Dr.

Valdez

CARDIOVASCULAR
PHARMACOLOGY
 Drugs and the cardiovascular
system
Types of drugs used to improve cardiovascular
function :
▪ Antihypertensive
▪ Diuretic
▪ AntiCHF-inotropics
▪ Antiarrhythmic
▪ Antiangina
▪ Antilipidemic
 Antihypertensive drugs
▪ Antihypertensive drugs act to reduce blood
pressure, are used to treat hypertension
▪ Mean arterial pressure= CO x Peripheral
resistance >>>>>*Decrease in either CO or
peripheral resistance will decrease BP
▪ Fatal sequelae of hypertension:stroke, MI and
renal failure
▪ Acco. To JNC guidelines
Normal BP <120/80mm Hg
Prehypertension 120—139/80-89
Stage I hypertension 140-159/90-99
Stage II hypertension >160/100
▪ What is responsible for moment to moment changes in
BP –Baroreceptor reflexes (aortic arch,carotid sinuses)
Antihypertensive drugs by
their mechanism of action
▪ Diuretics
a. Thiazides (HCTZ,cholorothiazide, chlorthalidone)
b. Loop diuretics (furosemide, bumetanide,
ethacrynic acid,torsemide)
c. Potassium sparing diuretics
▪ Drugs that interfere with RAS
a. ACE inhibitors
b. ARB’s (Angiotensin II receptor antagonists)
c. Aldosterone antagonists
d. Direct renin inhibitor
▪ Drugs that decrease PVR or CO
a. Direct vasodilator
1. CCB
2. Nitrates ,Hydralazine, Minoxidil, etc
b. SNS depressants
1. α and β blockers
2. Clonidine/α methyldopa
*Some of these drugs are also useful in the
treatment of angina and HF
▪ The choice of these drugs depends on
whether the patient has a compelling
indication, such as heart failure, history of an
MI, high risk of coronary artery disease (CAD),
diabetes, or chronic kidney disease.
▪ A combination of drugs may be used.
Diuretics
▪ Diuretics lower BP by reduction of blood volume
and alteration of vascular smooth muscle tone
▪ Thiazides (HCTZ,) often used for mild and
moderate hypertension
▪ Loop diuretics (furosemide) are usually required
for severe hypertension
▪ Thiazides are used orally
▪ Loop diuretics are used orally and parenterally
depending on urgency of the situation
Ex. Severe hypertension with rapidly progressing organ
damage furosemide is give IV
▪ Potassium sparing diuretics (Spironolactone,
triamterene, Amiloride)
▪ Thiazide diuretics (chlorothiazide, metolazone,
hydroclorothiazide) inhibit Na and Chloride
reabsorption in the distal tubule . This loss of
ions increase urine volume.
-used in the treatment of mild hypertension
▪ Loop diuretics (furosemide,bumetanide) inhibit
Na/K/2Cl transporter)chloride reabsorption in
the thick ascending loop of Henle- commonly
used to reduce pulmonary edema and CHF
because of rapid onset of action
▪ Toxicities: Hypokalemia,hyponatremia
*Thiazides may also raise blood glucose, lipids
and uric acid
*Loop diuretics is ototoxic (triamterene most
ototoxic)
▪ Potassium sparing diuretics
(spironolactone,amiloride,triamterene,
eplerenone) enhance sodium excretion and
retain potassium by an action in the distal
tubule
-Potassium sparing diuretics are often used in
combination with the other diuretics to help
maintain potassium balance .
- They cause hyperkalemia,metabolic acidosis
and gynecomastia
Sympatophlegic drugs
Sympatholytic drugs reduce blood pressure by inhibiting or
blocking the SNS.
They are classified by their site or mechanism of action
▪ Central-acting sympathetic nervous system inhibitors (
α-2 agonists =clonidine and methyldopa)
▪ α-1 blockers (Selective :doxazosin, prazosin, and
terazosin Non selective: phenoxybenzamine,
Phentolamine Tolazoline
▪ Mixed α- and β-adrenergic blockers (carvedilol and
labetalol)
▪ Postganglionic sympathetic neuron blockers (guanadrel,
guanethidine, and reserpine == rarely used
▪ Ganglion blockers (trimethaphan) - nicotinic cholinergic
receptor antagonist ==rarely used
 Pharmacokinetics
▪ Most sympathophlegic drugs are absorbed well
from the GI tract, distributed widely, metabolized in
the liver, and excreted primarily in urine.
▪ Clonidine is active as given whereas methyldopa is a
prodrug that must be converted in the CNS to
α-methylnorepinephrine
▪ Duration of action of oral clonidine- 8-12 hrs, Oral
methydopa duration of action 12-24 hrs
▪ Trimethaphan- is given by IV infusion and the
duration of action is 1-3 min
▪ Reserpine- orally active and has duration of
12-48 hrs, while guanethidine has duration of
action of several days
▪ α- blockers
(phenoxybenzamine,tolazoline,prazosin)
are orally active agents with duration of
action of 10-24 hrs
▪ β-blockers are orally active except for Esmolol
(IV only) with duration of action varies 6-24 hrs
Esmolol duration of action is 15 min
-Metoprolol and propranolol are absorbed from
the GI tract, whereas atenolol or nadolol is not
completely of absorbed.
-Propranolol is highly protein-bound; the otherβ-
adrenergic blockers are poorly protein-bound.
- Propranolol and metoprolol are metabolized in
the liver, and their metabolites are excreted in
urine.
-Atenolol and nadolol are not metabolized and are
excreted unchanged in urine
Pharmacodynamics
▪ All sympathophlegic drugs inhibit stimulation
of the SNS, causing dilation of the peripheral
blood vessels or decreased cardiac output,
thereby reducing blood pressure
▪ α 2 agonists Clonidine and methyldopa
(active metabolite α-methylnorepinephrine)
activate α 2 receptors in the brain and reduce
sympathetic outflow reducing CO and
peripheral resistance
▪ Trimethaphan blocks the nicotinic channel in
autonomic ganglion cells and prevents
sympathetic stimulation
▪ Reserpine and Guanithedine alter the storage
and release of NE
-Reserpine blocks uptake of cathecholamines
and serotonin into storage vesicles thereby
depleting transmitter stores in the nerve endings
Guanethidine prevents release of transmitter
vesicles and also depletes NE stores
▪ Selective α1blockers ( Prazosin, Doxazosin,
and Terazosin) block α1 receptors causing a
decrease in peripheral resistance
▪ Nonselective α blockers
(Phenoxybenzamine,tolazoline)
▪ β Blockers decrease BP and block β-adrenergic
receptor sites in the heart muscle and the
conduction system >>>>>decreases the heart rate
and reduces the force of the heart’s contractions,
resulting in a lower demand for oxygen.
* Also prevents sympathetic stimulation of the heart
Nonselective- β Blockers
(propranolol,nadolol,pindolol,timolol
β1 selective – atenolol,metoprolol, acebutolol,
Drugs with reduced CNS effect-atenolol
Partial agonist β –blockers with some intrinsic
sympathomimetic activity-pindolol
β-blocker lacking in local anesthetic effects –Timolol
Mixed α and β blocking activity Carvedilol and
Labetalol
▪ Drugs with some vasodilating action(NO
mediated activity –Nebivolol
▪ β blocker with a very short duration of action-
Esmolol
▪ Acebutolol,Penbutolol,Esmolol- Selective β
blocker with ISA
▪ Pindolol-nonselective β blocker with ISA
 Pharmacotherapeutics
▪ If BP fails to control with β-blockers and diuretics, an
α- blocker, such as prazosin, or a mixed α- and β-
blocker, such as labetalol, may be used
▪ Nonselective α- blockers are of no value in chronic
hypertension because of tachycardia.
▪ If the patient fails to achieve the desired blood
pressure, the physician may add a drug from a
different class, substitute a drug in the same class,
or increase the drug dosage.
▪ Centrally acting sympathophlegics are α 2-
selective agonists (Clonidine and methyldopa) useful
in mild to moderate Hypertension
▪ Trimethaphan is rarely used parenteral agent for the
rapid reduction of severely elevated blood pressure
▪ Selective α1 blocker ( Prazosin, doxazosin and
terazosin) which are used for mild to moderate
hypertension
Nonselective α blocker(phenoxybenzamine
phentolamine,tolazoline), is used for severe
hypertension
▪ β-blockers-Are used as monotherapy for mild
hypertension and as part of polypharmacy for
moderate and severe hypertension
* β blockers may be particularly useful in patients
with angina and those with migraines
*Esmolol is used for hypertensive emergencies and
acute ventricular arrhythmias
Drug Interactions
▪ Carvedilol taken with antidiabetics may
result in increased hypoglycemic effect.
▪ Carvedilol taken with CCB may result in
increased conduction disturbances.
▪ Carvedilol taken with digoxin may result
in increased digoxin levels.
▪ Clonidine plus TCA ay increase blood
pressure.
▪ Clonidine taken with CNS depressants
may worsen CNS depression.
▪ Reserpine taken with diuretics or other
hypotensive agents can increase the
hypotensive effects of reserpine.
▪ Reserpine taken with cardiac glycosides can
lead to cardiac arrhythmias.
▪ Lidocaine toxicity may occur when lidocaine is
taken with beta-adrenergic blockers.
▪ The requirements for insulin and oral
antidiabetics can be altered by β- blockers.
▪ The ability of theophylline to produce
bronchodilation is impaired by nonselective
β blockers.
▪ Antacids reduce absorption of β-blockers.
▪ NSAIDs can decrease the hypotensive effects of β-
adrenergic blockers.
▪ Digoxin and CCB’s can have negative additive
effects on SA or AV node conduction when
administered with a β- blocker.
▪ Diuretics or other hypotensive agents can
potentiate the hypotensive effects of beta-
adrenergic blockers.
Adverse reactions to
sympathoplegics
α-adrenergic blockers Methyldopa
▪ Hypotension ▪ Sedation
▪ salt and water ▪ Bradycardia
retention (Edema ) ▪ Hemolytic anemia -rare
Clonidine- Guanethidine
▪ Sudden cessation may ▪ Fluid retention
cause severe rebound
▪ Orthostatic
hypertension
hypotension
 Reserpine
Guanadrel
▪ diarrhea
▪ Difficulty breathing
▪ Blurred vision
▪ Excessive urination
▪ Bradycardia
▪ Fainting
▪ Bronchoconstriction
▪ Orthostatic
hypotension ▪ Decreased libido
▪ Severe depression
β- blockers
▪ bradycardia ▪ hypotension/dizziness
▪ brochoconstriction ▪ Sexual dysfunction
▪ angina ▪ GI:nausea and
▪ fluid vomiting , diarrhea
retention/peripheral ▪ Suddenly stopping a
edema β- blocker may
▪ heart failure trigger:
▪ AV block - rebound hypertension
 Vasodilators
▪ Direct vasodilators (for severe hypertension) Both
types decrease systolic and diastolic blood pressure.
▪ Direct vasodilators act on arteries, veins, or both.
Hydralazine Minoxidil
Diazoxide Nitroprusside
▪ Hydralazine: release of NO from drug or
endothelium
▪ Minoxidil and Diazoxide-hyperpolarization of
smooth muscle membrane through opening of K+
channels
▪ Hydralazine and minoxidil are usually used orally to
treat resistant or refractory hypertension.
▪ Nitroprusside-Dilates both arterial and venous
vessels resulting in reduced PVR and venous return
MOA- activation of guanylyl cyclase either via release of NO or
by direct stimulation of the enzyme leading to increased cGMP
which relaxes vascular smooth muscle
▪ Parenteral drugs- Diazoxide and nitroprusside are
reserved for use in hypertensive crisis.
▪ Calcium channel blockers ( CCB) produce
arteriolar relaxation by preventing the entry of
calcium into the cells. This prevents the
contraction of vascular smooth muscle.
-CCB for mild to moderate hypertension
Nicardipine and clevidipine- use d for severe
hypertension
▪ Fenoldopam- a peripheral arteriolar dilator
used for hypertensive emergencies and post op
hypertension
MOA-acts as an D1 dopamine agonist resulting in
dilation of peripheral arterioles and natriuresis
used for acute treatment of severe hypertension
-rapidly metabolized primarily by conjugation.
Half-life 10 minutes
-Administered by continuous IV infusion
- Major toxicities- reflex tachycardia, headache,
flushing
Pharmacokinetics
▪ Most of these drugs are absorbed rapidly and
well-distributed.all metabolized in the liver, and
most are excreted by the kidneys.
▪ Hydralazine- orally active and has duration of
action 4-8 hrs
▪ Minoxidil- orally active with duration of action
4-5 hrs
▪ Nitroprusside- is used for IV infusion, releases
NO in the blood, duration of action- few
seconds, rapidly metabolized to cyanide and
thiocyanate
▪ Diazoxide- is used IV , a potassium channel
opener, less used frequently. -duration of action
several hours
▪ Non-DHP CCB’s (verapamil, diltiazem) –L-
type calcium channel blockers with similar
efficacy in depressing cardiac and vascular
smooth muscle.
-orally active , with half lives 6-7 hrs
▪ DHP- CCB’s (nifedipine) produce greater L-
type calcium channel blockade in vessels than
in heart
-orally active with half-lives 6-24 hrs
 Pharmacodynamics
▪ Direct vasodilators relax peripheral vascular
smooth muscle, causing the blood vessels to
dilate,reduces total peripheral resistance,
which lowers blood pressure.
▪ Hydralazine and Nitroprusside- releases NO in
the blood results to vasodilation
▪ Minoxidil and Diazoxide- opens potassium
channel and hyperpolarization
▪ Calcium channel blockers (Verapamil, Diltiazem,
Nifedipine)- block L-type calcium channels
Pharmacotherapeutics

