Pharmacology

Abstract

Pharmacology is the detailed study of drugs – their chemical and physical properties, biochemical and physiological effects, and pharmacokinetics (alterations of the drug on the body) and phamacodynamics (the mechanism of actions). As there is no ideal drug in existence, it is the responsibility of every member of the healthcare team to promote therapeutic effects and minimize drug-induced harm to each patient. This section discusses the pharmacokinetic processes and pharmacodynamic principles, along with a selection of cardiac medication pearls to help the prescriber carry out the therapeutic objective-to provide maximum benefit with minimum harm to each patient with each medication prescribed.

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

Pharmacology is the detailed study of drugs – their chemical and physical properties, biochemical and physiological effects, and pharmacokinetics (alterations of the drug on the body) and phamacodynamics (the mechanism of actions). As there is no ideal drug in existence, it is the responsibility of every member of the healthcare team to promote therapeutic effects and minimize drug-induced harm to each patient. This section discusses the pharmacokinetic processes and pharmacodynamic principles, along with a selection of cardiac medication pearls to help the prescriber carry out the therapeutic objective-to provide maximum benefit with minimum harm to each patient with each medication prescribed.

General Pharmacology

Pharmacokinetics: Action of the Body to the Drug

• Absorption: the movement of a drug into the bloodstream

  • Variability in absorption and bioavailability based on route of administration (PO, IM, IV, SC, mucosal, etc.)

  • Factors affecting absorption: dose administered, percentage of dose that is ‘active’ and bioavailability of drug

  • Bioavailability: the rate or percentage of drug dose reaching systemic circulation. 100 % bioavailability with IV administration, but variable bioavailability with other routes of administration.

    • Factors affecting bioavailability: characteristics of medication dosage form, solubility, administration route, metabolism in the gut wall or liver (first-pass effect) and the permeability of the gastrointestinal tract (i.e. edematous tract due to heart failure may not be able to absorb as much drugs through the gut wall).

• Distribution: the process of the dispersion of the drug into the bloodstream and surrounding tissues

  • Influenced by lipid solubility (i.e. in general, water-soluble drugs are limited to the vascular space and cannot easily cross the blood–brain barrier while lipid-soluble drugs are distributed more widely and can better cross the blood–brain barrier), degree of ionization, blood flow and binding affinities to proteins in plasma and specific tissues

  • During constant infusion or multiple doses of a medication, drug levels rise in the blood and tissue until they reach a plateau, or steady state

    • At steady state, the rate of drug administration equals rate of drug elimination

    • Generally takes 4–5 half-lives to reach desired steady-state drug concentration

  • Volume of distribution (the volume of body fluid that the medication is distributed in) can help to estimate loading dose (i.e. large volume of distribution  =  low concentration of the drug)

  • Protein binding

    • Describes a drug’s affinity for plasma protein

    • Drugs are either bound or unbound

    • The less bound a drug is the more drug circulating throughout the body that is “active”

    • Only unbound drug undergoes metabolism in liver and elimination

    • Coumadin is 97 % protein bound. Dramatic implications may ensue when another medication is added that is protein bound as well

      • Protein-bound medications compete for proteins, resulting in larger amounts of both medications’ free drug concentrations and risk for side effects.

• Metabolism

  • Complex or lipid-soluble drugs undergo hepatic metabolism to a water-soluble metabolites which can then be excreted. These metabolites can be biologically active or inactive leading to either therapeutic effects or increase toxic side effects related to the medication administered

    • i.e. procainamide is metabolized into NAPA in the body, a Class III antiarrhythmic with a therapeutic level of 10–20 mcg/mL. Toxic levels of NAPA can manifest in the prolongation of action potential, prolonged QT interval and ultimately Torsades de Pointes. Even if procainamide level is not toxic, NAPA level may be

  • Phase 1 (mainly oxidation of the drug to make it more water-soluble) and Phase 2 (mainly conjugation of the drug)

  • Oxidation is mainly through the cytochrome P450 (CYP450) system. The most drugs are metabolized by CYP3A (>50 %), CYP2D6 (genetic polymorphism leads to decreased enzyme levels in up to 25 % in Caucasian and African population resulting in hypersensitivity to medications such as b-blockers, propafenone), CYP2C9 and CYP1A2 families of the CYP450 system (Table 33-1). Note that CYP450 activity can decrease with increasing age and lead to increased drug levels/toxicity.

