anti hypertensive drugs part 1
Post on 16-Jul-2015
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TOPICS TO BE DISCUSSED
▪ Diuretics
▪ ACE inhibitors
▪ Angiotensin receptor blockers
▪ Calcium channel blockers
Diuretics
First line of drugs for mild to moderate Hypertension Used in patients with adequate renal function.They do not lower BP in normotensives.
Diuretics-Definition And Classification
Def : These are the drugs which cause a net loss of sodium and water in urine.
Classification :
1) Thiazides : Hydrochlorothiazide, Chlorthalidone, Indapamide.
2) High ceiling : Furosemide.
3) Potassium sparing : Spironolactone , Amiloride.
Thiazides-Mechanism of Action
inhibit Na+ and Cl- transporter in distal convoluted tubules
increased Na+ and Cl- excretion
ADVANTAGES OF USING THIAZIDES
▪ During long term treatment with thiazides – heart rate and cardiac output remain unaffected.
▪ It has no effect on capacitance vessels .
▪ Sympathetic reflexes are not impaired.
▪ Postural hypotension is rare.
Pharmacokinetics
orally administered
poor absorption
onset of action in ~ 1 hour
wide range of T 1/2 amongst different thiazides, longer then loop diuretics
free drug enters tubules by filtration and by organic acid secretion
Therapeutic Uses
hypertension
congestive heart failure
hypercalciuria: prevent excess Ca2+ excretion to form stones in ducts
osteoperosis
nephrogenic diabetes insipidus
treatment of Li+ toxicity
Side Effects
hypokalemia
increased Na+ exchange in CCD
hyponatremia
hyperglycemia
diminished insulin secretion
elevated plasma lipids
hyperuricemia
hypercalcemia
Contraindications
▪ Pregnancy
▪ Gout
▪ Severe renal or hepatic impairment
▪ Pre-existing hypercalcaemia
▪ Hypokalemia
Loop Diuretics
▪ The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics.
▪ Loop diuretics cause decreased renal vascular resistance and increased renal blood flow.
▪ Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it.
Loop diuretics-mechanism of action
inhibits apical Na-K-2Cl transporter in thick ascending loop of henle
competes with Cl- binding site
enhances passive Mg2+ and Ca2+ excretion
increased K+ and H+ excretion in CCD
inhibits reabsorption of ~25% of glomerular filtrate
Pharmacokinetics
orally administered, rapid absorption
rapid onset of action
bound to plasma proteins
Therapeutic Uses
edema: cardiac, pulmonary or renal
chronic renal failure or nephrosis
hypertension
Hypercalcemia
acute and chronic hyperkalemia
Adverse Effects
hypokalemia
Hyperuricemia
metabolic alkalosis
hyponatremia
ototoxicity
Mg2+ depletion
Drug interactions
▪ NSAIDs
▪ Lithium
▪ K+ depleting agents
▪ Antidiabetic drugs
▪ Thiazides
▪ Captopril
▪ Cephalosporins
K+ sparing diuretics
▪ Spironolactone or Amiloride lower B.P slightly
▪ They are used only in conjugation with thiazide diuretics to prevent K+ loss
augment anti-hypertensive action
used in HTN due to primary hyperaldosteronism
Mechanism of Action
K+ sparing diuretics function in CCD
decrease Na+ transport in collecting tubule
Triamterene/Amiloride
inhibit apical Na+ channel
Spironolactone
competitive antagonist for mineralocorticoid receptor
prevents aldosterone stimulated increases in Na+ transporter expression
Pharmacokinetics
Spironolactone
orally administered
Amiloride
•oral administration, 50% effective
•not metabolized
•not bound to plasma proteins
•Triamterine
•oral administration, 50% effective
•60% bound to plasma proteins
•liver metabolism, active metabolites
Therapeutic Uses
primary hyperaldosteronism
congestive heart failure
cirrhosis
nephrotic syndrome
in conjunction with K+ wasting diuretics
Adverse Effects
hyperkalemia: monitor plasma [K+]
spironolactone: gynecomastia
triamterene: megaloblastic anemia in cirrhosis patients
amiloride: increase in blood urea nitrogen, glucose intolerance in diabetes mellitus
RENIN ANGIOTENSIN-ALDOSTERONE SYSTEM
▪ A system which works to increase Blood pressure when the pressure within the kidney drops.
▪ As a result of low blood pressure and/or oxygenation in the nephron, renin is released from Juxtaglomerular cells.
▪ Renin travels to the liver via the cardiovascular system and combines with angiotensinogen to form Angiotensin 1.
▪ Angiotensin 1 travels through the cardiovascular system and arrives at the lungs where it is changed into Angiotensin 2.
▪ The alveoli use Angiotensin Converting Enzyme also known as Kinase2 to cause this conversion.
CONTD...
▪ Angiotensin 2 is a powerful vasoconstrictor which causes a rise in peripheral resistance and increases pressure.
▪ Angiotensin 2 works to increase the release of Aldosterone from the adrenal glands.
▪ Aldosterone causes renal retention of sodium and water, which further increases blood pressure by increasing volume.
Introduction
These drugs block the ACE that cleaves Angiotensin-1 to form potent vasoconstrictor Angiotensin-2.
These are first choice of drugs in All grades of essential as well as Reno-Vascular Hypertension.
