Hypertension

Pathophysiology
Arterial pressure = cardiac output X Peripheral Resistance
Cardiac output = heart rate X stroke volume
Starling's Law: ↑ ventricular stretch
↑ myocardial contraclity
↑ blood volume returning
↑ ventricular dilaon
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)

Modern Pharmacy Academy

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:

Modern Pharmacy Academy

1. ↑ urinary excreon of Na+ / water due to ↓ Na / Cl
reabsorption
2. ↑ urinary excreon 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 anhypertensives 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 reabsopron
↓ polyuria and polydipsia
in diabetes insipidus (instead of ADH) .

Modern Pharmacy Academy

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+, Ca2+, Mg2+, 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.

Modern Pharmacy Academy

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 excreon

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).

Modern Pharmacy Academy

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)

Modern Pharmacy Academy

Mechanism: ↓ cAMP
↓ heart contracon and rate. Other: ↓
rennin secretion
↓ cardiac output, central ↓ in sympathec
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)

Modern Pharmacy Academy

Timolol: mainly for ocular hypertension (B1/B2).
Esmolol: ultrashort duration of action, IV.
Carteolol: ↓ lipid solubility
↓ CNS penetraon.
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 filtraon.
Contraindications:

• Ca channel blockers
• CHF
cardiac decompensation due to ↓ contracbility and ↓
electrical conduction
• DM
may mask tachycardia (hypoglycemia), ↓ BG
• COPD, asthma, bronchospams (selectivity is dose dependent)
• Peripheral vascular disease / Raynaud’s phenomenon

vasoconstriction

Modern Pharmacy Academy

 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 ↓ sympathec 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,

Modern Pharmacy Academy

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 duraon.
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.

Modern Pharmacy Academy

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

Not routenily Used Vasodilator Very powerfull

Hypotention & reilex taclycardic

Dilatate arteries Dilatate veins Dilatate both artery & veins

( afterload) ( preload) ( after & preload)

Diazoxide:- Nitrate:- Na+ Nitroprusside:-

The only thiazide but (also for angina) D.O.C in hypertensive
not diuretic crisis (200 / 140)

Minoxidil:- Morphine:- S.E

K+ channel opener (pain killer). - Methemoglobinemia
S.E : hair Used MI – pain - cyanide toxility
:. TTT of alopecia - avoid in water
(topically) - sold in waer photolysis
- bloodess surgery.
Hydralazine:-
S.E SLE.

Vasodilator increase NO nitric oxide (EDRF)

Modern Pharmacy Academy

Endothelium drived relaxating factor which activate
adenylcyclase
ATP adenyl cyclase C – AMP (2nd messeger)

TTT of raynald's disease. Used in Africans.

Modern Pharmacy Academy

 C.C.B

SE Ankle edema.

Non-dehydropyridine Dihydropyridine "X-dipine"

Verapamil & diltiazem Nifedipine first pass effect
S.E Constipation Amlodipine S.E pruritis
Nimodipine lipophilic
Pass BBB
Vasodilator Used to TTT cerebral spams.
- Ve inotropic effect Vasodilator

• C/I in CHF Has no cardiac effect.

• Used in angina • Has no significance in CHF
• Used in arrithymia • Has no sighnificance in
• Used in HT angenia
• C/I W B.B • Has no sighnificance in
arrithymia
• Used in HT
• Used W B.B

Modern Pharmacy Academy

 Angiotensin converting enzyme Angiotensin II receptor blockrer
inhibitor

ACEI ARBs
X – PRIL X – SARTAN
S.E: dry cough & angioedema due S.E: no dry cough
to bradykinen accumulation. No angioedema
No bradykinen accumulation
- Proteinuria (esp. captopril) No proteinuria
- Used in diabetic W nephro &
neuropatny 2nd line after ACEI in diabetic W
nephro & neuropathy.
More effective Less effective.
High S.E Low S.E

- First line in CHF C/I in CHF

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

Modern Pharmacy Academy

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)

Modern Pharmacy Academy

 Proximal tubules
“carbonic anhydrase

inhibitor “ Distal tubule “ Thiazide “

Ascending “ loop “

Loop of Henile
Collecting dust
K+ sparing diuretic

Modern Pharmacy Academy

 K+ - Sparing Diuretic

Aldosetcrone Na+
Antagonist Channel Blocker
- Spironolactone - triametricne
- eplerinone - amiloride

• Triametrene
• Nitrate
Hb Met.Hb
• Na+ nitroprusside
Fe+2 • paracetamol
Fe+3
Good O2 Low O2

Carrying Carrying

Capacity Capacity

Modern Pharmacy Academy

 With low

Blood flow
RAAS
Secrate
Bradykinnen inactive peptide
(Vasodilator) Rennin

Angiotensinogen Angiotensin I
inactive ( Weak vasodilator)
(ACE)
Angiotensin

Converting

Enzyme

Angiotensin II

Bind to the receptor

Potent aldosterone
Vasodilator - Na+ retension
- K+ excretion

Modern Pharmacy Academy

Thiazide loop K+ Carbonic osnotic
Sparing anhydrase
Diuretic inhibitor
Cause hypokalemia and Cause hypokalemia and
metabolic alkalosis metabolic acidosis
Act as urine alkalinizer
C/I with Digoxin Safe with Digoxin
Cause Glucemia
Hyper Uricemia
Lipidemia

Cause
hypercalcemia hyporcalcemia
Used in
Kidney
stones

Stones are ca-oxalate

Modern Pharmacy Academy