    Table 33-1 Medications that affect hepatic metabolism

  • Clearance of a drug is one of the most important factors to understand, as it helps in dosing the patient to maintain a therapeutically effective level of the drug.

  • Drug clearance occurs through both metabolism (biotransformation) and excretion.

    • Genetics (polymorphism), concurrent disease, age or drug-drug interactions can affect drug clearance

  • First-pass effect (important drugs are listed in Table 33-2)

    Table 33-2 Drugs with a significant first pass effect

    • Concentration of drug is greatly reduced before it reaches systemic circulation, typically metabolized during absorption in the liver

    • Greatly reduces bioavailability of the drug

    • Suppositories, IV, IM, sublingual and inhaled medications bypass first-pass effect

• Elimination

  • Final route of exit from the body; expressed in terms of half-life or clearance.

  • Excretion occurs through the kidneys primarily, but also through bile, sweat, saliva, breast milk and exhalation.

  • Renal Drug Excretion is the net effect of glomerular filtration, secretion, and passive reabsorption

    • With renal dysfunction, may need to decrease medication doses if renally cleared (i.e. digoxin)

  • Half-life: time for serum concentration of drug to decrease by 50 % (hours)

    • Determined by clearance and volume of distribution

    • Poor indicator of the efficacy of drug elimination and plasma drug concentration at steady state

    • Typically takes 4–5 half lives to clear medication from system

    • Clearance: volume of serum from which drug is removed per time (mL/min or L/h)

Pharmacodynamics: The Drug’s Effect on the Body

• Dose–response relationship

  • the effect of a drug based on the concentration that is present at the site of action

  • In most cases a maximum value is approached where a further increase in concentration is not effective

  • ED50  =  dose producing a response that is 50 % of the maximum value

  • Depends on both exposure time and exposure route

• Drug toxicity

  reduced clearance  =  drug accumulation and toxicity

• Drug-Drug Interactions

  • Most common with cardiac medications, and may result in increased absorption, additive or antagonistic effects, as well as induced or inhibited metabolism.

Cardiac Medication Pearls

Anticoagulants

• Heparin: accelerates the action of antithrombin III which rapidly inactivates the clotting factors

  • Oral bioavailability 0 %, thus IV or subcutaneous route is mandatory

  • Adverse effects: bleeding, heparin induced thrombocytopenia

  • Action can be reversed by protamine sulfate

• Warfarin sodium: Vitamin K antagonist (prevents formation of new clotting factors in liver)

  • Oral bioavailability is >95 %

  • Onset of action  =  8–12 h

  • Effects can be reversed by Vitamin K, but take 24 h

  • Oral vitamin K (5–10 mg) is as effective as subcutaneous for reversing excessive anticoagulation.

  • Intravenous vitamin K may be slightly faster, though this is debated.

  • Contraindicated in pregnancy

    • May result in aplasia cutis congenita

  • Numerous drug-drug interactions to remember (Table 33-3).

    Table 33-3 Drugs with important interactions with warfarin sodium

• Non-warfarin oral anticoagulants

  • Dabigatran

    • Direct thrombin inhibitor

    • Rapidly effective, high oral bioavailability

    • No monitoring generally necessary, though dose reduction recommended in elderly patients and in those with reduced renal function.

    • Cleared via P-glycoprotein pumps, thus may be used in patients with moderately impaired renal function (though risk for bleeding increases in end-stage renal disease).

    • More reliable anticoagulation with lower risk for bleeding compared to warfarin in clinical trials of non-valvular atrial fibrillation.

    • Down sides: twice daily dosing, no specific antidote, high incidence of dyspepsia (related to acidic preparation).

