Cardiovascular system
Antiarrythmics
Classification
Class I: Membrane stabilizing agents:
a. Moderatly decrease dv/dt of 0 phase:
quinidine, procainamide, disopyramide, moricizine
b. Little decrease in dv/dt of 0 phase:
lidocaine, mexiletine
c. Marked decrease in dv/dt of 0 phase:
Propafenone, flecainide
Class II: Antiadrenergic agents: Propranolol, esmolol, sotalol
Class III: Agents widening AP: Amiodarone, bretylium, dofetilide,
ibutilide
Class IV: Calcium channel blockers: Verapamil, diltiazem
Verapamil
Verapamil, in addition to its use as
antiarrhythmic agent, it is employed in management of variant (Prinzmetal’s)
angina and effort-induced angina pectoris. It selectively inhibits
voltage-gated calcium channel that is vital for action potential genesis in slow
response myocytes, such as those found in sinoatrial and A-V nodes.
Electrophysiological
Actions
Sinoatrial
Node: Spontaneous phase 4 depolarization, a characteristic of normal
sinoatrial nodal cells, relies on progressive inhibition of an outward potassium
current and an increase in slow inward current that is carried by Na+ and
Ca+ ions.Verapamil decreases rate of rise and slope of slow
diastolic depolarization, the maximal diastolic potential, and membrane
potential at peak of depolarization in sinoatrial node.
Atrium:
Verapamil fails to exert any significant electrophysiological effects
on atrial muscle.
A-V
Node: Verapamil impairs conduction through A-V node and prolongs A-V
nodal refractory period at plasma concentrations that show no effect on His-
Purkinje system.
The important electrocardiographic change
produced by verapamil is prolongation of PR interval, a response consistent
with known effects of drug on A-V nodal transmission. Verapamil has no effect
on intraatrial and intraventricular conduction. The predominant
electrophysiological effect is on A-V conduction proximal to His bundle.
Hemodynamic
Effects: Usual IV doses of verapamil are not associated with marked
alterations in arterial blood pressure, peripheral vascular resistance, heart
rate, left ventricular end diastolic pressure, or contractility.
Pharmacokinetics
Oral bioavailability 20–35%, Onset of
action 1–2 hours, Peak response 1–2 hours, Duration of action 8–10 hours,
Plasma half-life 2.8–7.4 hours, Primary route of metabolism Hepatic; active,
metabolite, Primary route of excretion Renal (30%, unchanged), and Therapeutic
serum concentration 0.125–0.4 µg /mL
Clinical
Uses
a.
It is useful for slowing the ventricular
response to atrial tachyarrhythmias, such as atrial flutter and fibrillation.
b.
It is also effective in arrhythmias
supported by enhanced automaticity, such as ectopic atrial tachycardia and
idiopathic left ventricular tachycardia.
Adverse
Effects:
Orally administered verapamil is well tolerated by most patients.
Most complaints are of constipation and gastric discomfort. Other complaints
include vertigo, headache, nervousness, and pruritus.
Contraindications
Verapamil must be used with extreme caution
or not at all in patients who are receiving β-adrenoceptor blocking agents.
Normally, negative chronotropic effect of verapamil will in part be overcome by
increase in reflex sympathetic tone. The latter is be prevented by simultaneous
administration of a β-adrenoceptor blocking agent, which exaggerates depressant
effects of verapamil on heart rate, A-V node conduction, and myocardial
contractility. The use in children less than 1 year is controversial.
Antiarrythmics
Arrhythmia is a
disturbance or irregularity in heart rate, rhythm, or both, which requires
administration of one of antiarrhythmic drugs. An arrhythmia may occur as
result of heart disease or from disorder that affects cardiovascular function.
Conditions such as emotional stress, hypoxia, and electrolyte imbalance also
may trigger an arrhythmia.
Quinidine
Quinidine shares all of the pharmacological
properties of quinine, including antimalarial, antipyretic, oxytocic, and
skeletal muscle relaxant actions.
Pharmacological actions:
1. Cardiac
action:-
a.
Automaticity: by inhibiting fast sodium
channel during deplorization, it inhibits upstroke AP and depresses diastolic
deplorization and hence depresses automaticity of ectopic pacemaker tissues.
b.
Excitability: It depresses the excitability
of the cardiac tissue (by increasing the threshold potential) and hence weak
ectopic impulse become ineffective.
c.
Conduction velocity: quinidine slows the
rate of rise of action potential and thus decrease the conduction velocity in
all cardiac tissue (increase ERP, decrease excitability) also contribute to
this.
d.
Refractory period: by depressing potassium
efflux during repolarization, quinidine prolongs repolarization and hence
increase ERP of cardiac tissue. Thus it avoids reentry early or delay after
depolarization.
e.
Contractility: it has calcium channel
blockade property and hence has negative inotropic effect.
f.
ECG effect: increase Q-T interval, decrease
in amplitude or inversion of T-wave and depression of ST segment.
2. Extracardiac
action: alpha adrenergic property decreases blood pressure, anticholinergic
property and possess anti-malaraial activity lesser than quinine.
Pharmacokinetics:
Oral bioavailability Almost complete
absorption, Onset of action 1–3 hours,
Peak response 1–2 hours, Duration of action 6–8 hours, Plasma half-life 6
hours, Primary route of Hepatic; active metabolite, metabolism Primary route of
10–50% renal (unchanged), excretion, Therapeutic serum 2–4 µg /mL concentration
Clinical Uses
(1)
abolition of premature complexes that have
an atrial, A-V junctional, or ventricular origin;
(2)
restoration of normal sinus rhythm in
atrial flutter and atrial fibrillation after controlling ventricular rate with
digitalis;
(3)
maintenance of normal sinus rhythm after
electrical conversion of atrial arrhythmias;
(4)
prophylaxis against arrhythmias associated
with electrical countershock;
(5)
termination of ventricular tachycardia; and
(6)
Suppression of repetitive tachycardia associated
with Wolff-Parkinson-White (WPW) syndrome.
