Transcript Pharmacology I for dental students Course Description: It

Pharmacology II
Lecture 7
Cardiovascular system
Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Head of Department of Pharmacology and Medical Sciences, Faculty of
Pharmacy- Al azhar University
Dr. Mahmoud H. Taleb
1
I - Treatment of Congestive Heart Failure
Congestive heart failure (CHF) is a condition in which the
heart is unable to pump sufficient blood to meet the needs of
the body. CHF by an impaired ability of the cardiac muscle to
contract or by an increased workload imposed on the heart.
CHF is accompanied by abnormal increases in blood volume
and interstitial fluid; the heart veins, and capillaries are
therefore generally dilated with blood. Hence the term "
congestive " heart failure, since the symptoms include
pulmonary congestion with left heart failure, and peripheral
oedema with right heart failure.
Underlying causes of CHF include atherosclerosis, heart
diseases, hypertensive heart diseases , valvular heart diseases,
dilated cardiomyopathy and congenital heart diseases. The
therapeutic goal for CHF is to increase cardiac output.
Dr. Mahmoud H. Taleb
2
Compensatory physiological response in CHF
The failing heart evokes three major compensatory mechanism to enhance cardiac
output
Increased sympathetic activity: Baroreceptor sense a decrease in blood
pressure, and trigger activation of β- adrenergic receptors in the heart. This results
in an increase in heart rate and a greater force of contraction of the heart muscle,
in addition, vasoconstriction enhances venous return and increases cardiac
preload. and therefore , can contribute to further decline in cardiac function.
2- Fluid retention: A fall in cardiac output decreases blood flow to the kidney,
prompting the release of rennin, with a resulting increase in the synthesis of
angiotensin II and aldosterone. This results in increased peripheral resistance and
retention of sodium and water. Blood volume increases, and more blood is
returned to the heart. If the heart is unable to pump this extra volume, venous
pressure increases and peripheral oedema and pulmonary oedema occur.
3- Myocardial hypertrophy:
The heart increases in size and the chambers dilate. Initially, stretching of the
heart muscle leads to a stronger contraction of the heart. However, excessive
elongation of the fibers results in a weaker contraction 4
Dr. Mahmoud H. Taleb
3
Three classes of drugs have been shown to be clinically
effective in reducing symptoms and prolonging life :
1- vasodilators that reduse the blood in myocardium
2- diuretic agents that decrease extracellular fluid
volume and
3- inotropic agents that increase the strength of
contraction of cardiac muscle these agents relieve the
symptoms of cardiac insufficiency but do not reverse
the underlying pathological condition.
Dr. Mahmoud H. Taleb
4
Figure (2) Compensatory physiological response in CHF
Dr. Mahmoud H. Taleb
5
Therapeutic strategies in CHF
CHF is typically managed by reduction in physical activity, low dietary
intake of sodium and treatment by vasodilators, diuretics and inotropic agents
e.g. cardiac glycosides.
Dr. Mahmoud H. Taleb
6
1- Cardiac glycosides ( Digoxin, Digitoxin, Quabin)
The cardiac glycosides exert their effects through actions both on the rate
and rhythm and on the force of contraction of the heart.
Inhibition of Na+- K+-ATP ase an enzyme responsible for transport of Na+
& K+ in & out the cell. Na+ - input → ↑ Sodium concentration inside the
cells → increased transmembrane exchange of sodium & calcium
increase the intracellular Ca2+ →Increase contraction of cardiac muscle
( +ve inotropic effect),. An increased myocardial contraction leads to
decrease in end diastolic volume, thus increasing the efficiency of
contraction, resulting improved circulation, leads to reduced sympathetic ,
which then reduced peripheral resistance. Vagal tone is also enhanced so
the heart rate decreases, and myocardial oxygen demand is diminished
(Positive inotropic effect).
Therapeutic uses:
Digoxin therapy is indicated in patients with severe left ventricular systolic
dysfunction after initiation of diuretic and vasodilator therapy.
Dr. Mahmoud H. Taleb
7
Mechanism of action of cardiac glycoside:
Figure ( 3 ) Mechanism of action of cardiac glycosides
Dr. Mahmoud H. Taleb
8
The cardiac glycosides exert their effects through actions both on the rate and
rhythm and on the force of contraction of the heart.
Inhibition of Na+- K+-ATP ase an enzyme responsible for transport of Na+ & K+
in & out the cell. Na+ - input → ↑ Sodium concentration inside the cells →
increased transmembrane exchange of sodium & calcium increase the
intracellular Ca2+ →Increase contraction of cardiac muscle ( +ve inotropic
effect),. An increased myocardial contraction leads to decrease in end diastolic
volume, thus increasing the efficiency of contraction, resulting improved
circulation, leads to reduced sympathetic , which then reduced peripheral
resistance. Vagal tone is also enhanced so the heart rate decreases, and myocardial
oxygen demand is diminished (Positive inotropic effect).
