Cardiovascular pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Scope
- 5% of questions of the boards
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.
- Drugs affected grapefruit juice (may increase drug levels):
- Dihydropiridine calcium channel blockers
- Lovastatin
- Simvastatin
- Cyclosporine
- Tacrolimus
- Sildenafil
- Drugs that are not affected:
Hepatic Metabolims
- beta blockers reduce hepatic blood flow, deompensated CHF affects liver blood flow
Know inhibitors\ allopurinal cipr cimet dilt eryth isoiz PPI
Inducers barb carb Know Inducers
Pharmacodynamics
Effect of drug on the body
Drug Drug Interactions
Nitrates with PD5 inhibitors
Digoxin
- Other meds
- Hypokalemia, often dont get dig toxic unless hypok, start on diuretic, then pt becoes dig toxic
- Other drugs
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
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 target affected by genetics
- Genetics may influence induction and inhibition (breakdown) of drugs, increase or reduce activity of drug
- Example CYP2D6: metoprolol, propafenone, tamoxifen affected. Poor metabolizers in 10% of northern europeans. Metoprolol is not broken down and easily od, codeine does not work. East africans can be ultrametabolizers: lopressor does not work, codeine toxic
- Clopidogrel
- Absorption variable
- 15% taken in is active
- 2 steps to turn it into the active drug
- CYP2c19 very important in metabolizing the drug to the active metabolite
- 2 and *3 polymorphisms are inactive, drug not activated, inadequate activity. Increase adverse events, stent thrombosis.
- Routine testing not recommedned
- If *2 or *3 allele present, then alternate therapy recommended. Pt with stent thrombosis may undergo testing and switch.
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