Adverse Effects
Diarrhea, upper gastrointestinal distress, and light-headedness.
Other common effects include fatigue, palpitations, headache, anginalike pain,
and rash. These effects are dose related and reversible with cessation of
therapy. In some patients, quinidine administration may bring on
thrombocytopenia due to formation of a plasma protein–quinidine complex that
evokes a circulating antibody directed against blood platelet.
Large doses of quinidine can produce a syndrome known as cinchonism,
characterized by ringing in ears, headache, nausea, visual disturbances or
blurred vision, disturbed auditory acuity, and vertigo.
Larger doses can produce confusion, delirium, hallucinations, or
psychoses.Quinidine can decrease blood glucose concentrations, possibly by
inducing insulin secretion.
Contraindications:
complete A-V block with an A-V pacemaker or idioventricular
pacemaker; this may be suppressed by quinidine, leading to cardiac arrest.
Persons with congenital QT prolongation may develop torsades de pointes
tachyarrhythmia and should not be exposed to quinidine.
Owing to negative inotropic action of quinidine, it is
contraindicated in congestive heart failure and hypotension. Digitalis intoxication
and hyperkalemia can accentuate depression of conduction caused by quinidine.
Myasthenia gravis can be aggravated severely by quinidine’s
actions at neuromuscular junction. The use of quinidine and quinine should be
avoided in patients who previously showed evidence of quinidine-induced
thrombocytopenia.
Drug
Interactions:
Quinidine can increase plasma
concentrations of digoxin, which may in turn lead to signs and symptoms of
digitalis toxicity.
Gastrointestinal, CNS, or cardiac toxicity
associated with elevated digoxin concentrations may occur.
Drugs that have been associated with
elevations in quinidine concentrations include acetazolamide, antacids
magnesium hydroxide and calcium carbonate, and H2-receptor
antagonist cimetidine. Cimetidine inhibits hepatic metabolism of quinidine.
Phenytoin, rifampin, and barbiturates
increase hepatic metabolism of quinidine and reduce its plasma concentrations.
Congestive
cardiac failure
Congestive heart failure (CHF), a condition
in which the heart cannot pump enough blood to meet the tissue needs of body.
While the term “congestive heart failure” continues to be used by some, a more
accurate term is simply “heart failure.”
Mechanism of action of digoxin:
Refer Q. No. 3 (5 marks)
Anti-hypertensive
Classification
1. Drugs
acting centrally
a.
Alpha2 adrenergic receptor stimulants: clonidine,
methyldopa
b.
Selective imidazole receptor stimulants: moxonidine
2. Drugs
acting on the autonomic ganglia: Ganglia blocking agents: trimethaphan
3. Drugs
acting on the postganglionic sympathetic nerve endings
a.
Adrenergic neurone blockers: guanethidine, bethanidine,
debrisoquine, bretylium
b.
Catecholamine depletors: reserpine
4. Drugs
acting on adrenergic receptors
a.
Alpha-adrenergic blocking agents; Phentolamine,
phenoxybenzamine, prazosin, indoramin,
b.
Beta-adrenergic blocking agents: propronolol, atenolol,
metoprolol
c.
Both alpha and beta adrenergic blocking drugs:
labetolol
5. Drugs
acting directly on vascular smooth muscle:
a.
Arteriolar vasodilators: calcium channel blockers,
hydralazine, dizoxide, minoxidil
b.
Arteriolar-venular vasodilators: sodium nitroprusside
6. Potassium
channel activators: diazoxide, minoxidil, pincidil, nicorandil
7. Drugs
which block rennin-angiotensin aldosterone axis
a.
Those which block rennin release: beta-adrenergic
blockers
b.
Those which block conversion of angiotensin I to II by
inhibiting ACE: captopril, enalapril
c.
Those which competitively blocker angiotensin II at
vascular receptor sitesL Losartan
d.
Those which counter the action of aldosterone:
spinolactone
8. Oral
diuretics: Thiazides
9. Misc:
metyrosine
Phenoxybenzamine
binds covalently to α-receptors, causing
irreversible blockade of long duration (14–48 hours or longer). Selective for α1 receptors but less than prazosin.
The drug also inhibits reuptake of released norepinephrine by presynaptic
adrenergic nerve terminals. It blocks histamine (H1), acetylcholine,
and serotonin receptors as well as α-receptors.
Pharmacologic actions: It is related to antagonism of α-receptor–mediated events. It attenuates
catecholamine-induced vasoconstriction. While phenoxybenzamine causes
relatively little fall in blood pressure in normal supine individuals, it
reduces blood pressure when sympathetic tone is high, eg, as a result of
upright posture or because of reduced blood volume. Cardiac output may be
increased because of reflex effects and because of some blockade of presynaptic
α2 receptors in cardiac
sympathetic nerves.
Absorbed after oral administration, bioavailability is
low and its kinetic properties are not well known. The drug is usually given
orally, starting with low doses of 10–20 mg/d and progressively increasing the
dose until desired effect is achieved. A dosage of less than 100 mg/d is
sufficient to achieve adequate α-receptor
blockade.
The major use of nonselective agents, phenoxybenzamine is
in treatment of pheochromocytoma and in other clinical situations associated
with exaggerated release of catecholamines.
Adverse effects are postural hypotension and tachycardia.
Nasal stuffiness and inhibition of ejaculation also occur. It enters central
nervous system, it may cause less specific effects, including fatigue,
sedation, and nausea.
ACE inhibitors
Captopril
is first such agent to be developed for treatment of hypertension. Many
of the orally active ACE inhibitors are prodrugs. These include perindopril,
quinapril, benazepril, ramipril,
lisinopril,moexipril, enalapril, trandolapril, and fosinopril. These
drugs have proven to be very useful for treatment of hypertension because of
their efficacy and their very favorable profile of adverse effects, which
enhances patient adherence.