Therapeutic uses:
Digoxin therapy is indicated in patients with severe left ventricular systolic
dysfunction after initiation of diuretic and vasodilator therapy.
Dr. Mahmoud H. Taleb
9
Toxicity of cardiac glycoside
** Symptoms: 3 group of symptoms occur in digitalis toxicity:
GIT effects: Anorexia- nausea, vomiting, diarrhea and abdominal cramp.
CNS effects: headache, malaise, lethargy, fatigue, dizziness, stupor,
delusion , parasthesia ,various type of scotoma, neurological pain,
hallucination, yellow or green vision.
Cardiac effects: Bradycardia. Partial or complete heart block,
arrhythmias. Ventricular extrasytole, paroxysmal tachycardia and
ventricular tachycardia.
** The cardiotoxic effects of digitalis are probably due to an
excessive loss of K+
( intracellular) , resulting from
inhibition of membrane Na+- ATP ase
** Treatment of cardiac arrthymia due to digitalis toxicity:
1- Stop administration of digitalis
2- Kcl
3- Ca2+-ion chelating agents e.g.EDTA
4- Atropine
5- Specific antiarrhythmic drugs
6- Digoxin –specific Fab fragments
Dr. Mahmoud H. Taleb
10
Long- term digoxin treatment during pregnancy may shorten the duration
of pregnancy and retard intrauterine growth, resulting in low birth weight
and shorter labor. Nevertheless, digoxin is the drug of choice for fetal
supraventricular tachycardia, it is generally considered a safe drug during
pregnancy, with no risk of teratoginicity, but overdose cab be detrimental to
the mother and lethal to the fetus.
Drug interactions
Digitalis action may be enhanced by substances that
1- Slow GI motility and thereby increase gastrointestinal absorption
2- Disrupt body electrolytes by lowering plasma potassium levels, eliciting
hypokalemia and hypomagnesia and hypercalcemia e.g. diuretics, amphotericin
B, oral and parental glucose.
3-Change renal clearance and or alter plasma protein binding
4-Stimulate ß- adrenoreceoptor and cause cardiac dysrhythmias
Digitalis action may be reduced by substances that
Reduce gastrointestinal absorption e.g. kaolin-pectin, antihyperlipidemic
agents, antacids.
Increase gastrointestinal motility e.g. metoclopramide
Stimulate hepatic microsomal enzymes e.g. phenytoin, ASA, barbiturate.
Spironolactone, phenylbutazone
Dr. Mahmoud H. Taleb
11
Other positive inotropic agents
*** ß - adrenergic agonist :
ß - adrenergic stimulation improve cardiac performance by positive inotropic
effects and vasodilation. Bobutamine is the most commonoly used , where it leads
tob an increase in the intracellular concentration of cAMP. This results in an
increase in intracellular calcium, which results in the activation of protein kinase.
Slow calcium channels are one important site of phosphorylation by protein kinas.
When phosphorylated, the entry of calcium ions into the myocardium increases
thus enhances contraction. Dobutamine must be given by IV infusion.
** Phosphodiasteras inhibitors
Amrinone and milrinone are phosphodiasteras inhibitors that increase the
intracellular concentration of cAMP. This results in an increase in intracellular
calcium, and thus cardiac contractility and improvement of myocardial function.,
they increase mortality in heart failure.
Dr. Mahmoud H. Taleb
12
II. Vasodilators
Vasodilatation may be produced by various types of pharmacological agents.
Nitroglycerine and various nitrates have been used in treatment of cardiac diseases.
Other drugs used for the same purpose include postganglionic blockers of
sympathetic nervous system, α-adrenergic blockers, β2 - adrenorenoreceptor
agonists, histaminergic or dopaminergic receptor agonists, blockers of calcium
channels in the muscle cell membrane, angiotensin- converting enzyme(ACE)
inhibitors, and drugs that relax vascular smooth muscle directly without acting on
any specific receptors. .
The three clinical indications for the use of vasodilators are angina pectoris,
hypertension, and refractory heart failure. Nitrites are used primarily for angina
pectoris; hydralazine, diazoxide, sodium nitroprusside, and minoxidil are used chiefly
for treatment of hypertensions; calcium channel blockers are used for both purpose
and various other agents are useful in the treatment of refractory heart failure.
Dr. Mahmoud H. Taleb
13
therapeutic application of these drugs.
* Nitrates and nitrites have effects on the veins.
