Hypertension

Some causes of hypertension• Renal artery stenosis • Chronic renal disease • Primary hyperaldosteronism (in aldosteron secretion due to a

tumor in adrenal cortex)• Stress • Hyperthyroidism (Thyrotoxicosis)• Pheochromocytoma (increase in NE)• Smoking• Atherosclerosis

Treatment of hypertension

In patients with mild elevation in blood pressure, non pharmacological treatment methods may be applicable. These treatment methods may include:

• · Stop smoking• · Lose weight• · Moderate alcohol consumption• · Exercise• · Reduce salt intake

Con: Treatment of hypertension

For more serious increases in blood pressure, the current drug treatment involves:

• 1. Diuretics• 2.sympatholytic agents : include β blockers and α blockers • 3. Vasodilators : include Ca2+ channel blockers and directly

acting vasodilators• 4. Angiotensin converting enzyme inhibitors and ARBs• 5. Centrally acting agents :to reduce sympathetic outflow

I- Diuretics1-They are called water piles , they decrease blood volume thus Venous return (preload) CO BP

• Loop diuretics: (furosemide, bumetanide, torsemide) are the most effective diuretics mainly used in emergency as in hypertensive crisis.

• Thiazide diuretics (chlorothiazid) act on the distal tubules and are less

effective than loop diuretics.

• Potassium sparing diuretics: not effective antihypertensive drugs because they have weak diuretic effect . However they are used with other diuretics to decrease their hypokalemic effect (which is dangerous on heart) .

ii-Adrenergic receptor blockers 1-β blockers

• 1. Blocking of the β 1 receptors of the heart: Reducing contractility. Causing bradycardia(-ve inotropic ,-ve chronotropic )

• 2. Blocking β receptors in the kidney: decrease the release of rennin • Non selective β1 & β2 blocker: Propranolol .• β1 selective: Atenolol ,Metoprolol,nadolol & timolol Non selective beta antagonists should be avoided since they can cause extra cardiac effects, most notably

bronchoconstriction. Even the relatively cardio selective antagonists may be capable of blocking β2 receptors, thus causing bronchoconstriction. Therefore, blockers are contraindicated in asthmatics

Other adverse effects:• Cold extremities (NA effect on BV. Will be on α1 receptors) so NOT taken by patients with PVD.• Bronchospasm (prevent dilation of the bronchi by circulating adrenaline)• CNS effects if the drug penetrates the BBB cause insomnia• Increased triglycerides since β receptors are also present in the liver to increase fat metabolism • Also they inhibit glycogenolysis (so can cause hypoglycemia)• They are contraindicated in diabetic patients because they mask symptoms of hypoglycemia

(tachycardia)& also can themselves produce hypoglycemia by inhibiting glycogenolysis & gluconogenesis).

• Bradycardia

2-α blockers α1 stimulation by NA or adrenaline causes vasoconstriction (and hence increased PR), α1 blockers block this effect, and so dilate blood vessels · They reduce plasma triglyceride and reduce LDL & cholesterol. Ex.: Prazosin & Terazosin

Adverse effects:• Postural hypotension (occurs on the first dose)Explanation: Sympathetic stimulation of α receptors is important to constrict blood vessels of the

legs to pump blood back to the heart upon standing. As α1 receptors are blocked, when changing from a supine position to a standing position, the blood will be pooled to the legs quickly, causing hypotension (may cause some people to get dizzy and faint)

• Failure to ejaculate• Reflex tachycardia & Na and water retention.

3-A combined α and β blocker Ex. labetalolIt is not used widely It is a logical choice for emergencies (hypertensive crisis) where you want to

reduce blood pressure quickly (by reducing CO and TPR at the same time)• Useful in pre ecclampsia of pregnancy• In treatmeant of pheochromocytoma before surgery.

III-Vasodilator a-Directly acting vasodilators

1-HydralazineMechanism of action The mechanism is unknown. It dilates arterioles· It is not used much

because it can cause reflex stimulation of the sympathetic nervous system. since the vasodilatation causes sever transient drop in blood pressure. This reflex stimulation causes increased heart rate and contractility, and also rennin release (causes marked fluid retention and edema).