Mechanism
of action
ACE inhibitors may prevent (or inhibit)
activity of angiotensin-converting enzyme, which converts angiotensin I
to angiotensin II, a powerful vasoconstrictor. Both angiotensin I and ACE are endogenous
substances. The vasoconstricting activity of angiotensin II stimulates
secretion of endogenous hormone aldosterone by adrenal cortex. Aldosterone promotes
retention of sodium and water, which may cause rise in blood pressure. By
preventing conversion of angiotensin I to angiotensin II, this chain of events
is interrupted, sodium and water are not retained, and blood pressure
decreases. The angiotensin II receptor antagonists act to block vasoconstrictor
and aldosterone effects of angiotensin II at various receptor sites, resulting
in lowering of blood pressure.
Captopril
It is an orally effective ACE inhibitor with
sulfhydryl moiety that is used in binding to active site of enzyme. Captopril
blocks blood pressure responses caused by administration of angiotensin-I and
decreases plasma and tissue levels of angiotensin-II.
Pharmacological
Actions
·
Treatment with captopril reduces blood
pressure in patients with renovascular disease and in patients with essential
hypertension.The decrease in arterial pressure is related to reduction in total
peripheral resistance.
·
Pharmacological effects of captopril are
attributable to the inhibition of angiotensin II synthesis. However, ACE is
relatively nonselective enzyme that also catabolizes a family of kinins to
inactive products. Bradykinin, acts as a vasodilator through mechanisms related
to production of nitric oxide and prostacyclin by vascular endothelium.
·
ACE inhibitor captopril prevents breakdown
of bradykinin.
·
Increases in bradykinin concentrations
after administration of ACE inhibitors contribute to therapeutic efficacy of
these compounds in treatment of hypertension and CHF.
·
The hypotensive response to captopril is
accompanied by fall in plasma aldosterone and angiotensin II levels and
increase in plasma renin activity.
·
Serum potassium levels are not affected
unless potassium supplements or potassium-sparing diuretics are used
concomitantly; results in severe hyperkalemia.
·
There is no baroreflex-associated increase
in heart rate, cardiac output, or myocardial contractility in response to the
decrease in pressure, because captopril decreases sensitivity of baroreceptor
reflex.
·
Captopril enhances cardiac output in
patients with congestive heart failure by inducing reduction in ventricular
afterload and preload.
·
Converting enzyme inhibitors decrease mass
and wall thickness of left ventricle in both normal and hypertrophied
myocardium.
·
ACE inhibitors lack metabolic side effects
and do not alter serum lipids.
Pharmacokinetics
The onset of action following oral administration of is about 15
minutes, with peak blood levels achieved in 30 to 60 minutes. Its apparent
biological half-life is approximately 2 hours, with its antihypertensive
effects observed for 6 to 10 hours. The kidneys play major role in inactivation
of captopril.
Clinical Uses
d. Captopril,
as well as other ACE inhibitors, is indicated in treatment of hypertension,
congestive heart failure, left ventricular dysfunction after myocardial
infarction, and diabetic nephropathy.
e. In
treatment of essential hypertension, captopril is considered first choice
therapy, either alone or in combination with thiazide diuretic because
thiazide-induced hypokalemia is minimized in presence of ACE inhibition, since
there is marked decrease in angiotensin II–induced aldosterone release.
Decreases in blood pressure are primarily attributed to decreased total peripheral
resistance or afterload.
f. It
can be used as monotherapy in treatment of congestive heart failure.
g. In
treatment of diabetic nephropathy associated with type I insulin-dependent
diabetes mellitus, captopril decreases rate of progression of renal insufficiency
and retards worsening of renal function.
Adverse
Actions
Approximately 10% of patients report dose-related maculopapular
rash that often disappears when dosage is reduced. Others are fever, persistent
dry cough, initial dose hypotension, and loss of taste that may result in
anorexia. These effects are reversed when drug therapy is discontinued. Serious
toxicities include proteinuria and glomerulonephritis; less common are
leukopenia and agranulocytosis.
Contraindications
Food reduces bioavailability of captopril by 30 to 40%,
administration of drug an hour before meals is recommended. All converting
enzyme inhibitors are contraindicated in patients with bilateral renal artery
disease or with unilateral renal artery disease and one kidney. Use under these
circumstances may result in renal failure or paradoxical malignant
hypertension.
Anti-anginals
Angina
is a disorder characterized by atherosclerotic plaque formation in
coronary arteries, which causes decreased oxygen supply to the heart muscle and
results in chest pain or pressure. Any activity that increases workload of
heart, such as exercise or simply climbing stairs, can precipitate an angina
attack.
Antianginal
drugs relieve chest pain or pressure by dilating coronary arteries, increasing
blood supply to the myocardium.
Classification
1.
Nitrates:
a. Short acting: Glyceryl trinitrate
b. Long acting: isosorbide mononitrate,
isosorbide dinitrate, Erythrityl tetranitrate, pentaerithrityl tetranitrate,
2.
Beta-blockers:
propranolol, metoprolol, atenolol,
3.
Potassium
channel openers: Nicorandil
4.
Calcium
channel blockers:
a. Phenyl alkylamine: verapamil
b. Benzothiazepine: diltiazem
c. Dihydro puridines: Nifedipine, amlodipine,
felodipine, nitrendipine, nimodipine
5.
Others:
dipyridamole, trimetazidine, oxyphedrine, ranolazine
Cardiotonics
Cardiac glycosides are used in treatment
of heart failure have been attributed to a positive inotropic effect on failing
myocardium and efficacy in controlling ventricular rate response to atrial
fibrillation. Cardiac glycosides also modulate autonomic nervous system
activity, and this mechanism contributes substantially to their efficacy in
management of heart failure.
