Topnotch Supplement Pharmacology Handout

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] TABLE OF CONTENTS TOPIC Basic Principles of Pharmacology Pharmacodynamics Pharmacokinetics Drug Metabolism Drug Evaluation and Regulation Autonomic Pharmacology Cholinoreceptor-Activating and Cholinesterase-Inhibiting Drugs Cholinoreceptor Blockers Adrenergic Pharmacology Sympatomimethics Adrenoreceptor Blockers Treatment of Glaucoma Drugs for Hypertension Drugs Used in the Treatment of Angina Pectoris Drugs used in Heart Failure Anti-Arrhythmic Drugs Diuretics Drugs used in the Treatment of Hyperlipidemia Histamine, Serotonin, Ergot Alkaloids Prostaglandins and Other Eicosanoids Bronchodilators & Other Drugs Used in

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BASIC PRINCIPLES OF PHARMACOLOGY INTRODUCTION DEFINITION OF TERMS DRUGS Any substance that brings about a change in biologic o function through its chemical actions 

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12 13 14 15 16 17 19 21 22 25 28 30 31 32

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PHARMACODYNAMICS Actions of a drug on the body  o Receptor interaction  Dose-response phenomena  Mechanisms of therapeutic  actions

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PHARMACOKINETICS Actions of the body on the drug o Concerned with: o  Absorption Distribution  Metabolism  Elimination 

MNEMONICS – Pharmacodynamics vs Pharmacokinetics pharmacoDynaMics pharmacoK ine ineTics

toxic

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  Aqueous Diffusion Diffusion Passive movement of non-protein-bound drugs between the blood and extravascular space through small waterfilled pores (exceptions: Brain, Testes, Eye and Placenta) Affected by drug concentration and charge Governed by Fick’s Law of Diffusion

Dissocation of Weak Acids

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HA Protonated R – COOH

A+ ↔ ↔ unprotonated + + ↔ R – COO-

H+ H+ H+

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Lipid Diffusion Movement of drugs through lipid memebranes (i.e. BBB, Placenta) separating body compartment, and from the ECF to the ICF Most important limiting factor for permeation Governed by Fick’s Law of Diffusion Very important for the diffusion of weak acids and weak bases 

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unprotonated (A-) form is more water-soluble and undergoes better clearance protonated (HA) form is more lipid-soluble and more likely to cross biological membranes

Dissocation of Weak Bases

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Transport by Special Carriers Drugs that do not readily cross through membranes membranes may be transported across barriers by mechanisms that carry similar endogenous substances Ions through Na/K pump o Neurotransmitter through reuptake transporters o Metabolites such as glucose through GLUT o Carriers for foreign molecules or xenobiotics or xenobiotics o NOT governed by Fick’s Law of   Diffusion and is capacitylimited 

BH Protonated R – NH3

B + ↔ ↔ unprotonated + R- NH2 + ↔

Weak Acids and Bases

H+ H+ H+

Above pKa: Unprotonated > protonated

At pH = pKa Unprotonated = protonated

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Below pKa:

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  Aqueous Diffusion Diffusion Passive movement of non-protein-bound drugs between the blood and extravascular space through small waterfilled pores (exceptions: Brain, Testes, Eye and Placenta) Affected by drug concentration and charge Governed by Fick’s Law of Diffusion

Dissocation of Weak Acids

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HA Protonated R – COOH

A+ ↔ ↔ unprotonated + + ↔ R – COO-

H+ H+ H+

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Lipid Diffusion Movement of drugs through lipid memebranes (i.e. BBB, Placenta) separating body compartment, and from the ECF to the ICF Most important limiting factor for permeation Governed by Fick’s Law of Diffusion Very important for the diffusion of weak acids and weak bases 

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unprotonated (A-) form is more water-soluble and undergoes better clearance protonated (HA) form is more lipid-soluble and more likely to cross biological membranes

Dissocation of Weak Bases

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Transport by Special Carriers Drugs that do not readily cross through membranes membranes may be transported across barriers by mechanisms that carry similar endogenous substances Ions through Na/K pump o Neurotransmitter through reuptake transporters o Metabolites such as glucose through GLUT o Carriers for foreign molecules or xenobiotics or xenobiotics o NOT governed by Fick’s Law of   Diffusion and is capacitylimited 

BH Protonated R – NH3

B + ↔ ↔ unprotonated + R- NH2 + ↔

Weak Acids and Bases

H+ H+ H+

Above pKa: Unprotonated > protonated

At pH = pKa Unprotonated = protonated

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Below pKa:

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] DRUG ABSORPTION

Rectal (Suppository) Route Partial avoidance of the first pass effect  Useful for large amounts of drugs with unpleasa nt tastes and for patients who are vomiting 

 Absorption Transfer of a drug from its site of administration to the bloodstream Affected by 3 major factors: Route of administration o Blood flor o Concentration o 

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CORRELATIONS – Anatomy – Rectal Route Why is there only partial bypass of the first-pass effect on rectal administration? Review the VENOUS DRAINAGE OF THE RECTUM Superior Rectal vein: IMV PV (first-pass) Middle Rectal vein: IIV  IVC Inferior Rectal vein: IPV  IIV  IVC 

ROUTES OF ADMINISTRATION

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Oral Route Offers maximum convenience Most common route of drug administration Absorption is slow and less complete Gastric contents o First-pass effect o A significant amount of the drug is  metabolized in the gut wall, portal circulation and liver before it reaches the ssystemic circulation   

Intravenous Route Instantaneous and complete absorption that bypasses firstpass effect (100% bioavailability) 

Inhalational Route Offers delivery closest to the target in respiratory diseases Rapid absorption with minimal systemic effects Convenient for drugs that are gases at room temperature (nitrous oxide, nitric oxide) or easily volatilized (anesthetics)   

Topical Route Application to skin, mucous membranes o f the eye, ear, nose, throat, airway, or vagina for local effect  Absorption varies with the area of application and drug formulation Increasing ability to retard evaporation o 

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SOLUBILITY Influences the concentration of the drug in the extracellular fluid surrounding blood vessels Most barriers in the body (BBB, placenta, glomerulus) are lipid-barriers Non-ionized, non-polar drugs are more lipido soluble and undergo more extensive distribution 

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MNEMONICS – Zero Order Kinetics What drugs display zero-order elimination kinetics? WHAT PET Warfarin Heparin Aspirin Tolbutamide Phenytoin Ethanol Theophylline     

BINDING Binding to macromolecules in the blood or tissue will tend to increase the drug’s concentration in that compartment  Acidic drugs are bound to albumin o Basic drugs are bound to orosomucoid o Bound drugs CANNOT cross membranes and exert their effect Only unbound drugs CAN cross membranes and exert their effect 

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DRUG METABOLISM Metabolism Drugs are chemically altered in the body Drugs may undergo 3 metabolic fates: Termination of drug action o Drug activation o Elimination without metabolism o  

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PRACTICE PROBLEM – Elimination Kinetics 1. Which drug displays first-order elimination? Zero-order elimination 0h 1h 2h 3h 4h 80mg 60mg 40mg 20mg 0mg  A 80mg 40mg 20mg 10mg 5mg B 2.

Compute the remaining concentration of Drug A and B every hour for 4 hours First-order elimination: Drug A t 1/2 1/2 = 2h Zero-order elimination: Drug B Rate = 50 mg/2h 0h 1h 2h 3h 4h 100mg  A 100mg B

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Graded-Dose Response Curves

Potency 

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Denotes the amount of the drug needed to produce a given effect Determined mainly by the affinity of the receptor for the drug Measurement: In grade dose-response curves, it is the dose o required to produce 50% of the maximal effect In quantal dose-response curves, three potency o 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 Fraction of the population that responds to each o dose against the log of the dose administered 

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Factors Affecting Dose Response Curves

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Competitive or Reversible Antagonists Bind to receptors in a reversible way without activating the effector system Shift DRCs to the RIGHT (increase ED50) but same maximal effect is reached Effects overcome by adding more agonist  Examples: β-blockers (Propranolol) o β-agonists (Isoproterenol) o 

 Apparent Volume of Distribution Volume at which drug would need to be uniformly distributed to produce an observed blood concentration 

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Purely pharmacokinetic parameter with no direct physical equivalent  Can be altered by liver and kidney disease

Volume of Distribution Non-competitive or Irreversible Antagonists Causes DOWNWARD shift of the DRC No horizontal shift of DRC (ED50 unchanged) unless spare receptors are present  Not overcome by adding more agonists Examples: Norepinephrine o Phenoxybenzamine o  

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Physiologic Antagonists Binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing Examples: Histamine & Epinephrine o Propranolol & Thyroid hormone o 

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Low Vd Medium Vd High Vd

Distribute in blood Distribute in extracellular space or body water Distribute in tissues

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Half-life

Constant for drugs following first-order kinetics Disease, age, and other variables usually alter clearance of a drug much more then Vd Half-life may not change despite a decreased cleareance if the Vd decreases at the same time

Therapeutic Window Safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug Minimum effective concentration usually o determines the desired trough levels of a drug given intermittently Minimum toxic concentration determines the o permissible peak plasma concentration

Bioavailability Fraction of the administered dose that reaches the systemic circulation Drugs administered intravenously have 100% bioavailability Reduced by incomplete absorption, first-pass metabolism, and pre-systemic redistribution Determined by computing the area under the plasma

 Adjustment of Dosage Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal function Impairment of hepatic clearance occurs when liver blood flow is reduced EXAMPLES: heart failure, severe cirrhosis, other o forms of liver failure

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 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 

