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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)
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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:
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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) .
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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.
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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).
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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)
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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)
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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
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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,
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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.
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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.
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Endothelium drived relaxating factor which activate
adenylcyclase
ATP adenyl cyclase C – AMP (2nd
messeger)
TTT of raynald's disease. Used in Africans.
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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
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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
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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)
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K+ sparing diuretic
Proximal tubules
Distal tubule “ Thiazide “
Collecting dust
Loop of Henile
“carbonic anhydrase
inhibitor “
Ascending “ loop “
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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
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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
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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