▪ Vasodilating drugs are usually combined

with other drugs to treat the patient with
moderate to severe hypertension
(hypertensive crisis)
▪ Calcium channel blockers ( CCBs )are
occasionally used alone to treat mild to
moderate hypertension with diabetes
 Adverse reactions to direct
vasodilators
▪ Direct vasodilators produce adverse reactions related to
reflex activation of the SNS producing vasoconstriction and
tachycardia.
▪ Hydralazine- tachycardia, edema, reversible lupus
▪ Minoxidil- tachycardia, salt and water retention, hirsutism
▪ Nitroprusside- Hypotension and tachycardia, accumulation of
metabolites cyanide and thiocyanate
▪ Diazoxide- tachycardia, edema, hyperglycemia
▪ Verapamil/Diltiazem- bradycardia, AV block,Heart failure,
constipation, edema
▪ Nifedipine- hypotension, Constipation, edema and rarely
bradycardia, constipation and edema
 Angiotensin antagonists
ACE inhibitors
▪ ACE inhibitors are typically used when β- blockers or
diuretics are ineffective.
▪ Useful as monotherapy in mild and moderate
hypertension, extremely beneficial in heart failure
and diabetes
▪ Commonly prescribed ACE inhibitors include:
benazepril captopril
enalapril trandolapril
fosinopril lisinopril
moexipril quinapril
ramipril.
 Pharmacokinetics
▪ ACE inhibitors are absorbed from the GI tract,
distributed to most body tissues,
metabolized in the liver, and excreted by the
kidneys.
▪ Ramipril is also excreted in stool.
▪ ACE inhibitors may be given once daily even
through their half lives are much shorter (1-2
hrs)
▪ Enalapril is the only ACE inhibitor that is
administered I.V.
Pharmacodynamics
▪ ACE inhibitors reduce BP by interrupting the
renin-angiotensin-aldosterone system.
Review: RAS
▪ Normally, the kidneys maintain blood pressure
by releasing the hormone renin.
▪ Renin acts on the plasma protein
angiotensinogen to form angiotensin I.
Angiotensin I is then converted to angiotensin II.
by ACE
Angiotensin II, a potent vasoconstrictor, increases
peripheral resistance and promotes the secretion
of aldosterone promotes the retention of sodium
and water, increasing the blood volume,
▪ ACE inhibitors block ACE thus reducing the
synthesis of angiotensin II from angiotensin I.
▪ As angiotensin II is reduced, arterioles dilate,
reducing peripheral vascular resistance.
▪ By reducing aldosterone secretion, ACE
inhibitors promote the excretion of sodium
and water, which reduces blood volume,
thereby lowering blood pressure.
▪ ACE inhibitor also inactivate bradykinin a
potent vasodilator peptide
Pharmacotherapeutics
▪ ACE inhibitors may be used alone or
combined with thiazide diuretic, to treat
hypertension
▪ Also be used to treat patients with heart
failure or following MI.
▪ Ramipril is also indicated to prevent major
cardiovascular events in patients with a
history of vascular disease or diabetes.
Drug interactions
▪ All ACE inhibitors enhance the hypotensive
effects of diuretics and other antihypertensives
such β-blockers.
▪ Can also increase serum lithium levels, possibly
resulting in lithium toxicity.
▪ When ACE inhibitors are used with potassium-
sparing diuretics, potassium supplements,
hyperkalemia may occur
▪ . Patients taking ACE inhibitors should avoid
taking NSAIDs which may alter renal function.
▪ Antacids may impair the absorption of fosinopril,
and quinapril
Adverse reactions to ACE
inhibitors
-hypotension
-dry cough due to increased levels of kinins
-angioedema due to increased production of
kinins
-GI reactions
-Hyperkalemia
-Severe renal damage in fetus- contra indicated
in pregnancy (category C and D)
Angiotensin II receptor blockers
▪ Angiotensin II receptor blockers (ARBs) lower BP
by blocking the vasoconstrictive effects of
angiotensin II.
‘Sartans’ :
Candesartan
Eprosartan
Irbesartan
Losartan
Olmesartan
Telmisartan
Valsartan
Pharmacokinetics