• In order for hydralazine to be useful, it needs to be combined with a β blocker (to prevent the cardiac effects) and a diuretic (to overcome the fluid retention).

Side effects:• · Headache (due to vasodilatation)• · Nausea• · Tachycardia & edema (reflex stimulation of sympathetic) SO; Need to be used in conjunction with β blockers and diuretics• · A systemic lupus like condition may develop in some people

Con: a-Directly acting vasodilators 2-Minoxidil Relaxes blood vessels by opening K+ channels· This causes K+ to rush out of the

cell, hyperpolarizing the smooth muscle and so making it less excitableAdverse effects:• ·Water & Salt retention Reflex stimulation of sympathetic NS.• · TachycardiaSO: Need to be used in conjunction with β blockers and diuretics• · Causes hair growth (hirsiutism)· Another therapeutic use of this drug is in the

treatment of baldness

3-Sodium nitroprusside

• A nitrovasodilator (Releases NO which directly relaxes smooth muscle in blood vessels)·

• Only route of administration is intravenously·• Reserved for acute use only (i.e.) It is used in emergency situations where a rapid drop in blood pressure is

required· Since the drug contains cyanide, cyanide poisoning may develop

b-Calcium channel blockers

• The depolarization of vascular smooth muscle relies on the influx of Ca2+ (rather than Na+· )These drugs relax (VD) arteriolar smooth muscle by reducing calcium entry via L type calcium channels (which are also present in the heart)· There are various types of Ca2+ channels blockers:

• · Nifedipine: arterioselective• · Amlodipine: arterioselective• · Diltiazem: cardioselective• · Verapamil: cardioselectiveAdverse effects:• · Flushing• · Edema• · Dizziness• Bradycardia ,AV blockade (with cardioselective agents)· • Verapamil must not be given to patients with a heart problem because it

can slow down the heart sufficiently to cause cardiac failure. Verapamil must also never be used in conjunction with a βblocker because of their additive effects on depressing the heart…………complete heart block

IV-Angiotensin converting enzyme inhibitorsACEIs

• Angiotensin converting enzyme is found widespread throughout the body. It acts mostly in the lungs, but is also found in the brain, kidney and on endothelium· ACE inhibitors prevent the conversion of angiotensin I to angiontensin II· ACE is also responsible for the inactivation of bradykinin, so that inhibition of this enzyme also leads to increased bradykinin levels· Bradykinin can act as a local vasodilator agent. However, the adverse effects of bradykinin (mainly cough) are what limits the usefulness of ACE inhibitors

• Ex.: Captopril & Enalapril

Adverse effects:• · Dry cough (due to bradykinin)• · Loss of taste• · Severe hypotension• · Rash• · Angioedema (due to bradykinin)• Hyperkalemia (due to decreased aldosterone)

Con: Angiotensin converting enzyme inhibitors

Advantages of ACE inhibitors over other therapies:• There is no reflex sympathetic (NO tachycardia or edema) • Less adverse effects on lipid profile and glucose than diuretics

and β blockers• The most beneficial effect is its inhibition of cardiovascular

remodeling due to effect of Ang II on heart . (i.e )Evidence has shown that cardiac hypertrophy and vascular

changes are the result of angiotensin II having a trophic effect. Therefore, reduction in the amount of angiotensin helps prevent the cardiac enlargement.

V-Angiotensin II receptor antagonists

Ex. Lorsatan & valsartanAngiotensin II binds to 2 receptors:• AT1 and AT2 receptors· AT1 receptor is the one we are interested in because most

of the known actions of angiotensin II is mediated by AT1The AT1 receptors are distributed widely:Vascular smooth muscleAdrenal cortex KidneyBrainARBs:• · It is selective for AT1 receptors• · It inhibits the cardiovascular effects of angiotensin II• · Similar efficacy to ACE inhibitors but without the bradykinin associated side

effects: There is no cough and no chance of angioedemaHowever, other side effects may be:• · Pathological effects on the fetus• · GI adverse effects• · Hyperkalemia (due to decreased aldosterone)