2. Etiology of Hypertension
• A specific cause of hypertension established in only 10–15% of
patients.
• Patients in whom no specific cause of hypertension are said to have
essential or primary hypertension.
• Patients with a specific etiology are said to have secondary
hypertension.
• Genetic factors, psychological stress, and environmental and dietary
factors as contributing to the development of hypertension.
• The heritability of essential hypertension is estimated to be about
30%.
6. Normal Regulation of Blood Pressure
According to the hydraulic equation, arterial blood pressure (BP) is
directly proportionate to the product of the blood flow (cardiac
output, CO) and the resistance to passage of blood through pre-
capillary arterioles (peripheral vascular resistance, PVR)
BP = CO × PVR
7. Blood pressure is maintained by….
• Physiologically, moment-to-moment regulation of cardiac output and
peripheral vascular resistance exerted at three anatomic sites arterioles(1),
post-capillary venules (capacitance vessels)(2), and heart(3).
• Kidney(4) – by regulating the volume of intravascular fluid
• Baro-reflexes mediated by autonomic nerves (combination with humoral
mechanisms, including the renin-angiotensin-aldosterone system)
• Local release of vasoactive substances: nitric oxide, endothelin-1
• In hypertensive – Baro-reflex and renal blood-volume control system – set
at higher level
• All anti-hypertensives act via interfering with normal mechanisms
8. Treatment is crucial– why?
•Symptomatic treatment is Mandatory:
•Damage to the vascular epithelium, paving the
path for atherosclerosis (IHD, CVA) or
nephropathy due to high intra-glomerular
pressure
•Increased load on heart due to high BP can cause
CHF
•Hypertension, even asymptomatic needs
treatment
12. •Basic role:
• Initially ↓ BP & thus CO.
• Eventually CO returns to normal but is accompanied by a ↓ in PVR
•LOOP DIURETICS
•THIAZIDES & RELATED DRUGS
•POTASSIUM SPARING DIURETICS
1. Diuretics
13.
14. Thiazide diuretics:
• Examples: hydrochlorothiazide and
Chlorthalidone, INDAPAMIDE Strongest
vasodilator effect), METOLAZONE
• MOA: Inhibits Na + Cl + symporter at the
distal convulated tubules of nephrone
and lower blood pressure initially by
increasing sodium and water excretion.
CLINICAL INDICATIONS
• Hypertension / Edema
• Nephrotic diabetes insipidus
• Calcium nephrolithiasis
PK:
• orally active.
• All thiazides are
ligands for the organic
acid
secretory system of the
nephron, and as such,
they may compete with
uric acid for elimination
so?
15. Adverse Effects:
• Hypokalemia – muscle pain and fatigue
• Hyperglycemia: Inhibition of insulin release due to K+ depletion
(proinsulin to insulin) – precipitation of diabetes
• Hyperlipidemia: rise in total LDL level – risk of stroke
• Hyperuricemia: inhibition of urate excretion
• Sudden cardiac death – torsade's de pointes (hypokalemia)
• All the above metabolic side effects – higher doses (50 – 100 mg
per day)
• But, its observed that these adverse effects are minimal with low
doses (12.5 to 25 mg) - Average fall in BP is 10 mm of Hg
16. Thiazide- Current application
• Effects of low dose:
• No significant hypokalemia so, Low incidence of arrhythmia
• Lower incidence of hyperglycemia, hyperlipidemia and hyperuricemia
• Reduction in MI incidence
• Reduction in mortality and morbidity
• JNC recommendation:
• JNC recommends low dose of thiazide therapy (12.5 – 25 mg per day) in
essential hypertension
• Preferably should be used with a potassium sparing diuretic as first
choice in elderly
• If therapy fails – another antihypertensive but do not increase the
thiazide dose
• Loop diuretics are to be given when there is severe hypertension with
retention of body fluids
17. loop diuretics/high ceiling diuretic
• Example: FUROSEMIDE (Lasix),
BUMETANIDE, TORSEMIDE, ETHACYRINIC
ACID
• MOA: Inhibits Na+-K+-2Cl+ symporter
• Also Inhibits reabsorption of Ca+ & Mg+
• It acts promptly, even in patients with poor
renal function or who have not responded
to thiazides or other diuretics.
• Loop diuretics cause decreased renal
vascular resistance and increased renal
blood flow.
• Note: “Loop diuretics increase the Ca2+
content of urine, whereas thiazide
diuretics decrease it.”
• ADVERSE EFFECTS
• Hypokalemic metabolic
alkalosis, ↓ Na ↓ Cl
• ↓ K ↓ Ca ↓ Mg ↑
Uric Acid ↑ calcinuria
• Orthostatic
hypotension.
• Allergic rxs
• Ototoxicity ( ethacrynic
acid)
22. ANGIOTENSIN CONVERTING ENZYMES
INHIBITOR (ACE-I)
•↓ PVR by ↓ level of vasoconstriction
•↓ blood volume by ↓ aldosterone
secretion
•CAPTOPRIL
•LISINOPRIL
•ENALAPRIL
23. CAPTOPRIL (capoten)
•Reversibly inhibits angiotensin converting enzyme (
Kinase III) preventing the conversion of angiotensin I
into the vasoconstrictor angiotensin II
•↓ AT II levels ↓ aldosterone ↓ Na & H2O
retention
•↓ AT II levels ↑ renin release & the formation of
AT I
•ACEi ↑ bradykinin ↑ PG synthesis (vasodilators)
even increased the formation of cough (dry) (side
effect)
24. •USES:
• Hypertension: choice for white and young population effective
similarly if combine with diuretics in black too.