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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, Furanocoumarins present in grapefruit juice, azole antifungals, and the HIV protease inhibitor ( Ritonavir ) Metabolism may be decreased by reduction in blood flow to metabolizing organ EXAMPLE: Propranolol reduces hepatic blood flow o 

Phase 2 Reactions Involve conjugation of subgroups to –OH, –NH2, and –SH functions on the drug molecule Makes the drug more polar and less lipid-soluble o than the original drug molecule EXAMPLES: glucoronate, acetate, glutathione, o 

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Reproductive Toxicity Involves the study of the fertility effects of the candidate  drug and its teratogenic and mutagenic toxicity FDA uses a 5-level descriptive scale to summarize  information regarding the safety of drugs in pregnancy

Mutagenesis Induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities EXAMPLES: aflatoxin, cancer chemotherapeutic o drugs, and other agents that bind to DNA

FDA Drug Categories

 Ames Test  Standard in vitro test for mutagenicity Uses a special strain of Salmonella that naturally depends on specific nutrients Loss of this dependence signals a mutation

Category A

B

C

D

X

Description Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and ther is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease fertility) that was not confirmed in controlled studies in women in the first t rimester (and ther is no evidence of a risk in later trimesters) Either studies in animals have revealed adverse effects on the 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 potential benefit justifies the potential risk to the fetus There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective) Studies in animals or human beings have demonstrated fetal

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Dominant Lethal Test  In vivo mutagenicity test carried out in mice Male animals are exposed to the test substance before mating Abnormalities in the results fo the subsequent mating signal a mutation in the male’s germ cells  

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Carcinogenesis Induction of malignant characteristics in cells Difficult and expensive to study High degree of correlation between mutagenicity in the Ames test and carcinogenicity in some animal tests EXAMPLES: coal tar, aflatoxin, nitrosamines, o urethane, vinyl chloride, polycyclic aromatic   

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 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 Must demonstrate that their generic drug molecule o is bioequivalent  

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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 

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] CHOLINERGIC PHARMACOLOGY   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

CHOLINORECEPTOR-ACTIVATING AND CHOLINESTERASE-INHIBITING DRUGS

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DIRECT – ACTING CHOLINOMIMETICS, MUSCARINIC BETANECHOL Cholinomimetic (direct – acting, muscarinic ) Class Activates muscarinic (M3) receptors MOA Bladder and bowel atony (post-surgery or spinal cord Uses injury) Cyclospasm, Diarrhea, Urinary urgency, Vasodilation, SE Reflex tachycardia, Sweating MNEMONICS – Betanechol B = Betanechol = Bowel and Bladder Atony

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] INDIRECT – ACTING CHOLINOMIMETICS MOA of Indirect-Acting Cholinomimetics Bind to cholinesterase and undergo prompt hydrolysis Alcohol portion released o Acidic portion retained and released slowly o  Prevents the binding and hydrolysis of endogenous acetylcholine   Amplify acetylcholine effects wherever ACh is released No significant actions at uninnervated sites where ACh is NOT normally released 

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EDROPHONIUM Cholinomimetic (indirect – acting) Class Inhibits acetylcholinesterase. Amplifies endogenously MOA released acetylcholine Myasthenia gravis (diagnosis – Tensilon test ), Uses Differentiation of cholinergic crisis and mysthenic crisis Miosis, Salivation, Nausea, Vomiting, Diarrhea, SE Bradychardia Very short-acting upon intravenous administration Notes

MNEMONICS – ORGANOPHOSPHATE POISONING! What are the signs and symptoms of organophosphate poisoning? DUMBBELSS! Diarrhea Urination Miosis Bronchospasm Bradycardia Excitation (skeletal muscle and CNS) Lacrimation Sweating Salivation TREATMENT OF ORGANOPHOSPHATE POISONING  ATROPINE Class MOA Uses

SE NEOSTIGMINE PYRIDOSTIGMINE, PHYSOSTIGMINE SimD Cholinomimetic (indirect – acting) Class

Notes

Cholinergic Antagonist (muscarinic) Competitively blocks ALL muscarinic receptors Mydriatic, Cycloplegic,  Antidote for (first choice), organophosphate poisoning Bradycardia, Hypersalivation Tachycardia, Mydriasis, Cycloplegia, Skin flushing, Delirium, Hallucinations No effect on the nicotinic signs of toxicity

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] MNEMONICS – Muscarinic Antagonists for Parkinsonism Try to park your Benz, Beep here! TRIhexyphenidyl BENZtropine BIPeriden IPRATROPIUM TIOTROPIUM SimD Cholinergic anragonists (muscarinic ) Class Blocks muscarinic receptors in bronchial smooth MOA muscle. Prevents vagal-stimulated bronchoconstriction. Uses ASTHMA, COPD Dry mouth, Cough, Nasal dryness SE More effective and less toxic than beta-agonists in Notes patients with COPD and Heart disease KEY LEARNING POINTS – Ipratropium in COPD Why is ipratropium the preferred bronchodilator in patients with comorbid COPD and heart disease? Less likely to cause tachycardia; and  Cardiac arrhythmias  SCOPOLAMINE Cholinergic antagonists (muscarinic ) Class Competitively blocks ALL muscarinic MOA Antagonizes histamine and serotonin

receptors.

MNEMONICS – Succinylcholine Kapag nakapag-DEPOsit ka sa toilet, SUCCess yun! (DEPOlarizing = SUCCinylcholine

 ADRENERGIC PHARMACOLOGY NOREPINEPHRINE Primary transmitter at the sympathetic post-ganglionic neuron-effector cell synapses in most tissues EXCEPTIONS! o Eccrine sweat galnds   Vasodilator sympathetic fibers in skeletal muscle 

MNEMONICS – Dopamine / Norepinephrine Dopamine vasoDILATES renal blood vessel while; Norepinephrine vasoCONSTRICTS them

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] SITES OF AUTONOMIC DRUG ACTION STEPS INHIBITORS CHOLINERGIC ADRENERGIC SYNTHESIS Hemicholinium Metyrosine STORAGE Vesamicol Reserpine RELEASE Botulinum Guanethidine TERMINATION Metabolism Neostigmine MAOIs, COMTIs Reuptake NONE Cocaine, TCAs Drug Effects on Adrenergic Transmission Used in treatment of several diseases (pheochromocytoma, hypertension) Block sympathetic but NOT parasympathetic o functions Other drugs promote catecholamine release Predictably cause sympathomimetic effects o 

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 Adrenoceptors Receptor Alpha1 (α1)

Alpha2 (α2)

Location Effector tissues Smooth muscle Glands Nerve endings Smooth muscle

G

2 nd Messenger ↑ IP3, DAG

Gq Gi

↓ cAMP

Major Functions ↑ Ca2+, causes contraction, secretion ↓ transmitter release, causes contraction

Miscellaneous Adrenergic Effects Beta – 3 (β3) Adrenergic Effects Tissue Actions fat cells Stimulates lipolysis 

Dopamie – 1 (D1) Adrenergic Effects Tissue Actions Renal and other splanchnic Dilates (↓ resistance) blood vessels 

Dopamine – 2 (D2) Adrenergic Effects Tissue Action Nerve terminals Inhibits adenylyl cyclase 

SYMPATHOMIMETICS

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Dose-Dependent Actions of Dopamine LOW DOSE (1-5 mcg/kg/min) Vasodilation in the splanchnic and renal vascular o beds via D1 receptors Increased renal blood flow and urine output o

Selective Beta-2 ( β2) Agonists

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MEDIUM DOSE (5-15 mcg/kg/min) Increased renal blood flow, heart rate, cardiac o contractility, and cardiac output via β1 receptors HIGH DOSE (>15 mcg/kg/min) Vasoconstriction and increased blood pressure via o α receptors

ISOPROTERENOL Sympathomimetic (beta non-selective ) Class Non-selectively activates β adrenergic receptors MOA β1: increased HR, conduction and contractility β2: bronchodilation Uses ASTHMA Cardiovascular disturbance, Arrhythmias SE Selective Alpha-1 ( α1) Agonists PHENYLEPHRINE PSEUDOEPHEDRINE SimD

 ALBUTEROL/SALBUTAMOL TERBUTALINE, RITODRINE SimD Sympathomimetic (beta-2 selective ) Class Activates β2 receptors in bronchial smooth muscle. MOA Causes bronchodilation. Uses Acute asthma attacks  (drug of choice), TOCOLYSIS for preterm labor (terbutaline and ritodrine) Tachycardia, Tremors, Nervousness, Restlessness, SE Arrhythmias when used excessively, Loss of responsiveness (tolerance, tachyphylaxis) May precipitate arrhythmias in patients with concurrent Notes COPD and heart disease Clinical Applications of Sympathomimetics Clinical Condition Acute heart failure Septic shock Hemostasis Decongestion Spinal shock Bronchospasm Premature labor Hypertension

Desired Parameter

Sympathomimetic of choice

Increased cardiac output Vasoconstriction Temporary maintenance of BP Bronchodilation Uterine smooth muscle relaxation Decrease BP

β1 & D1 agonists α1 agonists β2 agonists α2 agonists

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] KEY LEARNING POINTS – Alpha-1 Selectivity What is the pharmacologic advantage of α1 selectivity? Relax tachycardia is less common and less severe  MNEMONICS – Isoproterenol ISOproterenol is NOT a beta blocker! It is a non-selective beta agonist. I SOrry ka! Akala ko beta blocker ka!

