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BP = CO x PVR
• Reduce peripheral
vascular resistance
(vasodilators)
BP = CO X T PVR
Hypertension
A. Non-pharmacological - lifestyle
a) b -adrenoreceptor antagonists
Mechanism of action:
b-adrenoreceptor antagonists
cardio-selective:
b1 blockers atenolol, metoprolol
b1 blockers with ISA acebutol
b1,2 + a1 blockers labetalol, carvedilol
cardio non-selective:
b1 + b2 blockers nadolol, propranolol,
-cardioselectivity ( acebutolol,atenolol,bisoprolol,metoprolol ).
-positive data in heart failure ( carvedilol,metoprolol,bisoprolol ).
-or postinfarct ( carvedilol,metoprolol,timolol ).
-lipid insolubility&no hepatic metabolism (atenolol,nadolol ,
sotalol ).
-long acting (nadolol).
-ISA in selected patients to help avoid bradycardia ( pindolol ,
acebutolol ).
-added a blockade to achieve more arterial dilation(carvedilol).
-well studied antiarrhythmic properties (sotalol).
1. Drugs influencing sympathetic nerves
Adverse effects
b) a -adrenoreceptor antagonists
Mechanism of action:
- vasodilatation (reduce vascular resistence) and decreased blood
pressure by antagonizing of tonic action of noradrenaline on a1
receptors (vascular smooth muscle)
competitive with:
a. short-term action:
a non-selective - phentolamine
a1 selective - prazosin
b. long-acting
a1 antagonists - doxazosin, terazosin
SE :-
- the main manifestations are:
- drowsiness, weakness, orthostatic hypotension (first dose –
bedtime administration) - and for the nonselective agents, reflex
tachycardia - in patients with coronary disease, angina may be
precipitated by the tachycardia (less frequent in selective alpha1-
blockers)
- urinary incontinece
Adverse effects:
Indications
Mechanism of action
- ACEI regulates balance between bradykinin (vasodilatation,
natriuresis) and angiotensin II (vasoconstriction, Na+-retention)
Angiotensin II
- vasoconstriction
- noradrenaline release from sympathetic nerve terminals
- stimulate aldosterone secretion from the zona glomerulosa of the adrenal
cortex
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Angiotensin I Bradykinin
(inactive) (active vasodilator)
angiotensin-
ACE converting
inhibitors enzyme
renin
angiotensin II
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Mechanism of action:
However, ACE inhibitors are effective in many patients with low renin as
well as those with high renin hypertension and there is only a poor
correlation between inhibition of plasma-converting enzyme and chronic
antihypertensive effect, possibly because of the importance of
converting enzyme in various key tissues rather than in the plasma.
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
ACE inhibitors
Drug Duration of
effect (hours)
Short-acting: captopril 6-8
Medially-acting: enalapril 12
quinapril
perindopril
Long-acting:
lisinopril 24
spirapril
ramipril
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Adverse effects and contraindications of ACEI:
Therapeutic combination:
- useful interaction ACEIs with diuretics: Converting enzyme inhibitors interrupt
by diuretics increased plasma renin activity (and the consequent activation of
angiotensin II and aldosterone) and enhance the antihypertensive efficacy of
diuretics, as well as reducing thiazide-induced hypokalemia.
- adverse interaction ACE inhibitors with potassium-sparing diuretics and
potassium supplements, leading to hyperkalemia especially in patients with renal
impairment.
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Minoxidil
- therapy of severe hypertension resistant to other drugs
- prodrug its metabolite (minoxidil sulfate) is a potassium channel
opener ( repolarization + relaxation of vascular smooth muscle)
- more effect on arterioles than on veins
- orally active
- Adverse: Na+ and water retention → coadministration with beta-
blocker and diuretic is mandatory for this drug, oedemas,
hypertrichosis, breast tenderness
3.Direct vasodilators
Diazoxide
- given by rapid iv. injection (less than 30 seconds)* in hypertensive
emergencies
- potassium channel opener
- glucose intolerance due to reduced insulin secretion (used in
patients with inoperable insulinoma)
- adverse: Na+ and water retention, hyperglycaemia, hirsutism
Hydralazine
- rapidly and fairly absorbed after oral administration
- arteriolar resistance
- useful for hypertensive crisis during pregnancy
- AE: Na+ and water retention,headache,systemic lupus erythematosus
– suspected if there is unexplained weight loss, arthritis,reflex
tachycardia
3. Direct vasodilators
Sodium nitroprusside
verapamil, diltiazem
- effects on the voltage-dependent channels in cardiac conducting
tissue
- vasodilatation
- it also blocks Ca2+ entry in gastrointestinal smooth muscle and
consequently causes constipation.
-verapamil is drug of second choice in the Tx of SVT.
-verapamil is contraindicated in patient with 2nd or 3rd degree heart
block,also patient with WPW syndrome
-oral verapamil not given to patient taking i.v b blocker & the reverse
is true.
4. Calcium channel blocker
Thiazides
Mechanism of action:
Mechanism of action:
- they inhibit the co-transport of Na+, K+ and Cl-
- of Ca2+ and Mg2+ excretion
- they have useful pulmonary vasodilating effects (unknown mechanism)
Clinical uses:acute pulmonary oedema,hpertensive crisis,heart failure,
Oedema state,CRF when there is fluid retention,hypercalcaemia,forced
diuresis)
Lumen – Thick ascending Interstitium -
urine limb blood
Furosemide
Toxicity:
- hypokalemic metabolic alkalosis (increased excretion of K+)
- ototoxicity (dose dependent, reversible)
- decrease of Mg2+ plasma concentration (hypomagnesemia)
- hyperuricemia (competition with uric acid about tubular secretion)
- sulfonamide allergy
- risk of dehydration (> 4 L urine/ 24 h)
• Rare or uncommon:
• chest pain
• palpitations
• tingling feeling, especially in the hands or feet
vasopeptidase inhibitor (VPI)
• Blood homeostasis and vascular tone are regulated through
at least 3 major closely interrelated pathways in which zinc
metallopeptidases modulate the concentration of vasoactive
mediators
• Bosentan (Tracleer®)
antagonist of ETA and ETB
endothelin receptors, inhibit
vasoconstriction mitogenic
effect induced by endogenous
endothelins.
• decreases systolic and diastolic
arterial pressure.
• Bosentan is metabolized by
P450 cytochrome
• Bosentan is enzymatic inducer,
and drug interactions have
described.
• Administered by oral route
62.5mg-125mg tablet approved in
pulmonary hypertension
NADPH oxidase inhibitors
• NADPH oxidases have
recently been shown to
contribute to the
pathogenesis of
hypertension through
production of ROS
Thank you...