CARDIOVASCULAR

DRUGS
By Salahadin A.
 INTRODUCTION

Cardiovascular (=Circulatory) system – heart and blood vessels

Arteries – transport blood to tissues

Capillaries – sites of exchange, fluid O2, CO2, nutrients etc.

Venules – collect blood from capillaries

Veins – transport blood back to heart

Blood moves within vessels – higher pressure to lower pressure

Resistance to flow depends on vessel diameter, length and viscosity of blood

Cardiac blood flow

The mammalian heart is a double pump in which the right side operates as a
low-pressure system delivering de-oxygenated blood to the lungs, while the left
side is a high pressure system delivering oxygenated blood to the rest of the body.

The walls of the right ventricle are much thinner than those of the left, because
the work load is lower for the right side of the heart.

The ventricular muscle is relatively stiff, and it would take some time to fill
with venous blood during diastole.
Regulation of cardiac output
CO = SV x HR
~ 5L /minute; dependent on:
Heart rate
Stroke volume
Preload
Afterload

Starling’s Law
Ventricular contraction is proportional to muscle fiber stretch
Aortic output pressure rises as the venous filling pressure is increased
Increased venous return – increase cardiac output – up to a point!
Cardiac electrical activity
•Cardiac muscle does not require any nervous stimulation to contract.

•Each beat is initiated by the spontaneous depolarization of pacemaker cells in the

sino-atrial (SA) node.

•These cells trigger the neighboring atrial cells by direct electrical contacts and a
wave of depolarization spreads out over the atria, eventually exciting the atrio-
ventricular (AV) node.
• Contraction of the atria precedes that of the ventricles, forcing
extra blood into the ventricles .

• The electrical signal from the AV node is carried to the ventricles

by a specialised bundle of conducting tissue (the bundle of His)

• The conducting tissues are derived from modified cardiac muscle

cells, the Purkinje fibers.
Most commonly encountered CVS
disorders are;
 HTN-an elevated BP

CHF-heart is unable to pump as to the body’s blood and

oxygen demand.

Angina pectoris-pain on the chest associated with an

imbalance b/n oxygen demand and supply to the heart.

Cardiac Arrhythmia (Disrythmia)-loss of normal rhythm of

the Heart.
 I. Antihypertensive drugs
BP is determined by ;
CO
PVR
BP is mainly regulated by combined interaction of the NS,
endocrine and renal system.
Normal BP is 120/80 mmHG
BP arises from two forces i.e from the heart as it pumps and force
of the arteries when they resist flow.
The RAAS is also a series of reactions to help regulate
Bp i.e When BP decreases (systolic BP < 100mmHg ),
kidneys release renin to blood, renin splits
angiotensinogen to smaller angeotensin I and then
ACEs convert it to an active Angeotensin II. Renin also
increases aldosterone release to enhance Na and water
retention.
 Hypertension - sustained elevation in blood pressure over 120/80

Etiology of HTN- Silent killer b/c no symptoms till vital organs are damaged.
 Primary (essential) hypertension – unknown etiology; cases (90%)

The causes are multifactorial

Genetics may be involved
 Secondary hypertension: Known cause;

Renal artery stenosis - excessive release of rennin

Phaeochromocytoma (Tumor of the adrenal medulla)
Excess glucocorticoids: water reabsorption
Dietary factors, stress etc….
Diagnosis ;
is based on measurement of blood pressure on three separate occasions.
Accordingly, a systolic BP of 130 mm Hg or greater and/or a diastolic BP of
80 mm Hg or greater, taken on two different occasions in an individual who is
not acutely ill, establishes the diagnosis of HTN.

Major Risk factors

• Smoking, dyslipedemia, diabetes mellitus

• Age > 60yrs, Sex (men and postmenopausal women)

• Family history of cardio-vascular disease

Hypertensive Crisis: - There are two major forms:

1. Hypertensive Emergencies

 Severe hypertension with target organ damage.

 hypertensive encephalopathy, intracranial hemorrhage, unstable angina, acute
myocardial infarction, pulmonary edema and dissecting aortic aneurysm, and
eclampsia.

 The therapeutic goal is to rapidly reduce blood pressure to

prevent or limit target organ damage.
2. Hypertensive Urgencies

Very high BP (diastolic BP > 120-130) without target organ

damage

These are situations in which it is desirable to reduce the

blood pressure within a few hours.
hypertension with optic disk edema, progressive target organ
complication and severe preoperative hypertension.
 Classification of Blood Pressure
Classification of Blood Pressure in Adults
(Age ≥18 Years)
Classification Systolic/ diastolic BP
Normal <120 and <80 mm Hg
Pre hypertension 120–129 or <80
Stage 1 hypertension 130–139 or 80–89
Stage 2 hypertension ≥140 or ≥90
 Antihypertensive cont’d
Complications of hypertension
• The most dangerous complications are end organ damage.
• Atherosclerosis
• Cardiac failure due to myocardial infarct
• Occlusion of a coronary artery as a result of atheroma and superimposed
thrombus
• Poor perfusion of the heart muscle due to excessive cardiac hypertrophy
• Renal failure (kidney damage)
• Stroke
• Damage to the eye, Blood Vessels etc…
 Antihypertensive cont’d
Treatment of hypertension
Goals;
Most patients for general prevention <120/80 mm Hg
 this goal is lowered to less than 130/80 mm Hg for patients with diabetes, significant
chronic kidney disease, known coronary artery disease (myocardial infarction, stable
angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke,
transient ischemic attack, peripheral arterial disease, abdominal aortic aneurism), or a 10%
or greater 10-year risk of fatal coronary heart disease or nonfatal myocardial infarction
patients with left ventricular dysfunction (heart failure) have a BP goal of less than 120/80
mm Hg
Drug choice depends on ;
Age
Race
Severity of HTN
Presence of other Diseases
SE and cost
Non Pharmacologic Approach;

All patients with prehypertension and hypertension should be prescribed

lifestyle modifications

Freedom from side effect compared with drug therapy

In serious increases in BP; drug treatment is involved.

Stop smoking
Lose weight
Decrease in excessive alcohol consumption
Exercise
Reduce salt intake
 Antihypertensive cont’d
Pharmacological treatment of hypertension

• Principal site of regulatory site or mechanism

- Diuretics: deplete salt and blood volume

- Sympathoplegics: reduce sympathetic tone

- Angiotensin antagonists: block action of angiotensin

- Vasodilators: dilate resistance and/or capacitance vessels

Potential drug targets:

CNS, ANS: decrease sympathetic tone

Heart: decrease cardiac output
Veins: dilate => decrease preload
Arterioles: dilate => decrease afterload
Kidneys: increase diuresis; inhibit RAAS
Antihypertensive Drugs
Four major drug categories
1.Sympathetic nervous system suppressors:
a1 and b1 antagonists
a2 agonists
2. Direct vasodilators:
Calcium channel antagonists/blockers -CCB
Potassium channel agonists
3. Renin-angiotensin system targeting drugs:
ACE inhibitors - ACEI
Angiotensin II receptor antagonists/blockers- ARB
4. Diuretics:
Thiazides
Loop diuretics
K+ - sparing diuretics
 RAAS-targeting drugs

Renin-angiotensin –aldosterone system

• Important role in regulating blood volume, arterial pressure, and cardiac and vascular function.