TREATMENT OF GLAUCOMA Complex Organ Control: The Eye! Reciprocal control of the PUPIL SANS (pupillary dilator muscle) o PANS (pupillary constrictor) o 

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

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CILIARY MUSCLE (controls accommodation) PANS (primary control of muscarinic receptors o Insignificant contributions from the SANA o CILIARY EPITHELIUM Important receptors with permissive effect on o aqueous humor secretion

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

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: No comorbidities? < 140/90  Diabetes mellitus? < 130/80  Chronic kidney disease? < 130/80 

CLONIDINE Sympathetic Outflow Blocker Class Activates α2 adrenergic receptors. MOA α2: decreases central sympathetic outflow Hypertension, Cancer pain, Opioid withdrawal Uses Sedation, Rebound hypertension, Dry mouth SE

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] PROPRANOLOL PINDOLOL, TIMOLOL, LABETALOL, CARVEDILOL, SimD NADOLOL Adrenergic antagonists (beta non-selective ) Class Blocks β1 and β2 receptors. Blocks sympathetic effects MOA on heart and BP. Reduces renin release Angina prophylaxis, Hypertension, Arrhythmias, Uses Migraine, Performance anxiety, Hyperthyroidism Bronchospasms, AV block, Heart failure, CNS sedation, SE Erectile dysfunction, Asthma, DM Masks symptoms of hypoglycemia in diabetics. Notes LABETALOL has combined α  and β  blockade (may be used in Pheochromocytoma )

NIFEDIPINE AMLODIPINE, FELODIPINE, NICARDIPINE, SimD NISOLDIPINE Class Dihydropyridine Calcium channel Blockers Block voltage-gated L-type calcium channels MOA (vascular > cardiac) Angina, Hypertension Uses Constipation, Pretibial edema, Nausea, Flushing, SE Dizziness, Gingival hyperplase (less chance) 3. Parenteral Vasodilators

KEY LEARNING POINTS – Pheochromocytoma What drugs are used to control blood pressure in pheochromocytoma? PHENOXYBENZAMINE (irreversible alpha selective)   PHENTOLAMINE (reversible) LABETALOL 

NITROPRUSSIDE Vasodilator Class Relaxes venous and arteriolar smoth muscle. Decreases MOA both preload and afterload. Activate guanidyl cyclase. Increases cGMP release Hypertensive emergency, Acute heart failure, Uses Cardiogenic shock, Controlled hypotension Hypotension, Headache, CYANIDE TOXICITY SE

CARDIOACTIVE DRUGS! Singh – Vaughan Williams Classification  Class I – Rapid Sodium channel Blockers  Class II – Beta receptor Blockers Class III – Potassium channel Blockers 

FENOLDOPAM Class Dopamine agonist Causes arteriolar vasodilation of the afferent and MOA efferent arterioles. Increases renal blood flow. Hypertensive emergency ( 2nd  type of hypertension) Uses

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 2.  Angiotensin Receptor Blockers LOSARTAN CANDESARTAN, VALSARTAN, IRBESARTAN, SimD EPROSARTAN, TELMISARTAN Angiotensin Receptor Blockers (ARB) Class Blockes Angiotensin (AT1 receptors) in vascular smooth MOA muscle and adrenal cortex. Decreases aldosterone secretion. Hypertension, Heart failure, Diabetic nephropathy Uses Hypotension, Teratogen, Hyperkalemia SE Slows ventricular remodeling and increases survival in Notes heart failure Delays progression of diabetic nephropathy! KEY LEARNING POINTS – Hyperkalemia Why do patients taking Angiotensin antagonists (ACE-Is/ARBs) develop hyperkalemia?  ACE-Is/ARBs reduce aldosterone levels and causes potassium retention 3. Renin Antagonists  ALISKIREN Renin Antagonist Class Inhibits renin. Prevents conversion of Angiotensinogen MOA

VASODILATORS 1. Nitrates  AMYL NITRITE Ultra short-acting Nitrate Class Releases nitric oxide (NO), increases cGMP (cyclic MOA Guanosine Monophosphate) and relaxes smooth muscles, especially vascular Uses CYANIDE POISONING

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 2. Calcium Channel Blockers

METABOLISM MODIFIERS

NIFEDIPINE AMLODIPINE, FELODIPINE, NICARDIPINE, SimD NISOLDIPINE Class Dihydropyridine Calcium channel Blockers Block voltage-gated L-type calcium channels MOA (vascular > cardiac) Angina, Hypertension Uses Constipation, Pretibial edema, Nausea, Flushing, SE Dizziness, Gingival hyperplasia (less chance)

TRIMETAZIDINE VASTAREL SimD Metabolism Modifier Class Impairs glucose utilization through Fatty acid MOA metabolism. Inhibit beta oxidation of Fatty acids by inhibiting 3ketoacyl thiolase which enhances glucose oxidation Notes FIRST CYTOPROTECTIVE ANTI-ISCHEMIC AGENT

VERAPAMIL DILTIAZEM SimD Class Non-dihydropyridine Calcium channel Blocker Block voltage-gated L-type calcium channels MOA (cardiac > vascular) Angina, Hypertension, Supraventricular tachycardia, Uses Migraine Constipation, Pretibial edema, Nausea, Flushing, SE Dizziness, Gingival hyperplasia, Heart failure, AV block, Sinus node depression

DRUGS USED IN HEART FAILURE

DILTIAZEM Class Non-dihydropyridine Calcium channel Blocker Block voltage-gated L-type calcium channels MOA

Pathophysiology of Congestive Heart Failure Fundamental physiologic defect is decrease in cardiac output relative to the needs of the body Frequently associated with chronic hypertension, valvular disease, coronary artery disease, and cardiomyopathies 

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Therapeutic Strategies for CHF Removal of retained salt and water with diuretics Reduction of afterload and salt and water retention by means of ACE Inhibitors Reduction of excessive sympathetic stimulation by means of beta-blockers  

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] MNEMONICS – Narrow Therapeutic Index What drugs have narrow therapeutic index? WALA na Cyang PaPa!! VasTeD na!!! Warfarin  Aminoglycosides  Lithium  Amphotericin B   Carbamazepine Phenobarbital  Phenytoin  Vancomycin  Theophylline   Digoxin Digitalis Toxicity Increased by HYPOKALEMIA, HYPOMAGNESEMIA   and HYPERCALCEMIA (same as Thiazide) Loop diuretics  and Thiazides  may significantly o reduce serum potassium and precipitate digitalis toxicity Digitalis-induced vomiting may deplete serum o magnesium and similarly facilitate toxicity 

Treatment of Digitalis Toxicity CORRECTION OF POTASSIUM/MAGNESIUM DEFICIENCY ANTI-ARRHYTHMIC DRUGS  

6. Vasodilators NITROPRUSSIDE or NITROGLYCERIN for acute severe failure with congestion Dramatically effective in CHF due to increased afterload (eg, continuing hypertension in an individual who has just had an infarct) HYDRALAZINE   and ISOSORBIDE DINITRATE   has been shown to reduce mortality in African Americans Calcium channel blockers are of NO VALUE in CHF 

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MNEMONICS – Survival in CHF What drugs have been shown to improve survival in cases of heart failure?  ABA!! Buhay ka pa!! ACE Inhibitors  Beta-blockers  Aldosterone Antagonists 

 ANTI-ARRHYTHMIC DRUGS

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] MOA of CLASS 1 Anti-arrhythmics ALL group 1 drugs slow or block conduction in ischemic and depolarized cells; and slow or abolish abnormal pacemakers Most selective agents (GROUP 1B) have significant effects on sodium channels in ischemic tissue, BUT negligible effects on normal cells Use dependent or state dependent in their action! Selectively depress tissues that are frequently o depolarizing Selectively depresses tissues that are relatively o depolarized during rest  AMIODARONE has class A1 activity

2. Class 1B Anti-arrhythmics

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MOA of GROUP 1B Anti-arrhythmics REDUCES AP duration Slows recovery of sodium channels from inactivation leading to prolonged ERP Selectively affects ischemic or depolarized Purkinje  and ventricular tissue Because these agents have little effect on normal o cardiac cells, they have LITTLE EFFECT on the ECG  

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KEY LEARNING POINTS – CLASS 1 Anti-arrhythmics What are the effects of class 1 anti-arrhythmics on action potential duration? CLASS 1A: prolongs AP duration CLASS 1B: shortens AP duration CLASS 1C: no effect on AP duration   

1. Class 1A Anti-arrhythmics PROCAINAMIDE Class 1A Anti-arrhythmic Class Use- and State-dependent block I Nachannels; Some block MOA of IK channels.

