Cardiovascular pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Scope
- 5% of questions on the cardiovascular boards pertain to cardiovascular pharmacology.
Pharmacokinetics
Pharmacokinetics is the effect of the body on the drug.
Potency vs Efficacy
- Potency is a meaningless measure of the effect of drug on a per mg basis. Says nothing aobut the clinical effectiveness of the drug.
- Efficacy is the clinical effectiveness of drug.
- A new more potent medicine will achieve the desired effect at a lower dose. It may not be more effective.
Drug Distribution
Hydrophilic Drugs
- These drugs stay in the intravascular space
- Cleared by kidney
- Don't cross the lipid blood brain barrier
- Examples include: Atenolol, nadolol, sotalol
- Muscle is high in water content.
- Women have less muscle mass thereby lowering the volume of distribution of hydrophilic drugs.
- Older patients have less muscle mass thereby lowering the volume of distribution of hydrophilic drugs.
- Elderly women have less total body water thereby lowering the volume of distribution of hydrophilic drugs.
- Water soluble (hydrophilic) drugs are associated with a higher drug effect in patients with a lower volume of distribution like elderly women (e.g. alcohool in a woman).
- Impaired kidney function affects hydrophilic drugs as impaired kidney function affects the volume of distribution.
- Avoid these drugs in renal insufficiency
- Hydrophiic drugs do not diffuse into brain. This is very important in the selection of beta blockers
- Hydrophilic drugs that don't cross the blood brain barrier:
- Lipophilic drugs do cross the blood brain barrier (don't give these drugs to a depressed patient):
Lipophilic Drugs
- Examples include propranolol,lopressor, metoprolol, lebatolol
- Cleared by the liver
- Cross the lipid blood brain barrier
Intestinal Metabolism
Grapefruit Juice
- Grapefruit juice blocks the intestinal cytochrome Cyp3A4 metabolism but not that in the liver.
- May drugs that undergo major intestinal CYP3A metabolism
- Variable effect because patients are so variable in the expression of CYP3A
- One glass of grapefruit juice may irreversibly inhibits CYP3A system up to 3 days
- Drugs affected by grapefruit juice:
- Dihydropiridine calcium channel blockers
- Lovastatin
- Simvastatin
- Cyclosporine
- Tacrolimus
- Sildenafil
- Drugs that are not affected:
Hepatic Metabolism
- Drugs can either inhibit or induce hepatic metabolism.
Inducers
The following drugs induce hepatic metabolism:
Inhibitors
- Beta blockers and decompensated heart failure reduce hepatic blood flow and reduce hepatic metabolism
- The following drugs inhibit hepatic metabolism:
- Diltiazem, Verapamil
- Protease Inhibitors
- Allopurinol
- Ciproflaxacin
- Cimetidine
- Erythromycin
- Isoniazid
- Itraconazole, ketoconazole
Pharmacodynamics
Pharmacodynamics relate to the effect of the drug on the body (in essence the obverse of pharmacokinetics).
Digoxin
- Amiodarone and verapamil can increase the levels of digoxin
- Hypokalemia can tip the patient over into dig toxicity, often after starting a diuretic.
Teratogenicity
Drugs to be Avoided in Pregnancy
- Drugs cross placenta
- No drug is completely safe
- Lithium is associated with Ebstein's anomaly
- Warfarin is associated with facial and CNS abnormalities
- ACE inhibitors are associated with oligohydroamnios
- ARB are teratogenic
- Alcohol
- Barbiturates
- Heparin causes osteoporosis in the mother but has no effect on the fetus
Drugs that are More Acceptable to use in Pregnancy
Drugs in Lactation
Drug Overdose Management
Beta Blocker
Calcium Channel Blocker
Caffeine
Cardiotoxicity of Non-Cardiovascular Drugs
Type I Irreversible Cardiotoxcity (e.g.CHF with anthracylines)
- Cardiotoxicity is related to the cumulative dose: 400 to 500 mg / m2 is teh threshold where toxicity begins
- This level of exposure occurs at about one year
- There is a progressive asymptomatic progression in left ventricular dysfunction
- Progression of disease may persist after discontinuation of anthracycline therapy
- Risk factors include age extremes: younger and old age
- Pathphysiology is increased apoptosis and accelerated myocyte death
- Goal: minimize further exxposure, treat CHF symptoms, avoid re-exposure and minimizes re-exposure.
Type II Reversible Cardiotoxicity
- With these agents re-challenge may be safe
- Examples:
- Sorefenib (Nexavar) used in the treatment of hepatocellular carcinoma, metastatic renal cell cancer
- Imatinib (Gleevec)
- Sunitinib (Sutent)
Drug Interactions
PDE 5 Inhibitors
- Nitrates cause hypotension when administered with PDE5 inhibitors such as viagra
- This is due to excessive cyclic GMP induced vasodilation
ACE Inhibitors, Spironolactones and Postassium
- Dangerous combination
St. John's Wart
- Commonly taken
- Interacts with amiodarone
Supplements that Increase Bleeding Effect
- Ginger
Adverse Drug Reactions
- 4th leading cause of death
- One third are preventable, but often we don't know what the patient is taking
- Elderly and youngerly are at increased risk
- Elderly are at risk because of reduced muscle mass, water soluble drug concentration increased, decreased renal function, cognitive decline and mix up of med doses, non-compliance, co-morbidities
- Polypharmacy: If a patient is administered over 5 drugs, there is a higher risk of drug interactions. Elderly are often on over 10 drugs
Pharmacogenomics
- Role of inheritance in variation in drug response
- Metabolism, absorption, interaction of drug with the target may also be affected by genetics
- Genetics may influence induction and (breakdown) of drugs, increase or reduce activity of drug
Cyp2D6
- The following drugs are affected by alterations in metabolism mediated by this enzyme: tamoxifen, metoprolol, propafenone
- Poor metabolizers: observed in 10% of northern europeans. Metoprolol is not broken down and these patients are susceptible to overdosing of beta-blcokers but codeine does not work in these patients.
- Ultrametabolizers: East africans can be ultrametabolizers: lopressor does not work, codeine can be toxic
Clopidogrel
- Pro-drug
- Absorption variable
- 15% of ingested drug is converted ot active metabolite in two step process in liver
- CYP2c19 very important in metabolizing the drug to the active metabolite
- The *2 and *3 polymorphisms are inactive, drug not converted to active meatbolite, inadequate activity. Increase adverse events, stent thrombosis.
- Routine testing not recommended
- If *2 or *3 allele present, then alternate therapy recommended. Pateint with stent thrombosis on clopidogrel may undergo genetic testing and switch to a newer antiplatelet agent.
Warfarin
- INR is related to efficacy and bleeding
- Order of magnitude different doses of warfarin due to genetic difference
- Half of variability is due to geneitc variability
- CYP2C: responsible for metabolism (pharmacokineteics). There are slow and fast metabolizers
- VKORc1: affects target of effect of warfarin (pharmacodynamics)
- Not clear if testing is cost-effective