• Most important site for renin release is the kidney: sympathetic stimulation (acting via b-adrenoceptors),
renal artery hypotension and decreased sodium delivery to the distal tubules stimulate release of renin by
the kidney.

• Renin acts upon a circulating substrate, angiotensinogen (produced mainly by the liver) which undergoes
proteolytic cleavage to form decapeptide angiotensin I (AT I).

• Vascular endothelium, particularly in the lungs, contains angiotensin converting enzyme (ACE), which
cleaves off two amino acids to form the octapeptide, angiotensin II (AT II).
The RAAS pathways and effects on the body
Angiotensin II

• Constricts vessels thereby increasing vascular resistance and arterial pressure

• Stimulates the adrenal cortex to release aldosterone, which acts upon the kidneys to increase
sodium and fluid retention .

• Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the pituitary which acts
upon the kidneys to increase fluid retention

• Facilitates norepinephrine release and inhibits re-uptake from nerve endings, thereby enhancing
sympathetic adrenergic function
• Stimulates cardiac and vascular hypertrophy
AT-II production and its effects;
ACE - Inhibitors
• Captopril
– First ACE inhibitor
– Given po
– Frequent side effect: cough (reduced inactivation of kinins)
• Enalapril

• Benazepril
• Ramipril
• Lisinopril
• Etc…
AT II Receptor Antagonists
Do not interfer with kinin processing => no cough

• Losartan

• Candesartan
• Eprosartan
• Valsartan
• Irbesartan
• Etc…
 Antihypertensive cont’d

Angiotensin converting enzyme inhibitors

• ACE inhibitors prevent the conversion of angiotensin I to II
• ACE (kininase2): also responsible for inactivation of bradykinin
• Bradykinin can act as a local vasodilator agent. However, the adverse effects of bradykinin limit
the usefulness of ACE inhibitors.
• Captopril
• Excreted by the kidneys
• Orally available
• 65% bioavailability
• Half life 2 hours
 Antihypertensive cont’d
• Adverse effects :
• Dry cough (due to bradykinin)
• Loss of taste
• Severe hypotension
• Rash
• Angioedema (due to bradykinin)
• Enalapril
• prodrug
• Converted to enalaprilat via hepatic hydrolysis
• Much longer half-life than captopril (20 - 24 hours)
• Adverse effects:
• Milder due to the lack of the sulfhydryl groups which were present on
captopril
 Antihypertensive cont’d
 Angiotensin II receptor antagonists/blockers (ARB’s)
• Angiotensin II binds to 2 receptors:
• AT1 and AT2 receptors
• Known actions of angiotensin II is mediated by AT1
• The drug Losartan
• selective for AT1 receptors
• more complete inhibition of angiotensin action
• Similar efficacy to ACE inhibitors but without the bradykinin associated side
effects:
• There is no cough and no chance of angioedema
• However, other side effects may be:
• GI adverse effects
• Hyperkalemia (due to decreased aldosterone)
 Antihypertensive cont’d

DIURETICS
• Increase Na+ excretion & water loss, reducing plasma volume
• Reduces the cardiac output, hence lowering blood pressure
• Reduce BP by 10-15 mmHg and provide adequate control of mild to moderate
HPN
• Thiazides
– Hydrochlorthiazide, chlorthalidone
– With 6-8 wks they reduce Peripheral resistance as cardiac output and blood
volume reduces
• High ceiling (loop) diuretics
– Furosemide, ethacrinic acid
– The antihypertensive effect is mainly due to reduction of blood volume
•
Normal Regulation of Fluid and Electrolytes by the Kidneys

The two kidney produce approximately

 120ml/min filtration
But only 1ml/min urine produced
>99% reabsorbed.
The filtrates include Na+, K+, and Cl-.
The kidney regulates the ionic composition and volume of urine by
 the active reabsorption or secretion of ions and/or
 the passive reabsorption of water at five functional zones along the nephron. namely,
the proximal convoluted tubule, the descending loop of Henle, the ascending loop of Henle,
the distal convoluted tubule, and the collecting tubule and duct.
Nephron, the functional unit of the kidney
 Proximal convoluted tubule
• Almost all the glucose, bicarbonate, amino acids, and other metabolites are
reabsorbed.
• Approximately two-thirds (65%) of the Na+ is also reabsorbed.
• Chloride enters the lumen of the tubule in exchange for a base anion, such as
formate or oxalate, as well as paracellularly through the lumen.
• Water follows passively from the lumen to the blood to maintain osmolar
equality.
• The Na+ that is reabsorbed is pumped into the interstitium by Na+/K+ adenosine
triphosphatase (ATPase)
• Carbonic anhydrase in the luminal membrane and cell of the proximal tubule
modulates the reabsorption of bicarbonate.
 Ascending loop of Henle
The cells of the ascending tubular epithelium are unique in being impermeable
to water.
 Active reabsorption of Na+,K+, and Cl- is mediated by a Na+/K+/2Cl-
cotransporter.
 Both Mg2+ and Ca2+ enter the interstitial fluid via the paracellular pathway.
The ascending loop is thus a diluting region of the nephron.
Approximately 25 to 30% of the tubular NaCl returns to the interstitial fluid
Because the ascending loop of Henle is a major site for salt reabsorption, drugs
affecting this site, such as loop diuretics are the most efficacious of all the
diuretic classes.
 Distal convoluted tubule

The cells of the distal convoluted tubule are also impermeable to water.
About 10 % of the filtered NaCl is reabsorbed via a Na+/Cl- transporter that is
sensitive to thiazide diuretics.
Calcium reabsorption is mediated by passage through a channel and then
transported by a Na+/Ca2+-exchanger into the interstitial fluid.
The mechanism thus differs from that in the loop of Henle.
Additionally, Ca2+ excretion is regulated by parathyroid hormone in this portion
of the tubule.
 Collecting tubule and duct