▪ ARBs are highly bound to plasma proteins.

▪ ARB’s are orally active and have duration of
action 4-10 hrs
Pharmacodynamics
▪ ARBs -block the binding of angiotensin II type
1 (AT1 receptors in the heart blood
vessels,adrenal cortex and kidneys .
▪ This prevents angiotensin II from exerting its
vasoconstricting properties and from
promoting the excretion of aldosterone
result in lowered blood pressure.
▪ ARBs don’t inhibit the conversion of
angiotensin I to angiotensin II, nor do they
cause a breakdown in bradykinin
Pharmacotherapeutics
▪ ARBs are used in patients who can not tolerate
ACE inhibitors
▪ ARBs may be used alone or in combination with
other drugs such as a diuretic.
▪ Valsartan may also be used as an alternative to
an ACE inhibitor for the management of heart
failure.
▪ Irbesartan and Losartan protect the renal
system, they are often prescribed for patients with
type 2 diabetes.
▪ Losartan is also used to reduce the risk of stroke
in high-risk patients with hypertension and LVH
Drug interactions
▪ When losartan is taken with fluconazole can increase
blood level of losartan leading to hypotension.
▪ NSAIDs reduce the antihypertensive effects of
ARBs.
▪ Rifampin may increase metabolism of losartan and
decrease its antihypertensive effect.
▪ Candesartan may increase blood levels of lithium,
leading to lithium toxicity.
▪ When digoxin is taken with telmisartan, an
increased blood level of digoxin may occur, possibly
leading to digoxin toxicity.
▪ Potassium supplements may increase the risk of
hyperkalemia when used with ARBs.
Adverse reactions to ARBs
▪ Adverse reactions to angiotensin II receptor
blockers (ARBs) :
-headache and fatigue
-less cough
-angioedema
-GI reactions
-increased serum potassium level
- Renal damage in fetus –contraindicated in
pregnancy
Aldosterone antagonists
▪ Spironolactone and Eplerenone
▪ They act in the distal Na+/K+ exchange
accounts for reabasorption of only 2%
filtered sodium
▪ Have marked antihypertensive effect
prolonging the survival of selected patients
with HF and can prevent hypokalemia when
combined with loop diuretics or thiazides
▪ Toxicity- Hyperkalemia
Renin inhibitor

▪ Aliskiren – a selective renin inhibitor is

available for treatment of hypertension
▪ It directly inhibits renin thus acts earlier in the
RAS than ACE inhibitors or ARBS
▪ Toxicity- cough , edema, diarrhea
Drugs used in ischemic heart
disease and CHF
▪ Ischemic heart disease is simply when the
O2 supply of the heart does not match the
demand-this means that coronary blood vessels
have reduced diameter limiting the blood flow to
the heart
▪ Pharmacologically the treatment of coronary
artery disease focuses on the reduction of
myocardial O2 demand
▪ To reduce myocardial O2 demand, β blockers
can be used to decrease HR and contractility
▪ CCB reduce SVR and decrease myocardial
contractility
▪ Nitrates will produce venous dilation which
will decrease preload and decrease O2
demand by the heart
▪ Antiplatelet drugs such as aspirin will
prevent thrombus formation in the coronary
arteries
▪ Lipid lowering drugs have been shown to
reduce the risk of heart attacks in patients
with CAD
▪ Unstable angina is treated with NTG,
antiplatelet and anticoagulant drugs
▪ AMI is treated with thrombolytic agents
▪ CHF occurs when the heart can no longer
pump enough blood to meet the demands of
the body.
▪ Standard treatment of heart failure for
hospitalized patients has been loop diuretics
with a vasodilator that is rapidly acting.
▪ Sometimes a drug that increase contractility
is also added or used in place of the
vasodilator
▪ Treatment of heart failure is targeted
toward:
A. Reduction of cardiac overload
- ACE inhibitors( Captopril,Lisinopril,Enalapril)
- Β blockers
- ARB’s (Angiotensin II receptor blockers)
- Vasodilators ( hydralazine,Nitroprusside)
- NTG
- Nesiritide( recombinanthuman BNP)
B. Control of excess fluids
-Diuretics
C. Enhancement of contractility (Inotropics)
-Sympathomimetics ( Dobutamine and
Dopamine)
-Cardiac glycosides (Digoxin)
-Phosphodiesterase 3- inhibitors (Milrinone
Amrinone)
 Inotropics
▪ Inotropic drugs (cardiac glycosides &
phosphodiesterase (PDE) inhibitors), increase
the force of the heart’s contractions.
▪ The drugs have a positive inotropic effect.
▪ Cardiac glycosides also slow the heart rate
(negative chronotropic effect) and slow
electrical impulse conduction through the
atrioventricular (AV) node (negative
dromotropic effect).
Cardiac glycosides

▪ Cardiac glycosides were isolated from the

Digitalis purpurea plant.
▪ The most frequently used cardiac glycoside is
digoxin and digitoxin
 Pharmacokinetics

▪ The oral elixir and tablet form are absorbed

most efficiently
▪ Digoxin is distributed widely throughout the
body, with highest concentrations in the heart
muscle, liver, and kidneys.
▪ Digoxin binds poorly to plasma proteins.
▪ Most of the drug is excreted by the kidneys as
unchanged drug.
▪ Cardiac glycosides have low therapeutic
index
▪ Digoxin has a long half-life
▪ Avoid giving a loading dose to a patient with
heart failure to avoid toxicity.
Pharmacodynamics
▪ Cardiac glycosides improve myocardial
contractility via inhibition of Na+K+ATPase in
cardiac myocytes and enhance release of
intracellular calcium from the sarcoplasmic
reticulum.
▪ Slow the ventricular rate in atrial flutter-fib by
increasing the sensitivity of the AV node to
vagal stimulation.
Pharmacotherapeutics

▪ Treat heart failure and atrial arrhythmias

▪ Treat supraventricular tachycardia or
paroxysmal atrial tachycardia .
Drug interactions