These drugs lower BP by reducing peripheral vascular resistance without reflexively increasing Cardiac output rate or contractility.
They have Renal blood flow improving action and also have potential to retard Diabetic Nephropathy
More effective in younger hypertensives than in elderly.
More effective when given in conjugation with Diuretics or Beta blockers.29
Pharmacokinetics
▪ All ACEs except Captopril and Lisinopril are connverted to active metabolites.
▪ Enalapril : Converted to Enalaprilat, t ½ is 11 hours, renallyexcreted , unchanged .
▪ Captopril Short t ½ of 3 hours.
▪ lisinopril : water soluble , not hepatically metabolised.
Clinical uses of ACEIs
▪ Treatment of hypertension .
▪ Treatment of heart failure .
▪ Secondary prevention after myocardial infarction .
▪ Diabetic nephropathy in insulin dependent diabetes .
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Side effects
▪ Cough that is nonproductive not dose related caused by accumulation of kinins in the lung .
▪ Postural hypotension can occur , particularly after the first dose .
▪ Rashes .
▪ Angioedema .
▪ Hyperkalemia.
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Contraindications
▪ Pregnancy
▪ Bilateral renal Artery Stenosis
▪ Aortic Valve Stenosis
▪ K+ supplements
Interactions
▪ Drug-drug :
Digoxin: may increase digoxin level by 15% to 30%.
Iithium :increase lithium levels and symptoms of toxicity possible.
K sparing diuretics , K supplements may cause hyperkalemia.
▪ Drug-food:
salt substitutes containing K : increase K level .
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Introduction
▪ Angiotensin 2 is a very potent chemical that causes the muscles surrounding the blood vessels to contract, thus narrowing of vessels causing high Blood pressure.
▪ The angiotensin II receptor blockers (ARBs) are alternatives to the ACE inhibitors.
▪ These drugs allow angiotensin1 to be converted to angiotensin2 but block the receptors that receive Angiotensin2
▪ block vasoconstriction and release of Aldosterone
▪ ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics.
Angiotensin Receptor
▪ Distinct subtypes of Ang2 receptors are designated as AT1 and AT2.
▪ The AT1 receptor subtype is located predominantly in vascular and myocardial tissue and also in the brain, kidney, and adrenal glomerulosa cells , which secretes Aldosterone.
Mechanism of Action
▪ Block AT1 receptors in
Vascular Smooth muscle Adrenal Cortex
Vaso dilatation Reduced Aldosterone Secretion
Contd...
▪ they do not inhibit AT2 receptors.
▪ Have no effect on bradykinin metabolism and are more selective blockers of angiorensin effects than ACE inhibitors.
Therapeutic uses
Hypertension
Treatment of congestive heart failure
May be used alone or with other agents such as Diuretics.
Adverse effects
▪ Dizziness
▪ headche
▪ skin rash
▪ fatigue
▪ taste disturbances
no cough or angioedema
Advantages of ARBs over ACE inhibitors
Do not induce cough
Low incidence of Angioedema, rash , dysguesia.
They are as effective as ACE inhibitors in CHF, MI and Diabetic Nephropathy.
Introduction
▪ Calcium-channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective.
▪ They are effective in treating hypertension in patients with angina or diabetes.
▪ High doses of short-acting calcium channel blockers should be avoided because of increased risk of myocardial infarction due to excessive vasodilation and marked reflex cardiac stimulation.
CCBs – Mechanisms of Action
They act by inhibiting L type of voltage sensitive calcium channels in smooth muscles and heart.
This causes decreased peripheral smooth muscle tone, decreased systemic vascular resistance
Result : decreased blood pressure
CCBs Act Selectively on Cardiovascular Tissues
Neurons rely on N-and P-type Ca2+ channels
Skeletal muscle relies primarily on [Ca]i
Cardiac muscle requires Ca2+ influx through
L-type Ca2+ channels- contraction - upstroke of AP
Vascular smooth muscle requires Ca2+ influx
through L-type Ca2+ channels for contraction
Pharmacokinetics
▪ Well absorbed through GIT.
▪ First pass metabolism.
▪ Highly bound to plasma proteins.
▪ Metabolism in liver.
▪ Excreted through urine.
USES OF CCBs..
1. angina pectoris - Due to decrease in myocardial oxygen consumption, and dilatation of
coronary arteries.
2. supraventicular arrhythmias - because of its depressant action on S-A and A-V nodes.
3. hypertension - they control blood pressure by their vasodilatory effect.
4. Migraine
5. raynaud’s phenomenon - due to their vasodilatory property.
Side Effects of calcium antagonists1. Arterial dilation: headache, flush, dizziness,ankle swelling2. Bradycardia and AV block 3. cardiodepression.4. Constipation5. Haemorrhagic gingivitis
ADVERSE EFFECTS..
Postural hypotension
palpitation
reflex tachycardia
edema
dizziness
constipation
sedation
A-V block
headache
fatigue
lowered B.P.
CONTRAINDICATIONS
o Heart failure
o Bradycardia
oAtrioventricular block.
o Dihydropyridine calcium-channel blockers should not be used in people with uncontrolled heart failure.
ConcomitantDisease
Diuretics ACE inhibitors ARBs Calcium channel blockers
High risk Angina Pectoris
Diabetes
Recurrent Stroke
Heart Failure
Previous MI
Chronic Renal Disease
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