LIDOCAINE MEXILETINE, TOCAINIDE, PHENYTOIN SimD Class 1B Anti-arrhythmics Class Highly-selective use- and state-dependent INa block; MOA Minimal effect in normal tissue; NO EFFECT on I K Drug of choice for Ventricular arrhythmias postUses myocardial infarction ; Digoxin-induced arrhythmias CNS stimulation, Cardiovascular depression, SE Arrhythmias, Allergy, Seizure,  AGRANULOCYTOSIS* (Tocainide) Hyperkalemia exacerbates cardiac toxicity Notes Lidocaine is the LEAST cardiotoxic among conventional anti-arrhythmias

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Summary of the Clinical Uses of Class I Anti-arrhythmics Class 1A All types of Arrhythmias o Arrhythmias in acute phase of Myocardial o Infarction Procainamide and Amiodar one for __________________ o Class 1B Acute ventricular arrhythmias, especially post-MI o Atrial arrhythmias due to Digitalis o Class 1C Refractory arrhythmias o 

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CLASS 2 ANTI-ARRHYTHMICS MOA of CLASS 2 Anti-arrhythmics Primarily cardiac beta-adrenoceptor blockade and reduction in cAMP Reduction of both sodium and calcium currents o Suppression of abnormal pacemakers o AV node is particulary sensitive to blockers PR interval is usually prolonged o Act on PHASE 4 SOTALOL and AMIODARONE also have group 2 effects

DOFETILIDE IBUTILIDE SimD Class 3 Anti-arrhythmics Class Selective IK  block; Prolonged action potential and QT MOA interval Treatment and prophylaxis of ATRIAL FIBRILLATION Uses SE Torsades de Pointes SOTALOL Class 3 Anti-arrhythmics Class IK block and beta-adrenoceptor block MOA Ventricular arrhythmias, Atrial fibrillation, Uses Supraventricular tachycardia Dose-related torsade de pointes, Excessive betaSE blockade (sinus bradycardia, asthma)

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PROPRANOLOL METOPROLOL, TIMOLOL SimD

 AMIODARONE DRONEDARONE SimD Class 3 Anti-arrhythmics Class Strong IK block produces marked prolongation of action MOA potential and refractory period. Group 1 activity slows conduction velocity; Group 2  and 4 activity  confer additional antiarrhythmic activity Uses REFRACTORY ARRHYTHMIAS , Used off-label in many arrhythmias

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] DILTIAZEM Class Non-dihydropyridine Calcium channel Blocker Block voltage-gated L-type calcium channels MOA (cardiac > vascular) Angina, Hypertension, Supraventricular tachycardia, Uses Vasospasm, RAYNAUD’S PHENOMENON Constipation, Pretibial edema, Nausea, Flushing, SE Dizziness, Heart failure, AV block, Sinus node depression Summary of the Effects of Anti-arrhythmics Drugs Class

Prototype

1A

Procainamide

Effects on AP duration PROLONGS

1B 1C 2 3 4

Lidocaine Flecainide Propranolol Dofetilide Verapamil

SHORTENS NO EFFECT NO EFFECT PROLONGS NO EFFECT

Effects on ECG PROLONGS PR interval, PROLONGS QRS duration, PROLONGS QT interval NO EFFECT on normal cells PROLONGS QRS duration PROLONGS PR interval PROLONGS QT interval PROLONGS PR interval

MISCELLANEOUS ANTI-ARRHYTHMICS  ADENOSINE Miscellaneous Anti-arrhythmic Class Increase in diastolic Ik   of AV node that causes marked MOA hyperpolarization and conduction block; Reduced I Ca

CARBONIC ANHYDRASE INHIBITORS Proximal Convoluted Tubule isosmotic reabsorption of amino acids, glucose,

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] HYDROCHLOROTHIAZIDE CHLORTHALIDONE, INDAPAMIDE, METOLAZONE SimD Thiazide Diuretics Class Inhibit Na/Cl transporter in distal convoluted tubule. MOA Causes moderate diuresis and reduced excretion of calcium. Hypertension, Heart failure, Hypercalciuria, Renal Uses calcium stones, Nephrogenic diabetes insipidus Hypokalemic metabolic alkalosis, Dilutional SE hyponatremia, Potassium wasting, Hyperglycemia, Hyperlipidemia, Hyperuricemia, Hypercalcemia, Sulfa allergy Synergistic effect with loop diuretics. Notes Efficacy decreased by NSAIDs.

FUROSEMIDE BUMETANIDE, TORSEMIDE, SimD ETHACRYNIC ACID ( Phenoxy- derivative) Loop Diuretic Class Inhibit Na/K/2Cl transporter in thick ascending limb of MOA loop of Henle. Causes powerful diuresis and increased calcium excretion Heart failure, Pulmonary edema, Hypertension, Uses Hypercalcemia, Acute renal failure, ANION OVERDOSE

MNEMONICS – Thiazide Diuretics HYPER GLUC!! HyperGlycemia   HyperLipidemia HyperUricemia  HyperCalcemia  POTASSIUM – SPARING DIURETICS Cortical Collecting Ducts Last tubular site of sodium reabsorption 

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] OSMOTIC DIURETICS MOA of Osmotic Diuretics Remains in the lumen and “holds” water by virtue of its osmotic effect Reabsorption of water is also reduced in the descending limb of the loop of Henle and the collecting tubule

SUMMARY TABLE! DRUG

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 ACETAZOLAMIDE

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MANNITOL GLYCERIN, ISOSORBIDE, UREA SimD Osmotic Diuretic Class Osmotically retains water in tubule by reducing MOA reabsorption in proximal tubule, descending limb of Henle’s loop, and collecting ducts; In the periphery, mannitol extracts water from cells Uses RHABDOMYOLYSIS , Hemolysis, Increased intracranial pressure, Acute glaucoma Transient volume expansion (hyponatremia, pulmonary SE edema; followed by hypernatremia), Headache, Nausea, Vomiting, Diarrhea

 ADH AGONISTS / ANTAGONISTS Medullat Collecting Duct  Reabsorption of water occurs under the control of  ANTIDIURETIC HORMONE (ADH) Site of action of ADH agonists and antagonists 

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FUROSEMIDE

HYDROCHLOROTHIAZIDE

SPIRONOLACTONE

MOA/ LOCATION Inhibition of carbonic anhydrase in PCT Inhibition of Na/K/Cl cotransporter in Thick ascending limb of the loop of Henle Inhibition of NaCl cotransporter in DCT Blocks Na channels, Blocks aldosterone in collecting tubules

Urinary Electryolytes ↑Na, K ↓HCO3

Blood pH Acidosis

↑Na, K, Ca, Mg, Cl

Alkalosi s

↑Na, K, Cl ↓Ca

alkalosis

↓K+ ↑Na (small)

acidosis

DRUGS USED IN THE TREATMENT OF

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] STATINS/HMG-COA REDUCTASE INHIBITORS

CHOLESTEROL ABSORPTION BLOCKERS

MOA of Statins Inhibition of hepatic cholesterol synthesis contributes a small amount to drug effect Greater cholesterol-lowering effect derived from the compensatory response of the liver Increased number of high-affinity LDL receptors, o which clear LDL and VLDL remnants from the blood Direct anti-atherosclerotic effects Prevent bone loss

MOA of Ezetimibe Converted in the liver to the active glucuronide form Inhibits NPC1L1 transporter  (a specific transport process in jejunal enterocyte) that mediates gastrointestinal uptake of cholesterol and phytosterols Prevents absorption of dietary cholesterol and cholesterol that is excreted in bile Reduces cholesterol in tightly regulated hepatic o pool Compensatory increase in the synthesis of higho affinity LDL receptors increases the removal of LDL

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SIMVASTATIN ATORVASTATIN, ROSUVASTATIN, FLUVASTATIN, SimD PRAVASTATIN, LOVASTATIN, PITAVASTATIN Reversible competitive inhibitor of HMG-COA reductase Class Inhibits rate-limiting enzyme in cholesterol MOA biosynthesis. Increased hepatic cholesterol uptake. Increased high-affinity LDL receptors. Decreased LDL levels. Hypercholesterolemia (high LDL), Acute coronary Uses syndromes, Ischemic stroke Hepatotoxicity, Myopathy, Rhabdomyolysis, SE Gastrointestinal distress, Teratogen Increased risk of Myopathy  and Rhabdomyolysis Notes

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EZETIMIBE Sterol Absorption Blocker Class Selective inhibitor of the NPC1L1 transporter, MOA decreasing intestinal absorption of cholesterol and other phytosterols Hypercholesterolemia (high LDL), Phytosterolemia Uses SE HEPATOTOXICITY (increased with statin use), Myositis Synergistic LDL-lowering effect with statins Notes SITOSTEROL Sterol Absorption Blocker Class

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] FIBRATES MOA of Fibrates Ligands for the peroxisome proliferator-activated receptoralpha (PPAR-α) protein Increased synthesis by adipose tissue of o lipoprotein lipase  Enhances clearance of triglycerides In the liver, fibrates stimulate fatty acid oxidation Limits supply of triglycerides and decreases VLDL o synthesis Decreases expression of apoC-III Impedes the clearance of VLDL o Increases the expression of apoA-I and apoA-II, o which in turn increases HDL levels Little or no effect on LDL concentrations 

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DISADVANTAGEOUS ANTI-HYPERLIPIDEMIC COMBINATIONS! COMBINATION DISADVANTAGE Fibrate + Resin Increased risk of cholelithiasis Statin + Resin Impaired statin absorption Statin + Fibrate Increased risk of myopathy and rhabdomyolysis CORRELATIONS – Biochemistry – Lipoproteins Which anti-hyperlipidemic drugs are indicated for the inherited lipoproteinemias? I IIA

Condition

Cause

Primary hyperchylomicronemia

Deficiency in LPL or ApoC-II Defect in LDL receptors

Familial hypercholesterolemia

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GEMFIBROZIL FENOFIBRATE, BEZAFIBRATE SimD Fibric Acid Derivative Class Activates PPAR-α and increases expression of MOA lipoprotein lipase and apolipoproteins (apoA-I and apoA-II). Lowers triglycerides. Increases HDL Drug of choice for HYPERTRIGLYCERIDEMIA , Uses Hypercholesterolemia (low HDL, high LDL), Fat redistribution syndrome