  • Rivaroxaban

    • Factor Xa inhibitor

    • Rapidly effective, high oral bioavailability, once-daily dosing.

    • As with dabigatran, rivaroxaban may be as effective as warfarin with lower risk for bleeding.

    • As with dabigatran, rivaroxaban has predictable dose responsiveness, predictable anticoagulation, and lacks an antidote.

• Apixaban

  • Factor Xa inhibitor

  • Rapidly effective, high oral bioavailability, twice daily dosing

  • As with dabigratran, apixaban may be as effective as warfarin, with lower risk for bleeding

  • As with dabigatran, apixaban has predictable dose responsiveness, predictable anticoagulation, and lacks an antidote

Antiplatelet Agents

• Aspirin

  • Works via irreversible inactivation of cyclo-oxygenase-1 (lasts for life of the platelet)

  • Enteric coating reduces gastrointestinal intolerance, but may retard absorption of drug

  • While clearly indicated for those with coronary artery disease and acute coronary syndrome, debate exists about use of aspirin for primary prevention.

• Clopidogrel, prasugrel

  • Thienopyridines that work via irreversible blockade of ADP-mediated platelet activation via the P2Y12 receptor.

  • Prasugrel is more potent. Both are taken with aspirin.

  • Metabolism of clopidogrel is through the liver, requiring modification to active drug; prasugrel does not require such processing.

  • Some patients show genetically-based impaired activation of clopidogrel, which may result in inadequate antiplatelet effects.

  • Certain drugs that affect cytochrome P450 3A4 may affect metabolic activation of clopidogrel. Among these are proton pump inhibitors. Despite this biological basis, clinical data are heavily conflicting as to whether proton pump inhibitors truly result in a clinical impairment of clopidogrel effectiveness, and thus this topic is best viewed as a hypothesis.

  • Prasugrel may have an edge for those resistant to clopidogrel effects, and is indicated for those intolerant to clopidogrel.

  • Prasugrel is contraindicated in patients with low body weight and/or a history of cerebrovascular disease, given the higher risk for bleeding.

• Ticagrelor

  • Non-thienopyridine, reversible P2Y12 inhibitor.

  • Does not require hepatic activation like clopidogrel.

  • In the PLATO study, twice daily ticagrelor was superior to clopidogrel in patients with acute coronary syndromes [1].

  • Approved for use with low-dose aspirin only.

Angiotensin Converting Enzyme (ACE) Inhibitors

Inhibit ACE and prevents the inactivation of bradykinin

• Venous tone and total peripheral resistance is decreased

• Side effects

  • Postural hypotension

  • Dry cough (as a result of bradykinin accumulation in the lungs)

  • Hyperkalemia

  • Azotemia

  • Angioedema

  • Changes in taste (ageusia, dysgeusia).

• Contraindications

  • Pregnancy (see below)

  • Severe aortic stenosis

  • Severe renal insufficiency

  • Hyperkalemia

  • History of angioedema

Angiotensin II Receptor Blockers

Inhibit binding of angiotensin II to its receptor

• Venous tone and total peripheral resistance is decreased

• Side effects

  • Postural hypotension

  • Hyperkalemia

  • Azotemia

• Contraindications

  • Pregnancy (see below)

  • Severe aortic stenosis

  • Severe renal insufficiency

  • Hyperkalemia

  • Concomitant use of ACE inhibitor in the context of chronic kidney disease

• Thiazide diuretics

  • Initial hypotensive effect (related to reduction of blood volume and cardiac output)

    • Resolves after 6–8 weeks when blood volume normalizes

  • Peripheral vascular resistance decreases

    • Slow loss of sodium leads to decreased intracellular fluid smooth muscle sodium, resulting in decrease in intracellular fluid muscle calcium and ultimately vascular tone decreases.

