Cardiovascular pharmacology: Difference between revisions
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==Scope== | ==Scope== | ||
*5% of questions | *5% of questions on the cardiovascular boards pertain to cardiovascular pharmacology. | ||
==Pharmacokinetics== | ==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. | |||
==Hydrophilic== | ===Drug Distribution=== | ||
* | ====Hydrophilic Drugs==== | ||
*These drugs stay in the intravascular space | |||
*Cleared by kidney | *Cleared by kidney | ||
* | *Don't cross the lipid blood brain barrier | ||
Atenolol, | *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]] | |||
:Lipophilic drugs do cross the blood brain barrier (don't give these drugs to a depressed patient): | |||
::*[[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== | ==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== | ||
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==== | |||
=====Cardiovascular Drugs===== | |||
*[[Amiodarone]] | |||
*[[Flecainide]] | |||
*[[Propafenone]] | |||
*[[Quinidine]] | |||
*[[Spironolactone]] | |||
*[[Verapamil]] | |||
=====Non-CV Drugs===== | |||
*[[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 | ==Drug Overdose Management== | ||
===Digoxin=== | ===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== | ==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 | |||
==References== | ==References== | ||
Latest revision as of 05:06, 1 October 2012
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.
Drugs that Reduce the Clearance of Digoxin
Cardiovascular Drugs
Non-CV Drugs
Drugs that Increase the Absorption of Digoxin
Drugs that Decrease the Absorption of Digoxin
Drugs that Increase the Clearance of Digoxin
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
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:
- Simvastatin 20 mg should be the maximum dose when prescribed with:
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
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