Drugs used in hypertension

Dr. R. Pilviniene

DEFINITION

• Hypertension is defined as sustained elevation of resting systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of90 mmHg or greater, or taking antihypertensive medication.

The Merck Manual, Eighteenth edition, 2006

TYPES OF HYPERTENSION

• Primary hypertension (formerly essential) – Most common (90%)

– Specific cause cannot be established

• Secondary hypertension– Hypertension with identified cause

CAUSES OF SECONDARY HYPERTENSION

• Renal– Renal parenchymal diseases (glomerulonephritis)– Renovascular diseases

• Endocrine– Pheochromacytoma– Hypertiropidism– Primary hyperaldosteronism

• Drugs– Contraceptives– Sympathomimetics– Corticosteroids– Cocaine

• Unknown

HYPERTENSION: PREDISPOSING FACTORS

• Age > 60 years.• Sex (men and postmenopausal women).• Family history of cardiovascular disease.• Smoking.• High cholesterol diet.• Co-existing disorders such as diabetes,

obesity and hyperlipidaemia.• High intake of alcohol.• Sedentary life style.

Major factors controlling blood pressure

ARTERIAL BLOOD PRESSURECARDIACOUTPUT

PERIPHERAL RESISTANCE

~~

X

Heart rate

Contractility

Filling pressure

Bloodvolume

Venous tone

Arteriolar volume

TREATMENT STRATEGIES

• Reduction of blood volume.

• Reduction symphathetic tone.

• Reduction smooth vascular tone.

• Reduction of angiotensin effects.

Compensatory responses to decreased blood pressure when treating hypertension

Hypertension

Treatment

Decreased blood pressure

Sympathetic outflow Renin release

Tachycardia Salt and H2O retension

Increased blood pressure

Betablockers, reserpine

Diuretics AKF inh.- -

Diuretics Sympatoplegics- adrenoblockers

Vasodilators Angiotensin antagonists

ACE inhibitors

AT receptors blockers

CNSsympathetic outflow

Ganglia

Nerve terminal

α ir βreceptors

Older oral

Ca2+

blockers

Parenteral

Drugs Used in Hypertension

SYMPATHOLYTICS-ADRENOBLOCKERS

• Centrally acting drugs– Clonidine, methyldopa (α2 agonists)

• Ganglio-blocking drugs– Hexamethonium, trimethapan

• Postganglionic sympathetic terminal – blockers (peripheraly acting)– Reserpine, guanethidine

• Adrenoreceptor blocking agents– Prazosin (α1 - selective);– Phentolamine, phenoxybenzamine (non-selective α ) – Propranolol ( β -blocker).

CENTRALLY ACTING SYMPATHOPLEGIC DRUGS

METHYLDOPA:

• Is a prodrug; it is converted to methyl- norepinephrine in the brain.

• Methyl norepinephrine is a FALSE MEDIATOR of the adrenergicreceptors.

• Effects: peripheral resistance,

blood pressure.• Side effects; sedation, drowsiness

CENTRALLY ACTING SYMPATHOPLEGIC DRUGS

CENTRALLY ACTING SYMPATHOPLEGIC DRUGS

Clonidine• Was the drug used to identify the 2 receptor.

• Action: Acts by reducing the sympathetic outflow in the CNS (centers controlling blood pressure).

• Uses: mild to moderate hypertension.• Enters CNS given orally.• Side effects:

– Sedation, drying of nasal mucosa.– Rebound hypertension, following abrupt withdrawal.

GANGLION- BLOCKING DRUGS

Hexamethonium, trimethapan

• Nicotinic blockers are very efficacious, bet side effects are severe.

• Side effects: – Parasympathetic blockade: blurred vision,

constipation, urinary hesitancy.– Sympathetic blockade: sexual dysfunction,

orthostatic hypotension.

ADRENERGIC NEURON – BLOCKING AGENTS

Reserpine– Blocks NA from entering to the

vesicles, thus NA levels decrease due to exposure to MOA

– Gradual decrease of BP– Gradual slowing of cardiac rate.– Side effects: depression.

Guanethidine– Lowering of NA release from

sympathetic nerve endings– At high doses can produce profound

sympathoplegia– Rarely used in hypertension– Side effects: orthostatic

hypotension; sexual dysfunction.

Long duration of action (both): days to weeks.

Adrenoreceptor blocking agents

• Non-selective α (prevents vasocostriction) – Phentolamine, phenoxybenzamine

• Long duration of action (24 h after single use)• Therapeutic use: Pheochromacytoma.• Are of value in chronic hypertension

– postural hypothension, tachycardia.

• α1 – selective (prevents vasocostriction) – Prazosin, terazosin

• Are useful in chronic hypertension. • Free of severe side effects.

Adrenoreceptor blocking agents

• Propranolol ( non selective β -blocker)– Primary (early) antihypertensive effect:

• Reduction of cardiac output.

