, James L. JanuzziJr.2 and James L. JanuzziJr.3
(1)
School of Nursing, Massachusetts General Hospital Institute of Health Professions, Boston, MA, USA
(2)
Harvard Medical School, Boston, USA
(3)
Cardiac Intensive Care Unit, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Abstract
Pharmacology is the detailed study of drugs – their chemical and physical properties, biochemical and physiological effects, and pharmacokinetics (alterations of the drug on the body) and phamacodynamics (the mechanism of actions). As there is no ideal drug in existence, it is the responsibility of every member of the healthcare team to promote therapeutic effects and minimize drug-induced harm to each patient. This section discusses the pharmacokinetic processes and pharmacodynamic principles, along with a selection of cardiac medication pearls to help the prescriber carry out the therapeutic objective-to provide maximum benefit with minimum harm to each patient with each medication prescribed.
Abbreviations
ACE
Angiotension converting enzyme
AV
Atrioventricular
CCB
Calcium channel blocker
ED50
Median effective dose
IM
Intramuscular
IV
Intravenous
PO
By mouth ‘per os’
SC
Subcutaneous
Introduction
Pharmacology is the detailed study of drugs – their chemical and physical properties, biochemical and physiological effects, and pharmacokinetics (alterations of the drug on the body) and phamacodynamics (the mechanism of actions). As there is no ideal drug in existence, it is the responsibility of every member of the healthcare team to promote therapeutic effects and minimize drug-induced harm to each patient. This section discusses the pharmacokinetic processes and pharmacodynamic principles, along with a selection of cardiac medication pearls to help the prescriber carry out the therapeutic objective-to provide maximum benefit with minimum harm to each patient with each medication prescribed.
General Pharmacology
Pharmacokinetics: Action of the Body to the Drug
Absorption: the movement of a drug into the bloodstream
Variability in absorption and bioavailability based on route of administration (PO, IM, IV, SC, mucosal, etc.)
Factors affecting absorption: dose administered, percentage of dose that is ‘active’ and bioavailability of drug
Bioavailability: the rate or percentage of drug dose reaching systemic circulation. 100 % bioavailability with IV administration, but variable bioavailability with other routes of administration.
Factors affecting bioavailability: characteristics of medication dosage form, solubility, administration route, metabolism in the gut wall or liver (first-pass effect) and the permeability of the gastrointestinal tract (i.e. edematous tract due to heart failure may not be able to absorb as much drugs through the gut wall).
Distribution: the process of the dispersion of the drug into the bloodstream and surrounding tissues
Influenced by lipid solubility (i.e. in general, water-soluble drugs are limited to the vascular space and cannot easily cross the blood–brain barrier while lipid-soluble drugs are distributed more widely and can better cross the blood–brain barrier), degree of ionization, blood flow and binding affinities to proteins in plasma and specific tissues
During constant infusion or multiple doses of a medication, drug levels rise in the blood and tissue until they reach a plateau, or steady state
At steady state, the rate of drug administration equals rate of drug elimination
Generally takes 4–5 half-lives to reach desired steady-state drug concentration
Volume of distribution (the volume of body fluid that the medication is distributed in) can help to estimate loading dose (i.e. large volume of distribution = low concentration of the drug)
Protein binding
Describes a drug’s affinity for plasma protein
Drugs are either bound or unbound
The less bound a drug is the more drug circulating throughout the body that is “active”
Only unbound drug undergoes metabolism in liver and elimination
Coumadin is 97 % protein bound. Dramatic implications may ensue when another medication is added that is protein bound as well
Protein-bound medications compete for proteins, resulting in larger amounts of both medications’ free drug concentrations and risk for side effects.
Metabolism
Complex or lipid-soluble drugs undergo hepatic metabolism to a water-soluble metabolites which can then be excreted. These metabolites can be biologically active or inactive leading to either therapeutic effects or increase toxic side effects related to the medication administered
i.e. procainamide is metabolized into NAPA in the body, a Class III antiarrhythmic with a therapeutic level of 10–20 mcg/mL. Toxic levels of NAPA can manifest in the prolongation of action potential, prolonged QT interval and ultimately Torsades de Pointes. Even if procainamide level is not toxic, NAPA level may be
Phase 1 (mainly oxidation of the drug to make it more water-soluble) and Phase 2 (mainly conjugation of the drug)
Oxidation is mainly through the cytochrome P450 (CYP450) system. The most drugs are metabolized by CYP3A (>50 %), CYP2D6 (genetic polymorphism leads to decreased enzyme levels in up to 25 % in Caucasian and African population resulting in hypersensitivity to medications such as b-blockers, propafenone), CYP2C9 and CYP1A2 families of the CYP450 system (Table 33-1). Note that CYP450 activity can decrease with increasing age and lead to increased drug levels/toxicity.
