Hypertension Pathophysiology - 1 File Download

Modern Pharmacy Academy

Hypertension

Pathophysiology

Arterial pressure = cardiac output X Peripheral Resistance

Cardiac output = heart rate X stroke volume

Starling's Law: ↑ ventricular stretch � ↑ myocardial contrac�lity

↑ blood volume returning � ↑ ventricular dila�on

Initiators of baroreceptor reflexes: stretch receptors located in

the wall of large chest and neck arteries

Causes of hypertension: Cushing's disease, oral contraceptives,

acromegaly, polycystic kidney disease

Hypertension of unknown etiology: essential hypertension,

Endocrine hypertension: pheochromocytoma (tumor causing ↑

in catecholamine release)

Renal hypertension: chronic pyelonephritis.

Neurogenic hypertension: familial dysautonomia

Anesthetized patients general anesthetics increase the

myocardial muscle sensitivity to endogenous catecholamine so

antihypertensives (clonidine )given before surgery

Africans: use Ca channel blockers and diuretic (CaD) (ACE

inhibitors/beta blockers�less effective)


Generally, avoid prescribing two drugs from the same therapeutic

class.

Effectiveness of antihypertensive drugs is highly unpredictable,

requires dose/drug adjustments.

Withdrawal antihypertensives gradually to reduce SE (e.g. MI with

b-blocker)

Elderly: esp. vulnerable to CNS SE, orthostatic hypotension.

Lower doses may be needed.

Diuretics

Use: recommended (with beta blockers) as initial therapy for BP.

Diuretics are also used for CHF, edema, fluid retention.

Precaution: take during the day to avoid interruption of sleep due

to frequent urination. May raise lithium level (CI)

Thiazide diuretics

Examples: Chlorthiazide, hydrochlorthiazide, cyclothiazide,

polythiazide, trichlormethiazide, methyclothiazide,

hydroflumethiazide, benzthizide, bendroflumethiazide,

chlorthalidone, metolazone, indapamide. Structure: most are

related to sulfonamides.

Mechanism: Act on Na+/Cl

- co-transporter at the distal

convoluted tubule. Other actions: directly dilate arterioles, ↓

total fluid (extravascular) volume, ↓ cardiac output.

Effects:


1. ↑ urinary excre�on of Na+ / water due to ↓ Na / Cl

reabsorption

2. ↑ urinary excre�on of K+ and bicarbonate �

hypokalemia� ↑ potassium dietary intake, use supplements

/ potassium sparing diuretics

3. ↑ blood glucose (hyperglycermia, care with diabetics), ↑

uric acid retention (hyperuricemia, care with gout), ↑ serum

lipids (hyperlipidemia), ↑ calcium levels (hypercalcemia)

4. ↑ effect on other an�hypertensives by ↓ re-expansion of

extracellular / plasma volumes.

SE: electrolyte imbalance (↓K, ↓Mg, ↑Ca�dehydration,

postural hypotension, dizziness, headache, fatigue, hypovolemic

shock, arrhythmia, palpitation), metabolic alkalosis, ↓ K �

muscle cramps, light sensitivity / rash (use sunscreen), ↑ uric acid

/ gout, ↑ lipoproteins, ↑ BG, sulfonamide hypersensitivity.

Interactions: NSAIDs (e.g. ibuprofen) � ↓ renal perfusion � ↓

effect of thiazides. Sulfasenstivity. Hyperlipidemia � ↑ risk of

coronary artery disease. Digitoxin (↑ toxicity due to

hypokalemia)

↓ urinary Ca excretion � use for kidney stones (calcium

nephrolithiasis).

Metolazone: most effective thiazide diuretic.

Chronic use�↑ water reabsopr�on�↓ polyuria and polydipsia

in diabetes insipidus (instead of ADH) .


Loop (high-ceiling) diuretics Examples: furosemide, torsemide, bumetanide (all are

sulfonamide derivatives), ethacrynic acid. Most intense, shortest

duration action.

