Antihypertensive Drugs

Diuretics

Thiazidess & related drugs

Hydrochlorothiazide

chlorothalidone

Loop diuretics

Furosemide

Bumetanide

Ethacrynic acid

K- sparing diuretics

spironolactone

triametrine

omiloxide

Sympatholytic agents

Centrally acting drugs

Methyldopa

Clonidine

Guanfacine

Ganglionic blockers

Trimethaphan

Adrenergic neuron

blockers

Guanithidine Reserpine

Adrenergic receptor blockers

β-blockers

- propanolol - Metoprolol

- Atenolol

α-blockers

-Prazosin

Mixed blockers

-Labetalol

Direct vasodilators

Arterial vasodilators

K- channel agonists

-Hydrolazine - Minoxidil - Diazoxide

Ca- channel blockers

- verapamil - Nifidipine

Arterial & venous

vasodilator

SodiumNitroPrusside

ACE inhibitors

- Captopril - Enalapril

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 Loop diuretics K- sparing diuretics

Mechanism

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

1) More potent than thiazides as diuretics BUT less potent as antihypertensive

2) The antihypertensive effect of loop diuretics is related ↓ BV

Indicated in cases of

- Mild or moderate hypertension (lowering BP by 10-15 mmHg)

- In sever hypertension in combination with other antihypertensive drugs

- 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 Ganglionic blockers

( Symp. & para.) Adrenergic neuron blockers

Clonidine Methyldopa Trimethaphan Guanethidine Reserpine

Mechanism

1) Central action stimulates the central presynaptic α2-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

Converted into α-methyl NE (potent α2- adrenergic agonist) in the CNS, this would lead to decrease in sympathetic outflow (M Dopa αM NE α2 agonist ↓NE ↓Symp.)

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

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 ↓

- 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

Therapeutic uses

- Moderate Hypertension

- prophylactic treatment for margin

moderate & sever forms in hypertension

- In malignant hypertension

- Acute pulmonary edema due to hypertensive cardiac failure

- Hypertensive encephalopathy

Little use due to side effects

Little use due to its side effects

Side effects

- Sedation & dry mouth - Postural hypotension - Rebound hypertension if

clonidine is suddenly withdrawn Guanfacine ~ clonidine

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

- Postural hypotension & Tachycardia

- Constipation, dry mouth, urinary retention

- Mydriasis - Impotence

- Postural hypotension and hypotension following exercise

- Diarrhea and delayed ejaculation

- Postural hypotension

- Sedation, nightmars and severe mental depression

- Diarrhea and increase gastric acid secretion

Adrenergic receptor Blockers

Propranolol (β) Metoprolol & Atenolol (β) Prazosin (α) Labetalol (Mixed)

Mechanism

1- β1 β2 antagonists

2- Depresses renin-angiotensin- aldosterone system by inhibition of renin production (β2 effect)

β1- selective blockers, both have side effects fewer than propranolol

blocking of α 1 receptors in arterioles and venules Has a vascular smooth muscle relaxant effect

- It blocks α & β receptors , β blocking is predominant

- Reduces the sympathetic vascular resistance without significant alteration in HR or COP

- reduces plasma renin activity

Therapeutic uses

- Lowers BP in mild & moderate hypertension

- Prevent reflex tachycardia that often results from treatment with direct vasodilators in case of sever hypertension

For treatment of hypertensive patients who suffer from asthma, diabetes or peripheral vascular disease

Treatment of severe hypertension in combination with other antihypertensive agents

- Hypertension of pheochromocytoma (adrenal gland tumors that produce xss adrenalin)

- Hypertensive emergencies

Side effects

- May increase plasma triglycerides and decrease HDL-cholesterol

- Nervousness, Nightmares, Mental depression and increase intensity of angina

- Asthma, peripheral vascular insufficiency and diabetes

- Postural hypotension and tachycardia are observed with 1st dose

- Angina pectoris & fluid retention

- Drowsiness, headache, GIT disturbance, blurred vision, dry mouth

Similar to non-selective β-blockers

β 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

Direct Vasodilators

Arterial vasodilators Arterial & venous vasodilator

K+ channel agonists Ca+ Channel blockers Na Nitroprusside

Hydralazine & Minoxidil Diazoxide Verapamil & Nifidipine

Mechanism

Relaxation of smooth muscle of arterioles, ↓systemic vascular resistance

Effective in long acting arteriolar dilator

Inhibit Ca+ influx in arterial smooth muscle leading to dilation of peripheral arterioles