  • Adverse effects

    • Hypokalemia

    • Hyponatremia

    • Hyperuricemia, gout

    • Hyperglycemia

    • Rarely, erectile dysfunction

  • Contraindications

    • Use with caution in the elderly

    • Pregnancy

α Blockers

• Block effects of epinephrine and norepinephrine at the level of the α receptor

• Side effects

  • Orthostatic hypotension

  • Peripheral edema

• Contraindications

  • History of intolerance

• Central α agonist (clonidine)

  • Acts as an α2 agonist

  • Side effects

    • Lightheadedness, fatigue, dizziness, constipation

    • Rebound hypertension if abruptly stopped

  • Contraindications

    • Category C in pregnancy

β Adrenergic Blockers

• Decrease cardiac output and inhibit renin

• Side effects

  • Bradycardia, hypotension (rare)

  • Fatigue, particularly centrally acting agents such as propranolol or nadolol

  • Erectile dysfunction

  • Bronchospasm; a history of asthma is not a contraindication to beta blocker use

  • Peripheral vasospasm

• Contraindications

  • History of severe bronchospasm to beta blockers

  • Severe bradycardia; use caution when combining with calcium channel blockers

  • Renal failure (nadolol, atenolol), hepatic failure (metoprolol)

  • In later pregnancy may lead to intrauterine growth retardation and neonatal hypoglycemia

Calcium Channel Blockers

• Two general classes: dihydropyridines and non-dihydropyridines.

  • Dihydropyridine examples include nifedipine, amlodipine, and felodipine.

  • Non-dihydropyridines include diltiazem and verapamil

• Calcium channel blockers block calcium influx from activated and inactivated calcium channels and lowers blood pressure as a result

  • Total peripheral resistance is also reduced

  • Myocardial inotropy is reduced, particularly by non-dihydropyridines

  • Non-dihydropyridines also result in bradycardia and PR interval increases (verapamil  >  diltiazem).

• Side effects

  • Edema (predominantly dihydropyridines)

  • Hypotension

  • Bradycardia, heart block (non-dihydropyridines)

  • Headache

  • Rash

• Contraindications

  • Severe renal failure

  • Heart failure

Oral Vasodilators

• Hydralazine

  • Direct effect on arterial tone

  • Short acting preparations necessitate frequent dosing, which limits utility

  • Adverse effects include a lupus-like syndrome due to autoantibodies against histone proteins, and myocardial ischemia due to reflex tachycardia

• Minoxidil

  • Direct effect on arterial tone

  • Effective antihypertensive but side effects (hirsuitism) limit use.

Intravenous Vasodilators

• Nitroprusside

  • Arteriolar and venous dilator

  • Red blood cells metabolize medication, releasing cyanide that is ultimately metabolized to thiocyanate

  • Adverse reactions: accumulation of cyanide (metabolic acidosis, arrhythmias and potential for fatality); accumulation of thiocyanate (confusion, increased reflexes, psychosis, and convulsions)

• Diazoxide

  • Dilation of arterioles which open potassium channels in smooth muscles. Once the membrane stabilizes contraction is less likely

  • Contraindicated in patients with diabetes due to adverse effect of hyperglycemia (50 %)

• Fenoldopam

  • Selective D1 receptor antagonist

  • Dilation of arteries and arterioles, reduces afterload, and promotes sodium excretion

  • Side effects include headache, flushing, nausea, reflex tachycardia, and increased ocular pressure (thus contraindicated in patients with glaucoma).

Antiarrhythmics

• May be divided into classes (Table 33-4)

  Table 33-4 Anti-arrhythmic drugs

  • Class IA: Sodium channel blockers that affect QRS width by lengthening the action potential.

  • Class IB: Sodium channel blockers that do not affect QRS width; shorten action potential.

  • Class IC: Sodium channel blockers that do not affect QRS width or action potential

  • Class II: Block sympathetic nervous system function

  • Class III: Prolong repolarization by effecting potassium efflux

  • Class IV: Calcium channel blockers

• Use dependent: when medications have stronger effects at increased heart rates-i.e. flecainide and propafenone. In order to monitor for side effects such as QRS widening, use a test that increase heart rate such as treadmill exercise stress test.