The principal cells of the collecting tubule and duct are responsible for Na+, K+,
and water transport,
whereas the intercalated cells affect H+ secretion.
The sodium enters the principal cells through channels but relies on a Na+/K+-
ATPase to be transported into the blood.
Aldosterone receptors in the principal cells influence Na+ reabsorption and K+
secretion.
 Antidiuretic hormone (ADH; vasopressin) receptors promote the reabsorption of
water from the collecting tubules and ducts
Sites of transport of solutes and water along the nephron.
Diuretic drugs
 Thiazide diuretics
 Hydrochlorthiazide
 Chlorthiazide
 Loop diuretics
 Furosemide
 Bumetanide
 Torsemide
 ethacrinic acid
 Potassium sparing diuretics
 Spironolactone
 Carbonic anhydrase inhibitors
 Acetazolamide
 Osmotic diuretics
 Mannitol
Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs.
 Thiazides
Inhibition of a Na+/Cl- cotransporter on the luminal membrane of the distal
convoluted tubule
Increased excretion of Na+ and Cl-
Loss of K+
Loss of Mg2+: occur with chronic use of thiazide diuretics
Decreased urinary calcium excretion: Thiazide diuretics decrease the Ca2+
content of urine by promoting the reabsorption of Ca2+.
This contrasts with the loop diuretics, which increase the Ca2+ concentration of the urine.
Reduced peripheral vascular resistance
S/E-Hypokalemia, Hyponatremia, Hyperuricemia (gout attack), Hypercalcemia,
Hyperglycemia (impaired release of insulin)
 Loop or High-Ceiling Diuretics

Inhibit the cotransport of Na+/K+/2Cl- in the luminal membrane in the

ascending limb of the loop of Henle.
Compared to all other classes of diuretics, these drugs have the highest efficacy
in mobilizing Na+ and Cl from the body.
They produce copious amounts of urine.
Furosemide is the most commonly used of these drugs.
Ethacrynic acid shows greater side effects and its use is therefore limited.
Bumetanide is much more potent than furosemide
S/E-Ototoxicity, Hyperuricemia, Acute hypovolemia, Hypomagnesemia,
Hyponatremia
 Potassium-Sparing Diuretics

Act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion

most often in combination with a thiazide
Aldosterone antagonist: Spironolactone
prevents Na+ reabsorption and,
therefore, prevents K+ and H+ secretion
 Diuretics cont’d

Carbonic anhydrase inhibitors:

Inihibit the enzyme carbonic anhydrase in renal tubule cells and lead
to increased excretion of bicarbonate, sodium and potassium ion in
urine
In eye it cause reduction in formation of aqueous humor
Used in acute angle glaucoma
Adverse effect:
• Drowsiness, hypokalemia, metabolic acidosis and epigastric
 Diuretics cont’d

Osmotic diuretics:
• Freely filtered at the glomerulus and relatively inert
pharmacologically and undergo limited reabsorption of renal
tubule
• They adminstered to increase osmolality of plasma & tubular fluid.
• Sometimes they produce nausea, vomiting, electrolyte imbalances
• They are used in cerebral edema and management of poisoning
 Calcium-Channel Blockers

Calcium-channel antagonists block the inward movement of calcium by binding

to L-type calcium channels in the heart and in smooth muscle of the coronary
and peripheral vasculature.
 This causes vascular smooth muscle to relax, dilating mainly arterioles.
Calcium-channel blockers are recommended when the preferred first-line
agents are contraindicated or ineffective.
 CCB’s …
Inhibit calcium entry into cells of the arteries
=> decreased afterload
Dihydropyridines:
Target specifically L-type channels on vascular smooth muscle cells
No cardiac effects (“Vasoselective Ca++ antagonists”)
Can cause peripheral edema
dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine,
nifedipine, and nisoldipine)
Nifedipine-Prototype
Nicardipine
Nimodipine
Nisoldipine
 cont’d

• Relax arteriolar smooth muscle by reducing calcium entry ·

• Dihydropyridines
• Nifedipine more vascular selectivity
• Amlodipine
Non dihydropyridines
• Diltiazem
• Verapamil least vascular selectivity
• Adverse effects:
• Flushing
• Oedema
• Dizziness
• Verapamil must also never be used in conjunction with b blocker
 Direct vasodilators
-include oral drugs like hydralazine and minoxidil
- used for long term outpatient treatment of HTN
- Parentrals include- nitroprusside, diazoxide w/c
are used in HTN emergency.
• Hydralazine [Dilates arterioles but not veins]
• Mechanism of action unknown
• combined with -blocker (to prevent the cardiac effects) and a diuretic (to
overcome the fluid retention).
• Useful in severe HTN at a dose of 40-200mg/d
• Side effects:
• Headache (due to vasodilation)  Tachycardia
• Nausea  Angina
• Reflex stimulation of the heart: precipitate an ischaemic attack
• Treatment restricted to people who are resistant to other drugs
 Antihypertensive cont’d

• Minoxidil (k channel Agonist)

• Increases outward K+ current => membrane hyperpolarization, which
inhibits Ca++ channel activity
• Used only for severe, treatment-resistant hypertension
• Efficacious orally active vasodilator
• Relaxes blood vessels by opening K+ channels stabilizing membrane
potential and makes contraction less likely.
• Causes K+ to rush out of the cell
• Arterial selective and used in patients not responding to hydralazine.
• Need to be used in conjunction with b blockers and diuretics b/c it causes
reflex sympathetic stimulation and Na and fluid retention.
• Adverse effects:
• Salt retention, Tachycardia ,Angina
• Major side effect: Hirsutism => used topically to treat baldness
(Rogaine®)
• Sodium nitroprusside Antihypertensive cont’d

• Releases NO - relaxes smooth muscle in blood vessels

• Dilates arterial and venous vessels
• Only route of administration is intravenously
• Reserved for acute use only ( only to treat hypertensive emergencies)
• It is light sensitive, & the solution must be made on the spot
• The drug contains cyanide - cyanide poisoning may develop causing Serious toxicity:
metabolic acidosis, arrhythmias, excessive hypotension and death
• CN- poisoning can be managed by prophylaxis administration of Na-thiosulphate .
 Sympatholytic agents in the treatment of hypertension
A. Older agents
 These drugs lower blood pressure by preventing normal physiologic release of
norepinephrine from postganglionic sympathetic neurons
Guanethidine
Highly polar; does not get into the CNS, acts peripherally
Taken into secretory vesicles and depletes NE in the pre synaptic terminal
Decrease blood pressure by venodilation, thus reducing venous return and
hence reducing cardiac output
Side effect:
Postural hypotension
Weakness
Impotence
Diarrhea
 Antihypertensive cont’d
• Reserpine
• Blocks NE transport into synaptic vesicles
• May also interfere with uptake mechanisms
• Enters the CNS
• Side effects:
• Sedation
• Depression
• Parkinsonism
 Antihypertensive cont’d
B. Centrally acting antihypertensive
methyldopa [prodrug]: (250, 500mg tablet)
• Enters the CNS via active transport into the brain
• Converted to methyl NE, 2 agonist
• Adverse effects:
• Dreams, sedation, depression
• Dry mouth (due to inhibition of the medullary areas controlling
salivation)
Clonidine:

• Selective 2 agonist

• Lipid soluble drug , so enter BBB

• Can cause rebound hypertension on cessation
• SEs are dry mouth, , sedation etc…
• C/I in patients with depression
 Antihypertensive cont’d

C. adrenoceptor antagonist
• dilates blood vessels
• reduce plasma triglyceride, reduce LDL; raise in HDL

-blocker
• Prazosin
• Terazosin

Dilate both resistance and capacitance vessels.

