Drugs pharmacology in heart disease

Drugs Pharmacology in Heart Disease

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.FarjooM.H.Farjoo

Drugs Pharmacology in Heart Disease

Principles of Drug Therapy Variability in Drug Effect Dosage Optimization Drug Therapy in the Elderly Polypharmacy Adherence


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)


Principles of Drug Therapy Cont’d

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.


Principles of Drug Therapy Cont’d

The risks of drug therapy may be: Related to its pharmacological actions:

Excessive hypotension due to antihypertensives Bleeding due to anti platelet drugs (Abciximab,

Dipyridamol).

Unrelated to its action: Rhabdomyolysis with HMG-CoA reductase inhibitors 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.


Pharmacokinetic Parameters Cont’d

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.

Therapeutic margin



An example is terfenadine, which is eliminated exclusively by CYP3A.

Terfenadine is a highly potent QT-prolonging agent. Coadministration of terfenadine with CYP3A

inhibitors (ketoconazole, Erythromycin) leads to marked QT prolongation, and torsades de pointes.

CYP3A inhibition also increases the risk of rhabdomyolysis with some HMG-CoA reductase inhibitors and Fibrates.

ECG

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.



Heart disease carries with it a number of disturbances of drug elimination and sensitivity.

Patients with LVH have baseline QT prolongation, and thus risks of QT-prolonging antiarrhythmics may increase.

In heart failure, hepatic congestion can lead to decreased clearance and an increased toxicity with usual doses of lidocaine and beta 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 (an anti ADP receptor drug)

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 the 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.

Large IV bolus


Dosage Optimization Cont’d

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 drug effects are achieved, increasing drug dosage may be considered.

low doses


Dosage Optimization Cont’d

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.


Drug Therapy in the Elderly Cont’d

Systolic dysfunction with hepatic congestion is more common in the elderly.

Vascular disease and dementia are common in the elderly and can lead to increased postural hypotension.

Thus therapies such as 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 dosage adjustment increase the risk of intracranial hemorrhage in older age.

Dosage/weight adjustments should be made especially for drugs with low therapeutic index.



Adverse drug events account for up to 5 percent of hospital admissions.

Digoxin, warfarin, diuretics, and Ca2+ channel blockers have “preventable” adverse effects in elderly.

The risk of side effects with cardiovascular drugs is 2.4 times that of other medications in hospitalized patients



“Inappropriate” drugs in the elderly include: Amiodarone Clonidine Disopyramide Ethacrynic acid Guanethidine

Medications in patients with life expectancy too short to achieve long-term benefits merits discontinuation.


Polypharmacy

The most important principle in polypharmacy is to recognize the high potential for drug interactions.

A complete medication history should be obtained from each patient at regular intervals.

Patients omit topical medications, eye drops, “health food” supplements, and drugs prescribed by other practitioners.


Polypharmacy Cont’d

Even high dosages of grapefruit juice, which contains CYP3A and P-glycoprotein inhibitors, can affect drug responses.

Beta blocker eye drops (timolol) can produce systemic beta blockade 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 Cont’d

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.

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Drugs pharmacology in heart disease

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