* Sodium nitroprusside acts on both arterioles and on veins.
* Hydralazine and diazoxide act mainly on arteries.
In addition, vasodilators can differ in their action in various vascular areas; i.e., some
will increase blood flow mainly in the coronary arteries while others act chiefly in the
renal, mesenteric, or skin vessels.
Blood flow in all tissues depends on the balance between vascular resistance and
cardiac output. The relative contribution of cardiac and local factors to the regulation of
blood flow is quite different in various tissues. Hence, it's easy to understand that a
vasodilator that increases cardiac output may increase blood flow
more in a particular
vascular area in which perfusion depends mainly on the cardiac output, than another
vasodilator that is without such cardiac effect.
The extent of vasodilation depends a great deal on the preexisting state of the
vessels. Drug-induced relaxation can be best demonstrated in vessels that have been
previously contracted.
Dr. Mahmoud H. Taleb
14
Clinical indications for the use of vasodilators
Hypertension
This is the main indication for the use of vascular smooth-muscle relaxants
other than the nitrates. Diastolic hypertension is consequent to increased
peripheral resistance, and therefore the rationale for lowering arterial pressure by
using drugs that relax vascular smooth muscle is obvious. Previously, their use
was limited because they tended to case tachycardia and increased cardiac
contractility by activation of baroreceptor reflexes. These compensatory changes
counterbalance the antihypertensive effect of vasodilators. Today, vasodilators are
used together with β-blockers to treat hypertension, to counteract the reflex
tachycardia and increased cardiac output.
The antihypertensive effect can be balances by the concomitant use of diuretics. In
more severe hypertension, diuretics are used in combination with β-blocking
drugs, vasodilators or other drugs acting on the sympathetic nervous system.
Diuretics decrease extracellular and plasma volume; this action and their vascular
effects enhance the lowering of blood pressure caused by vasodilators. In addition,
diuretics prevent retention of salt and water, which is a frequent consequence of
the excessive capillary permeability to Na+ that is caused by vasodilators.
Dr. Mahmoud H. Taleb
15
. Baroreceptors and the sympathetic nervous system
Baroreflexes involving the sympathetic nervous system are
responsible for rapid moment regulation of blood pressure.
A fall in blood pressure causes pressure- sensitive neurons
( baroreceptors in the aortic arch and carotid sinuses) to send fewer
impulses to cardiovascular centers in the spinal cord. This prompts
a reflex response of increased sympathetic and decreased
parasympathetic output to the heart and vascular, resulting in
vasoconstriction and increased cardiac output. These changes result
in a compensatory rise in blood pressure
Dr. Mahmoud H. Taleb
16
Figure (4) Baroreceptor reflex mechanism
Dr. Mahmoud H. Taleb
17
3- Renin- angiotensin- aldosterone system.
The kidney provides for the long-term control of blood pressure by
altering the blood volume .Baroreceptors in the kidney respond to
reduced arterial pressure (and to sympathetic stimulation of
B-adrenoceptors) by releasing the enzyme renin (see Figure )This
peptidase converts angiotensinogen to angiotensin I, which is in turn
converted to angiotensin II in the presence of angiotensin converting
enzyme (ACE)
Dr. Mahmoud H. Taleb
18
Figure (5) Renin- angiotensin- aldosterone system reflex mechanism.
Dr. Mahmoud H. Taleb
19
2- Hypertension
Hypertension is the most common cardiovascular
disease. Thus, the third National Health and Nutrition
Examination Survey (NHANES III), conducted from
1992 to 1994, found that 27% of the USA adult
population had hypertension.
The prevalence varies with age, race, education, and
many other variables.
Sustained arterial hypertension damages blood vessels
in kidney, heart, and brain and leads to an increased
incidence of renal failure, coronary disease, cardiac
failure, and stroke.
Dr. Mahmoud H. Taleb
20
Diagnosis
The diagnosis of hypertension is based on repeated reproducible measurements of
elevated blood pressure. In fact, hypertension is usually asymptomatic until overt
end organ damage is imminent or has already occurred.
Etiology
1- Primary, idiopathic or essential hypertension: due to unknown cause.
2- Secondary hypertension: may be due to :
Renal disease e.g. Glomerulonephritis.
Endocrinal disorders e.g. Acromegaly, Cushing syndrome.
Renovascular disease e.g. Renal artery stenosis
Catecholamine- producing tumor.
Toxemia of pregnancy
Use of certain drugs e.g. oral contraceptive, adrenal steroids.
Predisposing factors to the occurrence of hypertension as environmental
factors, stressful lifestyle, high dietary intake of sodium, obesity, and
smoking.
