Hypertension

most common CV disease

24% total USA population

increased incidence of Renal Failure, Coronary Disease, CF & Stroke.

Diagnosis

repeated BP measurement 3 times,

normal: 120/90mm Hg

often asymptomatic

Essential Hypertension

unknown cause through multi-factors such as:

Hyperlipidemia

Diabetes

Genetic, family hxy

Diet

Stress

5-10% Identifiable Causes:

Renal Artery Constriction

Coarctation of Aorta

Phaeochromocytoma (tumor of adrenal glands)

Cushing's Disease (hypercortisolism)

Primary Aldosteronism (elevated aldosterone)

Treatments

4 sites of regulations

Arterioles: resistance

Venules: capacitance

Heart: pump output

Renal angiotensin system: volume (triggered by low BP)

Major Drug Groups:

Diuretics: pee more

Sympathoplegics: block SNS

Vasodilators

Angiotensin Antagonists

Diuretics

2 main actions:

↓ Blood volume

affect smooth muscle tone

1, Tiazides: hydrochlorothiazide (mild/mod HT)

block Na/Cl symporter, Ca reabsorption

distal convoluted tubule

orally active, maybe used as mono-therapy

Toxicity: K depletion/hypokalemia

2, Loop Diuretics: furosemide( severe HT)

Block Na/K/2Cl symporter, Ca excretion

thick ascending loop and convoluted loop

Oral & IV

Toxicity: K depletion/Hypokalemia

may cause arthythmias

Sympathoplegics Targets:

Centrally acting agents

Ganglion Blockers: nicotinic antagonist

Postganglionic sympathetic neuron blocker

Adrenoceptor blockers: found in heart and blood vessel.

1, Centrally Acting Agents: α₂-selective agonists

when α₂ gets stimulated, they reduce the amount of NE release into CNS.

eg: Clonidine (mild/mod HTN).It block SNS.

Minimal toxicity.

Methyldopa

2, Ganglion Blockers:

Nicotinic cholinoreceptor antagonists

eg: Trimethaphan (severe HTN)

blocks nACh R in autonomic ganglia

Toxicity: intolerable, used rarely due to CNS, PNS effect, orthostatic htn, constipation, blurred vision

3, Postganglionic SNS blockers

Reserpine, Guanethidine

rarely used
Reserpine blocks uptake

Guanethidine prevents neurotransmitter release.

Toxicity: Intolerable, depression, sexual dysfxn, ortho htn

4, Adrenoceptor Blockers:

α₁ and β₁ receptor antagonists

eg: Prazosin: block α₁ receptor

Propanolol: block β₁ receptor

B blocker works more on the blood vessel whereas a blocker works on the heart.

Vasodilators:

dilate arterioles in diff mechanisms:

1, release of nitric oxide

2, Open K channel, hypopolarization

3, Block L-type Ca channels, reduce the tone

Vasodilators

They all reduce excitability therefore reduce the tone

1, Nitrovasodilators:

eg: Hydralazine, Nitroprusside

It activate soluble Guanylate Cyclase, it negatively regulates the Ca channel. It shuts Ca channel, less Ca gets in, so less smooth muscle tone.

2, K channel Agonist

eg: Minoxidil sulfate, Diazoxide

severe HTN, for HTN emergency!!

it interfere not only with the blood vessel but also the heart.

3, Ca channel Blockers

3 types of Ca channels

L-, T-, and N-type

L-type opens long, important in regulating contractility of blood vessel. Main target of HTN drugs

T-type is transient

N-type is presynaptic

3 main classes of blockers

Vasoselective: Dihydropyridines (Nifedipine)

Cardiac & Vascular Acting:

Phenylalkylamines (Verapamil)

Benzothiazines ( Diltiazem  )

Due to difference in frequence of Ca channel activity

They are selective in different tissue

Each drug has a distinct allosteric binding site

Ca channel blockers

Verapamil, Diltiazem, Nifedipine

voltage & frequency dependent block

Nifedipine Adverse Effects:

17%-20% pts experience:

Hypotension, H/A, Peripheral edema

Angiotensin Antagonists

1, ACE inhibitors: Captopril

prevents the conversion from angiotensin 1 to angiotensin 2

Angiotensin 2 is responsible for vasoconstriction & aldosterone secretion

2, Angiotensin Receptor inhibitor (AT₁-type): Losartan

Captopril cause irritable cough, not good for pregnant women.

Therefore they develope Losartan.

Losartan has less toxicity

Captopril and Losartan are for Mild-Mod HTN

for mono-therapy

ACE inhibitor also prevent breakdown of Bradykinin

 maximize efficacy and minimize toxicity, we combine drug from different group

eg: diuretic+sympathoplegic+vasodilator

For emergency or malinant htn, pt are hospitalized and treated with parenteral vasodilator, B-blocker, and loop diuretic

Multiply possibilities of untreated HTN:

Heart: hypertrophy, MI, HF

Brain: stroke

Kidney: renal failure, chronic kidney disease

Vasculature: peripheral vascular disease

Eye: retinopathy