Mechanisms of Action: Inhibition
of Na+,K+-ATPase. All cardiac glycosides are
potent and highly selective inhibitors of active transport of Na+
and K+ across cell membranes. This biological effect is accomplished
by binding to a specific site on α subunit of Na+,K+-ATPase,
the cellular Na+ pump. The binding of cardiac glycosides to Na+,K+-ATPase
and inhibition of cellular ion pump is reversible and entropically driven.
Mechanism of Positive Inotropic Effect: Both Na+ and Ca2+ ions enter cardiac muscle cells during each depolarization. Ca2+ that enters cell via L-type Ca2+ channel during depolarization triggers release of stored intracellular Ca2+ into cytosol from sarcoplasmic reticulum via ryanodine receptor. This Ca2+-induced Ca2+ release increases level of cytosolic Ca2+ available to interact with contractile proteins, thereby increasing force of contraction. During myocyte repolarization and relaxation, cellular Ca2+ is re-sequestered by sarcoplasmic reticular Ca2+-ATPase, and is removed from cell by Na+-Ca2+ exchanger and by sarcolemmal Ca2+-ATPase.
Schematic diagram of Mechanism of action of digoxin is
shown below
Pharmacological
Actions
a.
Cardiac glycosides
increase contraction of cardiac sarcomere by increasing free calcium
concentration in vicinity of contractile proteins during systole.
b.
The increase in
calcium concentration is result of a two-step process: first, an increase of
intracellular sodium concentration because of Na+/K+
ATPase inhibition; and second, reduction of calcium expulsion from cell by
sodium-calcium exchanger caused by increase in intracellular sodium.
d.
The net result of
action of therapeutic concentrations of cardiac glycoside is distinctive
increase in cardiac contractility.
e.
In isolated
myocardial preparations, the rate of development of tension and of relaxation
is increased, with little or no change in time to peak tension. This effect
occurs in both normal and failing myocardium, but in animal or patient, the
responses are modified by cardiovascular reflexes and pathophysiology of heart
failure.
ii.
Electrical
Effects
a.
The effects of digitalis
on electrical properties of heart are mixture of direct and autonomic actions.
b.
Direct actions on
membranes of cardiac cells follow a well-defined progression: prolongation of action potential, followed by
shortening (especially the plateau phase). The decrease in action potential
duration is result of increased potassium conductance caused by increased
intracellular calcium.
c.
Effects of Digoxin on Electrical Properties of
Cardiac Tissues.
|
Tissue or Variable
|
Effects at Therapeutic
Dosage
|
Effects at Toxic Dosage
|
|
Sinus node
|
↓ Rate
|
↓ Rate
|
|
Atrial muscle
|
↓ Refractory period
|
↓ Refractory period, arrhythmias
|
|
Atrioventricular node
|
↓ Conduction velocity,
↑refractory period
|
↑Refractory period, arrhythmias
|
|
Purkinje system, ventricular muscle
|
Slight ↓ refractory period
|
Extrasystoles, tachycardia, fibrillation
|
|
Electrocardiogram
|
↑ PR interval, ↓ QT interval
|
Tachycardia, fibrillation, arrest at
extremely high dosage
|
d.
At higher concentrations, resting membrane
potential is reduced (made less negative) as a result of inhibition of sodium
pump and reduced intracellular potassium.
e.
As toxicity
progresses, oscillatory depolarizing after potentials appear following normally
evoked action potentials. The afterpotentials (also known as delayed
afterdepolarizations, DADs) are associated with overloading of
intracellular calcium stores and oscillations in free intracellular calcium ion
concentration.
f.
When afterpotentials
reach threshold, they elicit action potentials (premature depolarizations or
ectopic "beats") that are coupled to preceding normal action
potentials.
g.
If afterpotentials
in Purkinje conducting system regularly reach threshold in this way, bigeminy
will be recorded on electrocardiogram.
h.
With further
intoxication, each afterpotential-evoked action potential will itself elicit a
supra threshold afterpotential, and self-sustaining tachycardia will be
established. If allowed to progress, such a tachycardia may deteriorate into
fibrillation; in case of ventricular fibrillation, arrhythmia will be rapidly
fatal unless corrected.
2.
Autonomic actions of
cardiac glycosides on heart involve both parasympathetic and the sympathetic
systems.
a.
In lower portion of
dose range, cardioselective parasympathomimetic effects predominate. In fact,
these atropine-blockable effects account for significant portion of early
electrical effects of digitalis.
b.
This action involves
sensitization of baroreceptors, central vagal stimulation, and facilitation of
muscarinic transmission at cardiac muscle cell.
c.
Because cholinergic
innervation is much richer in atria, these actions affect atrial and atrioventricular
nodal function more than Purkinje or ventricular function.
d.
Some cholinomimetic
effects are useful in treatment of certain arrhythmias. At toxic levels,
sympathetic outflow is increased by digitalis.
e.
This effect is not
essential for typical digitalis toxicity but sensitizes myocardium and
exaggerates all toxic effects of drug.
f.
The most common
cardiac manifestations of digitalis toxicity include atrioventricular
junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, and
second-degree atrioventricular blockade. However, it is claimed that digitalis
can cause virtually any arrhythmia.
Cardiac glycosides affect all excitable tissues,
including smooth muscle and central nervous system. The gastrointestinal tract
is most common site of digitalis toxicity outside heart. The effects include
anorexia, nausea, vomiting, and diarrhea. This toxicity may be partially caused
by direct effects on gastrointestinal tract but is result of CNS actions.
Central nervous system effects include vagal and
chemoreceptor trigger zone stimulation. Less often, disorientation and
hallucinations—in elders—and visual disturbances are noted. The latter effect
may include aberrations of color perception. Gynecomastia is a rare effect reported
in men taking digitalis.
Absorption and
Distribution
Digoxin is absorbed 65–80% after oral administration.
Absorption of other glycosides varies from zero to nearly 100%. Once present in
blood, all cardiac glycosides are widely distributed to tissues, including CNS.