Adverse effects:
• Postural hypotension (occurs on the first dose)
• Failure to ejaculate
Labetalol
• an 1 antagonist and a non-selective b antagonist (weak)

• not used widely

• Choice for emergencies where you want to reduce blood pressure
quickly (by reducing CO and TPR)
• Useful in pre ecclampsia of pregnancy
 Antihypertensive cont’d
- BLOCKERS
• Reduce BP by: Blocking 1 receptors of the heart and the kidney
• Propranalol - non selective
• Atenolol - 1 selective
• Metoprolol-more selective for 1 (good for asthmatics)
• adverse effects:
• Cold extremities and bronchospasm( 2 effect)
• Dreams, insomnia
• Increased triglycerides since b receptors are also present in
the liver to increase fat metabolism
• Withdrawal syndrome
• e.g. Propranolol may result in tachycardia
 Antihypertensive cont’d
SUMMRY OF ANTIHPERTENSIVE DRUGS

• Initial treatment with nonpharmacologic

• Drug therapy in mild hypertension with monotherapy of:

• Thaizide diuretic
• beta blockers [ in young patients, patients with tachycardia, angina,
hypertension]
• Calcium channel blockers
• Angiotensin converting enzyme inhibitor
• Central sympathoplegic agent
Any one of the following classes of drugs could be used as first step agents:
Diuretics, Beta blockers, Calcium antagonists and Angeotensin Converting
enzyme Inhibitors (ACEIs).
A. First line drugs for non -Emergency conditions
 Hydrochlorothiazide, 12.5- 50 mg/day, p.o.
S/E: hypokalemia, hyponatrimia, glucose intolerance,hyperuricemia
C/I: gouty arthritis, diabetis mellitus, hypokalemia,
Dosage forms: tablet, 25mg
AND/OR
 Nifedipine, 10 –40 mg, p.o., tid.
S/E: flushing, oedema of ankle, headache, gingival hypertrophy
C/I: unstable angina, hypotension
Drug Interaction: Cimetidine may enhance it’s anti-hypertensive
effect
Dosage forms: tablet, 10 mg, 20 mg; capsule, 5 mg, 10 mg, 20 mg
AND/OR
 Propranolol 40-160 mg p.o divided in to 2-4 doses
B. Alterative
 Enalapril, 2.5- 40mg p.o., once or divided into two doses daily.
AND /OR
 Methyldopa, 250-2000 mg p.o. in divided doses
S/E: dry mouth, water and salt retention, and drowsiness,fever,hepatitis.
C/I: active hepatic disease
Dosage forms: tablet, 250 mg, and 500 mg
OR
 Hydralazine, 10-20 mg, slow i.v. can be given in severe HTN.
S/E: nausea, headache, weakness, palpitation, flushing.
C/I: porphyria, aortic stenosis, lupus erythematosis renal failure
Dosage forms: injection, 20m/ml in 1ml ampoule
OR
 Atenolol, 50 – 100 mg p.o daily.
Dosage forms: tablet, 50 mg, 100 mg
C. Treatment of Hypertensive Emergency

Hydralazine, 5 mg i.v. every 15-min should be given until the mean arterial BP is
reduced by 25% (within minutes to 2 hours), then towards 160/100 mm Hg within
2-6 hours.
Depending on the underlying condition/target organ damage, furosemide, 40 mg
i.v. can be used according to BP response.
D. Treatment of Hypertensive Urgency
Nifedipine, 20-120 mg p.o in divided doses per day could be used.
OR
Captopril, 25-50 mg p.o three times daily
S/E: tachycardia, weight loss, stomatitis, photosensitivity
C/I: porphyria
Dosage forms: Tablet, 12.5 mg, 25 mg, 50 mg, 100 mg.
 Antihypertensive cont’d

• Black patients respond well to diuretic and CCB than to beta-blockers and ACE
inhibitors
• If monotherapy is unsuccessful, thiazide diuretic can be combined with beta-
blockers, CCB, or ACE inhibitors
• If hypertension is still not under control, a vasodilator such as hydralazine can be
combined.
List of common Anti-hypertensive drugs and their dosage
Drugs used in the treatment of hypertensive crisis
 Patients with Compelling Indications

The JNC7 report identifies six compelling indications.

Left Ventricular Dysfunction: Systolic Heart Failure
ACE inhibitor therapy reduced CV morbidity and mortality;
diuretics provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often
needed
Bisoprolol, carvedilol, and metoprolol succinate are the only β-blockers proven to be
beneficial in left ventricular dysfunction.
Post-Myocardial Infarction
β-Blockers decrease cardiac adrenergic stimulation and reduce the risk of a subsequent MI
or sudden cardiac death, as demonstrated in clinical trials.
ACE inhibitors improve cardiac remodeling, cardiac function, and reduce CV events post-
MI.
Coronary Artery Disease
β-Blocker therapy has the most evidence demonstrating benefits in these patients.
β-Blockers are first-line therapy in chronic stable angina and have the ability to reduce BP,
improve myocardial oxygen consumption and decrease demand.
Diabetes Mellitus
All patients with diabetes and hypertension should be treated with either an ACE inhibitor
or an ARB
Pharmacologically, both of these agents should provide nephroprotection as a result of
vasodilation in the efferent arteriole of the kidney.
Chronic Kidney Disease

In addition to lowering BP, ACE inhibitors and ARBs reduce intraglomerular pressure,

which can theoretically provide additional benefits by further reducing the decline in kidney

function.

ACE inhibitors and ARBs have been shown to reduce progression of chronic kidney disease

in diabetes
 II. Heart failure

Heart failure (HF) is a complex, progressive disorder in which the heart is

unable to pump sufficient blood to meet the needs of the body.
CHF is characterised by inadequate contractility, so that the ventricles have
difficulty in expelling sufficient blood => rise in venous blood pressures
Raised venous pressures impair fluid drainage from the tissues and produce a
variety of serious clinical effects:
Right sided heart failure causes lower limb oedema. Blood pooling in the
lower extremities is associated with intravascular clotting and thromboembolism
Left sided heart failure produces pulmonary oedema and respiratory distress
ETIOLOGY
NYHA Functional Classification
Classification of severity

class:

I – no limitation of physical activity

II – slight limitation
III – marked limitation
IV – symptoms occur at rest
AHA HF staging system
 TREATMENT

Chronic Heart Failure

■ DESIRED OUTCOMES
The goals of therapy in management of chronic heart failure are to:
improve the patient’s quality of life
relieve or reduce symptoms;
prevent or minimize hospitalizations for exacerbations of heart failure;
slow progression of the disease process; and
prolong survival.
• Treatment options:
• 1. Diuretics
• Loop diuretics
• Thiazides
• Spironolactone
• 2. ACE inhibitors & AT II antagonists
• 3. Vasodilators
• Nitrates
• 4. Cardiac Glycosides
Drugs with positive inotropic effect Heart failure