▪ Antacids, barbiturates, cholestyramine , kaolin

and pectin, neomycin, rifampicin
metoclopramide, and sulfasalazine reduce the
therapeutic effects of digoxin.
▪ Calcium , quinidine, verapamil, cyclosporine,
tetracycline, clarithromycin, propafenone,
amiodarone, spironolactone, erythromycin,
hydroxychloroquine, itraconazole, and
omeprazole increase the risk of digoxin
toxicity.
▪ Amphotericin B, thiazide diuretics, and
steroids taken with digoxin may cause
hypokalemia can increase the risk of digoxin
toxicity.
▪ Succinylcholine and thyroid preparations
increase the risk of arrhythmias when they
are taken with digoxin.
▪ St. John’s wort can increase digoxin levels
and risk of toxicity.
 Adverse reactions to cardiac
glycosides

▪ Adverse reactions to digoxin :

GI disturbances vomiting- earliest sign of
Digitalis toxicity
Rash
Fever
Eosinophilia
Arrhythmias
 Digoxin toxicity
Most common early indicators Gastrointestinal disturbances
of toxicity >>>>>>>>>>>>>>>>> Abdominal pain,Anorexia
Diarrhea .Nausea Vomiting

Cardiac
▪ Bradycardia
▪ Atrial tachycardia
Neurologic
-Yellow-green visual disturbances
▪ Second-degree AV block - Hallucinations -Coma
(Wenckebach) -Confusion -Depression
▪ Sinoatrial arrest or block -Disorientation –Insomnia
▪ Third-degree AV block -Lethargy -Headache
(complete) -Irritability -Seizures
▪ Ventricular arrhythmias -Personality changes
-Restlessness
PDE3 inhibitors

▪ PDE inhibitors are used for parenteral short-

term management of end stage heart failure
who have become tolerant to beta blockers
▪ Specific PDE inhibitors :
inamrinone
milrinone
Pharmacokinetics

▪ Administered I.V., inamrinone is distributed

rapidly, metabolized by the liver, and
excreted by the kidneys.
Milrinone is also administered I.V.
- distributed rapidly and excreted by the
kidneys as unchanged drug.
Pharmacodynamics

▪ PDE inhibitors improve cardiac output by

strengthening contractions.
▪ These drugs move calcium into the cardiac
cell or to increase calcium storage in the
sarcoplasmic reticulum.
▪ By directly relaxing vascular smooth muscle,
they also decrease afterload and preload.
Pharmacotherapeutics
▪ Inamrinone and milrinone are used to
manage refractory heart failure
Adverse reactions to PDE
inhibitors
▪ Adverse reactions to phosphodiesterase (PDE)
inhibitors are uncommon, but increases
significantly when a patient is on prolonged
therapy.
▪ Adverse reactions:
-arrhythmias -nausea and vomiting
-headache -fever
-chest pain -hypokalemia
-thrombocytopenia (especially with
inamrinone)
Drug interactions

▪ PDE inhibitors may interact with

disopyramide, causing hypotension.
▪ Because PDE inhibitors reduce serum
potassium levels, taking them with thiazides
or loop diuretics may lead to hypokalemia
Diuretics

▪ Are useful in almost all cases of HF-reduce

preload and afterload
▪ Loop diuretics –furosemide particularly
effective in acute HF, acute pulmonary edema
and in severe chronic HF
▪ Thiazides- may be adequate in mild HF
▪ Spironolactone- reduce aldosterone effects,
have shown to reduce morbidity and
mortality
Angiotensin Converting
enzyme antagonists
▪ ACE inhibitors (captopril) reduce morbidity and
mortality in patients with severe chronic HF
▪ First line agents along with diuretics in HF used
orally
▪ Angiotensin II antagonists (losartan) are used if
ACE inhibitors are not tolerated
▪ They reduce remodelling and sympathetic
excess in chronic HF
▪ Toxicities- cough, renal damage in fetus in
pregnancy
β- blockers
▪ Carvedilol and metoprolol have shown to
prolong life in chronic HF, used orally
▪ Mechanism in HF unclear, but may involve
reduced renin and angiotensin production
and decrease apoptosis of cardiac cell
▪ Toxicities-may worsen HF, AV blockade,
hypotension and sedation
β agonist and Dopamine
▪ Dobutamine is β-1 selective agonist drug
given parenterally for severe HF
▪ Duration of action short (minutes) –given by
IV infusion
▪ Dopamine- has similar benefits and toxicities
in acute HF, depending upon the dose.
▪ Dopamine and dobutamine increase cardiac
force and reduce afterload resulting in
increase cardiac output
▪ Toxicities- tachycardia, arrhythmias and
angina
Vasodilators
▪ Nitroprusside and Nitroglycerin are administered
IV for acute decompensation in HF
▪ Their duration of action varies from 2-8 hrs
▪ Nesiretide (recombinant natriuretic peptide) –newer
vasodilator that also has natriuresis and diuretic
property, it is a peptide and is used IV in acute HF
▪ Isosorbide dinitrate and hydralazine are
occasionally used in chronic HF
▪ Vasodilators reduce afterload (increasing EF) and
prelaod (reducing myocardial O2 requirement)
▪ Toxicities- all causes tachycardia.Nitrovasodilators-
orthostatic hyopotension, Nitroprusside-thiocyanate
toxicity. Nesiritide- can cause renal damage
Drug interactions

▪ The antihypertensive effects of hydralazine

and minoxidil are increased when they are
given with other antihypertensive drugs, such
as methyldopa or reserpine.
▪ Vasodilating drugs may produce additive
effects when given with nitrates, such as
isosorbide dinitrate or nitroglycerin.
 Antiarrhythmic drugs
▪ Antiarrhythmic drugs are used to treat arrhythmias, (result from
abnormalities of pacemaker activity or cardiac conduction)
▪ Treatment includes electrical devices (pacemakers and
defibrillators, electrical ablation of abnormal cardiac tissue )and
drugs
▪ Many antiarrhythmics are proarrhythmics ( capable of
worsening or causing arrhythmias)
▪ Antiarrhythmics are categorized into four classes (Vaughn-
Williams):
- Class I ( classes IA, IB, and IC ) 1
Phase
0
- Class II
- Class III

Phase o
-50
- Class IV
Phase 4

-100
Absolute RP
Relative RP
Supranormal period
Class I antiarrhythmics
( sodium channel blockers)
▪ Class I agents are subdivided into classes IA, IB,
and IC.
▪ The 3 subgroups of sodium channel blockers are
classified by their effects on action potential
duration
▪ Class I A antiarrhythmics .
Disopyramide
Procainamide
Quinidine
 Pharmacokinetics
▪ Class IA drugs are absorbed and metabolized
after oral administration
▪ Distributed through all body tissues.
▪ Quinidine is the only one that crosses the BBB,
half-life 6 hrs
▪ Procainamide has half-life of 2-4 hrs while
disopyramide has half life of 6-8 hrs
▪ Metabolized in the liver and excreted unchanged
by the kidneys.
▪ Acidic urine increases the excretion of quinidine.
Pharmacodynamics
▪ Class IA antiarrhythmics control arrhythmias by
altering the myocardial cell membrane and
interfering with ANS control of pacemaker cells.
▪ Class IA drugs slow the rate of rise of Phase 0 and
prolong the ERP of the ventricle
▪ ECG- decrease intraventricular conduction ( QRS
duration) and increase duration of the ventricular
AP and ERP ( QT interval)
Pharmacotherapeutics

▪ Class IA antiarrhythmics are prescribed to treat

atrial and ventricular arrhythmias (all-purpose
arrhythmias)
- PVC’s
-ventricular tachycardia
-atrial fibrillation
-atrial flutter
- paroxysmal atrial tachycardia
▪ Quinidine is related to quinine. Both have
antimalarial actions
 Drug interactions
▪ Disopyramide taken with macrolide antibiotics
can prolonged QT interval.
▪ Disopyramide plus verapamil may increase
myocardial depression and should be avoided in
patients with heart failure.
▪ Quinidine increases the risk of digoxin toxicity.
▪ CYP 450 inducers (Rifampin etc) can reduce the
effects of quinidine and disopyramide.
Adverse reactions to class IA
antiarrhythmics
▪ GI symptoms, such as diarrhea, cramping,
nausea, vomiting, anorexia, and a bitter taste.
▪ Induce torsade de pointes (polymorphic VT)
arrhythmias
▪ Quinidine can cause cinchonism (blurred vision,
tinnitus,headache disorrientation,psychosis),
thrombocytopenia and torsade
▪ Procainamide-can cause reversible lupus and
torsade
Class IB antiarrhythmics