IIB

Familial combined hypercholesterolemia

Overproduction of VLDL

III

Familial dysbetalipoproteinemia

Deficiency in ApoE

IV

Familial hypertriglyceridemia

Decreased clearance of VLDL

V

Familial

Decreased

combined

Lipid Profile ↑ CM ↑ TGs

10 Tx

20 Tx

Low-fat diet

Niacin Fibrate

↑ LDL N. VLDL

Statin

Niacin Ezetimibe

↑ VLDL 

Statin

↑ LDL

Statin

↑ VLDL ↑LDL ↑VLDL remnant ↑ CM ↑ TGs ↑ VLDL ↓/N. LDL ↑ TGs

Statin

Niacin Fibrate Niacin Ezetimibe Niacin Ezetimibe Statin

Fibrate Niacin Fibrate Niacin Fibrate

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] HISTAMINERGIC AGENTS

SEROTONERGIC AGENTS

HISTAMINE Formed from the amino acid HISTIDINE Metabolized by the enzyme monoamine oxidase  and diamine oxidase Excess production detected by measurement of IMIDAZOLE  ACETIC ACID in the Urine Important pathophysiologic roles: Seasonal rhinitis (hay fever ), Urticaria, and o Angioedema Control of acid secretion in the stomach o Triple Response (WHEAL, FLUSH and FLARE) Classic demonstration of histamine effect Redness o Swelling o Itch and Pain o Mediated mainly by H1 and H2 receptors Involves a small red spot at the center of an intradermal injection of histamine surrounded by a red edematous wheal

SEROTONIN (5-Hydroxytryptamine or 5-HT) Produced from the amino acid TRYPTOPHAN Metabolized by monoamine oxidase Excess production in the body is detected by 5HYDROXYINDOLE ACETIC ACID (5-HIAA) in the Urine Physiologic roles: Neurotransmitter in CNS and enteric nervous o system Local hormone that modulates gastrointestinal o activity

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Serotonin Receptors and Effects Type

Type

Distribution

Mechanism

H

Smooth

Gq; ↑ IP3

Prototype  Antagonists Diphenhydramine

Effects Pain and itching, bronchoconstriction,

Mechanism

5-HT1D

Brain

Gi; ↓ cAMP

5-HT2

Smooth muscle, Platelets

Gq; ↑ IP3, DAG

5-HT3

Area postrema (CNS), sensory and enteric nerves

Ligandgated Ion channel

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Histamine Receptors and Effects

Distribution

5-HT

G ↑ cAMP

Prototype  Antagonists ---

Effects

Ondansetron

Synaptic inhibition Vasoconstriction CNS excitation, Smooth muscle contraction or relaxation, vasodilation, diarrhea, bronchoconstriction Vomiting

Tegaserod

Intestinal motility

Ketanserin

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] ERGONOVINE METHYLERGONOVINE SimD 5-HT2-receptor Antagonists (uteroselective ) Class Mixed partial agonist effects at 5-HT2 and αMOA adrenoceptors. Causes marked smooth muscle contraction but blocks α-agonist vasoconstriction Uses POST-PARTUM BLEEDING, Migraine Gastrointestinal upset, Uterine spasms, Abortion SE

PROSTAGLANDINS AND OTHER EICOSANOIDS

Effects of Important Eicosanoids Eicosanoids LTB4 LTC4 LTD4 PGE1

G-Protein Gq Gq Gq , Gi Gs , Gq

PGE2

Gs , Gq

PGI2

Gs

PGF2α

Gq

TXA2

Gq

Effects Leukocyte chemotaxis Bronchoconstriction, slow-reacting substance of anaphylaxis Vascular smooth muscle relaxation, Protective effects on gastric mucosa, Maintains PDA (patent ductus arteriosus) Vascular smooth muscle relaxation, Increases uterine tone, Maintains PDA (patent ductus arteriosus) Vascular smooth muscle relaxation (peripheral, pulmonary, coronary) Increases uterine tone, decreases IOP (intraocular pressure) Platelet aggregation

MISOPROSTOL GEMEPROST SimD Prostaglandin E1 Analog Class Activates EP receptors. Causes increased HCO3 and MOA mucus secretion in stomach. Uterine contraction. Uses Peptic Ulcer Disease, Prevention of NSAIDs-induced gastric mucosal injury,  abortifacient Abdominal pain, Diarrhea, Uterine cramping, SE Miscarriage, Teratogenic effect (Moebius sequence) EICOSANOIDS

 ALPROSTADIL

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BRONCHODILATORS AND OTHER DRUGS USED IN  ASTHMA  ASTHMA Characterized by airway inflammation and episodic, reversible bronchospasm Major risk factor of asthma: INFECTION 

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Pathophysiology of Asthma Bronchoconstriction caused by release of several mediators from IgE-sensitized mast cells Chemotactic mediators attract inflammatory cells to the airways, leading to chronic inflammation Results in marked bronchial hyper-reactivity, partially mediated by vagal reflexes 

SALMETEROL FORMOTEROL, CLENETEROL, BAMBUTEROL SimD Beta-2-selective Agonist (long-acting ) Class Activates Beta-2 receptors in bronchial smooth muscle. MOA Causes bronchodilation. Potentiation of corticosteroid action. Asthma prophylaxis (not for acute relief) Uses Tachycardia, Tremors, Nervousness, Restlessness, SE Arrhythmias when used excessively, Loss of responsiveness (tolerance, tachyphylaxis) Increase asthma mortality when used alone; May Notes precipitate arrhythmias IPRATROPIUM TIOROPIUM SimD Class Muscarinic receptor Antagonist Blocks muscarinic receptors in bronchial smooth MOA muscle. Prevents vagal-stimulated bronchoconstriction. Asthma, COPD Uses Dry mouth SE More effective and less toxic than beta-agonists in Notes patients with COPD

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THEOPHYLLINE AMINOPHYLLINE, PENTOXIFYLLINE SimD Class Methylxanthine

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 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: Cirrhosis, DM, Skin pigmentation o OCCURRENCE: Persons with an inherited abnormality of iron o absorption Persons who receive frequent transfusion for o treatment of hemolytic disorders (eg, thalassemia major) TREATMENT: Phlebotomy o Chronic administration of DEFEROXAMINE or o DEFERASIROX 

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DEFEROXAMINE DEFERASIROX SimD Heavy metal Chelator Class Chelates excess iron MOA Acute iron poisoning, Hemochromatosis NOT Uses adequately treated by phlebotomy Hypotension, ARDs, Neurotoxicity, Increased SE

Pharmacodynamics of Vitamin B12 Essential in 2 reactions

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] OPRELVEKIN (IL-11) THROMBOPOIETIN SimD Megakaryocyte Growth Factor Class Recombinant form of an endogenous cytokine; Activate s MOA IL-11 receptors Secondary prevention of thrombocytopenia in patients Uses undergoing cytotoxic chemotherapy for non-myeloid cancers Fatigue, Headache, Dizziness, Anemia, Fluid SE 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 

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Glycoprotein Ia Ib IIb-IIIa IV V IX

Function Adhesion to collagen Binds vWF Def: Bernard-Soullier Syndrome (giant platelets) Binds fibrinogen & vWF Def: Glanzmann’s Thrombasthenia Binds Thrombospondin Binds Thrombin Associated with Ib complex

 ANTI-PLATELET DRUG  Arterial thrombosis  is the most common cause of acute Myocardial Infarction (MI), ischemic stroke, and limb gangrene Predominance of platelets in arterial thrombi 

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Plaque Disruption

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  ASPIRIN (ACETYLSALICYLIC ACID, ASA) SALSALATE, SODIUM SALICYLATE SimD Anti-Platelet Dug, Anti-inflammatory Drug Class Anti-pyretic, Analgesic Non-selective, irreversible COX 1 & 2 inhibitor. Reduces MOA platelet production of thromboxane A2, a potent stimulator of platelet aggregation. Prevention of arterial thrombosis (MI, TIA, CVD), Uses Inflammatory disorders (rheumatic fever, KAWASAKI DISEASE, juvenile rheumatoid arthritis) Gastrointestinal toxicity, Nephrotoxicity, Tinnitus, SE Hypersensitivity, Hyperventilation, HAGMA Toxic dose (150 mg/kg), Lethal dose (500 mg/kg) Notes Uncoupler of oxidative phosphorylation associated with REYE’S SYNDROME in children KEY LEARNING POINTS – Aspirin Toxicity How many 500 mg Aspirin tablets must be ingested to produce toxicity? Death? TOXIC DOSE = 150 mg/kg 150mg/kg x 70 kg/500mg/tab = 21 tabs LETHAL DOSE = 500 mg/kg 500 mg/kg x 70 kg/500mg/tab = 70 tabs

CLOPIDOGREL TICLOPIDINE, PRASUGEL SimD Anti-platelet Drugs (Thienopyridine ) Class Irreversibly inhibits binding of ADP to platelet MOA receptors, reducing platelet aggregation Prevention and treatment of Arterial Thrombosis Uses (stroke, transient ischemic attack/TIA, unstable angina), Prevention of restenosis after PCI, Acute coronary syndromes Bleeding, Nausea, Dyspepsia, Hematologic (neutropenia, SE leukopenia, thrombotic thrombocytopenic purpura) GI & Hematologic SE are more common with Ticlopi dine Notes Additive effects with Aspirin! DIPYRIDAMOLE CILOSTAZOL SimD Anti-platelet Drug Class Inhibits phosphodiesterase III and increases cAMP in MOA platelets and blood vessels. Inhibits platelet aggregation and causes vasodilation. Prevention of thromboembolic complications of cardiac Uses valve replacement, Secondary prevention of ischemic stroke (with aspirin), Intermittent claudication (cilostazol only) Headache (because it is a vasodilator), Palpitations SE Dipyridamole, by itself, has a little or no benefit. Notes

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 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 

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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 of cell injury and clear away debris, in preparation for tissue repair Causes pain and tissue damage 

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 ALTEPLASE ANISTREPLASE, RETEPLASE, STREPTOKINASE, SimD TENECTEPLASE, UROKINASE Thrombolytics Class Tissue plasminogen activator analog. Converts MOA plasminogen to plasmin, which degrades the fibrin and fibrinogen, causing thrombolysis. Acute myocardial infarction, Ischemic stroke, Uses

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 ANTI-INFLAMMATORY DRUGS 1. Non-Steroidal Anti-Inflammatory Drugs Classification of NSAIDs

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  Aspirin Overdose DOSAGE: Toxic dose: 150 mg/kg (21 aspirin 500 mg tabs) o Lethal dose: 30g (60 aspirin 500 mg tabs) o CLINICAL PRESENTATION HAGMA o Dehydration o Hyperthermia o Collapse o Coma o TREATMENT No specific antidote o Supportive management  o Activated charcoal / gastric lavage o Alkalinize the urine with BICARBONATE o

2.