1. Cardiac glycosides
• Includes digoxin and digitoxin
• Mechanism: The cardiac glycosides inhibit the Na+/K+-ATPase pump, which
causes an increase in intracellular Na+ => slowing of the Na+/Ca++-exchanger
=> increase in intracellular Ca++.
• slow the heart rate and increase the force of contraction

• Digitoxin: more lipid soluble and has long t1/2 than digoxin
Ion movements during the contraction of cardiac muscle. ATPase = adenosine triphosphatase.
 Con’d…

• Therapeutic use of cardiac glycosides

• Congestive heart failure
• Atrial fibrillation & Atrial flutter
• Paroxysmal atrial tachycardia
• Toxicity (low TI)
• GI: anorexia, nausea, vomiting, diarrhea
• Cardiac effect: bradycardia, heart block, arrhythmia
• CNS: head ache, hallucination, delirium, visual disturbance
 Con’d …
Improve cardiac performance (=positive inotrope)
Increases cardiac output
Decreased sympathetic tone
Increase urine output
Decreased renin release
Does not prolong life (only symptom relief)
 Heart failure
2. Biperidine derivatives ,e.g. amrinone & milrinone

Have a positive inotropic and vasodilator effects

Mechanism: inhibition of phosphodiesterase
Biperidine derivatives are used in cases of heart failure resistant to treatment with
cardiac glycosides or vasodilator

3. Beta-adrenergic stimulants, e.g. dobutamine & dopamine

Increase in myocardial contractility and increase cardiac output

Positive chronotropic effect of these drugs minimizes their use
Reserved for the management of acute failure or failure resistant to other agents
 Heart failure

4. Methylxanthines, e.g.theophilline
Aminophilline has positive inotropic, bronchodilator and modest effect on renal
blood flow
Aminophilline is used in management of acute left ventricular failure
Drugs without positive inotropic effect
1. Diuretics
Mild failure: thaizides; moderate/severe: frusemide
• In acute failure, diuretic reduces ventricular preload
 Heart failure
2. Vasodilators
They provide reduction in preload (through venous dilation) or reduction in
afterload (through arteriolar dilation) or both
Hydralazine: direct arteriodilator; reduce vascular resistance and increase
cardiac output
Sodium nitroprusside: mixed venous and arteriolar dilator used for acute
reduction of BP
Vasodilator agents: reserved for patients who are intolerant of or who have
contraindications to ACE inhibotors
 Heart failure

3. Angiotensin converting enzyme (ACE) inhibitors

Angiotensin II involved in undesirable compensatory response to HF

ACE inhibitors reduce peripheral resistance and reduces salt and water
retention by way of reduction of aldosterone secretion
Effects of angiotensin-converting enzyme (ACE) inhibitors.
Heart Failure
Summary
ACE inhibitors:
Enalapril
start with 2.5mg once to twice per day.
 Escalate dose to target of 10-20mg, BID
Dosage forms: Tablet, 2.5mg, 5mg, 10mg, 20mg, 40mg OR
Lisinopril,
start with 2.5-5mg,once daily.
Increase dose to target of 20 – 40mg once daily
Dosage forms: Tablet 2.5mg, 5mg, 10mg, 20mg OR
 Captopril
 start with, 6.25-12.5mg 3 times/dayp P.O.,.
Increase dose to target 50mg, TID
Dosage forms: Tablet, 12.5mg, 25mg, 50mg
Diuretics:
Furosemide,
40mg-80mg/day in two divided doses when there is evidence of fluid overload with
Spironolactone 25 to50mg/day or KCl 600 to 1200mg, BID
Dosage forms: Tablet, 40mg, 80mg
ARB’s:
 Valsartan,
 start with 40mg, BID; titrate to 80-160 mg, BID, maximum dose-320mg/day
 Dosage forms: Tablet, 40mg, 80mg, 160mg, 320mg, OR
Candesartan-
 start with 4 mg/day; increase dose as tolerated, target dose is 32mg/day
 Dosage forms: Tablet, 4mg, 8mg, 16mg
Treatment algorithm for patients with ACC/AHA stages A and B heart failure.
Treatment algorithm for patients with ACC/AHA stage C heart failure

ARA, aldosterone receptor antagonist;ISDN, isosorbide dinitrate

 Heart Failure

Most patients with symptomatic HF should be routinely treated with ACE

inhibitor, β-blocker, and a diuretic.
The benefits of these medications on slowing heart failure progression,
reducing morbidity and mortality, and improving symptoms are clearly
established.
Patients should be treated with a diuretic if there is evidence of fluid
retention.
Treatment with digoxin may also be considered to improve symptoms and
reduce hospitalizations.
 Heart Failure

In patients with heart failure, ACE inhibitors improve survival, slow disease
progression, reduce hospitalizations, and improve quality of life.
When ACE inhibitors are contraindicated or not tolerated, an angiotensin II
rereceptor blocker or the combination of hydralazine and isosorbide dinitrate
are reasonable alternatives.
only two ARB’s, candesartan and valsartan, are approved for the treatment
of heart failure
Patients with asymptomatic left ventricular dysfunction and/or a previous
myocardial infarction (stage B of the American College of Cardiologists/
American Heart Association [ACC/AHA] classification scheme) should also
receive ACE inhibitors,
with the goal of preventing symptomatic heart failure and reducing mortality.
 Heart Failure

The β-blockers carvedilol, metoprolol succinate

controlled-release/extended-release CR/XL, and bisoprolol
prolong survival,
decrease hospitalizations and
 the need for transplantation, and
 cause “reverse remodeling” of the left ventricle.
These agents are recommended for all patients with a reduced left
ventricular ejection fraction.
Therapy must be instituted at low doses, with slow upward titration to
the target dose.
Heart Failure
 Heart Failure

Although chronic diuretic therapy frequently is used in heart failure

patients, it is not mandatory.
Diuretic therapy along with sodium restriction is required only in
those patients with peripheral edema and/or pulmonary congestion.
Many patients will need continued diuretic therapy to maintain
euvolemia after fluid overload is resolved.
 Heart Failure

Digoxin does not improve survival in patients with heart failure but
does provide symptomatic benefits.
 Digoxin doses should be adjusted to achieve plasma concentrations
of 0.5 to 1.0 ng/mL; higher plasma concentrations are not associated
with additional benefits but may be associated with increased risk of
toxicity.
 Heart Failure

Aldosterone antagonism with low-dose spironolactone reduces

mortality in patients with New York Heart Association (NYHA)
classes III and IV heart failure and thus should be strongly considered
in these patients, provided that potassium and renal function can be
carefully monitored.
 Aldosterone antagonists should also be considered soon after
myocardial infarction in patients with left ventricular dysfunction and
either heart failure or diabetes.
 Heart Failure

The combination of hydralazine and nitrates improves the composite

end point of mortality, hospitalizations for heart failure, and quality of
life in African Americans who receive standard therapy.
The addition of hydralazine and nitrates is reasonable in patients with
persistent symptoms despite optimized therapy with an ACE inhibitor
(or angiotensin receptor blocker) and β-blocker
 III. Pharmacotherapy of angina pectoris

Medical term for chest pain or discomfort due to coronary heart disease. 

