Drugs pharmacology in heart disease

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

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

4. 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)

5. Principles of Drug Therapy
 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.

6. Principles of Drug Therapy
 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.

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

8. 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.

9. Pharmacokinetic Parameters
 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.

10. Therapeutic margin

11. Pharmacokinetic Parameters
 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.

12. ECG

13. 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.

14. Pharmacokinetic Parameters
 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).

15. Pharmacokinetic Parameters
 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.

16. 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.

17. 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.

18. 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

19. 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.

20. Large IV bolus

21. 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.

22. low doses

23. 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.

24. Drug Therapy in the Elderly
 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.

25. Drug Therapy in the 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.

26. 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.

27. 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.

28. 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.

30. Thank you
Any question?