Use: patients intolerant / irresponsive to thiazides, or with renal

impairment (↓↓ golmerular filtration rate). Very strong

diuretics�not routinely used for hypertension. Used in edema in

CHF / liver cirrhosis / kidney disease / lungs, hypercalcemia

Mechanism: Blocks Na+/K

+/2Cl

- co-transporter in the thick

ascending limb of Loop of Henle (luminal side)�↑ excretion of

water, Na+, K

+, Ca

2+, Mg

2+, Cl

- � metabolic alkalosis. ↑ BG, ↑

blood lipids, ↑ uric acid.

SE: dehydration, ↓ BP, hypovolemia, ↓ K, ↓ Ca, metabolic

alkalosis, ↑ uric acid, ↑ BG, ↑ lipids, tinnitus, transient hearing

loss (CI aminoglycosides), sulfonamide hypersensitivity, blurred

vision, blood toxicity, distal tubular hypertrophy (with chronic

use).

Interactions: like thiazeds�NSAIDs (e.g. ibuprofen) � ↓ effect,

aminoglycosides � ototoxicity, digoxin � ↑ toxicity (↓ K).

Potassium sparing diuretics

Examples: spironolactone, amiloride, triametrene.

Use: when if ↑ K+ loss and not corrected by supplements. May

combine with thiazides / loops to balance potassium. Least

potent diuretics.


Uses: prevent hypokalemia from thiazide / loop diuretics, edema

from CHF, liver cirrhosis, hyperaldosteronism (Spironolactone).

Triamterene, amiloride mechanism: block Na+ channels at

collecting duct � ↓ Na+ exchange with K

+ and H � ↓ K

+ and H

+

excretion � alkaline urine.

Triamterene SE: hyperkalemia, headache, dizziness, ↑ uric acid,

↓ dihyrofolate reductase � methemoglobinemia in case of

alcoholic cirrhosis. CI: history of kidney stones

Spironolactone: synthetic steroidal competitive inhibitor of

aldosterone at mineralocorticoid receptors at the collecting duct

� ↓ sodium-potassium exchange � ↓ potassium excre�on �

alkaline urine � use in hyperaldosteronism. SE: gynecomastia,

hirsutism, menstrual disruption, lethargy, hyperkalemia.

Interactions: ACE inhibitors and potassium supplements � ↑ risk

of hyperkalemia. Renal impairment.

Osmotic diuretics

Examples: mannitol, glycerin, urea

Mechanism: highly polar, water soluble inert chemicals, freely

filtered at the glomerulus but poorly reabsorbed from renal

tubules � ↑ osmolarity of glomerular filtrate � ↓ tubular

reabsorption of water � ↑ diuresis � ↑ water, Na+, Cl

-,

bicarbonate excretion � alkaline urine.

Use: prevent oliguria, anuria, ↓ cerebral edema, ↓ intracranial

pressure, ↓ intraocular pressure (glaucoma).


SE: headache, blurred vision. Not absorbed well by the gut

(causes osmotic diarrhea)� only given IV.

Carbonic anhydrase inhibitors Examples: acetazolamide, related to sulfonamides

Mechanism: ↓ carbonic anhydrase at the proximal tubules � ↓

sodium bicarbonate / Na reabsorption � ↑ water, Na+, K

+,

bicarbonate excretion � alkaline urine. ↓ affect due to Na

reabsorption in distal sites

Use: glaucoma (aqueous humor has ↑ bicarbonate), acute

mountain sickness, alkaline urine and ↑ excretion of acidic

drugs (aspirin, urate), edema.

SE: hyperchloremic metabolic acidosis (due to bicarbonate loss),

sulfonamide hypersensitivity, CNS depression, drowsiness, fatigue,

constipation, blood SE (bone marrow depression,

thrombocytopenia, hemolytic anemia, leukopenia,

agranulocytosis)

Sympatholytics

Beta blockers

Use: recommended (with diuretics) as initial therapy, especially

for patients with rapid resting heart rate (atrial fibrillation,

tachycardia), ischemic heart disease (angina pectoris, MI)


Mechanism: ↓ cAMP � ↓ heart contrac�on and rate. Other: ↓

rennin secretion �↓ cardiac output, central ↓ in sympathe�c

output. Block autonomic reflex response (e.g tachycardia).

examples

1- Non-selective PNT

Propranolol

Nadolol

Timolol "localy for glaucoma"

2- Partial agonist "ISA" :

Intrinsic sympathiomimetic activity.