Disease-Modifying Anti-Rheumatic Drugs (DMARDS)

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IBUPROFEN DICLOFENAC, DIFLUNISAL, ETODOLAC, FENOPROFEN, SimD FLURBIPROFEN, KETOPROFEN, MELOXICAM, NABUMETONE, NAPROXEN, OXAPROZIN, PIROXICAM, SULINDAC, TOLMETIN, MEFENAMIC ACID NSAIDs (non-selective ) Class Non-selective reversible COX-1 & COX-2 inhibitor. MOA Inhibits prostaglandin synthesis. Analgesia (musculoskeletal, headache, dysmenorrhea), Uses Antipyretic, Anti-inflammatory

RHEUMATOID ARTHRITIS Chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis It is the most common form of chronic inflammatory arthritis 

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Disease-Modifying Anti-Rheumatic Drugs (DMARDs) Heterogenous group of agents with anti-inflammatory actions used in several connective tissue diseases Cause slowing or even reversal of joint damage May take 6 weeks to 6 months for their benefits to become apparent  

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METHOTREXATE Disease-Modifying Anti-Rheumatic Drug, Class Cancer Chemotherapeutic Drug MOA Inhibits AICAR transformylase (phosphoribosylaminoimidazolecarboxamide formyltransferase) and Thymidylate synthase, with secondary effects on polymorphonuclear chemotaxis Rheumatoid arthritis, SLE, Juvenile rheumatic Uses (idiopathic) arthritis/JRA, Psoriatic arthritis, Ankylosing spondylitis, Polymyositis , Dermatomyositis, Wegener’s granulomatosis, Giant cell arteritis, Vasculitis

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] CYCLOPHOSPHAMIDE Disease-Modifying Anti-Rheumatic Drug, Class Cancer Chemotherapeutic Drug Forms phosphoramide mustard, which cross-links DNA MOA to prevent cell replication. Suppresses T-cell and B-cell function Rheumatoid arthritis, SLE, Vasculitis, Wegener’s Uses granulomatosis, Severe rheumatic diseases SE HEMORRHAGIC CYSTITIS Rescue agent is MESNA! Notes CYCLOSPORINE Disease-Modifying Anti-Rheumatic Drug Class Inhibits interleukin-1 and interleukin-2 receptor MOA production and secondarily inhibits macrophage T-cell interaction and T-cell responsiveness Rheumatoid arthritis, SLE, Polymyositis, Uses Dermatomyositis, Wegener’s granulomatosis, Juvenile rheumatoid arthritis, Tissue transplantation Nephrotoxicity, Hypertension, Hyperkalemia, SE Hepatotoxicity, Gingival hyperplasia, Hirsutism MYCOPHENOLATE MOFETIL Disease-Modifying Anti-Rheumatic Drug Class Active product (mycophenolic acid) inhibits inosine MOA monophosphate dehydrogenase (important enzyme in

Stages of Paracetamol Overdose Stage I

Time Period 0.5 to 24 hours

II

24 to 72 hours

II

72 to 96 hours

IV

4 days to 2 weeks

Manifestations Nausea, vomiting, diaphoresis, pallor, lethargy, malaise Elevated liver enzymes, oliguria, azotemia, increased PT, hyperbilirubinemia Jaundice, hepatic encephalopathy, bleeding diatheses, acute tubular necrosis, HAGMA, coma, death Recovery

Paracetamol Overdose DOSAGE: Toxic Dose: 150 mg/kg (21 Paracetamol 500 mg o tabs) Lethal Dose: 15g (30 Paracetamol 500 mg tabs) o TREATMENT: Antidote: N-ACETYLCYSTEINE o Supportive management o Gastric decontamination with activated charcoal o 

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DRUGS FOR THE TREATMENT OF GOUT GOUT  

Increased serum concentrations of uric acid Acute attacks involve joint inflammation initiated by precipitation of uric acid crystals

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  ALLOPURINOL Anti-gout Drug (xanthine oxidase inhibitor ) Class Active metabolite (alloxanthine) irreversibly inhibits MOA Xanthine oxidase and lowers production of uric acid Uses 1st   line treatment of chronic gout! Tumor lysis syndrome Gastrointestinal upset, Rash, Peripheral neuritis, SE Vasculitis, Bone marrow dysfunction, Aplastic anemia, CATARACTS Inhibit metabolism of and Notes mercaptopurine azathioprine. Withheld for 1 – 2 weeks after an acute episode of gouty arthritis (co-administered with colchicine or indomethacin to avoid an acute attack)

SEDATIVE-HYPNOTIC DRUGS

DEFINITION OF TERMS SEDATIVES (ANXIOLYTICS) Drugs that reduce anxiety and exert a calming o effect Degree of CNS depression should be the minimum o consistent with therapeutic efficacy HYPNOTICS Drugs that produce drowsiness and encourage the o onset and maintenance of a state of sleep Involve more pronounced CNS depression than o sedation 

FEBUXOSTAT Anti-gout Drug (xanthine oxidase inhibitor) Class Non-purine reversible inhibitor of xanthine oxidase MOA (more selective than allopurinol). Lowers production of uric acid Chronic gout, Tumor lysis syndrome, Allopurinol Uses intolerance Liver function abnormalities, Headache, SE Gastrointestinal upset Withheld for 1 – 2 weeks after an acute episode of gouty Notes arthritis (co-administered with colchicine or

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] BENZODIAZEPINES

Benzodiazepine Overdose DOSAGE: Toxic dose is 1000x the therapeutic dose o CLINICAL PRESENTATION: Slurred speech o Ataxia o Altered (decreased) mental status o Respiratory depression o TREATMENT: Antidote: FLUMAZENIL (a BZ receptor antagonist) o Activated charcoal is useless o 

MIDAZOLAM BROTIZOLAM, TRIAZOLAM, OXAZEPAM, ETIZOLAM SimD Benzodiazepine (short-acting ) Class Binds GABA-A receptor subunits to increase frequency MOA of chloride channel opening; Membrane hyperpolarization Acute anxiety, Panic attacks, Anesthesia, Induction, PreUses operative sedation SE ANTEROGRADE AMNESIA, Decreased psychomotor skills, Unwanted daytime sedation, Tolerance, Dependence liability, Rebound insomnia/anxiety Additive CNS depression with Ethanol Notes LORAZEPAM ALPRAZOLAM, ESTAZOLAM, CLONAZEPAM, SimD LORMETAZEPAM, NITRAZEPAM, TEMAZEPAM Benzodiazepine (intermediate-acting ) Class Binds GABA-A receptor subunits to increase frequency MOA of chloride channel opening; Membrane hyperpolarization Anxiety disorders, Insomnia, Skeletal muscle relaxation, Uses Seizure disorders, Tranquilizer SE ANTEROGRADE AMNESIA, Decreased psychomotor skills, Unwanted daytime sedation, Respiratory

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FLUMAZENIL Antidote (benzodiazepine antagonist ) Class Antagonist at benzodiazepine sites on GABA-A receptor MOA Benzodiazepine overdose Uses Agitation, Confusion, Precipitates, BENZODIAZEPINE SE WITHDRAWAL SYNDROME Seizures and arrhythmias may occur when administered Notes in patient who took both TCAs and Benzodiazepines. Available in IV! BARBITURATES THIOPENTAL METHOHEXITAL, THIAMYLAL SimD

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] MISCELLANEOUS (NEWER) HYPNOTICS

 ALCOHOL DEHYDROGENASE Cytosolic, NAD+-dependent enzyme Found mainly in the LIVER and GUT Accounts for the metabolism of low to moderate doses of ethanol Because of the limited supply of the co-enzyme NAD+, the reaction has zero-order kinetics Fixed capacity for ethanol metabolism of 7-10 g/h o Gastrointestinal metabolism of ethanol is lower in women than in men 

ZOLPIDEM ZALEPLON, ESZOPICLONE SimD Imidazopyridine Class Bind selectively to a subgroup of GABA-A receptors, MOA acting like benzodiazepines to enhance membrane hyperpolarization Uses INSOMNIA ONLY! Modest day-after psychomotor depression, Few SE amnestic effects, Tolerance, Dependence liability (less than benzodiazepines) Effects reversed with FLUMAZENIL! Notes Lack anti-convulsant, anti-anxiety and muscle relaxant effects MNEMONICS – Zolpidem zZzzZZzzzZZzzzZZz (sleep) Zolpidem, Zaleplon = SLEEP DISORDERS BUSPIRONE Anxiolytic Drug Class Partial agonist at 5-HT1A and possibly D2 receptors MOA Uses GENERALIZED ANXIETY DISORDER Non-specific chest pain, Tachycardia, Palpitations, SE Diziness, Nervousness, Tinnitus, Gastrointestinal

