Schizophrenia and other psychotic disorders, Bipolar
Oculogyric crisis
disorder, Anorexia nervosa, Depression
Parkinsonism 4 dys – 4 Tremor, Rigidity, Benztropine
mos Akinesia, Postural SE Extrapyramidal dysfunction (less), Hyperprolactinemia
instability (less), Postural hypotension, Weight gain,
Rabbit 4 mos – 4 Perioral tremor Benztropine Hyperglycemia (diabetes mellitus), Hyperlipidemia
Syndrome yrs
Tardive 4 mos – 4 Repetitive None QUETIAPINE
Dyskinesia yrs involuntary Class Atypical anti-psychotic
movement (tongue
MOA Block of 5-HT2 receptors >> D2 receptors
protrusion, lip
smacking/pursing) Uses Schizophrenia and other psychotic disorders, Bipolar
Akathisia Any time Restlessness, Decrease dose, disorder (manic episodes)
pacing, sitting up diphenhydramine SE Extrapyramidal dysfunction (less), Hyperprolactinemia
and down (less), Postural hypotension, Weight gain (less),
Neuroleptic Any time Fever, Withdraw drug, Somnolence, Fatigue, Sleep paralysis, Hypnagogic
Malignant encephalopathy, dantrolene, hallucinations, Cataracts, Priapism
Syndrome vitals unstable, diazepam, Notes QUIET-time! Sleep!
elevated CPK, dopamine agonist
Rigidity
RISPERIDONE
TYPICAL ANTIPSYCHOTICS Class Atypical anti-psychotic
CHLORPROMAZINE Uses Schizophrenia and other psychotic disorders, Bipolar
Class Typical anti-psychotic (Phenothiazine) disorder, Depression, Intractable hiccups, Tourette
syndrome
MOA Block of D2 receptors >> 5-HT2 receptors
SE Extrapyramidal dysfunction (less), Weight gain (less),
Uses Schizophrenia and other psychotic disorders
Insomnia, Hyperprolactinemia (marked),
SE Extrapyramidal dysfunction, Tardive dyskinesia,
Photosensitivity
Hyperprolactinemia, Atropine-like effects, Faliure of
Notes Only antipsychotic approve for schizophrenias in the
ejaculation, Postural hypotension, Marked sedation,
youth!
CORNEAL and LENS DEPOSITS, Neuroleptic malignant
Rise and shine!! – less sedating
syndrome, Contact dermatitis
ZIPRASIDONE
THIORIDAZINE
Class Atypical anti-psychotic
SimD FLUPHENAZINE, PERPHENAZINE,
PROCHLORPERAZINE, TRIFLUOPERAZINE MOA Block of 5-HT2 receptors >> D2 receptors
Class Typical anti-psychotic (Phenothiazine) Uses Schizophrenia and other psychotic disorders, Bipolar
disorder (acute mania)
SE Extrapyramidal dysfunction (less), Postural
Uses Schizophrenia and other psychotic disorders,
hypotension, QT prolongation (torsades)
Antiemesis (prochlorperazine)
Notes No atropine-like effects.
SE Extrapyramidal dysfunction, Tardive dyskinesia,
Little or no tendency to cause hyperglycemia.
Hyperprolactinemia, Atropine-like effects, Faliure of
Hyperprolactinemia or weight gain!
ejaculation, Postural hypotension, RETINAL DEPOSITS,
Increased mortality in elderly patients witn
Cardiotoxicity (arrhythmias)
dementia-related psychosis!
Notes Strongest autonomic effects!
Only antipsychotic with fatal overdose!
ARIPIPRAZOLE
Class Atypical anti-psychotic
HALOPERIDOL (Haldoe)
SimD DROPERIDOL
Uses Schizophrenia and other psychotic disorders, Bipolar
Class Typical anti-psychotic (Butyrophenone)
disorder, Depression, Autism, Cocaine dependence
SE Extrapyramidal dysfunction (less), Gastrointestinal
Uses Schizophrenia and other psychotic disorders,
upset, Tremor, Hypersensitivity (rare)
HUNTINGTON’S DISEASE, TOURETTE’S SYNDROME
Notes Least sedating atypical antipsychotic!
SE Extrapyramidal dysfunction (major), Tardive
No atropine-like effects
dyskinesia, Hyperprolactinemia, NEUROLEPTIC
Little or no tendency to cause hyperglycemia.
MALIGNANT SYNDROME
Hyperprolactinemia or weight gain!
Notes Weakest autonomic effects!
Least sedating among typical antipsychotics!
MNEMONICS – Neuroleptic Malignant Syndrome
What are the features of neuroleptic malignant syndrome?
ATYPICAL ANTIPSYCHOTICS
NEUROLEPTIC MALIGNANT SYNDROME!!
 Fever
CLOZAPINE  Encephalopathy
Class Atypical anti-psychotic  Vitals unstable
MOA Block of 5-HT2 receptors >> D2 receptors  Elevated CPK
Uses Schizophrenia (refractory, suicidal) and other psychotic  Rigidity
disorders
SE Extrapyramidal dysfunction (less), Hyperprolactinemia
(less), Postural hypotension, Weight gain,
Hyperglycemia (diabetes mellitus), Hyperlipidemia,
Myocarditis, Agranulocytosis, Seizures, Ileus,
Hypersalivation (sialorrhea)
Notes Only anti-psychotic that reduces the risk of SUICIDE!
LITHIUM
Clinical Use of Lithium