Typical angina pectoris “tight heart” is uncomfortable pressure, fullness,

squeezing or pain in the center of the chest

Angina pectoris develops as a result of an imbalance between the oxygen supply

and oxygen demand of the myocardium

Angina is a symptom of myocardial ischemia, which occurs when the

myocardium does not receive sufficient oxygen.
 Types of Angina

Typical or Stable angina

episodes of chest discomfort that are usually predictable, such as

on exertion or under stress
fixed obstruction produced by coronary atherosclerosis
produced by physical activity, emotional excitement, or any other
cause of increased cardiac workload.
promptly relieved by rest or nitroglycerin (a vasodilator).
 Cont’d

Unstable Angina
the chest pain is unexpected and usually occurs while at rest.  The
discomfort may be more severe and prolonged than typical angina
The symptoms are not relieved by rest or nitroglycerin.
Variant or Prinzmetal's or vasospastic angina
It nearly always occurs when a person is at rest, and does not follow
physical exertion or emotional stress.
 Variant angina is due to coronary artery spasm (Treatment: Ca++ channel
blockers).
may have significant coronary atherosclerosis
 Drugs used in angina pectoris

1. Organic nitrates [e.g. nitroglycine, isosorbide dinitrate]

 They are potent vasodilators

 Nitrates act by mimicking the vasodilator action of nitric oxide  relax smooth

muscle

 Onset of nitrates: 2-3minute

 Duration lasts for 2hrs from tongue or when chewed

 Adverse effect: flushing, weakness, dizziness, tachycardia, palpitation, vertigo,

sweating, syncope, localized burning with sublingual preparation

 Con’d

Isosorbide-dinitrate (ISDN)
More stable than nitroglycerol
Longer lasting effect
Tolerance can occur – give lowest dose possible
Nitroglycerin
 Organic nitrate
 Acts on vascular smooth muscle to promote vasodilation
 Primarily works on veins, only modest dilation of arterioles
 it causes dilation of the large veins, resulting in pooling of blood in the veins.
This diminishes preload
 Decreases oxygen demand by decreasing venous return => use in stable
angina
 Oral, sublingual, IV, buccal and transdermal administration
 Adverse effects – headache, tachycardia, hypotension
 Never to be combined with other drugs causing
vasodilation (Viagra®) or hypotension
It was originally believed that nitrates and nitrites dilated coronary blood
vessels, thereby increasing blood flow to the heart.

It is now believed that atherosclerosis limits coronary dilation and that the
benefits of nitrates and nitrites are due to dilation of arterioles and veins in
the periphery.

The resultant reduction in preload, and to a lesser extent in afterload,

decreases the workload of the heart and lowers myocardial oxygen demand.
 angina pectoris cont’d
2. Adrenergic blocking agents
Exercise and emotional excitement induce angina by increasing heart
rate, and myocardial contractility through increased sympathetic activity
Beta receptor blocking agents [atenelol, propranolol, metoprolol,
labetalol] prevent angina by blocking all these effects
Adverse effect: lethargy, fatigue, rash, cold hands and feet, nausea,
breathlessness, nightmare and bronchospasm.

Selective beta1-blockers have relatively less adverse effect

 angina pectoris cont’d

3. Calcium channel blockers

Interfere with calcium entry into myocardial and vascular smooth muscle
Nifedipine, felodipine, verapamil and diltiazem

Adverse effect: flushing, nausea/vomiting, headache, ankle swelling, dizziness,

constipation, etc

4. Miscellaneous drugs, e.g. aspirin

 Decreases thromboxane A2

 75mg per day produce antiplatelet activity and reduce the risk of
myocardial angina
 IV. Arrhythmias:

Abnormal rhythms of the heart that cause the heart to pump less
effectively
Arrhythmia occurs:
when the heart’s natural pacemaker develops an abnormal
rate or rhythm- aberrations in impulse generation (abnormal
automaticity)
when the normal conduction path is interrupted- defect in
impulse conduction
when another part of the heart takes over as pacemaker
• Electrical activity of heart
• Cardiac muscle action potential

Phase 0. Rapid depolarization of AP

due to the inward diffusion of sodium.
Phase 1. A brief period of initial repolarization
due to slow efflux of K+ & rapid decrease
of Na+ influx also influx of some Cl-

Phase 2. The plateau of action potential

-due to influx of Ca++.
-Now Ca++ influx & K+ efflux almost equal,
- so membrane potential is stable at level.
Phase 3. Rapid repolarization due to rapid
efflux of K+ as calcium channels close
Phase 4. The potential quickly reaches
7/3/22 03:55:20 AM
the resting membrane potential
Cardiovascular physiology 121
Types of arrhythmia:
• Tachycardia: unusually fast heartbeat
• Bradycardia: unusually slow heartbeat
• Atrial fibrillation: the atria quiver (rapid shaking movement) rather than
contract normally because of rapid and irregular electrical signals in the heart.
Beside the abnormal heart beat, there is also a risk that blood will pool in the
atria, possibly causing the formation of blood clots.
• Ventricular fibrillation: life threatening condition in which the heart ceases to
beat regularly and instead “quivers” or fibrillates very rapidly – sometimes at
350 beats per minute or more (causes 350,000 death/year in the US - “sudden
cardiac arrest”)
 Antiarrhthmics cont’d

• Pharmacotherapy of cardiac arrhthmias:

• Drugs used in the treatment of cardiac arrhthmias are traditionally classified
into:

1. Class I: Na+ channel blockers [quinidine, lidocaine, phenytoin, flecainide,]

2. class II: beta-adrenergic blockers [propranolol,Metoprolol, etc]
3. class III: K+ channel blockers [amiodarone, bretylium, sotalol, etc]
4. class IV: Ca2+ channel blockers [verapamil, etc]
5. class V: digitalis [digoxin]
Class I drugs
Antiarrhthmics cont’d

Quinidine
- Blocks Na+ channel so that it increase in threshold for excitability
- It is well absorbed
- Adverse effect: SA block, cinchonism, severe headache, diplopia and photophobia
Lidocaine
- Used commonly as local anesthetic
- Block both open and inactivated sodium channel
- Decrease automaticity
- Adverse effect: excessive dose cause cardiac arrest, dizziness, drowsiness,
seizures, etc
Flecainide
-
Class II drugs
Antiarrhthmics cont’d