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KEY LEARNING POINTS! Why is there Lactic acidosis and Hypoglycemia? Increased metabolism  inc. NADH:NAD+ ratio  diverts  pyruvate to lactate  & OAA to malate AFTERMATH: inhibits gluconeogenesis and stimulates  FA synthesis  CONSEQUENCE: hypoglycemia and hepatic fatty change (hepatocellular steatosis ) Overproduction of lactate  acidosis  Depletion of OAA shuts down the TCA cycle, shunts  acetyl-CoA into ketone production Breakdown of excess malate increases NADPH and thus  FA synthesis

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Progressive loss of liver function (reversible fatty liver to irreversible hepatitis, cirrhosis, and liver failure) Increased severity in females and those with o hepatitis B and C GASTROINTESTINAL SYSTEM Irritation, inflammation, bleeding and scarring of o gut wall Absorption defects and exacerbation of nutritional o deficiencies Increased risk of PANCREATITIS! o CENTRAL NERVOUS SYSTEM Peripheral neuropathy is the most common o neurologic abnormality in chronic alcoholics WERNICKE-KORSAKOFF SYNDROME  (ataxia, o confusion, paralysis of the extraocular muscles) o

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MNEMONICS – Wernicke-Korsakoff Syndrome Weird ACO = Wernicke-Korsakoff Syndrome  Ataxia  Confusion  Ophthalmoplegia What changes in the brain are seen in Wernicke-Korsakoff Syndrome? Hemorrhagic necrosis of the mammillary bodies  (recollecive memory )

MNEMONICS – Delirium Tremens H – A – D 48!! Hallucinations  Autonomic instability  Delirium  48 – 72 hours post-discontinuation  ALCOHOL WITHDRAWAL SYNDROME TREATMENT Correction of electrolyte imbalance o Administration of thiamine o Administration of a sedative hypnotics o Substituting a long-acting sedative hypnotic drug for alcohol and then gradually reducing (“tapering”) the dose of the long-acting drug Drug of choice is long-acting  (eg, diazepam, BENZODIAZEPINE chlordiazepoxide)  Short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is preferred in patients with compromised liver function 

Treatment of Alcoholism Opioid receptor antagonists (NALTREXONE) 

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 

ETHYLENE GLYCOL SOURCES o Industrial exposure (by inhalation or skin  absorption) Self-administration (eg, by drinking  antifreeze products) CLINICAL MANIFESTATION o  Severe acidosis and renal damage Due to accumulation of oxalic acid 

Treatment of Ethylene Glycol Poisoning ETHANOL Competes for oxidation by alcohol dehydrogenase o FOMEPIZOLE Slows or prevents formation of oxalic acid o 

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STATUS EPILEPTICUS Series of seizures (usually tonic-clonic) without o recovery of consciousness between attacks Life-threatening emergency o

 Antiseizure Drug Phenytoin Carbamazepine Valproic acid Phenobarbital Oxcarbazepine Clonazepam Diazepam Ethosuximide Gabapentin Pregabalin Vigabatrin Tiagabine Lamotrigine Levetiracetam Topiramate Felbamate Zonisamide

Na+ • • • • •

Ca2+

K +

GABA

Glutamate

Others

• • •

•  •

NMDA

•

• • •

• • •

• •

• • •

•

•

• • • • • • • 

• •

• • •

Carbonic anhydrase

NMDA Carbonic anhydrase

TRADITIONAL ANTISEIZURE DRUGS PHENYTOIN FOSYPHENYTOIN, MEPHENYTOIN, ETHOTOIN SimD Anticonvulsant Drugs (hydantoin ) Class

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] PHENOBARBITAL PRIMIDONE SimD Anticonvulsant Drug (barbiturates ) Class Bind to GABA-A receptor sites (distinct from MOA benzodiazepines); Increases duration of chloride channel opening Generalized tonic-clonic seizures, Partial seizures, Uses Status epilepticus, Insomnia, Hyperbilirubinemia Extension of CNS depressant actions, Tolerance, SE Dependence liability (greater than benzodiazepines),  Acute intermittent Porphyria Potent inducer of CYP450 enzymes. Notes Preferred antiseizure drug in children and pregnant women!

TOPIRAMATE Anticonvulsant Drug (monosaccharide derivative) Class Multiple actions on synaptic function, probably via MOA actions of phosphorylation (Na, Ca, GABA, AMPAglutamate, carbonic anhydrase) Generalized tonic-clonic seizures, Absence seizures, Uses Partial seizures, LENNOX-GASTAUT SYNDROME , WEST SYNDROME, Migraine Drowsiness, Dizziness, Ataxia, Psychomotor slowing, SE Memory impairment, Paresthesias, Weight loss, Acute myopia, Glaucoma, Urolithiasis Antiseizure drug with most number of mechanism of Notes action! Clinical Uses of Antiseizure Drugs

ETHOSUXIMIDE PHENSUXIMIDE, METHSUXIMIDE SimD Anticonvulsant Drug (cyclic ureide ) Class Decrease Ca2+ currents (T-type) in thalamus MOA Drug of choice for ABSENCE SEIZURES Uses Gastrointestinal distress, Lethargy, Headache, SE Behavioral changes

Seizure Type Generalized tonic-clonic Seizures Partial Seizures

Absence Seizures

DIAZEPAM Anticonvulsant Drug (benzodiazepine ) SimD Binds GABA-A receptor subunits to increase frequency Class

Myoclonic

and

Drugs of Choice VALPROIC ACID PHENYTOIN CARBAMAZEPINE CARBAMAZEPINE LAMOTRIGINE PHENYTOIN ETHOSUXIMIDE VALPROIC ACID

Alternative Drugs Phenobarbital, Lamotrigine, Topiramate Felbamate, Phenobarbital, Topiramate, Valproic acid Lamotrigine, Levetiracetam, Zonisamide, Clonazepam Clonazepam,

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Stages of Anesthesia STAGE 1

NAME Analgesia

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2

Disinhibition

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

3

Surgical Anesthesia

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4

Medullary Depression

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EVENTS Decreased awareness of pain, sometimes with amnesia Consciousness is impaired, NOT loss Patient is delirious or excited Amnesia occurs, reflexes are enhanced, and respiration is typically irregular Retching and incontinence may occur Patient is unconscious No pain reflexes, regular respiration, and maintained blood pressure Severe respiratory and cardiovascular depression that requires mechanical and pharmacologic support

INHALATIONAL ANESTHETICS INHALATIONAL ANESTHETICS Include Nitrous oxide, Halothane, Desflurane, Enflurane, Isoflurane, Sevoflurane, and Methoxyflurane Partial pressire of “tension” is a measure of concentration of inhaled anesthetics 



NITROUS OXIDE General Anesthetic (inhalational ) Class Facilitate GABA-mediated inhibition; Block brain NMDA MOA and ACh-N receptors Anesthesias for minor surgery and dental procedures, Uses Balanced anesthesia for major surgery Megaloblastic anemia on prolonged exposure, SE EUPHORIA  (laughing gas) Lowest potency (highest MAC) and least cardiotoxicity Notes among inhalational anesthetics Additive to CNS depression with many agents, especial ly opioids and sedative-hypnotics DESFLURANE General Anesthetic (inhalational ) Class Facilitate GABA-mediated inhibition; Block brain NMDA MOA and ACh-N receptors Uses General Anesthesia Bronchospasm (pulmonary irritant), Peripheral SE vasodilation Notes Contraindicated in Asthmatic patients! Additive to CNS depression with many agents, especially opioids and sedative-hypnotics SEVOFLURANE General Anesthetic (inhalational ) Class

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] INTRAVENOUS ANESTHETICS THIOPENTAL METHOHEXITAL, THIAMYLAL SimD General Anesthetic (intravenous ) Class Barbiturate (ultrashort-acting) Binds to GABA-A receptor sites (distinct from MOA benzodiazepines); Increases duration of chloride channel opening Anesthesia induction, Increased ICP Uses Extension of CNS depressant actions, Tolerance, SE Dependence liability (greater than benzodiazepines), Acute intermittent porphyria Additive to CNS depression with Ethanol. Notes Potent inducer of CYP450 enzymes. MIDAZOLAM BROTIZOLAM, TRIAZOLAM, OXAZEPAM, ETIZOLAM SimD General Anesthetic (intravenous ) Class Benzodiazepine (short-acting) Binds GABA-A receptor subunits to increase frequency MOA of chloride channel opening; Membrane hyperpolarization Acute anxiety, Panic attacks, Anesthesia induction, Uses Preoperative sedation Anterograde amnesia, Decreased psychomotor skills, SE

TRIVIA – Death of Michael Jackson! MICHAEL JACKSON (1958 – 2009) Immediate COD: acute propofol intoxication! Contributory factors: drug interactions (lorazepam, midazolam, diazepam)

LOCAL ANESTHETICS LOCAL ANESTHETICS Results when sensory transmission from a local area of the body to the CNS is blocked Local anesthetics can be administered locally by injection or topical application to the target area 

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MNEMONICS – Local Anesthetics How will you distinguish whether local anesthetics are esters or amides? ESTERS have only 1 “I” in their names!