Digoxin is not extensively metabolized in humans; almost
two thirds is excreted unchanged by kidneys. Its renal clearance is
proportionate to creatinine clearance.
USES
a. Digoxin therapy is indicated in patients with severe
left ventricular systolic dysfunction after initation of diuretic and
vasodilatation therapy. Digoxin is not indicated in patients with diastolic or
right-sided hear failure.
b.
Paroxysmal supraventriular tachycardia: it is common arrhythmia due to recentry phenomenon
taking place at SA or AV node. They frequently respond to digitalis, because of
reflex vagal activation which slows conduction of impulses.
c.
Congestive heart failure: digitalis is a drug of choice for low output heart
failure due to HT, IHD, or arrhythmias.
d.
Dilated heart: digitalis is preferred drug for patient having
dilated heart and low ejection fractionas it is helpful in restoring cardiac
compensation.
e.
It is used
to treat HF and atrial fibrillation. Atrial
fibrillation is cardiac arrhythmia characterized by rapid contractions
of atrial myocardium, resulting in an irregular and often rapid ventricular
rate.
Adverse
Actions
Cardiac side effects: include bradycardia, partial or complete
heart block, atrial or ventricular extrasystoles, coupled beats, ventricular
fibrillation and fatal cardia arrhythmias.
Extra cardiac side effects:
GIT: anorexia, nausea, vomiting, diarrhea, and abdominal cramps.
CNS: headache, fatigue, neuralgia, blurred vision, loss of color
perception.
Endocrinal: gyanecomastia in males.
CONTRAINDICATIONS
It is contraindicated in patients with known hypersensitivity,
ventricular failure, ventricular tachycardia, or AV block and in the presence
of digitalis toxicity.
PRECAUTIONS
Given cautiously in patients with electrolyte imbalance
(especially hypokalemia, hypocalcemia, and hypomagnesemia), severe carditis,
heart block, myocardial infarction, severe pulmonary disease, acute
glomerulonephritis, and impaired renal or hepatic function.
Organic
nitrates
Mechanism
of Vasodilator Action-It involves interaction with nitrate
receptors, present in vascular smooth muscle. The nitrate receptor possesses
sulfhydryl groups, which reduce nitrate to inorganic nitrite and nitric oxide
(NO). The formation of nitrosothiols, and free NO, has been proposed to
stimulate intracellular soluble guanylate cyclase, which leads to increase in
intracellular cyclic guanosine monophosphate formation. The increase in GMP
results in vascular smooth muscle relaxation, through inhibition of calcium
entry via L-type calcium channels, decreased calcium release from sarcoplasmic
reticulum, or via increase in calcium extrusion via sarcolemmal Ca2+ ATPase.
Schematic diagram of Mechanism of action of nitro-vasodilators is
shown below
i.
Angina: Diseases that predispose to angina
should be treated as part of a comprehensive therapeutic program with a goal to
prolong life. Conditions such as hypertension, anemia, thyrotoxicosis, obesity,
heart failure, cardiac arrhythmias, and acute anxiety can precipitate anginal
symptoms in many patients. The patient should be asked to stop smoking and
overeating; hypertension and hyperlipidemia should be corrected.
ii.
Sublingual Administration. Because of its
rapid action, long-established efficacy, and low cost, nitroglycerin given
sublingually is useful drug. The onset of action is within 1 to 2 minutes, but
effects are undetectable by 1 hour after administration. An initial dose of 0.3
mg nitroglycerin often relieves pain within 3 minutes.
iii.
Oral Administration. Oral nitrates often
are used to provide prophylaxis against anginal episodes in patients who have
more than occasional angina. They must be given in sufficient dosage to provide
effective plasma levels after first-pass hepatic degradation.
iv.
Cutaneous Administration. Application of
nitroglycerin ointment can relieve angina, prolong exercise capacity, and
reduce ischemic ST-segment depression with exercise for 4 hours or more.
v.
Transmucosal or Buccal Nitroglycerin.
This formulation is inserted under upper lip above incisors, where it adheres
to gingiva and dissolves gradually. Hemodynamic effects are seen within 2 to 5
minutes, and it is therefore useful for short-term prophylaxis of angina.
vi.
Congestive Heart Failure. The utility of
nitrovasodilators to relieve pulmonary congestion and to increase cardiac
output in congestive heart failure.
vii.
Unstable Angina Pectoris and
Non-ST-Segment-Elevation Myocardial Infarction. The term unstable angina
pectoris characterized by an acute or subacute worsening in a patient's
anginal symptoms. Along with nitrates and β adrenergic receptor antagonists,
antiplatelet agents are used in therapy for acute coronary syndrome. Nitrates
are useful both in reducing vasospasm and in reducing myocardial oxygen
consumption by decreasing ventricular wall stress. Intravenous administration
of nitroglycerin allows high concentrations of drug to be attained rapidly.
viii.
Acute Myocardial Infarction Nitroglycerin is
administered to relieve ischemic pain in patients presenting with MI, but
evidence that nitrates improve mortality in MI is sparse. Because they reduce
ventricular preload through vasodilation, nitrates are effective in relief of
pulmonary congestion.
ix.
Variant (Prinzmetal) Angina: Long-acting
nitrates alone are occasionally efficacious in abolishing episodes of variant
angina, additional therapy with Ca2+ channel blockers is required.
Clonidine
Mechanisms of Action-These
agents reduce sympathetic outflow from vasopressor centers in brainstem but
allow these centers to retain or even increase their sensitivity to
baroreceptor control. Accordingly, the antihypertensive and toxic actions of
these drugs are less dependent on posture than are effects of drugs that act
directly on peripheral sympathetic neurons.
Pharmacological
Actions
a. An
acute intravenous injection of clonidine may produce transient pressor response
due to stimulation of peripheral vascular α-receptors. The pressor response
does not occur after oral administration, because drug’s centrally mediated
depressor action overrides it.
b.
