Antihypertensive Drugs

Diuretics
Thiazidess & related drugs Hydrochlorothiazide chlorothalidone Loop diuretics Furosemide Bumetanide Ethacrynic acid K- sparing diuretics spironolactone triametrine omiloxide Centrally acting drugs Methyldopa Clonidine Guanfacine Trimethaphan

Sympatholytic agents
Ganglionic blockers Adrenergic neuron blockers Guanithidine Reserpine Adrenergic receptor blockers -blockers - propanolol - Metoprolol - Atenolol -blockers -Prazosin Mixed blockers -Labetalol

Direct vasodilators
Arterial vasodilators K- channel agonists -Hydrolazine - Minoxidil - Diazoxide Arterial & venous vasodilator SodiumNitr oPrusside

ACE inhibitors
- Captopril - Enalapril

Ca- channel blockers - verapamil - Nifidipine

Hassan Jamal

M.Hisham

Diuretics
Diuretics lower BP primary by depleting body Na+ stores. Na+ increases BV & PVR by: vessel stiffness & neural reactivity

Thiazides & related drugs 1) Initial in blood volume & COP 2) After chronic administration (6-8 weeks), COP gradually returns to normal while PVR declines due to: a. Loss of Na+ from arterial wall b. sensitivity of vascular or smooth muscle to NE Indicated in cases of Mild or moderate hypertension (lowering BP by 10-15 mmHg) In sever hypertension in combination with other antihypertensive drugs

Loop diuretics

K- sparing diuretics

Mechanism

1) More potent than thiazides as diuretics BUT less potent as antihypertensive 2) The antihypertensive effect of loop diuretics is related BV - Hypertension associated with reduced glomerular filtration rate ( GFR) Renal impairment - Heart failure or liver cirrhosis, where Na retention is marked - Hypertension in which multiple drugs with Na retaining properties are used (Contraceptives)

- Avoid excessive K depletion particularly in patients taking digitalis - Enhance the natriuretic effects of other duretics

Side effects

1) Hypokalemia (Except for K- sparing diuretics) 2) Impair glucose tolerance, diabetes mellitus and increase serum lipid conc. 3) Impotence loss of libido, diarrhea and gout

Sympathetic agents
Centrally acting drugs Clonidine
1) Central action stimulates the central presynaptic 2-receptors that are inhibitory to sympathetic outflow 2) Peripheral action - Reduces the release of NE from adrenergic nerve - Prevents cardiac responses to postganglionic adrenergic nerve stimulation - Has a weak direct peripheral vasodilation action

Ganglionic blockers ( Symp. & para.) Trimethaphan 1) sympathetic vasoconstriction tone leading to: a. Dilation of the arterioles b. Dilation of the veins 2) Produces a direct vasodilation action & histamine like effect

Adrenergic neuron blockers Guanethidine It inhibits the release of NE that occur when a normal action potential reaches sympathetic nerve ending thus tend to COP by bradycardia and relaxation of capacitance vessels With chronic therapy, COP returns to normal while PVR Reserpine - Blocks the ability of adrenergic transmitter vesicles to uptake and store biogenic amines by interfering with uptake mechanism, resulting in - Depletion of NE, Dopamine & serotonin in both central and peripheral vascular resistance

Methyldopa Converted into methyl NE (potent 2adrenergic agonist) in the CNS, this would lead to decrease in sympathetic outflow (M Dopa M NE 2 agonist NE Symp.)

Mechanism

Therapeutic uses

- Moderate Hypertension - prophylactic treatment for margin - Sedation & dry mouth - Postural hypotension - Rebound hypertension if clonidine is suddenly withdrawn Guanfacine ~ clonidine

moderate & sever forms in hypertension

Side effects

-Sedation on long term therapy - Impaired mental concentration & mental depression - Nightmares & vertigo

- In malignant hypertension - Acute pulmonary edema due to hypertensive cardiac failure - Hypertensive encephalopathy - Postural hypotension & Tachycardia - Constipation, dry mouth, urinary retention - Mydriasis - Impotence

Little use due to side effects

Little use due to its side effects

- Postural hypotension and hypotension following exercise - Diarrhea and delayed ejaculation

- Postural hypotension - Sedation, nightmars and severe mental depression - Diarrhea and increase gastric acid secretion

Propranolol () 1- 1 2 antagonists 2- Depresses renin-angiotensinaldosterone system by inhibition of renin production (2 effect)

Mechanism

Adrenergic receptor Blockers Metoprolol & Atenolol () Prazosin () 1- selective blockers, both blocking of 1 receptors in have side effects fewer arterioles and venules than propranolol Has a vascular smooth muscle relaxant effect

- Lowers BP in mild & moderate hypertension - Prevent reflex tachycardia that often results from treatment with direct vasodilators in case of sever hypertension - May increase plasma triglycerides and decrease HDL-cholesterol - Nervousness, Nightmares, Mental depression and increase intensity of angina - Asthma, peripheral vascular insufficiency and diabetes For treatment of hypertensive patients who suffer from asthma, diabetes or peripheral vascular disease Treatment of severe hypertension in combination with other antihypertensive agents -

