Drugs pharmacology in heart disease

Drugs Pharmacology in Heart Disease
By
M.H.Farjoo M.D. , Ph.D.
Shahid Beheshti University of Medical Sciences

Drugs Pharmacology in Heart Disease
 Principles of Drug Therapy
 Variability in Drug Effect
 Dosage Optimization
 Drug Therapy in the Elderly
 Polypharmacy

Principles of Drug Therapy
 The fundamental assumption for any drug is that the
benefit exceeds the risk.
 The goals of drug therapy in heart disease include:
 Acute correction of serious pathophysiology
 Symptom relief
 Changes in “surrogate” endpoints (blood pressure,
serum cholesterol, INR)

 A survey (CAST) tested the hypothesis that
suppression of ventricular ectopic beats would reduce
mortality.
 CAST proved that some antiarrhythmics suppressed
ventricular ectopic beats but increased mortality
threefold.
 In heart failure positive inotropic drugs are used but
increase mortality (drug-induced arrhythmias).
 Prescribers should be cautious about therapy in the
absence of controlled clinical trials.

 The risks of drug therapy may be:
 Related to its pharmacological actions:
 Excessive hypotension due to antihypertensives
 Bleeding due to anti platelet drugs
 Unrelated to its action:
 Rhabdomyolysis with statins (eg: atorvastatin)
 Angioedema due to ACEI therapy
 Torsades de pointes by thioridazine or pentamidine.

Variability in Drug Effect
 Variability in drug effect is due to:
 Pharmacokinetic parameters
 Pharmacodynamic parameters
 Pharmacogenomics parameters

Pharmacokinetic Parameters
 Cardiovascular disorders that impair cardiac output
may affect all the pharmacokinetic factors:
 Absorption of oral, SC, IM, and topical drugs is
erratic because of decreased blood flow to sites of
drug administration.
 Distribution is impaired because of decreased
blood flow to sites of drug action.
 Metabolism and excretion are impaired because of
decreased blood flow to the liver and kidneys.

 Failure of one metabolizing pathway will not affect a
drug using multiple elimination routes.
 A drug eliminated by one pathway will accumulate if
the pathway fails.
 In this case there is a risk of toxicity, especially if
therapeutic margin is narrow.

 An example is terfenadine, which is eliminated
exclusively by CYP3A.
 Terfenadine is a highly potent QT-prolonging agent.
 Terfenadine with CYP3A inhibitors (ketoconazole,
Erythromycin) causes QT prolongation, and torsades
de pointes.
 CYP3A inhibition also increases the risk of
rhabdomyolysis with some statins and Fibrates.

Torsade depointes
Polymorphic V.Tach. (torsades de pointes), which may degenerate into V. Fib.
There is a high risk of sudden death in this syndrome.

 Patients with LVH have baseline QT prolongation, so
risk of QT-prolonging antiarrhythmics increases.
 In heart failure, hepatic congestion decreases
clearance and an increases toxicity with usual doses
of lidocaine and β blockers.
 In heart failure renal perfusion is reduced and
requires dose adjustments.
 Heart failure causes redistribution of regional blood
flow => volume of distribution ↓ => drug toxicity ↑
(lidocaine).

 β blockers in patients with defective metabolism
produces exaggerated heart rate slowing.
 Digoxin is eliminated by P-glycoprotein-mediated
efflux into bile and urine.
 Inhibition of P-glycoprotein increases digoxin
concentrations.

Pharmacodynamic Parameters
 The effect of lytic therapy in a patient with or without
coronary thrombosis is different.
 The arrhythmogenic effects of digitalis depend on K+.
 The vasodilating effects of nitrates, beneficial in
angina, can be catastrophic in aortic stenosis.

Pharmacogenomics Parameters
 An example is resistance to antiplatelet actions of
aspirin and Clopidogrel (anti ADP receptor).
 DNA variants are recognized as contributors to
variability in drug action.
 There is associations between disease severity and
DNA polymorphisms.
 This affects β blockers, ACEI, Fluvastatin, Diuretics,
Antiplatelet drugs and Amiloride.

effect of a beta-receptor polymorphism on receptor
function in vitro. Patients with the hypofunctional
variant may display greater heart-rate slowing or
blood pressure lowering on exposure to receptor
blocking agents.
Beta blockers

Dosage Optimization
 When the goal of drug therapy is to acutely correct a
disturbance, drug should be administered IV.
 Large IV boluses has the risk of enhancing drug-
related toxicity.
 Even with the most urgent of medical indications, this
approach is rarely appropriate.
 An exception is adenosine, which must be injected as
a rapid bolus (1-2 Sec.) because rapid elimination
from plasma.

Dosage Optimization
 When adverse effects are serious, the treatment
should start at low doses.
 For example, the risk of torsades de pointes increases
with sotalol dosage, the starting dose should be low.
 Only when stable effects are achieved, increasing
dosage may be considered.
 Drug monitoring is best accomplished at the time of
anticipated peak drug concentrations.
 Assessing QT prolongation by sotalol or dofetilide is
accomplished 1 to 2 hours after a dose of drug at
steady state.

Drug Therapy in the Elderly
 Age is a major factor in determining drug doses and
sensitivity to drug effects.
 Elderly persons have reduced creatinine clearance,
even with a normal creatinine level
 Dosages of renally excreted drugs should be adjusted.
 Elderly have increased postural hypotension.
 Thus, sedatives, TCAs or anticoagulants should be
initiated only when the benefits outweigh the risk.

 Weight adjustment for loading doses of digoxin,
lidocaine and heparin are standard.
 Fibrinolytic drugs without adjustment increase the
risk of intracranial hemorrhage in older age.
 Dosage/weight adjustments should be made
especially for drugs with low therapeutic index.
 Digoxin, warfarin, diuretics, and CCBs have
“preventable” adverse effects in elderly.

 “Inappropriate” drugs in the elderly include:
 Amiodarone
 Clonidine
 Disopyramide
 Medications in patients with life expectancy too short
to achieve long-term benefits merits discontinuation.

Polypharmacy
 The most important issue is drug interactions.
 Patients omit topical drugs, eye drops, supplements,
and drugs prescribed by other practitioners.
 Grapefruit juice contains CYP3A and P-glycoprotein
inhibitors, and can affect drug responses.
 Timolol eye drops can produce systemic β blockade
toxicity in patients with defective metabolizing
activity.

Adherence
 Medication adherence is lower in older patients
compared with younger patients.
 Hospitalization for decompensated congestive heart
failure was due to noncompliance in 42% of elderly
patients.

Adherence
 Contributing factors for non-adherence include:
 The cost of medications
 Difficulty in reading small print of written directions
 Hearing impairment
 Impaired memory
 Inadequate instructions
 Complex dosing regimens
 Difficulties with packaging materials
 Insufficient education on medication use.

Drugs pharmacology in heart disease

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