▪ Class IB antiarrhythmics are used for treating

acute ventricular arrhythmias.
Lidocaine
Mexiletine- structurally
related to Lidocaine
Phenytoin
Tocainide
Pharmacokinetics

▪ Mexiletine is absorbed from the GI tract after

oral administration metabolized in the liver
and excreted in urine.
▪ Lidocaine is administered I.V.
▪ Lidocaine is distributed widely throughout
the body, including the brain.
▪ Lidocaine and mexiletine are moderately
bound to plasma proteins
Pharmacodynamics
▪ Class IB drugs are highly selective for
abnormal tissue and have little effect on
normal sinus rhythm ECG
▪ Have less of an effect on Phase O, but
decrease the AP duration and refractory
period
▪ Class IB antiarrhythmics especially affect the
Purkinje fibers and myocardial cells in the
ventricles, they are used to treat only
ventricular arrhythmias.
How Lidocaine works:
▪ Lidocaine works in injured or ischemic myocardial cells to
retard sodium influx and restore cardiac rhythm.
▪ When tissue damage occurs in the ventricles, ischemic cells can
create an ectopic pacemaker, which can trigger ventricular
arrhythmias.
▪ Ischemic myocardial cells allow a rapid infusion of sodium ions,
this causes the cells to depolarize much more quickly than
normal and then begin firing spontaneously
ventricular arrhythmia

-Lidocaine raises the cells’ electrical stimulation

threshold (EST) by slowing sodium’s influx
- The increased EST prolongs depolarization in the
ischemic cells and leads to normal sinus rhythm.
Adverse reactions to class IB
antiarrhythmics
▪ Class IB antiarrhythmics are usually the drug of
choice in acute care because they do not produce
immediate serious adverse reactions
▪ Drowsiness, light-headedness, paresthesia,
sensory disturbances, hypotension, and
bradycardia.
▪ Lidocaine toxicity rarely can cause seizures and
respiratory arrest .
▪ Adverse reactions to mexiletine atrioventricular
block, confusion, ataxia, double vision, nausea
and vomiting.
▪ Tocainide can cause pulmonary fibrosis
Pharmacotherapeutics

▪ Class IB antiarrhythmics are used to treat

ventricular ectopic beats, ventricular
tachycardia, and ventricular fibrillation.
Drug interactions

▪ Class IB antiarrhythmics may exhibit additive

or antagonistic effects when administered
with other antiarrhythmics
▪ Rifampicin may reduce the effects of
mexiletine.
▪ Theophylline levels increase when given with
mexiletine.
▪ Use of a β- blocker or disopyramide with
mexiletine may reduce the contractility of the
heart.
Class IC antiarrhythmics

▪ Class IC antiarrhythmics are used to treat

certain severe, refractory (resistant)
ventricular arrhythmias.
flecainide
propafenone
moricizine
Pharmacokinetics
▪ After oral administration, are absorbed well,
distributed in varying degrees, and probably
metabolized by the liver.
▪ Excreted primarily by the kidneys, except for
propafenone, which is excreted primarily in
stool.
▪ Flecainide has half life of 20 hrs
▪ After oral administration, about 38% of
moricizine is absorbed.
▪ Moricizine is highly protein-bound
Pharmacodynamics

▪ Class IC antiarrhythmics slow intraventricular

conduction selectively ( QRS duration)
▪ Class IC have the greatest effect on the early
depolarization and have less effect or no
change in AP duration and on the refractory
period of the ventricle.
▪ Propafenone- exhibit β adrenergic receptor
blockade (Class 2)
Pharmacotherapeutics

▪ Class IC antiarrhythmics are used to treat and

prevent life-threatening ventricular
arrhythmias (chronic ventricular
arrhythmias)
▪ They are also used to treat supraventricular
arrhythmias (Flecainide and propafenone)
▪ Moricizine is used to manage life-threatening
ventricular arrhythmias such as sustained
ventricular tachycardia.
 Drug interactions
▪ Class IC antiarrhythmics may exhibit additive
effects with other antiarrhythmics.
▪ When used with digoxin, increase the risk of
digoxin toxicity.
▪ Propafenone increases plasma concentrations of
warfarin and increases prothrombin times.
▪ Quinidine increases the effects of propafenone.
▪ Cimetidine may increase the plasma level and
the risk of toxicity of moricizine.
▪ Propanolol or digoxin given with moricizine may
increase the PR interval on the ECG
▪ Theophylline levels may be reduced in a patient
receiving moricizine.
▪ Ritonavir increases the plasma concentration
and the effects of propafenone.
▪ Propafenone increases the serum concentration
and the effects of metoprolol and propranolol.
Adverse reactions to Class I C
antiarhhythmics
▪ Development of new arrhythmias and
aggravation of existing arrhythmias.
▪ They are avoided in patients with structural
heart defects because of a high incidence of
mortality.
▪ Because propafenone has beta-blocking
properties, it may cause bronchospasm.
Class II antiarrhythmics
(Beta-blockers)
▪ β-adrenergic blockers used as antiarrhythmics
include:

esmolol
propranolol
metoprolol
timolol
Atenolol
Pharmacokinetics
▪ Propranolol are absorbed almost entirely from
the GI tract after an oral dose.
▪ Esmolol,given only by I.V has low lipid solubility.
▪ Propranolol has high lipid solubility and crosses
the blood-brain barrier.
▪ Propranolol undergoes significant first-pass
effect and distributed to the body.
▪ Esmolol is metabolized exclusively by red blood
cells (RBCs), with only 1% excreted in urine.
▪ Propranolol’s metabolites are excreted in urine.
Pharmacodynamics
▪ Class II antiarrhythmics block beta-adrenergic
receptor sites in the conduction system of the
heart slow AV conduction and therefore
prolong the PR interval
Pharmacotherapeutics

▪ Class II antiarrhythmic are useful in

suppressing the tachyarrhythmias that results
from increased sympathetic activity.
▪ Class II antiarrhythmics slow ventricular rates
in patients with atrial flutter, atrial fibrillation,
and paroxysmal atrial tachycardia.
 Drug interactions
▪ Administering these drugs with other
antihypertensives increases the
antihypertensive effect
▪ When given with NSAID’s, fluid and water
retention may occur
▪ Beta-adrenergic blockers given with verapamil
can depress the heart, causing hypotension,
bradycardia, AV block, and asystole.
▪ The risk of digoxin toxicity increases when
digoxin is taken with esmolol.
Adverse reactions to class II
antiarrhythmics
Common adverse reactions include:
▪ arrhythmias
▪ bradycardia
▪ heart failure
▪ hypotension
▪ GI reactions, such as nausea, vomiting, and
diarrhea
▪ bronchoconstriction
Class III antiarrhythmics
(Potassium channel-blockers
except Ibutilide)
▪ Class III antiarrhythmics are used to treat
ventricular arrhythmias.
Bretylium
Amiodarone – Dronedarone
dofetilide
ibutilide
sotalol
▪ Sotalol is a nonselective β-adrenergic blocker
(class II drug) that also has class III properties.
▪ Although sotalol is a class II drug, its class III
antiarrhythmic effects are more predominant,
especially at higher doses. Therefore, it is usually
listed as a class III antiarrhythmic.
 Pharmacokinetics
▪ Amiodarone is absorbed slowly after oral
administration,distributed extensively and
accumulates in many sites .
-It is highly protein-bound in plasma .. Half life- 40-
60 days
▪ Dofetilide is well absorbed from the GI tract,
70% is bound to plasma proteins.
▪ Ibutilide, which is administered only by I.V.
▪ Sotalol’s absorption is slow and varies between
60% and 100%, with minimal protein-binding.
Pharmacodynamics
▪ Class III antiarrhythmics suppress ventricular
arrhythmias.
▪ It displays class I,II, III and IV antiaarhythmic activity
▪ Class III antiarrhythmics have little or no effect on
phase O, but all prolong the refractory period and
duration of the action potential(Inc QT interval)
▪ Not all Class III drugs block potassium channels.
▪ Ibutilide promotes the influx of sodium through
slow inward sodium channels resulting in
prolongation of the action potential,slowing the
heart rate and conduction through the AVN
Pharmacotherapeutics
▪ Class III antiarrhythmics are used for life-
threatening lifet-hreatening ventricular
arrhythmias.
▪ Amiodarone is the first-line drug of choice
for ventricular tachycardia and ventricular
fibrillation.
▪ Dofetilide is used to convert AF and maintain
on sinus rhythm after cardioversion
▪ Ibutilide is indicated for the conversion of AF-
flutter to normal sinus rhythm
 Drug interactions
▪ Amiodarone increases phenytoin, procainamide,
and quinidine levels and the risk of digoxin
toxicity.
▪ Ibutilide should not be administered within 4
hours of class I or other class III antiarrhythmics
because it increases the potential for a
prolonged refractory period.
▪ Dofetilide should not be administered with CYP
inhibitors drugs because of their potential to
induce life-threatening arrhythmias.
▪ Sotalol should not be administered with
dolasetron or droperidol because of the
increased risk of life-threatening arrhythmias.
▪ Concomitant use of amiodarone and
fluoroquinolones, macrolide antibiotics, and
azole antifungals may cause prolongation of
the QTc interval, leading to torsades de
pointes
▪ Severe hypotension may develop from too-
rapid I.V. administration of amiodarone.
 Adverse reactions to class III
antiarrhythmics
▪ Common adverse effect aggravation of
arrhythmias, hypotension, nausea, and anorexia.
▪ Amiodarone contains iodine hypo or
hyperthyroidism may occur.
(Dronedarone does not contain iodine)
-Severe pulmonary toxicity ( 15% of patients )
-Vision disturbances and corneal microdeposits
▪ Amiodarone and ibultilide or sotalol may cause
sustained VT, prolongation of the QT interval,
hypotension, AV block, bradycardia, ventricular
arrhythmias, bronchospasm, .
Class IV antiarrhythmics

