Faculty of Pharmacy
Department of Pharmacology
5th year Pharmacy Students
Drug-Drug Interaction
Cardiovascular Drugs
ANTIARRHYTHMICS
class I drugs:
block the fast sodium channel and divided into three subgroups:
Class IA:
(quinidine, procainamide, disopyramide)
Class IB:
(mexiletine, phenytoin, and lidocaine)
Class IC:
(flecainide, propafenone)
Class II drugs:
block beta-adrenergic receptors and include:
They include propranolol, timolol, metoprolol, and
others.
Class III drugs:
block potassium channels and prolong repolarization.
They include sotalol, amiodarone, and bretylium
Class IV: drugs block the slow calcium channel and include
verapamil, diltiazem.
Drug Interactions (Selection; Amiodarone Preferred)
1-Phamacokinetic interactions:
1-Amiodarone inhibits the activity of two cytochrome P450
enzymes, CYP2D6 and CYP2C9. As a consequence, it reduce
the metabolism of certain drugs e.g. anticoagulants. The
anticoagulant effects of warfarin is significantly increased
when amiodarone is added.
2-Flecainide concentrations increase by an average of 60% with
concomitant amiodarone therapy. it is postulated that the
hepatic metabolism and/or renal clearance of flecainide may be
decreased.
3-Quinidine serum concentrations generally increase by about
33% in patients receiving concomitant amiodarone therapy. it
appears that hepatic and/or renal clearance may be
diminished and quinidine may also be displaced from tissueand protein-binding sites.
4-Procainamide and N-acetylprocainamide or NAPA
(a pharmacologically active metabolite) concentrations increase
approximately 55 % during the concomitant amiodarone
therapy due to a reduction in the renal clearance of both
parent and metabolite, as well as a reduction in hepatic
metabolism seem likely.
5-Amiodarone increases serum levels of digoxin when given
concomitantly result from an amiodarone-induced displacement of
digoxin from tissue-binding sites, an increase in bioavailability,
and/or a decrease in renal clearance.
6-Concurrent administration of amiodarone with coumarin or
indandione anticoagulants (warfarin) results in at least a
doubling of prothrombin time (PT)
7-Concomitant administration of amiodarone and phenytoin may
result in phenytoin Toxicity due to a amiodarone-induced
decrease in phenytoin metabolism
8-Two protease inhibitors, ritonavir and nelfinavir, are potent
P450 enzyme inhibitors produce a large increase in amiodarone
concentrations, due to the inhibition of its metabolism.
9-Paroxetine impairs metabolism of the CYP2D6 (cytochrome
P450 isoenzyme 2D6) pathway at therapeutic doses.
Competition for hepatic CYP2D6 (cytochrome P450 isoenzyme
2D6) by paroxetine may potentiate the toxicity of these
antiarrhythmics.
2-pharmacodynamic interactions
1-Concomitant administration of beta-blockers, or calciumchannel blockers with amiodarone may result in additive
electrophysiologic effects including bradycardia, sinus
arrest, and atrioventricular block.
sympatholytics
1-alpha-Blockers:
The selective alpha-1-blockers:
such as prazosin, terazosin, and doxazosin
are the only class of antihypertensive agents that may
have the combined effect of lowering low-density
lipoprotein (LDL)-cholesterol, raising highdensity lipoprotein
(HDL)-cholesterol levels, and improving insulin sensitivity
The alpha -blockers are associated with relatively
bothersome side effects, including dizziness (rarely
inducing syncope), headache, and weakness.
Indications and Usage
1- BENIGN PROSTATIC HYPERPLASIA (BPH)
2- HYPERTENSION
Pharmacodynamic interactions:
1- Combined use with other antihypertensive drugs (e.g.,beta
-blockers, calcium channel blockers, diuretics, ACE
inhibitors) can cause additive blood pressure lowering effects
with severe symptomatic hypotension.
Pharmacokinetic interaction:
1-Most (98%) of plasma doxazosin is protein bound. In vitro
data in human plasma indicate that doxazosin mesylate has no
effect on protein binding of digoxin, warfarin, phenytoin, or
indomethacin.
There is no information on the effect of other highly plasma
protein-bound drugs on doxazosin binding.
