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Drugs pharmacology in heart disease
 

Drugs pharmacology in heart disease

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    Drugs pharmacology in heart disease Drugs pharmacology in heart disease Presentation Transcript

    • Drugs Pharmacology in Heart Disease By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
    • Drugs Pharmacology in Heart Disease  Principles of Drug Therapy  Variability in Drug Effect  Dosage Optimization  Drug Therapy in the Elderly  Polypharmacy  AdherenceM.H.Farjoo
    • 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)M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • Variability in Drug Effect  Variability in drug effect is due to:  Pharmacokinetic parameters  Pharmacodynamic parameters  Pharmacogenomics parametersM.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • Therapeutic margin
    • Pharmacokinetic Parameters Cont’d  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.M.H.Farjoo
    • ECG
    • Torsade depointesPolymorphic V.Tach. (torsades de pointes), which may degenerate into V. Fib.There is a high risk of sudden death in this syndrome.
    • Pharmacokinetic Parameters Cont’d  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.M.H.Farjoo
    • Pharmacokinetic Parameters Cont’d  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).M.H.Farjoo
    • Pharmacokinetic Parameters Cont’d  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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • effect of a beta-receptor polymorphism on receptorfunction in vitro. Patients with the hypofunctional Beta blockersvariant may display greater heart-rate slowing orblood pressure lowering on exposure to receptorblocking agents.
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • Drug Therapy in the Elderly Cont’d  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.M.H.Farjoo
    • Drug Therapy in the Elderly Cont’d  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 patientsM.H.Farjoo
    • Drug Therapy in the Elderly Cont’d  “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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • 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.M.H.Farjoo
    • Thank you Any question?