The decrease in blood pressure produced by
clonidine correlates better with
decreased cardiac output than with reduction in peripheral vascular
resistance. The reduction in cardiac output is result of both decreased heart
rate and reduced stroke work; the latter effect is probably caused by
diminished venous return.
c.
Renal blood flow and glomerular filtration
are not decreased, although renal resistance is diminished. Like α-methyldopa,
it is useful agent for hypertension complicated by renal disease.
d. Plasma
renin activity is reduced by clonidine, presumably as a result of a centrally
mediated decrease in sympathetic stimulation of juxtaglomerular cells of
kidney.
Clinical Uses
a.
In mild and moderate hypertension that has
not responded adequately to treatment with a diuretic or a β-blocker.
b.
A vasodilator can be added to
clonidine–diuretic regimen in treatment of resistant forms of hypertension.
Such drug combinations can be quite effective, since reflex increases in heart
rate and cardiac output that result from vasodilator administration are reduced
or negated by clonidine-induced decreases in heart rate and cardiac output.
c.
It is useful in patients with renal
failure, since its duration of action is not altered by renal disease and it
does not compromise renal blood flow.
d.
To control diarrhea in diabetic patients
with autonomic neuropathy- Stimulation of a2 receptors in GIT
may increase absorption of sodium chloride and fluid and inhibit secretion of
bicarbonate.
e.
Used in differential diagnosis of patients with
hypertension and suspected pheochromocytoma.
f.
Useful in selected patients receiving anesthesia
because it may decrease the requirement for anesthetic and increase hemodynamic
stability
g.
Clonidine also is useful in treating and preparing
addicted subjects for withdrawal from narcotics, alcohol, and tobacco.
h.
Clonidine may help ameliorate some of the adverse
sympathetic nervous activity associated with withdrawal from these agents, as
well as decrease craving for the drug.
Absorption, Metabolism, and Excretion
Well absorbed after oral administration. Peak plasma levels occur
between 2 and 4 hours after drug administration and correlate well with
pharmacological activity.The plasma half-life in patients with normal renal
function is 12 hours. Urinary excretion of clonidine and its metabolites
accounts for almost 90% of administered dose, and fecal excretion accounts for
the rest. Approximately 50% of administered dose is excreted unchanged;
remainder is oxidatively metabolized in liver.
The major adverse effects are dry mouth and sedation. These
responses occur in 50% of patients and require drug discontinuation. Sexual
dysfunction also may occur. Marked bradycardia occur in some patients. Other
adverse effects are related to dose, and their incidence may be lower with
transdermal administration, since antihypertensive efficacy may be achieved
while avoiding high peak concentrations that occur after given orally. About
15% to 20% of patients develop contact dermatitis when using clonidine in
transdermal system. Withdrawal reactions
follow abrupt discontinuation of long-term therapy with clonidine in some
hypertensive patients.
Vasopressin
Vasopressin (Antidiuretic Hormone, ADH) is a
peptide hormone released by the posterior pituitary in response to rising
plasma tonicity or falling blood pressure. Vasopressin possesses antidiuretic
and vasopressor properties. A deficiency of this hormone results in diabetes
insipidus.
Pharmacological actions
Cardiovascular
System Vasopressin is a potent vasoconstrictor (V1-receptor-mediated),
and resistance vessels throughout circulation may be affected. Vascular smooth
muscle in skin, skeletal muscle, fat, pancreas, and thyroid gland appear most
sensitive, with significant vasoconstriction also occurs in GIT, coronary
vessels, and brain. Despite the potency of vasopressin as direct
vasoconstrictor, vasopressin-induced pressor responses in vivo are
minimal and occur only with vasopressin concentrations significantly higher
than those required for maximal antidiuresis. To a large extent, this is due to
circulating vasopressin actions on V1 receptors to inhibit
sympathetic efferents and potentiate baroreflexes. In addition, V2
receptors cause vasodilatation.
Blood
Coagulation. Activation of V2 receptors by vasopressin
increases circulating levels of procoagulant factor VIII and of von Willebrand
factor. These effects are mediated by extra-renal V2 receptors.
Vasopressin stimulates secretion of von Willebrand factor and of factor VIII
from storage sites in vascular endothelium.
Central
Nervous System: Vasopressin plays a role as neurotransmitter and/or
neuromodulator. Vasopressin may participate in acquisition of learned
behaviors, and in pathogenesis of psychiatric diseases such as depression. Vasopressin can modulate CNS autonomic
systems controlling heart rate, arterial blood pressure, respiration rate, and
sleep patterns, the physiological significance of these actions is unclear.
Finally, secretion of ACTH is enhanced by vasopressin released from
parvicellular neurons in PVN and secreted into pituitary portal capillaries
from axon terminals in median eminence. Vasopressin is not principal corticotropin-releasing
factor, vasopressin may provide for sustained activation of
hypothalamic-pituitary-adrenal axis during chronic stress. The CNS effects are
mediated predominantly by V1 receptors.
Renal
Actions of Vasopressin: V1 receptors mediate contraction of
mesangial cells in glomerulus and contraction of vascular smooth muscle cells
in vasa recta and efferent arteriole. V1 receptors also stimulate
prostaglandin synthesis by medullary interstitial cells. Since prostaglandin E2
inhibits adenylyl cyclase in collecting duct, stimulation of prostaglandin
synthesis by V1 receptors may counterbalance V2-receptor-mediated
antidiuresis. V1 receptors on principal cells in cortical collecting
duct may inhibit V2-receptor-mediated water flux via
activation of protein kinase C. V2 receptors mediate prominent
response to vasopressin, i.e., increased water permeability of
collecting duct.
Nonrenal Actions of
Vasopressin: At high concentrations, vasopressin stimulates contraction of
smooth muscle in uterus (via oxytocin receptors) and GIT (via
V1 receptors). Vasopressin is stored in platelets, and activation of
V1 receptors stimulates platelet aggregation. Also, activation of V1
receptors on hepatocytes stimulates glycogenolysis. The physiological
significance of these effects is not known.