▪ Class IV antiarrhythmics are composed of L-

type calcium channel blockers.
verapamil
diltiazem
▪ Used to treat supraventricular arrhythmias
Pharmacodynamics

▪ Class IV drugs block the slow inward calcium

current during phase 0 and 2 of the cardiac
cycle
▪ By slowing the inward calcium current these
drugs slow AV conduction and prolong the
PR interval
▪ These actions may terminate reentrant
arrhythmias that require AVN for conduction
Pharmacotherapeutics

▪ CCB’s are more effective against atrial the

ventricular arrhythmias
▪ May terminate reentrant arrhythmias
Adverse reactions

▪ Side effects of these drugs are the result of

their other actions such as vasodilation
Adenosine
▪ Adenosine is an injectable
antiarrhythmic indicated for acute
treatment of PSVT.
▪ an AV nodal blocking agent used
to treat paroxysmal
supraventricular tachycardia
Pharmacokinetics

▪ After I.V. administration, adenosine is

probably distributed rapidly throughout the
body.
▪ It is metabolized inside RBCs as well as in
vascular endothelial cells.
Pharmacodynamics

▪ Adenosine depresses the pacemaker activity

of the SA node, reducing the heart rate and
markedly slows and blocks AV conduction
▪ Stimulates α-1receptors which causes a
decrease in cAMP via Gi coupled second
messenger system, increases K+ efflux leading
to increased hyperpolarization, increases RF
in AV node
Pharmacotherapeutics

▪ Adenosine is especially effective against AV

nodal reentry arrhythmias
▪ Adenosine effectively resolves PSVT
▪ It is typically used to treat arrhythmias
associated with accessory bypass tracts, as in
Wolff-Parkinson-White syndrome
▪ Dose: 6 mg rapid IV push followed with NSS
flush. If not effective within 1-2 min give 12
mg repeat dose
Drug interactions

▪ Methylxanthines antagonize the effects of

adenosine
▪ Dipyridamole and carbamazepine potentiate
the effects of adenosine.
▪ When adenosine is administered with
carbamazepine, there’s an increased risk of
heart block.
Adverse reactions to adenosine

Common adverse reactions to adenosine

include:
▪ facial flushing
▪ hypotension
▪ dyspnea
▪ chest pain
Potassium and Magnesium ions

▪ Are useful in arrhythmias caused by digoxin

Antianginal drugs
▪ Angina is recurrent ,crushing pain in the chest
neck, or shoulder and arms that results from
myocardial ischemia caused by coronary blood
flow that is inadequate for the needs of the heart
▪ Although angina’s cardinal symptom is chest
pain, the drugs used to treat angina are not
typically analgesics.
▪ It occurs when O2 demand increases (effort
angina) or when a coronary artery reversibly
constricts (variant angina)
▪ ACS (unstable angina) signals impending MI and
is treated as medical emergency
▪ Antianginal drugs treat angina by reducing
myocardial oxygen demand , by increasing
the supply of oxygen to the heart, or both.
▪ Classes of antianginal drugs :
1.Nitrates
2. β-adrenergic blockers
3.Ca++ channel blockers
4.Na+ channel blocker -Ranolazine
 How antianginal drugs work
▪ Angina occurs when the coronary arteries supply
insufficient oxygen to the myocardium.
▪ This increases the heart’s workload :increasing heart
rate, preload, afterload , and force of myocardial
contractility.
▪ Antianginal drugs relieve angina by decreasing one
or more of these four factors.
-Nitrates (for treating acute angina)
- β-adrenergic blockers (for long-term prevention of
angina)
-Ca++ channel blockers (used when other drugs fail to
prevent angina).
-Na+ channel blocker-Ralonazine most often used in
patients who have failed other antianginal drugs
 Nitrates

▪ Nitrates are the drugs of choice for relieving

acute angina. Nitrates commonly prescribed
to treat angina include:
amyl nitrite
isosorbide dinitrate
isosorbide mononitrate
nitroglycerin
Pharmacokinetics