Propranolol:
• Myocaridial sympathetic beta-receptor stimulation
increases automaticity,
enhances AV conduction velocity and
 shortens the refractory period.
• Propranolol can reverse these effects.
Metoprolol
• most widely used in the treatment of cardiac arrhythmias.
• Compared to propranolol, it reduces the risk of bronchospasm.
• Therapeutic uses:
• useful in tachyarrhythmias
• Useful in patients with atrial fibrillation and flutter refractory to digitalis
Class III drugs Antiarrhthmics cont’d
Amiodarone:
• It has complex effects, showing Class I, II, III, and IV actions.
• Its dominant effect is prolongation of the AP duration and the
refractory period.
• Amiodarone has antianginal as well as antiarrhythmic activity.
• Used in tXt of refractory supraventricular tachyarrhythmia and
ventricular tachyarrhythmia
• It depresses sinus, atrial and AV nodal function
• Adverse effect: anorexia, nausea, abdominal pain, tremor, hallucination,
peripheral neuropathy, AV block
Class IV drugs

Verapamil and diltiazem :

Therapeutic uses:
 Verapamil and diltiazem are more effective against atrial than
against ventricular arrhythmias.
They are useful in treating reentrant supraventricular tachycardia and
in reducing the ventricular rate in atrial flutter and fibrillation.
Class V drugs
Antiarrhthmics cont’d
Digoxin:
• Prolongs the effective refractory period of AV node
• This action is important in slowing rapid ventricular rate in patients with atrial fibrillation
Others
1. Adenosine
• Adenosine is a naturally occurring nucleoside
• at high doses, the drug decreases conduction velocity, prolongs the refractory
period, and decreases automaticity in the AV node.
• Used acutely (i.v.) to reverse supraventricular tachycardia
• Adverse effects:
• Flushing (vasodilator effect)
• Bronchospasm
• Chest pain (due to bronchospasm)
2. Atropine
• Blocks parasympathetic activity to the heart
• Used to treat sinus bradycardia (< 60/min)
Summary of Drugs for arrhythmia
1. Atrial Fibrillation or Atrial flutter

 Atrial fibrillation is marked by disorganized, rapid, and irregular atrial

activation which results in irregular ventricular response.
 Atrial flutter is characterized by regular rapid atrial rate of 260–300 beats per
minute, which usually results in a regular ventricular response
First line:
Metoprolol, 2.5-5mg, IV, over 3–5 min, to maximum total dose 15mg
over 10-15 minutes
Dosage forms: 5ml ampoule of 1 mg/ml, 5mg/ml
Alternative
Digoxin, 0.25mg, IV, q2h until 1 mg total (digoxin is the first line medicine if atrial
fibrillation is associated with severe left Ventricular dysfunction)
2. Paroxysmal supra-ventricular tachycardia
Termination of acute episode :
First line :
Adenosine, I.V, very rapidly (over 1-2 seconds): Initial: 6mg; if not effective
within 1-2 minutes, 12mg may be given; may repeat 12mg bolus if needed.
Follow each dose with 20mL very rapid Normal saline flush.
Dosage forms: Injection, 3mg/ml
Alternatives:
 Verapamil, I.V, 2.5-5mg over 2 minutes; second dose of 5-10mg may be given after 15-
30 minutes; maximum total dose: 20-30mg
 Metoprolol, IV, 2.5-5mg every 2-5 minutes (maximum total dose: 15mg over a 10-15
minute period).
Digoxin, 0.5 to 1mg IV over a period of 10 to 15 min followed by 0.25mg every 2-4
hours with a total dose less than 1.5mg with in 24-hour period
 Supra V… con’d…

Prevention of recurrence (chronic therapy)

First line – beta blockers
 Metoprolol, Extended release: 25-200mg/day, P.O.
Atenolol, 25-100mg/day, P.O. or
 Propranolol 10-40mg P.O. 3-4 times daily
 Alternatives : Verapamil, immediate release 40-120mg, P.O.TID
or extended release 180-360mg/day
3. Ventricular Tachycardias
First line-Intravenous Amiodarone
Stable VT regimen:
Step 1: 150mg over first 10 minutes (dilute in 100mL D5W)
Step 2: 360mg over next 6 hours (dilute 500mL D5W): 1 mg/minute
Step 3: 540mg (dilute in 500 to 1000ml D5W) over next 18 hours:
0.5mg/minute
Pulseless VT (cardiac arrest) regimen: If unresponsive to defibrillation
attempts and CPR
Amiodarone, I.V push, 300mg (undiluted), if VT or VF recurs, administer
supplemental dose of 150mg and continue CPR.
Dosage forms: Injection, 50mg/ml
 VT con’d…

Alternative
Intravenous lidocaine :
Both stable VT and Pulseless VT(cardiac arrest) regimen: Lidocaine, I.V,
1-1.5mg/kg; repeat with 0.5-0.75mg/kg every 5-10 minutes if no response.
(maximum cumulative dose: 3mg/kg).
Prevention of recurrence
First line Amiodarone, P.O., 800-1600mg/day in 2 divided doses for 1-3
weeks, when adequate arrhythmia control is achieved, decrease to 600-
800mg/day in 1-2 doses for 1 month.
Maintenance: 400mg/day
4. Atrioventricular (AV) Block

AV block describes a delay/block of atrial impulses at the

atrioventricular node of varying severity.
For Acute termination:
First line
Isoproterenol, Continuous I.V. infusion: 2-10 ug/minute; titrate to
patient response
Dosage forms: Injection, 0.02mg/ml, 0.2mg/ml
Alternative
Adrenaline, I.V, infusion, 2-10 ug/minute
 Drugs used in hypotensive states and shock
• Antihypotensive agents
Agents intended to increase the volume of blood in active circulation [iv
fluid]
Vasoconstrictors [adrenaline, methoxamine, phenylphrine,
mephentermine, ephedrine, vasopressin, angiotensin]
• tXt of shock
Cardiogenic shock (pump failure) :
 dopamine 5-50mcg/kg/min IV diluted with dextrose 5% in Water, or
in sodium chloride solution 0.9%
Anaphlactic shock: Epinephrine[vasoconstrictor drug]
Hypovolemic shock:
Infusion of fluid (Normal saline or Ringer lactate) 1-2 liters
fast;
reassess the patient for adequacy of treatment; if needed repeat
the bolus with maximum tolerated dose being 60 – 80 ml/kg
with in the first 1 – 2 hr
Septic shock:
Dopamine, 5-50 mcg/kg/min IV diluted with dextrose 5% in
Water, or in sodium chloride solution 0.9%
AUTACOIDS
 autacoids

• Autacoids: endogenous peptides, prostaglandins, leukotrienes

and cytokines
• These are sometimes also called local hormones
 HISTAMINE
• It is potent tissue amine
• Formed by decarboxylation of histidine and major portion is stored in
mast cells and basophils

• Mechanisms of action:
• Stimulation of H1 receptors results in smooth muscle contraction,
increased vascular permeability, and mucus production
• These effects are blocked by H1 antagonists
• Action of H2 receptors increases gastric acid production, and this
effect is blocked by H2 blockers such as cimetidine
 Histamine cont’d

Pharmacological actions:
Cardiovascular system: histamine produces dilatation of capillaries and venules
accompanied by a fall in blood pressure. The mechanism is direct relaxation of
smooth muscles of blood vessels. The effect can not be adequately reversed by
antihistaminic agents but by adrenaline.
Smooth muscles: histamine directly stimulates the smooth muscles of various
tissues including the bronchi and uterus. Histamine induced bronchospasm is
effectively antagonized by adrenaline.
Exocrine glands: it stimulates HCl secretion by the gastric mucosa
CNS: histamine is formed locally in the brain and is believed to be a “waking
amine”
Miscellaneous actions: induction of itching and pain
 Histamine cont’d

• Histamine plays important role in anaphylaxis and other forms of allergic

reactions
• Its release may be induced by various agents including certain venoms, drugs,
trauma (thermal, chemical, radiation), and antigen-antibody reaction.