• Reverse use dependent: when medications have stronger effects at decreased heart rates-i.e. sotalol, dofetilide

• Adverse effects (Table 33-4)

• Contraindications

  • Commonly include renal failure, hepatic failure

Statins

• Inhibit rate limiting step of cholesterol biosynthesis. The liver then compensates and increases the low density lipoprotein (LDL) receptors, which decreases the amount of LDL circulating in the blood and decreases hepatic very low density lipoprotein production.

• Up to 55 % reduction in LDL, 35 % reduction in triglycerides, and small increase (10 %) of HDL.

• First pass metabolism

• Adverse effects

  • Hepatotoxicity: reversible and generally benign.

  • Myopathy: reversible, typically without evidence of muscle injury on testing.

  • Rhabdomylosis (risk increased if taking concurrently with fibric acid derivatives, niacin, or compounds that inhibit the cytochrome P450 system, such as grapefruit juice). Especially an issue for simvastatin at 80 mg dose.

  • Gastrointestinal upset

  • Neuropathy

  • Insomnia, memory loss

• Contraindications

  • Hepatic disease, jaundice, cholestasis

  • Pregnancy (Category X; see section “Special Topics: Pregnancy”)

  • Dose reductions for rosuvastatin recommended in Asians (starting dose of 5 mg), due to genetic predisposition to higher concentrations of active drug, and hence higher risk for adverse effects.

  • Due to drug-drug interactions, simvastatin should be avoided entirely when using antifungals, erythromycin, clarithromycin, HIV drugs, or nefazodone.

  • Due to drug-drug interactions, dose of simvastatin should be reduced if concomitantly used with calcium blockers, amiodarone, and cyclosporine.

Inotropic Agents (Table 33-5)

Table 33-5 Important inotropic agents

• Agents that increase or decrease the force of the heart’s contractions and/or stimulate vascular constriction or dilation.

• Act on α, β-1 and β-2 receptors

  • α: peripheral vasoconstriction and increased vascular resistance

  • β-1: increased heart rate, ventricular contractility and atrioventricular conduction velocity

  • β-2: peripheral vasodilation and bronchodilation

Special Topics: The Elderly Patient

• The elderly may be at higher risk for drug toxicities due to changes in pharmacokinetics:

  • Absorption rate may be delayed; delayed time to peak concentration

  • Changes in hepatic first-pass metabolism

  • Metabolic clearance may be reduced (examples  =  metoprolol, propranolol, verapamil)

  • Reduced renal function may reduce elimination.

    • Decreased lean body mass

      • Results in decreased volume of distribution

    • Decreased plasma protein (albumin)  →  increase percentage of unbound or free drug (example  =  warfarin)

• The elderly may be at higher risk for drug toxicities due to changes in pharma­codynamics:

  • Examples:

    • Decreased heart rate response to β blockers

    • Increased cardiac sensitivity to digoxin

Special Topics: Pregnancy

• General recommendations

  • Avoid medication use in first trimester when possible.

  • Topical route preferred over systemic agents.

• Effect of pregnancy on pharmacokinetics is substantial:

  • Absorption: Gastric emptying time prolonged

  • Distribution: Increased volume of water in body and hemodynamic changes result in dilutional hypoalbuminemia, particularly in last trimester

    • Results in decreased drug-binding capacity and increased distribution rates

  • Metabolism: Biotransformation largely depends on hepatic blood flow, drug-metabolizing enzymes and hormonal influence- all in altered states during pregnancy

  • Excretion: increases in glomerular filtration affect concentrations of drug.