▪ Nitrates given sublingually, orally or by

inhalation (amyl nitrite) are absorbed almost
completely.
▪ Oral nitrates are absorbed through the
mucous membranes of the GI tract, and only
about one-half of the dose enters circulation.
▪ Transdermal nitrates are absorbed slowly
▪ I.V. nitroglycerin, goes directly into
circulation.
Pharmacodynamics
▪ Nitrates relax vascular smooth muscle by their
intracellular converion to nitrite ions and then to NO
which in turn activates guanylate cyclase and increases
cGMP leading to dephosphorylation of myosin light
chain resulting in vascular smooth relaxation
▪ When the veins dilate, less blood returns to the heart this
reduces the amount of blood in the ventricles at the end
of diastole
▪ By reducing preload, nitrates reduce ventricular size and
ventricular wall tension reduces the O2
requirements of the heart.
▪ Nitrates decrease afterload by dilating the arterioles,
reducing resistance reducing the blood pressure
Pharmacotherapeutics
▪ Nitrates are used to relieve and prevent (effort
and variant) angina.
▪ Nitroglycerin, are the drugs of choice for relief of
acute angina because:
-have a rapid onset of action
- easy to take
-inexpensive.
▪ Long-acting nitrates (NTG, transdermal patch)
are convenient and can be used to prevent
chronic angina.
▪ Oral nitrates are used because they seldom
produce serious adverse reactions
Treatment of angina with
concomittant disease
Drug interactions
▪ Severe hypotension in patients taking alcohol.
▪ PDE5 drugs should not be taken within 24 hours
of nitrate administration because of possible
enhanced hypotensive effects.
▪ Absorption of sublingual nitrates may be delayed
when taken with an anticholinergic drug.
▪ Marked orthostatic hypotension may occur
when CCB’s, antihypertensives, β-blockers, or
phenothiazines and nitrates are used together
Adverse reactions to
nitrates
▪ Headache ( most common adverse reaction)
▪ Orthostatic Hypotension
▪ Reflex Tachycardia
▪ Dizziness
β-adrenergic antagonists
(beta blockers)
▪ β -adrenergic antagonists are used for long-
term prevention of angina.
Atenolol
Metoprolol
Nadolol
Propranolol
Pharmacotherapeutics
▪ β- blockers are indicated for long-term
prevention of angina.
▪ Because of their ability to reduce blood
pressure, β-adrenergic blockers are also first-
line therapy for treating hypertension.
▪ In ACS, metoprolol may be given initially I.V.,
and then orally.
▪ Metoprolol may also be used for heart failure.
Calcium channel blockers
▪ Calcium channel blockers are commonly used to
prevent angina( prophylaxis for effort or variant)
▪ Drug of choice to treat Prinzmetal’s angina.
▪ Also used as antiarrhythmics and to treat
hypertension. Calcium channel blockers used to
treat angina include:
▪ Amlodipine
▪ Nicardipine
▪ Nifedipine
▪ Diltiazem
▪ Verapamil
How calcium channel blockers
work
▪ Calcium channel blockers increase the
myocardial oxygen supply and slow the heart
rate (myocardial depressant).
▪ CCB’s produce these effects by blocking the slow
calcium channel.
▪ This action inhibits the influx of extracellular
calcium ions across both myocardial and vascular
smooth muscle cell membranes.
▪ No calcium dilation
▪ This calcium blockade causes the coronary
arteries to dilate, decreasing afterload and
increasing myocardial oxygen supply
Pharmacokinetics
▪ When administered orally, calcium channel
blockers are absorbed quickly and almost
completely
▪ Because of the first-pass effect,bioavailability
of these drugs is much lower.
▪ highly bound to plasma proteins
▪ metabolized rapidly and almost completely in
the liver.
Pharmacodynamics
▪ Calcium channel blockers prevent the passage of
calcium ions across the myocardial cell membrane
and vascular smooth-muscle cells.
▪ This causes dilation of the coronary and peripheral
arteries, decreases the force of the heart’s
contractions and reduces the workload of the heart.
▪ Also prevent arterioles to constrict reduce the
afterload, further decreases the oxygen demands of
the heart
▪ Diltiazem and Verapamil also reduce the heart rate
by slowing conduction through the SA and AV
nodes.In vasospastic angina, CCB prevent coronary
vasospasm
Pharmacotherapeutics

▪ Calcium channel blockers are used for long-

term prevention of angina only particularly
effective for preventing Prinzmetal’s angina.
Drug interactions
▪ Calcium salts and vitamin D reduce the
effectiveness of calcium channel blockers.
▪ Nondepolarizing blocking drugs may have an
enhanced muscle-relaxant effect when taken
with calcium channel blockers.
▪ Verapamil and diltiazem increase the risk of
digoxin toxicity, enhance the action of
carbamazepine, and may cause myocardial
depression.
 Adverse reactions to
calcium channel blockers
▪ Cardiovascular reactions are the most common
and serious adverse reactions to calcium channel
blockers.
-orthostatic hypotension
-heart failure
-hypotension.
▪ Diltiazem and verapamil can cause bradycardia,
satrioventricular block, dizziness, headache,
flushing, weakness, and persistent peripheral
edema.
Antilipid drugs
▪ Coronary heart disease (CHD) is the leading
cause of death worldwide
▪ CHD is correlated with elevated levels of LDL-C
and TG and low levels of HDL-C
▪ Antilipemic drugs are used in the treatment of
elevated serum lipids are targeted to decrease
production of lipoprotein or cholesterol, increase
degradation of a lipoprotein or increase removal
of cholesterol from the body.
▪ Lipoprotein are proteins that bind and transport
fats such as lipids, triglycerides in the blood.
▪ HDL are often referred to as the “good
cholesterol”
▪ LDL and VLDL are the “bad cholesterol”
The classes of antilipemic drugs :
▪ Bile-sequestering drugs
▪ Fibric acid derivatives
▪ 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors
▪ Nicotinic acid
▪ Cholesterol absorption inhibitors
▪ Drugs are used in combination with lifestyle
changes (such as proper diet, weight
reduction, and exercise) and treatment of an
underlying disorder causing the lipid
abnormality
Bile-sequestering drugs

▪ The bile-sequestering drugs are bile acid

binding resins:
cholestyramine
colestipol
colesevelam
.
Pharmacokinetics
▪ Bile-sequestering drugs are not absorbed
from the GI tract and are not metabolized
▪ Instead, they remain in the intestine, where
they combine with bile acids for about 5
hours.
▪ Eventually, they are excreted in stool.
Pharmacodynamics
▪ Bile-sequestering drugs lower LDL
▪ These drugs are resins nonabsorbable
macromolecules that bind to and prevent
cholesterol and bile acids from the gut
▪ Reduced cholesterol returning to the liver
stimulates the production of more LDL
receptors and increased clearance of LDL
particles.
▪ Resins tend to increase triglycerides
Pharmacotherapeutics
▪ Bile-sequestering drugs are the drugs of
choice for treating familial
hypercholesterolemia when the patient can
not lower his LDL levels through diet alone.
Drug interactions
Drug interactions of bile sequestering drugs :
▪ They may bind with other drugs in the GIT
decrease their absorption and effectiveness.
▪ Bile-sequestering drugs may reduce
absorption of fat-soluble vitamins.
-Poor absorption of vitamin K can affect
prothrombin times significantly, increasing the
risk of bleeding.
 Adverse reactions to bile-
sequestering drugs
▪ Resins have unpleasant gritty taste and
cause GI discomfort bloating and
constipation
▪ More severe reactions can result from long-
term use such as fecal impaction, vomiting,
diarrhea, and hemorrhoid irritation.
▪ Rarely, peptic ulcers and bleeding, gallstones,
and inflammation of the gallbladder may
occur.
Fibric acid derivatives

▪ Fibric acid is produced by several fungi.

▪ Two derivatives of this acid
fenofibrate
gemfibrozil
▪ These drugs are used primarily to reduce high
triglyceride levels and increase HDL levels.
Pharmacokinetics

▪ Fenofibrate and gemfibrozil are absorbed

readily from the GI tract and are highly
protein-bound.
▪ Fenofibrate is hydrolyzed while gemfibrozil
undergoes extensive metabolism in the liver.
▪ Both drugs are excreted in the urine.
Pharmacodynamics
▪ Fibric acid derivatives bind to peroxisome proliferator -
activated receptors (PPAR’s) which increases synthesis of
lipoprotein lipase and other enzymes involved in lipid
metabolism. This leads to:
-reduce cholesterol production early in its formation mobilize
cholesterol from the tissues
-increase cholesterol excretion
- decrease synthesis of triglycerides.
▪ Gemfibrozil produces two other effects:
-It increases high-density lipoprotein (HDL) levels in the
blood ( “good” cholesterol).
-It increases the serum’s capacity to dissolve additional
cholesterol.
▪ Fenofibrate is more effective than Gemfibrosil in lowering
TG levels
Pharmacotherapeutics

▪ Fibric acid drugs are used primarily to reduce

triglyceride levels, and secondarily blood
cholesterol levels.
▪ They are typically used to treat patients with
Type II (Familial hypercholesterolemia),
Type III( Familial dysbetalipoproteinemia),
Type IV (Familial hypertriglyceridemia),
Type V mild (Familial mixed
hypertriglyceridemia)
Drug interactions
▪ Fibric acid drugs may displace acidic drugs, such
as barbiturates, phenytoin, thyroid derivatives,
and cardiac glycosides.
▪ The risk of bleeding increases when fibric acid
derivatives are taken with oral anticoagulants.
▪ The hypoglycemic effects of repaglinide may be
increased and prolonged if taken with
gemfibrozil.
▪ Use of fibric acid derivatives and HMG-CoA
reductase inhibitors may increase the risk of
rhabdomyolysis.
HMG-CoA reductase inhibitors

▪ HMG-CoA-reductase are the first choice drugs

for treatment of most patients with
hypercholesterolemia.
▪ also known as the statins –inhibitors of
cholesterol synthesis.
Atorvastatin Fluvastatin
Lovastatin Pravastatin
Rosuvastatin Simvastatin
Pitavastatin
Pharmacokinetics