 Treatment of Bipolar Disorders (manic–depressive)
o Decreases manic behavior and reduces both the
frequency and the magnitude of mood swings
o Protective effects against suicide and self-harm
 Used concurrently with antidepressants during
maintenance therapy
o Monotherapy with antidepressants can precipitate
mania in bipolar patients
 Antipsychotic agents and/or benzodiazepines are
commonly required at initiation of treatment because of
slow onset of action
LITHIUM
Class Mood Stabilizer
MOA Uncertain. Decreases cAMP, Inhibits inositol-1-
phosphatase, causing depletion of inositol and inositol
triphosphate
Uses Bipolar disorder, Recurrent depression, Schizoaffective
disorder
SE Tremor, Sedation, Ataxia, Aphasia, Thyroid
enlargement, Nephrogenic diabetes insipidus, Edema,
Acneiform skin eruptions, Leukocytosis, Teratogen
(EBSTEIN ANOMALY), Bradycardia
Notes Contraindicated in Sick Sinus Syndrome!
Treat overdose with hemodialysis.
Lithium Overdose
 Threshold for toxicity is 2 mEq/L
 Therapeutic overdoses are more common than deliberate or
accidental ingestion
o Due to change in the patient’s status (diminished
serum sodium, use of diuretics of fluctuating renal
function)
 CLINICAL MANIFESTATIONS
o Neuromuscular excitability, tremors, twitching,
agitation, weakness, ataxia, leukocytosis,
bradycardia, hypotension
 TREATMENT
o Hemodialysis is preferred over peritoneal dialysis
SimD
Class
MOA
Uses
SE
Notes
Class
MOA
Uses
SE
Notes
ACKNOWLEDGEMENTS:
This Anatomy Supplement Handout was lovingly made by Mei Ann
Ty-Arias, MD. Her sources are:
1. Hi-Yield Anatomy
2. USMLE 1st Aid asdas
3. Kaplan Anatomy
4. Personal Notes asdddddd\
Addiitonal Tables on Muscles of the Upper & Lower Extremities were

provided by one of our previous students, Miguel Ramos, MD.
Thank you very much Mei Ann! & Migs =)
saasdasdasdasds
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MOVEMENT OF DRUGS IN THE BODY

PERMEATION – is the movement of drug molecules into and within

FICK’S Law of Diffusion PRACTICE PROBLEMS:

pH = pKa + log U/P

Weak Acids and Bases

MNEMONICS – BICARBONATE and AMMONIUM CHLORIDE

KEY LEARNING POINTS – IM Injections to Buttocks Transdermal Route

DRUG METABOLISM 2. Compute the remaining concentration of Drug A and B every

TERMINATION OF DRUG ACTION

Quantal Dose-Response Relationships

Quantal-Dose Response Curves

Variations in Drug Response

Idiosyncratic Drug Response

 If a drug is cleared partly by the kidney and partly by other

Cockroft – Gault Equation

PRACTICE PROBLEM – Bioavailability

Maintenance Dose Phase 1 Reactions

MNEMONIC – CYTOCHROME P450 INDUCERS

MNEMONICS – CYTOCHROME P450 INHIBITORS

FDA Drug Categories Ames Test

Drugs and Pregnancy Investigational New Drug (IND)

SANS PANS MNEMONIC – for Parasympathetic Nervous System

DIRECT – ACTING CHOLINOMIMETICS, MUSCARINIC

STEP 3 – RELEASE DIRECT – ACTING CHOLINOMIMETICS, NICOTINIC

Differentiate myasthenic crisis from cholinergic crisis.

MNEMONICS – Atropine Toxicity

HEXAMETHONIUM STEP 4 – TERMINATION

Drug Effects on Adrenergic Transmission  Dopamine – 2 (D2) Adrenergic Effects

Alpha – 1 (α1) Adrenergic Effects MOA of Sympathomimetics

Alpha – 2 (α2) Adrenergic Effects EPINEPHRINE

Beta – 1 (β1) Adrenergic Effects NOREPINEPHRINE

Selective Alpha-2 (α2) Agonists

Selective Beta-1 (β1) Agonists PRAZOSIN

PROPRANOLOL  CILIARY EPITHELIUM

Beta-Blockers in Diabetic Patients

Intrinsic Sympathomimetic Activity

MNEMONICS – Beta Blockers with ISA FLOW OF AQUEOUS HUMOR

DRUGS FOR HYPERTENSION SYMPATHOPLEGICS

CNS Sympathetic Outflow Blockers

1. CNS Sympathetic Outflow Blockers

CARDIOACTIVE DRUGS! FENOLDOPAM

MNEMONICS – Drug-induced Lupus!

2. Calcium Channel Blockers KEY LEARING POINTS – ACE-Inhibitors

KEY LEARNING POINTS – Hyperkalemia

Atherosclerotic Angina NITROGLYCERIN

Therapeutic Strategies in Angina

VERAPAMIL DRUGS USED IN HEART FAILURE

Effects of Drug Combinations

Treatment of Digitalis Toxicity

5. Phosphodiesterase Inhibitors CLASS 1 ANTI-ARRHYTHMICS

Non-selective PROPRANOLOL, MOA of CLASS 4 Anti-arrhythmics

MOA of CLASS 3 Anti-arrhythmics VERAPAMIL

Summary of the Effects of Anti-arrhythmics Drugs

NON-PHARMACOLOGIC TREATMENT ACETAZOLAMIDE

MNEMONICS – Metabolic Acidosis

Thick Ascending Limb of the Loop of Henle

MNEMONICS – Thiazide Diuretics

MNEMONICS – Potassium-sparing Diuretics

Which drugs can cause GYNECOMASTIA?

Blood pH: DECREASES pH (acidemia)

Blood pH: INCREASES pH (alkalemia)