Dr. Mahmoud H. Taleb
21
Basic Pharmacology of Antihypertensive agents
All antihypertensive agents act at one or more of the four anatomic control
sites depicted in Figure( 6) and produce their effects by interfering with
normal mechanisms of blood pressure regulation.
Figure . Sites of action of the major classes of antihypertensive
Dr. Mahmoud H. Taleb
drugs.
22
Treatment Strategy
Mild hypertension can often be controlled with
a single
drug. More severe hypertension may require treatment with several
drugs that are selected to minimize adverse effects of the combined
regimen. Treatment is initiated with any of four drugs, depending on
the individual patient:
a diuretic,
α-blocker,
an ACE inhibitor,
a calcium channel blocker.
If blood pressure is inadequately controlled, a second drug is added.
α -blocker is usually added if the initial drug was a diuretic, or a
diuretic is added if the first drug was α -blocker. A vasodilator can be
added as a third step for those patients who still fail to respond
Dr. Mahmoud H. Taleb
23
Dr. Mahmoud H. Taleb
24
Depressant of sympathetic activity
1- α- adrenergic blockers
The mechanism of hypotensive action is α- blockade →
peripheral peripheralresistance vasodilatation resulting
in reduction of blood pressure.
α- blockers, except prazocin are not used here, they cause
tachycardia & increase in C.O.P due to - reflex
sympathetic stimulation of heart - blockade of
presynaptic α2 receptors resulting in an increase of
NE release. They are mainly used in peripheral
vascular diseases.
Prazocin ( RX Minipress)


G.I.T disturbances.
Dry mouth, blurred vision, rash and pruritis.
Dr. Mahmoud H. Taleb
25
Mode of action:
Prazocin is a vascular smooth muscle relaxant
affecting arterioles more than venules.
Blocking of the postsynaptic α-adrenergic
receptor→ fall in peripheral resistance and blood
pressure.
Prazocin is a phosphodiasterase inhibitor→
accumulation of cAMP in vascular smooth
muscle, leads to vasodilatation.
Side effects:




Postural hypotension and tachycardia with the first dose .This
initial syncope can be avoided by: Giving the first dose at bed
time or the patient in relaxed position.
Angina pectoris.
Fluid retention, oedema.
Drowsness, headache.
Dr. Mahmoud H. Taleb
26
β -drenoceptor Antagonists Propranolol) Rx Inderal, Deralin, Propol),
Atenolol( Tenormin, Normetin, Cortenol, Atenol), pindolol (Rx Viskin),
Acebutolol (Rx Sectral) , Nadolol (Rx Corgard), Timolol (Rx Blocardan
) , Metaprolol (Rx Lopressor), Labetolol (Rx Trandate ), Carvedilol
(Rx Coreg) Bisoprolol (Rx Zebeta, Concor ,Cardioloc)
Actions
ii-

Figure . Action of β- adrenergic blockers
Dr. Mahmoud H. Taleb
27
B. Therapeutic uses
D. Adverse effects
Common effects: The β -blockers may cause CNS side effects
such as fatigue, lethargy, insomnia, and hallucinations; these
drugs can also cause hypotension.
The β blockers may decrease libido and cause impotence; druginduced sexual dysfunction can severely reduce patient
compliance
Alterations in serum lipid patterns: The β -blockers may disturb
lipid metabolism, decreasing high-density lipoproteins (HDL)
and increasing plasma triacylglycerol.
Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β -receptors.
Patients should be tapered off of β blocker therapy in order to
avoid precipitation of arrhythmias. The β blockers should be
avoided in treating patients with asthma, congestive heart failure,
and peripheral vascular disease.

Dr. Mahmoud H. Taleb
28
iii- α2- adrenergic agonist
Clonidine (Rx Catapress, Dikkinet, Clonirit)
Clonidine is given orally or I.M, resulting in a fall of blood pressure, and this is due to
decrease of C.O.P and PR.
Mechanism of action:
Central action
Clonidine has been claimed to stimulate the central presynaptic α2 receptors , which
are inhibitory to NE release → inhibition of sympathetic outflow.
Peripheral action




Clonidine prevents release of NE from adrenergic nerves→ prevent cardiac response to
postganglionic adrenergic nerves stimulation.
It has a weak direct peripheral vasodilator action.
It produces bradycardia , which is due to decreases of sympathetic and increases vagal
tone.
It decreases renin secretion.
Therapeutic uses
control of moderate hypertension.
Prophylactic for migraine.
Side effects
Mainly due to vagal tone stimulation
Sedation. Bradycardia, dryness of the mouth, nausea, impotence.
Dr. Mahmoud H. Taleb
29