Cardiovascular pharmacology

# 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:
- Atenolol.  This would be a good drug for rate control in atrial fibrillation in an older patient with depression.
- Nadolol
- Sotalol
- Propranolol
- Lopressor or metoprolol
- Labetalol

### 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:
- Warfarin
- Ramipril
- Isosorbide mononitrate

# Hepatic Metabolism
- Drugs can either inhibit or induce hepatic metabolism.

## Inducers
The following drugs induce hepatic metabolism:
- Barbiturates
- Carbamazepine
- Griseofulvin
- Phenobarbitone
- Phenytoin
- Rifampin

## 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.

### Drugs that Reduce the Clearance of Digoxin
- Amiodarone
- Flecainide
- Propafenone
- Quinidine
- Spironolactone
- Verapamil
- Benzodiazepines
- Cimetidine
- Indomethacin
- Macrolides

### Drugs that Increase the Absorption of Digoxin
- Atropine
- Propantheline

### Drugs that Decrease the Absorption of Digoxin
- Antacids
- Cholestyramine
- Colestipol
- Metoclopramide
- Neomycin
- Phenytoin
- Sulfasalazine

### Drugs that Increase the Clearance of Digoxin
- Thyroxine

# 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
- Beta blockers
- LMWH
- Heparin

# Drugs in Lactation

# Drug Overdose Management

## Digoxin
- Dialysis is not effective
- Administer digoxin antibodies

## Beta Blocker
- Glucagon
- Pacing
- Beta agonists

## Calcium Channel Blocker
- Inotropes
- Calcium
- Vasopressors
- Pacing

## Caffeine
- Beta-blockers

# 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 the 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
- Pathophysiology: increased apoptosis and accelerated myocyte death
- Treatment goals: minimize further exposure, treat CHF symptoms, avoid re-exposure and minimizes re-exposure.

## Type II Reversible Cardiotoxicity
- With these agents re-challenge may be safe
- There is cardiac dysfunction and not cardiac damage
- 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

## Avoid Drug Interactions with the LDL-Lowering Agents Simvastatin, Atorvastatin or Lovastatin
While LDL-lowering agents are widely prescribed in primary prevention, care should be taken to select the appropriate statin based upon concommittant medications.  As a result of the metabolism via the CYP 3A4 pathway, simvastatin, atorvastatin and lovastatin interact with the following agents and should be avoided.  The patient should be switched to pravastatin.
- HIV protease inhibitors
- Itraconazole (Sporanox)
- Ketoconazole (Nizoral)
- Posaconazole (Noxafil)
- Erythromycin
- Clarithromycin
- Telithromycin (Ketek)
- Grapefruit juice
- Nefazodone
- Gemfibrozil
- Cyclosporine
- Danazol

## Simvastatin Interactions
- Simvastatin 10 mg should be the maximum dose when prescribed with:
- Amiodarone
- Verapamil
- Diltiazem
- Simvastatin 20 mg should be the maximum dose when prescribed with:
- Amlodipine (Norvasc)
- Ranolazine (Ranexa)

## St. John's Wart
- Commonly taken
- Induces CYP3A4 and CYP2D9 and reduces the bioavialbility of numerous cardiac medications including:
- Amiodarone
- Calcium channel blockers (majority)
- Carvedilol
- Cyclosporine
- Flecainide
- Metoprolol
- Mexilitine
- Sirolimus
- Statins (majority)
- Tacrolimus
- Warfarin

# Supplements that Increase Bleeding Effect
- Garlic
- Ginger
- Ginko
- Saw Palmetto

# 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
- CYP2C9: 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