Dilates both arterial & venous vessels, resulting in ↓ PVR and venous return

K+ out, can’t Ca+2 in, relaxation

Therapeutic uses Out patient’s therapy of hypertension hypertensive emergencies

Mild to moderate hypertension, Angina or coronary spasm

Hypertensive emergencies severe cardiac failure

Side effects & toxicity

- ↑ 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

- Excessive hypotension with tachycardia and ↑ COP

- Hyperglycemia due to the inhibition of insulin release

- Salt & water retention

Slight tachycardia & in ↑ COP

Prolonged therapy leads to accumulation of: CN- / SCN-

1) 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

Angiotensin converting enzyme inhibitors (Captopril – Enalapril)

Action by renin-angiotensin –aldosterol system

Angiotensin 𝑅𝑒𝑛𝑖𝑛 𝑟𝑒𝑙𝑒𝑎𝑠𝑒𝑑 𝑓𝑟𝑜𝑚 𝑟𝑒𝑛𝑎𝑙 𝑐𝑜𝑟𝑡𝑒𝑥�⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯� Angiotensin I

𝑖𝑛 𝑡ℎ𝑒 𝑙𝑢𝑛𝑔 𝑏𝑦 𝐴𝐶𝐸�⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯� Angiotensin II

𝑖𝑛 𝑡ℎ𝑒 𝑎𝑑𝑟𝑒𝑛𝑎𝑙 𝑔𝑙𝑎𝑛𝑑�⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯� 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

Mechanism - 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

Therapeutics Treatment of: - sever or refractory hypertension -Hypertensive diabetic patients - Renal insufficiency to increase glomerular filtration rate

Side effects - Proteinuria - Neutropenia or Pancytopenia - Skin rashes, drug fever, taste impairment and dry cough

Management

Non pharmacological therapy:

- Low Na diet - Weight reduction - Stop smoking - Exercise - Cope with stress

Monotherapy therapy: - Diuretics - Sympatholytic - Vasodilators & Ca

channel blockers - ACE inhibitors

Combination therapy: - Diuretics & β-blockers - Diuretics & β-blockers &

vasodilators - Ganglionic blocker, loop

diuretics & vasodilators Emergencies :

- Diuretics - Vasodilators: Diazoxide

i.v, sod.nitroprossside i.v, hydralazine i.m

- Lobtalol, trimethaphan, reserpine, methyldopa

- Dialysis

• Contraceptives ( drugs with Na retaining prop.) Loop diuretics

• Digitalis ( K depletion) K-sparing diuretics

• Malignant hypertension –

pulmonary edema – hypertensive encephalopathy trimethaphan

• Pheochromocytoma

labetalol • Outpatient Hydralazine

& Minoxidil • Sever cardiac failure

sod.nitroprusside

Mild & Moderate - Thiazides - Ca+2 - Clonidine - Propranolol

Sever - ACE inh. - Methyl dopa - Prazosin (comb.) Use propranolol 2 prevent reflex tachycardia due 2 vasodilators

Emergencies - Diazoxide - Sod.Nitroprusside - Labitolol - Trimethaphan

(malignant) Diabetic

- ACE inh. - Β1 selective blockers

(Metoprolol, Atenolol) Impaired GFR

- ACE inh. - Loop diuretics

Angina / asthma - Ca+2 blockers - Β1 selective blockers

(Metoprolol, Atenolol)

Contraindications Diabetes

- Thiazide - Propranolol - Diuretics

Asthma / angina

- Β2 blockers (Propranolol, labetalol).

- Prazosin - K+ channel agonists

(Hydralazine, Minoxidil, Diazoxide)

Causes lipido / impotence - Diuretics - Trimethphan - Guanthidine (delayed

ejaculation)

Causes fluid retension - Prazosin - diazoxide