Pharmacokinetics.When
given orally, inactivated quickly by trypsin, which cleaves peptide bond
between amino acids 8 and 9. Inactivation by peptidases particularly in liver
and kidneys results in plasma half-life of 17 to 35 minutes. Following
intramuscular or subcutaneous injection, the antidiuretic effects last 2 to 8
hours.
Clinical Uses of Vasopressin
i.
It is used in treatment of diabetes
insipidus, a disease resulting from failure of pituitary to secrete
vasopressin or from surgical removal of pituitary. Diabetes insipidus is
characterized by marked increase in urination (as much as 10 L in 24 hours) and
excessive thirst by inadequate secretion of the antidiuretic hormone or
vasopressin.
ii.
Treatment with vasopressin therapy replaces
hormone in body and restores normal urination and thirst.
iii.
Vasopressin may also be used for prevention
and treatment of postoperative abdominal distention and to dispel gas
interfering with abdominal roentgenography.
ADVERSE REACTIONS
Local or systemic hypersensitivity reactions may occur in some
patients receiving vasopressin. Tremor, sweating, vertigo, nausea, vomiting,
abdominal cramps, and water
intoxication (overdosage, toxicity) may also be seen.
CONTRAINDICATIONS,
PRECAUTIONS, AND INTERACTIONS
a.
It is contraindicated in patients with
chronic renal failure, increased blood urea nitrogen, and those with allergy to
beef or pork proteins.
b.
It is used cautiously in patients with
history of seizures, migraine headaches, asthma, congestive heart failure, or
vascular disease and in perioperative polyuria.
c.
The drug must be used cautiously during
pregnancy and lactation.
d.
The antidiuretic effects of vasopressin may
be decreased when agent is taken with following drugs: lithium, heparin,
norepinephrine, or alcohol.
e.
Antidiuretic effect may be increased when
used with carbamazepine, clofibrate, or fludrocortisone.
Hypolipidemics
Classification:
a.
HMG-CoA
reductase inhibitors (statin): Lovastatin, simvastatin, pravastatin,
atorvastatin, rosuvastatin.
b.
Bile acid
sequestrants: cholestyramine, colestipol
c.
Activate
lipoprotein lipase: clofibrate, gemfibrozil, bezafubrate, fenofibrate
d.
Inhibit
lipolysis and triglyceride synthesis: Nicotinic acid
e.
Others:
ezetimibe, gugulipid.
Dyslipidaemia means
abnormalities of plasma lipids and lipoprotein concentration. These may
manifest in following ways:
a.
Elevated
total cholesterol levels.
b.
Elevated
low density lipoprotein cholesterollevels.
c.
Elevated
triglyceride levels.
d.
Decrease
high density lipoprotein cholesterol levels.
Complications
of dyslipidemia
Ezetimibe
Ezetimibe is first compound approved for
lowering total and LDL-C levels that inhibits cholesterol absorption by
enterocytes in small intestine. It lowers LDL-C levels by about 18% and is used
primarily as adjunctive therapy with statins.
Mechanism of Action: It is selective inhibitor of intestinal absorption of cholesterol
and phytosterols. A transport protein, NPC1L1, appears to be target of drug. It
is effective even in absence of dietary cholesterol because it inhibits
reabsorption of cholesterol excreted in bile.
Absorption, Fate, and Excretion:
Ezetimibe is highly water insoluble, precluding studies of its bioavailability.
After ingestion, it is glucuronidated in intestinal epithelium, absorbed, and
enters an enterohepatic recirculation. Excreted in feces and urine. Bile acid
sequestrants inhibit absorption of ezetimibe, and two agents should not be
administered together.
Adverse Effects and Drug Interactions: Allergic reactions, but no specific adverse effects have not been observed in patients taking ezetimibe. The safety of ezetimibe during pregnancy has not been established. Since all statins are contraindicated in pregnant and nursing women, combination products containing ezetimibe and statin should not be used by women in absence of contraception.
Therapeutic Uses: Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone.
Reductase Inhibitors & Ezetimibe: This combination is highly synergistic in treating
primary hypercholesterolemia and has some use in the treatment of patients with
homozygous familial hypercholesterolemia who have some receptor function.
Ternary Combination of Resins, Ezetimibe,
Niacin, & Reductase Inhibitors:These agents act in
complementary fashion to normalize cholesterol in patients with severe
disorders involving elevated LDL. The effects are sustained, and little
compound toxicity has been observed. Effective doses of individual drugs may be
lower than when each is used alone—eg. niacin may substantially increase effects
of other agents.
Antihypertensives
Classification
Calcium channel blockers:
a. Phenyl alkylamine: verapamil
b. Benzothiazepine: diltiazem
c. Dihydro puridines: Nifedipine, amlodipine,
felodipine, nitrendipine, nimodipine
Actions of calcium channel blockers
Systemic and coronary arteries are
influenced by movement of calcium across cell membranes of vascular smooth
muscle. The contractions of cardiac and vascular smooth muscle depend on
movement of extracellular calcium ions into these walls through specific ion
channels. Calcium channel blockers inhibit movement of calcium ions across cell
membranes. This results in less calcium available for transmission of nerve
impulses. This drug action of calcium channel blockers (slow channel blockers)
has effects on heart, including effect on smooth muscle of arteries and
arterioles. These drugs dilate coronary arteries and arterioles, which in turn
deliver more oxygen to cardiac muscle. Dilation of peripheral arteries reduces
workload of heart. An increased blood flow results in increase in oxygen supply
to surrounding tissues.
Schematic diagram of Mechanism of action of calcium channel blockers is
shown below
Uses
of Calcium channel blockers
a. It
is primarily used to prevent anginal pain associated with certain forms of
angina, such as vasospastic (Prinzmetal’s variant) angina and chronic stable
angina. They are not used to abort (stop) anginal pain once it has occurred.