– Secondary (later) antihypertensive effect:• Decrease in vascular resistance

– Reduced angiotensin level (reduces renin relese from kidney)

– Side effects:• Bronchoconstriction• Arythmias (quick discontinuation) • Sexual impaiment• Disturbances of metabolism (fasting hypoglicaemia)

• OLDER ORAL MinoxidilHydralazine

• PARENTERALNitroprusside

• CA2+ CHANNNELS BLOCKERS•Verapamil•Diltiazem •Nifedipine

VASODILATORS

OLDER ORAL VASODILATORSHydralazine• Mechanism of action: Release of nitric oxide from

endothelial cells.• Effects:

– direct vasodilatation (arterioles >veins) due to decreased systemic vascular resistance

– increase of cardiac output• Antihypertensive effect is rapid.

- Must be used in combination with beta blocker or loop diuretic.• Therapeutic uses: severe hypertension; HF.• Side effects:

– lupus – like syndrome (21%)– Compensatory responces:

• Tachycardia• Salt and water retention

OLDER ORAL VASODILATORS Minoxidil

• Mechanism of action: opens potassium channels - stabilizes membrane and makes contraction of the blood vessel less likely.• Effects: Dilates arterioles, not – veins

- Extremely efficacious (greater potential than of hydralazine)- Hypotensive effect may persist for 24 hours.- Must be used in combination with beta blocker or loop diuretic

•Toxicity:- Compensatory responses.- Hirsutism.

PARENTERAL VASODILATORSNitroprusside sodium

Chemical compositionNitrofericianid (Fe2+, CN- , NO)

Mechanism of actionRelease of NO

Activation of guanylyl cyclase

Increase of cGMP concentration in smooth muscle

Vasodilatation of arteries and veins.

PARENTERAL VASODILATORSNitroprusside sodium

• Therapeutic uses:– Hypertensive emergencies– Severe heart failure (in CHF patients – cardiac output increases)

• Metabolized very rapidly and must be given by continuous drip

• During the infusion of the drug BP must be constantly monitored because of hypotension.

• Toxicity:- Excessive BP lowering, - Cyanide accumulation ( treated by sodium thiosulfate): metabolic acidosis, arrhythmias, death.

ANGIOTENSIN ANTAGONISTS

• Angiotensin -converting enzyme (AKF) inhibitors– Captopril– Enalaprilis– Ramipril

• Angiotensin II competetive receptors blockers– Losartan– Valsartan

ANGIOTENSIN ANTAGONISTS ACE inhibitors

Differences

- Potency

- Route of elimination

- Duration of action

- Being prodrugs or active drugs

Captopril (prototype)Enalapril

Prodrug (deesterificated to active drug enalaprilat).Lisinopril – lysine derivate of enalaprilate.

Fosinopril, ramipril – long-acting drugs Prodrugs – hydrolysed to active in liver.

ANGIOTENSIN ANTAGONISTS ACE inhibitors

ANGIOTENSIN ANTAGONISTSMechanism of action

Angiotenzinogen Kininogen

Angiotenzin I Bradikinin Pg synthesis(inactiv peptid) (vazodilator)

Angiotenzin II Inactive metabolit

(vasoconstrictor)

Vasoconstriction Aldosteron Vasodilation

Peripheral resistance Na+ ir H2Oretention Peripheral resistance

BP BP

Renin Kalikrein

AACECE

AACECEinhibitorsinhibitors

AT AT blockersblockers

ANGIOTENSIN ANTAGONISTS ACE inhibitors (Captopril)

Effects

• Decrease of peripheral resistance– Blood pressure– ↓ afterload

• Decreased Na+ ir water retention– ↓ preload

• Are not associated with such compensatory response as activation of sympathetic nervous system.

ANGIOTENSIN ANTAGONISTS ACE inhibitors (Captopril)

Therapeutic uses

• HF• Hypertension• State after myocardial infarction

– Protect against sudden death and second myocardial infarction

• Non-diabetic nephropathy.– Protect against progression nephropathy due to

diminishing proteinuria.

ANGIOTENSIN ANTAGONISTS ACE inhibitors (Captopril)

Pharmacokinetics• Rapid absorbtion.• BA about 70 % (decreases if taken

concomitantly with food).• Captopril is distributed to most body tissues

(except - CNS).• Most – eliminated by kidneys – dose reduction in

renal insufficiency.

ADVERSE EFFECTS

• Hypotension• Renal Insufficiency (if bilateral renal artery stenosis)• Hyperkalemia – special group of patients (Na

restricted, on K-sparing diuretic, COX inhibitors, diabetic patients)

• Cough – dry, persistent (20 %). – Bardykinin induced

• Angioedema• Neutropenia, nephrotic syndrome, skin rash, taste disturbances. (captopril especially): • Contraindicated in pregnancy!

Kinin-related

SH group related

ANGIOTENSIN ANTAGONISTSCompetetive inhibitors of angiotensin II

Losratan • Effects – similar to ACE I (NOT AS EFFECTIVE

AS ACEIs) – Blocks AT generated effects but not by ACE – No effect on bradykinin. – ADRs – similar to ACEI, but less cough and

angioedema.– More complete AT inhibition.

• At present recommended for use in ACEI intolerant patients.

• Some suggestion that they may have benefit when added to ACEIs.

ACE Inhibitor AII Receptor Blocker

Blocks formationof AII incompletely

Blocks Kininase II

↑ Kinins↓ AII effects & aldosterone

PROTECTION

Blocks AT-1R

AT-2R Free

More completeInhibition of AII effects

Preserve Anti-proliferativeeffect