▪ Variable absorption (30-85%) of statins

following oral administration
▪ With the exception of pravastatin, all are
highly bound to plasma proteins and undergo
extensive first-pass metabolism.
▪ Excretion takes place principally through the
bile and feces, but some through the urine.
Pharmacodynamics
▪ HMG-CoA reductase inhibitors inhibit the
enzyme responsible for the conversion of HMG-
CoA to mevalonate, an early rate limiting step in
cholesterol synthesis.
▪ By inhibiting de novo cholesterol synthesis, they
deplete the intracellular supply of cholesterol
result in increased production of LDL binding
receptors on liver cells which increase clearance
of LDL particles from the blood stream.
▪ Thus LDL- cholesterol is reduced
▪ Pitavastatin,Atorvastatin and Rosuvastatin are
the most potent LDL-C lowering statins.
Pharmacotherapeutics
▪ Statins are used primarily to reduce LDL
cholesterol and total blood cholesterol levels.
▪ also produce a mild increase in HDL
cholesterol levels.
▪ Statins are used to treat primary
hypercholesterolemia (types IIa and IIb).
▪ these drugs are also used to reduce the risk of
CAD and to prevent MI or stroke in patients
with high cholesterol levels.
Drug interactions
▪ Taking a statin drug with amiodarone,
clarithromycin, cyclosporine, erythromycin,
fluconazole, gemfibrozil, itraconazole,
ketoconazole, or niacin increases the risk of
myopathy or rhabdomyolysis .
▪ Lovastatin, rosuvastatin and simvastatin may
increase the risk of bleeding when administered
with warfarin.
▪ If used in combination with other lipid lowering
drugs,statins should be administered 1 hour
before or 4 hours after the administration of bile-
sequestering drugs or Niacin.
Adverse reactions to HMG-CoA
reductase inhibitors
▪ HMG-CoA reductase inhibitors may alter liver
function studies
▪ Other hepatic effects may include pancreatitis,
hepatitis, and cirrhosis.
▪ Myalgia is the most common musculoskeletal
effect; arthralgia and muscle cramps may also
occur.
▪ Rhabdomyolysis (disintegration of muscle) is
rare severe re reactions may occur
▪ GI reactions -nausea, vomiting, diarrhea,
abdominal pain, flatulence, and constipation is
the most common side effects of statins.
Nicotinic acid
▪ Also known as niacin, nicotinic acid is a
water-soluble vitamin(Vit. B3) that decreases
cholesterol, triglyceride, and apolipoprotein
B-100 levels and increases the HDL level.
▪ At High doses, Niacin strongly inhibits
lipolysis in adipose tissue thereby reducing
production of FFA.
▪ FFA a major precursor for triglyceride
synthesis in the liver.
Pharmacokinetics

▪ Nicotinic acid is rapidly and extensively

absorbed following oral administration.
▪ The drug is available in immediate-release
and extended-release tablets.
▪ moderately bound to plasma protein (60% to
70%)
▪ The drug undergoes rapid metabolism by the
liver to active and inactive metabolites.
▪ About 75% of the drug is excreted in urine.
Pharmacodynamics
▪ The mechanism of action by which nicotinic acid
lowers triglyceride and apolipoprotein levels is
unknown.
▪ it may work by inhibiting hepatic synthesis of
lipoproteins that contain apolipoprotein
B-100, promoting lipoprotein lipase activity,
reducing free fatty acid mobilization from
adipose tissue
▪ At high doses, cause a decrease in the secretion
of VLDL particles from the liver into the blood
and decreased LDL formation
Pharmacotherapeutics
▪ Nicotinic acid is usually used in combination
with other drugs to lower triglyceride levels
in patients with type IV or V hyperlipidemia
who are at high risk for pancreatitis and to
lower cholesterol and LDL levels in patients
with hypercholesterolemia.
▪ It may also be used with other antilipid drugs
to increase HDL levels.
Adverse reactions to nicotinic acid
▪ High doses may produce vasodilation and cause flushing.
▪ To help minimize flushing, administer aspirin 30 minutes
before nicotinic acid
▪ Nicotinic acid can cause hepatotoxicity, hyperuricemia
and glucose intolerance.
▪ Other adverse reactions:nausea, vomiting, diarrhea, and
epigastric or substernal pain.
▪ Nicotinic acid and an HMG-CoA reductase inhibitor may
increase the risk of myopathy or rhabdomyolysis.
▪ Bile-sequestering drugs can bind with nicotinic acid and
decrease its effectiveness.
▪ Nicotinic acid is contraindicated in patients who are
hypersensitive to nicotinic acid and in those with hepatic
dysfunction, active peptic ulcer disease, or arterial
bleeding.
Cholesterol absorption
inhibitors
▪ Cholesterol absorption inhibitors inhibit the
absorption of cholesterol
Ezetimibe –new drug
Pharmacokinetics

▪ Ezetimibe is rapidly and extensively absorbed

following oral administration.
▪ It is readily absorbed and is highly bound to
plasma proteins.
▪ It is primarily metabolized in the small
intestine and excreted by the liver and
kidneys.
Pharmacodynamics

▪ Mechanism is unknown
▪ Ezetimibe reduces blood cholesterol levels by
inhibiting the absorption of cholesterol by the
small intestine by inhibiting sterol
transporter.
▪ This leads to a decrease in delivery of
intestinal cholesterol to the liver, reducing
hepatic cholesterol stores and increasing
clearance from the blood.
Pharmacotherapeutics
▪ Ezetimibe may be administered alone or with
dietary changes to treat primary
hypercholesterolemia .
▪ Used in combination with HMG-CoA
reductase inhibitors to treat primary
hypercholesterolemia and familial
hypercholesterolemia.
▪ Ezetimibe may also help lower total
cholesterol and LDL cholesterol, and increase
HDL cholesterol
Adverse reactions to
cholesterol absorption
inhibitors
The most common adverse reactions include:
▪ Fatigue
▪ abdominal pain and diarrhea
▪ pharyngitis and sinusitis
▪ arthralgia
▪ back pain
▪ cough.
▪ When these drugs are given with an HMG-
CoA reductase inhibitor, the most common
adverse reactions are
chest pain dizziness
headache abdominal pain
diarrhea pharyngitis
sinusitis URTI
arthralgia back pain
myalgia
Drug interactions

▪ Ezetimibe administered with cholestyramine

may lead to decreased effectiveness of
ezetimibe.
▪ Ezetimibe administered with cyclosporine,
fenofibrate, or gemfibrozil leads to increased
levels of ezetimibe.
MAB’s(PCSK9 inhibitors)

▪ Alirocumab, Evolocumab
▪ Are MABs that bind to proprotein convertase
subtilisin /kexin type 9 (PCSK9)
▪ This permits recycling of the LDL receptors
and enhanced clearance of cholesterol in
plasma
▪ These drugs are generally used as an adjunct
to diet and maximal doses of statins
 Pharma Quiz
1.Treatment with fenofibrate, a type of fibric acid derivative,
would have to proceed cautiously if the patient is also
receiving which drug?
A. Penicillin
B. Thiazide diuretic
C. Digoxin
D. Oral anticoagulant
2.A patient is taking lovastatin, an HMG-CoA reductase
inhibitor. Which parameter should the patient monitor
periodically?
A. Liver function test results
B. Electrolyte levels
C. Vision testing
D. Coagulation studies
3. A patient diagnosed with hypertension is most likely to be
prescribed which class of drugs first?
A. Angiotensin II receptor blocker
B. Beta-adrenergic blocker
C. Calcium channel blocker
D. Angiotensin-converting enzyme inhibitor
4. Nitrates are the drug of choice for relieving acute angina.
Nitrates work by:
A. promoting vasodilation, reducing preload, and increasing
afterload.
B. promoting vasodilation, reducing preload, and reducing
afterload.
C. promoting vasodilation, increasing preload, and
increasing afterload.
D. promoting vasodilation, increasing preload, and reducing
afterload.
5. Which arrhythmia can be treated with
lidocaine?
A. Atrial fibrillation
B. Atrial Flutter
C. Ventricular tachycardia
D. Paroxysmal SVT