Treatment of anaphylaxis:
• Exposure to the offending agent should be terminated
• Adrenaline [im or sc route]
• Hypotension should be corrected with infusion of intravenous fluids
• Corticosteroids are occasionally used
• Supportive measures: administration of oxygen and artificial respiration if
necessary
 Histamine cont’d

H1 Receptor antagonists: classified into

potent and sedative: such as diphenhyramine and promethazine
Potent but less sedative: such as cyclizine and chlorpheniramine
Less potent and less sedative: such as pheniramine
Non-sedative: such as terfenadine, loratadine and cetrizine
• Newer generation agents are relatively free of central depressant effects
• These possess anti-emetic effects
 Histamine cont’d

• Pharmacological actions of H1 antagonist:

• Antihistaminic actions: histamine blockade at various site
• Other effects: independent of antihistamine
• Sedation, drowsiness,
• Antimotion sickness effects [prometazine, diphenhydramine,
dimenhydinate]
• Promethazine and mepyramine have significant local anesthetic effect
• Majority possess atropine like effect
 Histamine cont’d
• Pharmacokinetics:
• Well absorbed following oral and parenteral administration
• Metabolized by the liver, degradation products are removed in the urine

• Therapeutic use:

• Allergic disorders: including urticaria, seasonal hay fever, atopic and contact
dermatitis, mild blood transfusion reaction.

• They are not effective in bronchial asthma and common cold.

 Histamine cont’d

• Other uses of antihistamine:

Diphenhydramine and promethazine are used as hypnotics
Dimenhydrinate and promethazine are employed in the prevention and
treatment of motion sickness, other vomiting disorders associated with
labyrinthine dysfunction as well as nausea and vomiting associated with
pregnancy
Diphenhydramine is used in the treatment of cough as combination
preparation with other agents
 Histamine cont’d

• Adverse effects antihistamine:

• Usually mild
• Sedation
• Dryness of mouth [anticholinergic]
 5-HYDROXYTREPTAMINE (SEROTONIN)

• Widely distributed in plants and animals

• Highest concentration in animals is found in the pineal gland

• Synthesized from the aminoacid tryptophan and acts on several types of receptors
• Pharmacological actions:
• 5-HT causes constriction of renal, splanchic, meningeal and pulmonary
arteries and veins
• Dilation of blood vessels of skeletal muscles, coronaries and skin capillaries
• Serotonin is distributed in the CNS, serving as neurotransmitter
• Altered functions may be responsible for disturbances in sleep, mood,
sleep behavior, motor activity, pain perception, migraine, temperature
regulation, psychiatric disorder and extrapyramidal activity
 SEROTONIN cont’d

• Serotonin Agonists:
• Sumatriptan: selective agonist 5-HT1 receptor; and is effective in treating
acute attacks of migraine, but not useful in the prevention. It releives nausea
and vomiting, but the head ache may recur
• It is administered orally or subcutaneous route
• Adverse effect: flushing and heat at the injection site, neck pain,
dizziness, angina and hypertension
• Buspirone: serotonin agonist; effective anxiolytic agent
 SEROTONIN cont’d

• Serotonin Antagonists:
• Methysergide: blocks the actions of 5-HT
• a weak direct vasoconstrictor effect. It is an effective prophylactic agent for
migrainous headaches. Bu has no effect in treating acute attacks, even may
worsen the condition.
• Cyproheptadine: It is used to relieve itching associated with skin disorders such as
allergic dermatitis. The common adverse effect is drowsiness.
• Ondansetron: is specific 5-HT3 receptor antagonist. It is useful in the management
of nausea and vomiting associated with cytotoxic therapy.
PROSTAGLANDINS
• origin from prostate gland
 Prostaglandin cont’d

• There is more than one form of cyclo-oxygenase (COX).

COX 1
This is a constitutive enzyme- always present and active
It is found in most cells
It is continuously forming prostaglandins in small amounts
The prostaglandins it produces are physiologically important (important under
normal conditions)
COX 2
not normally active
Its formation is induced by signals (mainly inflammatory)
It produces very high levels of prostaglandins in a short amount of time
(compared to COX 1 which produces small amounts over a prolonged time)
The prostaglandins produced are only released during pathological conditions
 Prostaglandin cont’d

Pharmacological actions of prostaglandins:

• Bronchial smooth muscle
• All prostaglandins cause bronchial relaxation.
• The exception is PGD2 which causes contraction of bronchial
smooth muscle
• Leukotrienes have been implicated in the involvement of asthma by
being bronchoconstrictors (more on leukotrienes later)
• Uterine smooth muscle
• PGE2 and PGF2a cause contraction of the pregnant uterus. (In the
non pregnant uterus, PGE2 may cause relaxation).
 Prostaglandin cont’d

• Gastrointestinal smooth muscle

• PGE2 and PGF2a cause the GIT to contract strongly. This can lead to side
effects such as abdominal pains, constipation
• PGE2 and PGI2 can inhibit gastric acid secretion
• More importantly, they can increase the flow of blood to the gastric lining (due
to vasodilator effect).
• Kidney arterioles
• Under normal physiological conditions, prostaglandins are of minimal
importance.
• However, under conditions where blood flow to the kidney’s is compromised,
prostaglandins become important in causing vasodilation of the arterioles,
maintaining GFR and preventing ischaemia of renal tissue.
 Prostaglandin cont’d
• Central nervous system
• PGE2 plays a part in the induction of fever,
• PGE2 and PGI2 are involved in the generation of pain. They are not algesic
(they do not cause pain directly) but are known as hyperalgesic.
• Inflammation
• Prostaglandins (and leukotrienes) play an important part in all stages of the
inflammatory reaction
• Therapeutic uses of its analogue eg misoprsitol:
• Cervical ripening and labor induction, control of postpartum hemorrhage,
induction of abortion and prophylaxis of NSAID- induced peptic ulcers. They
are also finding several other uses more recently such as erectile dysfunction
and glaucoma.
 Prostaglandin cont’d

• Adverse effects of prostaglandins:

Diarrhea, abdominal cramps, headache, nausea and vomiting
• CI
Pregnancy,
 Y o u
an k
Th Q ?
A n y

160