Therapeutic uses

- Postural hypotension and tachycardia are observed with 1st dose - Angina pectoris & fluid Similar to non-selective Side effects retention blockers - Drowsiness, headache, GIT disturbance, blurred vision, dry mouth blockers BP by COP. With continued treatment COP returns to normal but PVR is reset at lower level and thus BP remains low Ganglionic Blockers (Trimethaphan) The depolarizing blockers are not used in hypertension as they cause initial stimulation if the ganglia and thus tend to raise BP at first The competitive blockers suffer from the disadvantage of that they block both sympathetic and parasympathetic ganglia, with the exception of trimethaphan, so they have been replaced by drugs which have better selective action an sympathetic tone in the prolonged management of essential hypertension

Labetalol (Mixed) It blocks & receptors , blocking is predominant Reduces the sympathetic vascular resistance without significant alteration in HR or COP reduces plasma renin activity Hypertension of pheochromocytoma (adrenal gland tumors that produce xss adrenalin) Hypertensive emergencies

Direct Vasodilators
Arterial vasodilators K+ channel agonists Hydralazine & Minoxidil Diazoxide Relaxation of smooth Effective in long acting muscle of arterioles, arteriolar dilator systemic vascular resistance K+ out, cant Ca+2 in, relaxation Out patients therapy of hypertension - HR & stroke volume due to compensatory responses mediated by baroreceptors and sympathetic NS as well as renin and aldosterone leading to COP and renal blood fllow - Tachycardia, palpitation and angina - Headache, nausea, anorexia, sweating and flushing hypertensive emergencies - Excessive hypotension with tachycardia and COP - Hyperglycemia due to the inhibition of insulin release - Salt & water retention Ca+ Channel blockers Verapamil & Nifidipine Inhibit Ca+ influx in arterial smooth muscle leading to dilation of peripheral arterioles Mild to moderate hypertension, Angina or coronary spasm Slight tachycardia & in COP Arterial & venous vasodilator Na Nitroprusside Dilates both arterial & venous vessels, resulting in PVR and venous return Hypertensive emergencies severe cardiac failure Prolonged therapy leads to accumulation of: CN- / SCN1) Cyanide (metabolic acidosis, arrhythmias, excessive hypotension & death) 2) Thiocyanate (weakness, psychosis, muscle spasm & cconvulsion Both can be avoided by: Sodium thiosulfate as a sulfur donor or hydroxyl cobolamin Nausea, vomiting, sweating, restlessness, headache and palpitation

Mechanism

Therapeutic uses

Side effects & toxicity

Angiotensin converting enzyme inhibitors

(Captopril Enalapril)

Action by renin-angiotensin aldosterol system

Angiotensin Angiotensin I Angiotensin II Angiotensin III

- Angiotensin II has a vasoconstrictor and Na retaining activity - Booth Angiotensin II & Angiotensin III stimulate aldosterone release, which increase Na and water retention and thus the blood pressure increase - Inhibit the ACE and thus inhibit the action of renin- angiotensin- aldosterone system - They stimulate Kallikrein-Kinin system (bradykinin) which has a potent vasodilation effect. - The hypotensive effect of ACE inhibitor is associated with increasing glomerular filtration rate

Mechanism

Therapeutics Side effects

Treatment of: - sever or refractory hypertension -Hypertensive diabetic patients - Renal insufficiency to increase glomerular filtration rate - Proteinuria - Neutropenia or Pancytopenia - Skin rashes, drug fever, taste impairment and dry cough

Management Non pharmacological therapy:

Mild & Moderate - Thiazides - Ca+2 Contraceptives ( drugs with - Clonidine Na retaining prop.) Loop - Propranolol diuretics Sever - ACE inh. - Methyl dopa Digitalis ( K depletion) - Prazosin (comb.) K-sparing diuretics Use propranolol 2 prevent reflex tachycardia due 2 Malignant hypertension vasodilators pulmonary edema Emergencies hypertensive - Diazoxide encephalopathy - Sod.Nitroprusside - Labitolol trimethaphan - Trimethaphan (malignant) Pheochromocytoma Diabetic labetalol - ACE inh. - 1 selective blockers Outpatient Hydralazine (Metoprolol, Atenolol) & Minoxidil Impaired GFR - ACE inh. - Loop diuretics Sever cardiac failure Angina / asthma sod.nitroprusside - Ca+2 blockers - 1 selective blockers (Metoprolol, Atenolol)

Monotherapy therapy:
Diuretics Sympatholytic Vasodilators & Ca channel blockers ACE inhibitors

Low Na diet Weight reduction Stop smoking Exercise Cope with stress

Contraindications Diabetes - Thiazide - Propranolol - Diuretics Asthma / angina - 2 blockers (Propranolol, labetalol). - Prazosin
K+ channel agonists (Hydralazine, Minoxidil, Diazoxide)

Combination therapy:
-

Emergencies :

Diuretics & -blockers Diuretics & -blockers & vasodilators Ganglionic blocker, loop diuretics & vasodilators

Diuretics Vasodilators: Diazoxide i.v, sod.nitroprossside i.v, hydralazine i.m Lobtalol, trimethaphan, reserpine, methyldopa Dialysis

Causes lipido / impotence - Diuretics - Trimethphan - Guanthidine (delayed ejaculation) Causes fluid retension - Prazosin - diazoxide