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] ESTER LOCAL ANESTHETICS PROCAINE NOVOCAINE SimD Local Anesthetics (ester) Class Blockade of Na channels slows, then prevents axon MOA potential propagation Local anesthesia, Extravasation complications from Uses venipuncture, Inadvertent intra-arterial injections Light-headedness, Sedation, Restlessness, Nystagmus, SE Seizures, Respiratory and cardiovascular depression,  Antibody formation Notes Shortest half-life  among local anesthetics BENZOCAINE BUTAMBEN SimD Local Anesthetics (ester) Class Blockade of Na channels slows, then prevents axon MOA potential propagation Local anesthesia, Topical anesthesia (Oral spray) Uses Light-headedness, Sedation, Restlessness, Nystagmus, SE Seizures, Respiratory and cardiovascular depression, Skin irritation, Antibody formation Use cautiously when treating sunburns or large areas of Notes skin!

PRILOCAINE Local Anesthetics (amide) Class Blockade of Na channels slows, then prevents axon MOA potential propagation Local anesthesia, Dental anesthesia Uses Light-headedness, Sedation, Restlessness, Nystagmus, SE Seizures, Respiratory and cardiovascular depression, METHEMOGLOBINEMIA Administer methylene blue if patient develops Notes methemoglobinemia BUPIVACAINE Local Anesthetics (amide) Class Blockade of Na channels slows, then prevents axon MOA potential propagation Local anesthesia, Epidural anesthesia, Intrathecal Uses anesthesia Light-headedness, Sedation, Restlessness, Nystagmus, SE Seizures, Respiratory and cardiovascular depression, Severe cardiovascular toxicity, Hypotension, Arrhythmias (idioventricular rhythm – 240 bpm) Use with caution in pregnant women! Notes Contraindicated in intravenous regional anesthesia. Treat cardiotoxicity with INTRALIPID   (fat emulsion used in Total Parenteral Nutrition)

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] VECURONIUM Non-depolarizing Neuromuscular Blocker Class (intermediate-acting) Competitive antagonists at skeletal muscle nicotinic MOA acetylcholine receptors Skeletal muscle relaxation during intubation and Uses General anesthesia Respiratory paralysis, Apnea SE Reverse effects with NEOSTIGMINE! Notes Undergoes HOFFMANN Elimination in bile. Muscle relaxation is potentiated by inhaled anesthetics, aminoglycosides and quinidine

NON-DEPOLARIZING NEUROMUSCULAR BLOCKERS MOA of Non-Depolarizing Neuromuscular Blockers Surmountable blockers that prevent the action of ACh at the skeletal muscle end-plate Effects reversed by cholinesterase inhibitors Larger muscles are more resistant to neuromuscular blockade, but recover more rapidly ROCURONIUM  has the most rapid onset time (60-120 sec) Diaphragm is resistant to blockage 

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ROCURONIUM Non-depolarizing Neuromuscular Blocker Class (intermediate-acting) Competitive antagonists at skeletal muscle nicotinic MOA acetylcholine receptors Skeletal muscle relaxation during intubation and Uses General anesthesia Respiratory paralysis, Apnea, Hypersensitivity SE Reverse effects with NEOSTIGMINE! Notes SUGAMMADEX is a novel reversal agent for Rocuronium PANCURONIUM Non-depolarizing Neuromuscular Blocker Class

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DRUGS USED IN PARKINSONISM

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



PARKINSON’S DISEASE Also known as Paralysis agitans Neurodegenerative disease caused by degeneration of dopaminergic neurons in the substantia nigra (loss of 60% of dopamine-producing neurons) Progressive neurologic diseases characterized by shuffling gait, stoop posture, resting tremor, speech impediments, movement difficulties and an eventual slowing of mental processes and dementia  

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MNEMONICS – Parkinson’s Disease What are the primary signs of Parkinson’s Disease? PARKINSON’S DISEASE! It’s a TRAP!! Tremor  Rigidity  Akinesia 

WEARING – OFF PHENOMENA Deterioration of drug effect in between medication o doses Due to progressive destruction of nigrostriatal o neurons that occurs with disease progression

BROMOCRIPTINE PERGOLIDE SimD Anti-parkinsonism Drug (dopamine agonist ) Class Partial agonist at dopamine D2 receptors in the brain MOA Parkinson’s disease, Levodopa intolerance, Uses Hyperprolactinemia Anorexia, Nausea, Vomiting, Dyskinesias, Postural SE hypotension, Behavioral changes, Erythromelalgia, Pulmonary fibrosis PRAMIPEXOLE ROPINIROLE SimD Anti-parkinsonism Drug (dopamine agonist ) Class Partial agonist at dopamine D3 receptors in the brain MOA

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]  AMANTADINE Anti-parkinsonism Drug (anti-viral ) Class Potentiate dopaminergic function by influencing the MOA synthesis, release, or reuptake of dopamine. Antagonizes the effects of adenosine at adenosine A2A receptors Parkinson’s disease, Influenza Uses Behavioral changes (acute toxic psychosis), LIVEDO SE RETICULARIS (swelling of medium-sized blood vessel in lower extremeties), Gastrointestinal disturbances, Urinary retention, Postural hypotension, Peripheral edema May improve bradykinesia, rigidity and tremor Notes MNEMONICS – Livedo Reticularis! What drugs can cause livedo reticularis? A man reads FHM and GQ!! Amantadine  Hydroxyurea – chronic myelogenous leukemia  Minocycline   Gemcitabine – chemotherapeutic agent  Quinidine BENZTROPINE BIPERIDEN, TRIHEXYPHENIDYL, ORPHENADRINE SimD Anti-parkinsonism Drug (anti-cholinergic ) Class

Potency of Typical Antipsychotics LOW POTENCY Fewer extrapyramidal effects but more H1, α1, and o muscarinic blocking effects EXAMPLES: chlorpromazine, thioridazine, o mesoridazine HIGH POTENCY More extrapyramidal effects and less H1, α1, and o muscarinic blocking effects EXAMPLES: haloperidol, fluphenazine, droperidol o 



Dopamine Hypotheis Schizophrenia is caused by a relative excess dopamine in specific neuronal tracts in the brain Many antipsychotic drugs block brain dopamine o receptors (especially D2 receptors) Dopamine agonist drugs (eg, amphetamine, o levodopa) exacerbate schizophrenia Increased density of dopamine receptors has been o detected in certain brain regions Not fully satisfactory because antipsychotic drugs are only partly effective in most patients 



Dopamine Receptors Five different dopamine receptors (D1-D5) D2  receptors in caudate putamen, nucleus accumbens  

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] Neuroleptic-Induced Movement Disorders Disorder  Acute Dystonia

Timing 4hrs – 4 dys

Parkinsonism

4 dys – 4 mos

Rabbit Syndrome Tardive Dyskinesia

4 mos – 4 yrs 4 mos – 4 yrs

 Akathisia

Any time

Neuroleptic Malignant Syndrome

Any time

Characteristics Retrocollis, Opisthotonos, Oculogyric crisis Tremor, Rigidity, Akinesia, Postural instability Perioral tremor

Treatment Diphenhydramine

Repetitive involuntary movement (tongue protrusion, lip smacking/pursing) Restlessness, pacing, sitting up and down Fever, encephalopathy, vitals unstable, elevated CPK, Rigidity

None

Benztropine

Benztropine

Decrease dose, diphenhydramine Withdraw drug, dantrolene, diazepam, dopamine agonist

TYPICAL ANTIPSYCHOTICS CHLORPROMAZINE Typical anti-psychotic (Phenothiazine ) Class Block of D2 receptors >> 5-HT MOA

OLANZAPINE Atypical anti-psychotic Class Block of 5-HT 2 receptors >> D2 receptors MOA Schizophrenia and other psychotic disorders, Bipolar Uses disorder, Anorexia nervosa, Depression Extrapyramidal dysfunction (less), Hyperprolactinemia SE (less), Postural hypotension, Weight gain, Hyperglycemia (diabetes mellitus), Hyperlipidemia QUETIAPINE Atypical anti-psychotic Class Block of 5-HT 2 receptors >> D2 receptors MOA Schizophrenia and other psychotic disorders, Bipolar Uses disorder (manic episodes) Extrapyramidal dysfunction (less), Hyperprolactinemia SE (less), Postural hypotension, Weight gain (less), Somnolence, Fatigue, Sleep paralysis, Hypnagogic hallucinations, Cataracts, Priapism QUIET-time! Sleep! Notes RISPERIDONE Atypical anti-psychotic Class Block of 5-HT 2 receptors >> D2 receptors MOA Schizophrenia and other psychotic disorders, Bipolar Uses disorder, Depression, Intractable hiccups, Tourette syndrome

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] LITHIUM Clinical Use of Lithium Treatment of Bipolar Disorders (manic–depressive) Decreases manic behavior and reduces both the o frequency and the magnitude of mood swings Protective effects against suicide and self-harm o Used concurrently with antidepressants during maintenance therapy Monotherapy with antidepressants can precipitate o mania in bipolar patients Antipsychotic agents and/or benzodiazepines are commonly required at initiation of treatment because of slow onset of action 



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LITHIUM Class MOA

Uses SE

Mood Stabilizer Uncertain. Decreases cAMP, Inhibits inositol-1phosphatase, causing depletion of inositol and inositol triphosphate Bipolar disorder, Recurrent depression, Schizoaffective disorder Tremor, Sedation, Ataxia, Aphasia, Thyroid enlargement, Nephrogenic diabetes insipidus, Edema, Acneiform skin eruptions, Leukocytosis, Teratogen (EBSTEIN ANOMALY ), Bradycardia

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected] 2. USMLE 1 st  Aid 3. Kaplan Anatomy 4. Personal Notes 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 =)

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TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]

TOPNOTCH MEDICAL BOARD PREP ANATOMY SUPPLEMENT BY THE TOPNOTCH TEAM For inquiries visit www.topnotchboardprep.com.ph or email us at [email protected]