Table 33-1
Medications that affect hepatic metabolism
CYP450 Family
Cardiovascular drugs metabolized by the cytochrome family
Inhibitors
Inducers
CYP3A
Statins (except for pravastatin), CCB, amiodarone, cyclosporine, tacrolimus, quinidine, mexiletine
Grapefruit juice, CCB, amiodarone, antivirals, erythromycin, clarithromycin, itraconazole, ketoconazole
Rifampin, St. John’s wort, phenytoin, pioglitazone, efavirenz, nevirapine, barbiturates
CYP2D6
b-blockers, propafenone
Amiodarone, quinidine, fluoxetine, paroxetine
Rifampin
CYP2C9
Irbesartan, losartan, warfarin, carvedilol
Amiodarone, zafirlukast
Rifampin
Clearance of a drug is one of the most important factors to understand, as it helps in dosing the patient to maintain a therapeutically effective level of the drug.
Drug clearance occurs through both metabolism (biotransformation) and excretion.
Genetics (polymorphism), concurrent disease, age or drug-drug interactions can affect drug clearance
First-pass effect (important drugs are listed in Table 33-2)
Table 33-2
Drugs with a significant first pass effect
Diltiazem, verapamil
Labetalol, metoprolol, propranolol
Hydralazine
Nitroglycerin
Concentration of drug is greatly reduced before it reaches systemic circulation, typically metabolized during absorption in the liver
Greatly reduces bioavailability of the drug
Suppositories, IV, IM, sublingual and inhaled medications bypass first-pass effect
Elimination
Final route of exit from the body; expressed in terms of half-life or clearance.
Excretion occurs through the kidneys primarily, but also through bile, sweat, saliva, breast milk and exhalation.
Renal Drug Excretion is the net effect of glomerular filtration, secretion, and passive reabsorption
With renal dysfunction, may need to decrease medication doses if renally cleared (i.e. digoxin)
Half-life: time for serum concentration of drug to decrease by 50 % (hours)
Determined by clearance and volume of distribution
Poor indicator of the efficacy of drug elimination and plasma drug concentration at steady state
Typically takes 4–5 half lives to clear medication from system
Clearance: volume of serum from which drug is removed per time (mL/min or L/h)
Pharmacodynamics: The Drug’s Effect on the Body
Dose–response relationship
the effect of a drug based on the concentration that is present at the site of action
In most cases a maximum value is approached where a further increase in concentration is not effective
ED50 = dose producing a response that is 50 % of the maximum value
Depends on both exposure time and exposure route
Drug toxicity
reduced clearance = drug accumulation and toxicity
Drug-Drug Interactions
Most common with cardiac medications, and may result in increased absorption, additive or antagonistic effects, as well as induced or inhibited metabolism.
Cardiac Medication Pearls
Anticoagulants
Heparin: accelerates the action of antithrombin III which rapidly inactivates the clotting factors
Oral bioavailability 0 %, thus IV or subcutaneous route is mandatory
Adverse effects: bleeding, heparin induced thrombocytopenia
Action can be reversed by protamine sulfate
Warfarin sodium: Vitamin K antagonist (prevents formation of new clotting factors in liver)
Oral bioavailability is >95 %
Onset of action = 8–12 h
Effects can be reversed by Vitamin K, but take 24 h
Oral vitamin K (5–10 mg) is as effective as subcutaneous for reversing excessive anticoagulation.
Intravenous vitamin K may be slightly faster, though this is debated.
Contraindicated in pregnancy
May result in aplasia cutis congenita
Numerous drug-drug interactions to remember (Table 33-3).
Table 33-3
Drugs with important interactions with warfarin sodium
Increases anticoagulation effects:
Cimetidine
Alcohol
Disulfiram
Many antibiotics, notably including sulfa agents
Decreases anticoagulant effects:
Vitamin K
Barbiturates
Rifampin
Non-warfarin oral anticoagulants
Dabigatran
Direct thrombin inhibitor
Rapidly effective, high oral bioavailability< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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