• Choice of drugs, including contraindicated medications in pregnancy are listed in Table 33-6

  Table 33-6 Cardiovascular drugs and pregnancy

Special Topics: Drugs That Increase QT Interval and Risk for Torsades des Pointes (For More See www.qtdrugs.org)

• Antiarrhythmics: Class IA (quinidine, procainamide, disopyramide), Class III (sotalol, NAPA, ibutilide, dofetilide, amiodarone, azimilide)

• Antimicrobials: erythromycin, trimethoprim/sulfamethoxazole, itraconazole, ketoconazole, cloroquine, pentamidine, amantadine

• Antihistamine: terfenadine, astemizole

• Antidepressants: tricyclics

• Psych medications: haloperidol, droperidol, phenothiazines

• Others: vasopressin, organophosphate poisoning

Review Questions

• 1. A 68 year old woman is admitted with dyspnea, chest heaviness, and confusion. She has a past medical history notable for hypertension, chronic kidney disease, glaucoma, coronary artery disease, and diabetes mellitus. She admits to having missed doses of her “heart medications” due to recent problems with gout and feeling unwell. She also notes that she has been taking increased doses of non-steroidal anti-inflammatory drugs for the pain she is suffering. Medications on presentation include lisinopril 40 mg daily, clonidine 0.2 mg twice daily, metoprolol 50 mg twice daily, aspirin 325 mg daily, and simvastatin 20 mg at bedtime.

  On physical examination, she is confused, sleepy, and unable to give more history. Her heart rate is 50 bpm, and her blood pressure is 210/82 mmHg. Her exam is notable for arteriolar nicking of the vessels in her eye grounds, rales on pulmonary exam, and a loud S3 gallop. Laboratory examinations include a serum creatinine of 3.8 mg/dL (baseline of 1.6 mg/dL), normal liver functions, potassium of 4.9 mmol/L, and an electrocardiogram shows diffuse non-specific ST and T wave abnormalities.

  An intravenous line is started, and the patient is admitted to the intensive care unit.

  All of the following are true about this patient EXCEPT:

  • (a) The cause of her bradycardia is increased accumulation of metoprolol from acute renal failure

  • (b) Fenoldopam is contraindicated due to her history of glaucoma

  • (c) Withdrawal from a centrally acting α2 agonist may explain her hypertension

  • (d) Extended use of sodium nitroprusside may result in thiocyanate toxicity

  • (e) Lisinopril should be discontinued until her renal function and potassium are stabilized

• 2. A 27 year old woman in the second trimester of pregnancy develops progressive hypertension. She has no prior history of medical problems, and other than a blood pressure of 168/92 mmHg, she is physically well.

  All of the following are true about this patient EXCEPT:

  • (a) Calcium channel blockers are reasonable choices for her hypertension

  • (b) β blockers are to be avoided in mid- to late pregnancy

  • (c) An angiotensin converting enzyme inhibitor is a reasonable choice for her hypertension

  • (d) Alpha methyl dopa is a reasonable choice for her hypertension

  • (e) Hydralazine is a reasonable choice for her hypertension

• 3. A 42 year old man develops a rapid pulse. Soon after, he loses consciousness, without prodrome. After waking, he is fully conscious, but dizzy. On arrival of the Emergency Medical Service, he is noted to have a heart rate of 300 bpm and blood pressure of 70/30 mmHg. Before a rhythm strip can be obtained, his heart rate drops to 50 bpm.

  He has a past medical history notable for atrial fibrillation, for which he takes flecainide 100 mg twice daily; aspirin is taken for stroke prophylaxis. He has no other medical history, is an avid marathon runner, and denies any anginal symptoms.

  What is the most likely cause of his rapid heart rhythm?

  • (a) Incessant ventricular tachycardia from flecainide

  • (b) Ventricular flutter due to coronary ischemia and the concomitant use of a Ib agent

  • (c) A Stokes-Adams attack from atrial fibrillation

  • (d) Atrioventricular reentrant tachycardia through a concealed pathway, potentiated by flecainide

  • (e) Atrial flutter with 1:1 conduction

Answers

• 1. (a) Metoprolol is cleared hepatically. All other answers are true.

• 2. (c) Angiotensin converting enzyme inhibitors are strictly contraindicated in pregnancy.

• 3. (e) Flecainide has dual effects to promote such a scenario: it slows the flutter rate, and has anti-cholinergic effects on the atrioventricular node, potentially promoting rapid conduction. Class Ic agents should never be employed without concomitant use of an agent that slows conduction.