When angina is caused by coronary artery spasm, these drugs are recommended
when the patient cannot tolerate therapy with the beta-adrenergic blocking
drugs or the nitrates.
b. It
is used as antianginals.
c. Verapamil
affects conduction system of heart and may be used to treat cardiac
arrhythmias.
d. Diltiazem,
nicardipine, nifedipine, and verapamil also are used in treatment of essential
hypertension
contraindications,
PRECAUTIONS, AND INTERACTIONS
a. It
is contraindicated in patients who are hypersensitive to drugs and those with
sick sinus syndrome, second- or third-degree AV block (except with a
functioning pacemaker), hypotension (systolic less than 90 mm Hg), ventricular
dysfunction, or cardiogenic shock.
b. It
is used cautiously during pregnancy and lactation and in patients with CHF,
hypotension, or renal or hepatic impairment.
c. The
effects of the calcium channel blockers are increased when administered with
cimetidine or ranitidine.
d. A
decrease in effectiveness of calcium channel blockers may occur when agents are
administered with phenobarbital or phenytoin.
e. Calcium
channel blockers have an antiplatelet effect (inhibition of platelet function)
when administered with aspirin, causing easy bruising, petechiae (pinpoint
purplish red spot caused by intradermal hemorrhage), and bleeding.
f. There
is an additive depressive effect on myocardium when calcium channel blockers
are administered with β-adrenergic blocking drugs.
g. When
calcium channel blockers are administered with digoxin, there is an increased
risk for digitalis toxicity.
Atenolol
Atenolol, are members of β1-selective
group.
These agents may be safer in patients who
experience bronchoconstriction in response to propranolol. Since their β1
selectivity is modest, they should be used with caution, if at all, in patients
with history of asthma.
However, in selected patients with chronic
obstructive lung disease, the benefits may exceed risks, eg, in patients with
myocardial infarction.
Beta1-selective antagonists may be
preferable in patients with diabetes or peripheral vascular disease when
therapy with a β-blocker is required since β2 receptors are probably important
in liver (recovery from hypoglycemia) and blood vessels (vasodilation).
It is not
appreciably metabolized and excreted to a considerable extent in urine.
Patients with reduced renal function should receive reduced doses of atenolol.
It is claimed that
atenolol produces fewer central nervous system-related effects than other more
lipid-soluble β-antagonists.
Uses: Angina pectoris, hypertension, myocardial,
infarction (MI)
Adverse effects: Fatigue, hypotension, weakness,
blurred vision, stuffy nose, impotence, decreased libido, rash, CHF,
bradycardia, pulmonary edema
Flouxetine: it is used alone or with alprazolam can be used to control
panic disorders, it is used in treating bilumina nervosa, but dose required is
higher. It is mainly used as antidepressants.
Reserpine at low doses, in
combination with diuretics, in the treatment of hypertension, especially in
elders.
Role of
sugar moiety in cardiac glycosides
If
a sugar molecule is joined together with non-sugar molecule by an ether linkage
it is called glycoside. On hydrolysis with mineral acid, all glycosides split up
into sugar and non-sugar residues. In cardiac glycosides the sugar part is 1 or
4 molecules of digitoxose while non-sugar part is a steroidal lactone. The
pharmacological activity of cardiac glycosides resides in its non-sugar moiety
called aglycone. The sugar part, governs the pharmacokinetic characteristics
such as lipid solubility and cell permeability.
Reserpine
Reserpine is prototypical drug interfering
with norepinephrine storage. It lowers blood pressure by reducing
norepinephrine concentrations in noradrenergic nerves in such a way that less
norepinephrine is released during neuron activation. It does not interfere with
the release process per se as does guanethidine. Reserpine inhibits only the
second uptake process.
Pharmacological Effects: Both cardiac output and
peripheral vascular resistance are reduced during long-term therapy with
reserpine. Orthostatic hypotension may occur but does not usually cause
symptoms. Heart rate and renin secretion fall. Salt and water are retained,
which commonly results in "pseudotolerance.".
Therapeutic Uses: At low doses,
in combination with diuretics, in treatment of hypertension, in elders.
Reserpine is used once daily with a diuretic, and several weeks are necessary
to achieve maximum effect.
Adverse effects are due to its effect on CNS, the use of reserpine has diminished. Sedation and inability to concentrate or perform complex tasks. More serious is psychotic depression can lead to suicide. Reserpine-induced depression may last several months after drug is discontinued. Other effects include nasal stuffiness and exacerbation of peptic ulcer disease, is uncommon with small oral doses.
Potassium channel activators
Ex: diazoxide, minoxidil,
pincidil, nicorandil
Mechanism of action:These cause dilation of blood
vessels by activating potassium channels in vascular smooth muscle. An increase
in potassium conductance results in hyperpolarization of cell membrane, which
will cause relaxation of vascular smooth muscle.
Schematic diagram of Mechanism of action of Potassium channel activators is
shown below
Simvastatin
It is an antihyperlipidemic drugs, it is an HMG-CoA
reductase inhibitors. HMG-CoA (3-hydroxy-3-methyglutaryl coenzyme A)
reductase is an enzyme that is catalyst in manufacture of cholesterol.
These drugs appear to have one of two activities, namely, inhibiting
manufacture of cholesterol or promoting breakdown of cholesterol. This drug
activity lowers blood levels of cholesterol and serum triglycerides and
increases blood levels of HDLs.
Uses: it
is used along with a diet restricted in saturated fat and cholesterol, are used
to treat hyperlipidemia when diet and other nonpharmacologic treatments alone
have not resulted in lowered cholesterol levels.
Adverse
effects: are mild and transient and do not require discontinuing therapy.
Others are nausea, vomiting, constipation, abdominal pain or cramps, and
headache. A rare, but more serious, adverse reaction is rhabdomyolysis.
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