Beta -Blocking Agents
Propranolol, Metoprolol Atenolol, Nadolol ,Pindolol and Labetalol
Mechanism of action:
binding to beta-adrenergic receptors, which is sufficiently
high to antagonize the binding of endogenous agonists like
norepinephrine and epinephrine at blood and tissue
these agents have been classified according to their:
• relative selectivity for the beta-1 or beta-2adrenergic
receptors
• their ability to bind other adrenergic receptors, usually
alpha receptors
Drug interactions:
DIGITALIS
Digoxin and digitoxin
Mechanism of action:
-Inotropic drug:
make positive inotropic effect enhance cardiac muscle
contractility as result of increased cytoplasmic calcium
concentration and thus increase cardiac output
-Improvement of depressed myocardial contractility so, increases
cardiac output, promotes diuresis,
Drug Interactions
Pharmacokinetics
• Cholestyramine, colestipol, kaolin-pectin may reduce digoxin
absorption.
• Metoclopramide may reduce the absorption of digoxin tablets.
• Cyclosporine may increase digoxin levels, due to reduced
clearance.
renal
• Erythromycin, clarithromycin, and tetracyclines may increase
digoxin (not capsule form) blood levels in a subset of patients.
• Itraconazole may increase digoxin blood levels in some patients.
• Propylthiouracil (and methimazole) may increase digoxin blood
levels by reducing thyroid hormone.
• Rifampin reduces the intestinal absorption of digoxin, an
effect that probably occurs by the induction of intestinal Pglycoprotein. It is likely that anticonvulsants
• Sulfasalazine can decrease digoxin absorption to a variable
degree.
Pharmacodynamics
• Amiloride may reduce the inotropic response to digoxin.
• Levothyroxine (and other thyroid supplements) may decrease
digoxin blood levels.
• Penicillamine has been associated with reductions in digoxin blood
levels.
• Amiodarone reduces renal and non renal clearance of digoxin and
may have additive effects on heart rate.
• Succinylcholine administration to patients on digoxin has
been associated with an increased risk of arrhythmias
• Verapamil , diltiazem
increased serum digoxin concentrations.
DIURETICS
Mechanism of action:
Diuretics act by diminishing sodium-chloride reabsorption at
different sites in the nephron ,thereby increasing urinary sodium
chloride and water loss.
The diuretics are generally divided into three major classes,
1.Loop diuretics act in the thick ascending limb of the loop of
Henle.
2. Thiazide-type diuretics in the distal tubule and connecting
segment (and perhaps the early cortical collecting tubule).
3. Potassium-sparing diuretics in the aldosterone-sensitive principal
cells in the cortical collecting tubule.
4. Others: acetazolamide inhibits the activity of carbonic
anhydrase, which plays an important role in proximal
bicarbonate, sodium, and chloride reabsorption. As a result,
this agent produces both NaCl and NaHCO3 loss.
Thiazide Diuretics
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in
the management of edema and hypertension. In
hypertension, thiazide diuretics are often used as initial
therapy, either alone or in combination with other agents.
Drug Interactions
1-HCTZ can have additive effects when administered with
other antihypertensive drugs or diuretics.
2-HCTZ can interfere with the hypoglycemic effects of oral
hypoglycemics, which could lead to a loss of diabetic
control.
3-HCTZ-induced electrolyte disturbances (e.g., hypokalemia,
hypomagnesemia, hypercalcemia) can predispose patients to
digoxin toxicity, resulting in possibly fatal arrhythmias.
4- Administration of HCTZ to patients receiving
nondepolarizing neuromuscular blockers can cause prolonged
neuromuscular blockade due to HCTZ-induced hypokalemia.
.
Loop Diuretics
Mechanism of Action
Loop diuretics act by inhibition of NaCl reabsorption in the thick
ascending limb of the loop of Henle. They inhibit the
Na/K/2Cl transport system in the luminal membrane,
resulting in:
1.Reduction in sodium chloride reabsorption.
2. loop diuretics increase magnesium and calcium
excretion.
Drug Interactions
1-The bronchodilator theophylline may be able to reach higher
blood levels when used in conjunction with furosemide.
2-Furosemide may lead to displacement of plasma protein binding
warfarin and clofibrate
3-Loop diuretics reduce lithium renal clearance and can
increase
lithium serum concentrations
4-Loop diuretics can increase the risk of digitalis-induced
cardiac toxicity
5-Furosemide may increase renal toxicity of cephalosporin
antibiotics.
4-Loop diuretics can increase the risk of digitalis-induced
cardiac toxicity
5-Furosemide may increase renal toxicity of cephalosporin
antibiotics.