PCP A

PINDOLOL,CARTELOL , PENBUTOL dosen't

mask hypoglancemic

Acebutolol used in D.M

3- α,B blocker :- LC Labetalol (racemic mixture)

Crvidilol (approves in CHF)

Safe W asthma safe W diabetis

4- selective B1 blocker :- - other - olol

Esmolol, Bisoprolol. (ultrashort acting)


Timolol: mainly for ocular hypertension (B1/B2).

Esmolol: ultrashort duration of action, IV.

Carteolol: ↓ lipid solubility�↓ CNS penetra�on.

Propranolol: -ve inotrophic/chronotropic � ↓ oxygen demand �

angina

Side effects, interactions, and precautions:

• Withdrawal syndrome if suddenly d/c �↑ anginal aGacks, MI,

rebound in BP above normal

• ↑ lipids, hypertriglyceridemia

• Impotence and ↓ libido � ↓ compliance

• NSAID’s � may ↓ effect of beta blockers

• ↑ SE with neurologic disorders if drug enters CNS � ↑ poor

memory, depression, fatigue, lethargy

• ↓ kidney blood flow � ↓ glomerular filtra�on.

Contraindications:

• Ca channel blockers

• CHF �� cardiac decompensation due to ↓ contrac�bility and ↓

electrical conduction

• DM �may mask tachycardia (hypoglycemia), ↓ BG

• COPD, asthma, bronchospams (selectivity is dose dependent)

• Peripheral vascular disease / Raynaud’s phenomenon �

vasoconstriction


Peripherial alpha-1 blockers

Examples (x-osin): prazosin, terazosin, doxazosin

Mechanism: block peripheral postsynaptic alpha-1 adrenergic

receptors � vasodilation (arterioles and veins).

First dose syncope: within 60 min of first dose � postural

hypotension, dizziness, headache, palpitation, tachycardia,

sweating. Minimize by starting with low dose at bedtime.

Other SE: diarrhea, weight gain, edema, dry mouth, sexual

dysfunction.

Uses: refractory ↑ BP, CHF,

Central alpha-2 agonists

Mechanism: act on central presynaptic alpha-2 inhibitory

receptors to ↓ sympathe�c flow to cardiovascular system � ↓

peripheral resistance

Examples: methyldopa, clonidine, guanabenz, guanfacine.

General SE: rebound hypertension (if abruptly d/c), sedation, dry

mouth

Methyldopa: SE: hemolytic anemia (+ve Coomb’s test) with

prolonged use, SLE, orthostatic hypotension, fluid accumulation,


fever/flu-symptoms (due to liver damage). CI: MAOI (↓

methyldopa activity), hepatic disease. Safest in pregnancy.

Clonidine: safer with renal impairment. ↓ BP, heart rate. SE:

depression (CI: alcohol), initial ↑ then ↓ in BP (with IV). No

orthostatic hypotension (cardiovascular reflex blocked). Available

as weekly patch. Also analgesic (alpha-2 agonist in spinal cord)

and used pre-anesthetically to ↓ BP. Rapid onset, long dura�on.

Guanabenz/guanfacine: SE: dizziness, ↓ heart rate. CI: other

sedatives, coronary insufficiency, MI, hepatic/renal disease.

Postganglionic adrenergic neuron transmitter blockers

Use: ↑↑ SE � avoid if possible, obsolete. Possibly for severe

refractory hypertension (other drugs ineffective).

Guanethidine / Guanadrel: very powerful � not first choice for

↑BP. Mechanism: ↓ release norepinephrine from adrenergic

nerve endings (depletes NEp). Does not enter CNS � not

sedation. ↑↑ SE: sodium / water retention, orthostatic

hypotension, impotence, diarrhea. CI: cocaine/TCA � ↓ effect

Reserpine: Low dose with other antihypertensives (e.g. diuretics).

Mechanism: depletes catecholamines centrally and peripherally.

SE: drowsiness, dizziness. CI: depression (cause nightmares,

suicide), peptic ulcer.


used in hypertensive crisis I.V only Fast acting Not first line.

Not routenily Used Vasodilator Very powerfull

Hypotention & reilex taclycardic

Vasodilator increase NO nitric oxide (EDRF)

Dilatate arteries

( afterload)

Diazoxide:-

The only thiazide but

not diuretic

Minoxidil:-

K+ channel opener

S.E : hair

:. TTT of alopecia

(topically)

Hydralazine:-

S.E SLE.

Dilatate veins

( preload)

Nitrate:-

(also for angina)

Morphine:-

(pain killer).

Used MI – pain

Dilatate both artery & veins

( after & preload)

Na+

Nitroprusside:-

D.O.C in hypertensive

crisis (200 / 140)

S.E

- Methemoglobinemia

- cyanide toxility

- avoid in water

- sold in waer photolysis

- bloodess surgery.


Endothelium drived relaxating factor which activate

adenylcyclase

ATP adenyl cyclase C – AMP (2nd

messeger)

TTT of raynald's disease. Used in Africans.


C.C.B

SE Ankle edema.

Non-dehydropyridine Dihydropyridine "X-dipine"

Verapamil & diltiazem

S.E Constipation

Vasodilator

- Ve inotropic effect

• C/I in CHF

• Used in angina

• Used in arrithymia

• Used in HT

• C/I W B.B

Nifedipine first pass effect

Amlodipine S.E pruritis

Nimodipine lipophilic

Pass BBB

Used to TTT cerebral spams.

Vasodilator

Has no cardiac effect.

• Has no significance in CHF

• Has no sighnificance in

angenia

• Has no sighnificance in

arrithymia

• Used in HT

• Used W B.B


C/I in Affrican's (no effect).

C/I W K+ sparing diretic as they make hyperkalemia.

All ACEI are once daily Ramipril:- the most effective ACEI

Except captopril Fosinopril has active metabolite

Angiotensin converting enzyme

inhibitor

Angiotensin II receptor blockrer

ACEI

X – PRIL

S.E: dry cough & angioedema due

to bradykinen accumulation.

- Proteinuria (esp. captopril)

- Used in diabetic W nephro &

neuropatny

More effective

High S.E

- First line in CHF

ARBs

X – SARTAN

S.E: no dry cough

No angioedema

No bradykinen accumulation

No proteinuria

2nd

line after ACEI in diabetic W

nephro & neuropathy.

Less effective.

Low S.E

C/I in CHF


Enalopril prodrug Enaloprilat "active"

.

Hypertensive crisis

Definition: systolic > 200 or diastolic > 140 � ↑↑ quick organ

damage.

Reduction of BP must be gradual (15 mmHg over first hour) to

avoid compromising organ perfusion (esp. cerebral)

Drugs: vasodilatos (nitroprusside, hydralazine, diazoxide,

nicardipine, nitroglycerin), enalaprilat, adrenergic inhibitors

(labetolol, esmolol, phentolamine (alpha blocker)), fenoldopam

(dopamine D1 agonist, vasodilator), trimethaphan (ganglionic

blocker)


K+ sparing diuretic

Proximal tubules

Distal tubule “ Thiazide “

Collecting dust

Loop of Henile

“carbonic anhydrase

inhibitor “

Ascending “ loop “


K+ - Sparing Diuretic

Aldosetcrone Na+

Antagonist Channel Blocker

- Spironolactone - triametricne

- eplerinone - amiloride

Hb Met.Hb

• Triametrene

• Nitrate

• Na+ nitroprusside

• paracetamol Fe

+2 Fe

+3

Good O2

Carrying

Capacity

Low O2

Carrying

Capacity


RAAS

Bradykinnen inactive peptide

(Vasodilator)

Angiotensin I ogenAngiotensin

Bind to the receptor

Potent aldosterone

Vasodilator - Na+

retension

- K+

excretion

Rennin

With low

Blood flow

Secrate

inactive ( Weak vasodilator)

(ACE) Angiotensin

Converting

Enzyme

Angiotensin II


K+ Carbonic osnotic

Sparing anhydrase

Diuretic inhibitor

Thiazide loop

Cause hypokalemia and

metabolic acidosis

Act as urine alkalinizer

Cause hypokalemia and

metabolic alkalosis

Safe with Digoxin C/I with Digoxin

Cause

Hyper

hyporcalcemia

Cause

hypercalcemia

Used in

Kidney

stones

Stones are ca-oxalate

Glucemia

Uricemia

Lipidemia

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Hypertension Pathophysiology - 1 File Download