• Congestive heart failure
• Myocardial infarction
• Scleroderma renal crisis
• Diabetic nephropathy/ decrease albuminuria: along with AT
receptor blockers
•ADVERSE EFFECTS: dry cough, headache, fatigue,
hypotension, skin rash, dysgeusia, hyperkalemia, proteinuria, Acute
renal failure, angioedema bz of bradykinin (rare but lethal)
25. Contraindication
• Potassium levels must be monitored - potassium
supplements (or a high potassium diets) or potassium-
sparing diuretics
• The risk of angioedema and first-dose syncope
drug may be first administered in the close
observation
• Patients with severe bilateral renal artery stenosis
• Fetotoxic so…?
26. ANGIOTENSIN II RECEPTOR ANTAGONISTS
• Alternatives to the ACE inhibitors
• Inhibits the vasoconstrictor & aldosterone secreting effects of angiotensin II
• Converted to a 5 carboxylic acid metabolite
• ↓ AT II levels ↓ aldosterone levels ↓ Na & H2O retention
• Also ↑ renin release & the formation of angiotensin 1
• Possess uricosuric effects
27. •USE:
• HYPERTENSION,
• decrease the nephrotoxicity of diabetes an attractive therapy in
hypertensive diabetics
•ADVERSE EFFECTS:
• Headache
• Hypotension
• Hyperkalemia
• do not increase bradykinin levels so no ………?
•Contraindications:
• pregnancy, fetal exposure >>>hypotension, renal failure, anuria, skull
hypoplasia, death
28. 4. Direct renin inhibitor:
• Examples: Aliskiren, Remikiren, Enalkiren
• As effectively as ARBs, ACE inhibitors, and thiazides
• MOA: ….?
• Side effects: diarrhea, especially at the higher doses, cough and
angioedema (less than ACEi)
• Hyperkalemia significantly in patients who received both
valsartan and aliskiren.
• Contraindicated during pregnancy
38. MINOXIDIL
• Arteriolar smooth muscle vasodilator
• Increases K efflux by opening K channels hyperpolarization
relaxation of smooth muscle
• Vasodilatation ↓ PVR
• More potent than hydralazine
• USE : hypertension and alopecia
• Adverse Effects: edema, reflex tachycardia, flushing, hypertrichosis
39. 2. Arteriolar + venous dilators : Sodium Nitroprusside
• IV formulations are preffered bcz Nitroprusside is
poisonous if given orally because of its hydrolysis to
cyanide
• Nitric Oxide>>>> cGMP ↓ Ca ions in arteriolar &
venous vessels causing vasodilatation ↓ preload &
afterload
• USES: hypertensive emergencies, CHF
• Adverse Effects: hypotension, arrhythmias,
• Cyanide toxicity, thiocyanate poisoning
40. HYPERTENSIVE EMERGENCIES
1. DIAZOXIDE:
Activates ATP sensitive K + channels causing
hyperpolarization of arterioles smooth muscle cells
arteriolar vasodilatation
Stimulates reflex sympathetic tone ↑ CO, HR,
contractility
USES: Hypertensive Emergencies
Adverse effects: edema, tachycardia, hyperglycemia
41. 2. SODIUM NITROPRUSSIDE-- repeat
• IV formulations are preffered bcz Nitroprusside is
poisonous if given orally because of its hydrolysis to
cyanide
• Nitric Oxide>>>> cGMP ↓ Ca ions in arteriolar &
venous vessels causing vasodilatation ↓ preload &
afterload
• USES: hypertensive emergencies, CHF
• Adverse Effects: hypotension, arrhythmias,
• Cyanide toxicity, thiocyanate poisoning
42. 3. TRIMETHAPHAN
• Ganglionic blocking agent which competitively antagonizes
postsynaptic acetylcholine receptors
• ↓ both arterial BP & the upslope of the arterial pressure wave
in the aorta
• Direct peripheral vasodilatation & release of histamines
• USES: hypertensive emergencies
• ADVERSE EFFECTS: orthostatic hypotension, constipation,
urinary retention, blurred vision, dry mouth, impotency
43. 4. LABETALOL: IV
• MIXED ADRENERGIC
ANTAGONIST
• WITH INTRINSIC
SYMPATHOMIMETIC ACTIVITY
• USES: Hypertensive
emergencies
• HYPERTENSION
• ADVERSE EFFECTS: orthostatic
hypotension, dizziness
5. Fenoldopam: IV
• Peripheral dopamine 1 receptor
agonist
• Can be safely used in all
hypertensive emergencies
• Particularly in patients with renal
insufficiency
6. Nicardipine: IV
• A calcium-channel blocker,
Inhibition of insulin release due to K+ depletion – pptn of diabetes
a type of ventricular tachycardia with a spiral-like appearance ("twisting of the points") and complexes that at first look positive and then negative on an electrocardiogram. It is precipitated by a long Q-T interval, which often is induced by drugs (quinidine, procainamide, or disopyramide) but which may be the result of hypokalemia, hypomagnesemia, or profound bradycardia. The first line of treatment is IV magnesium sulfate, as well as defibrillation if the patient is unstable
Joint National Committee: Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
Use in some androgenic process issues
Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness
Nitroprusside is light sensitive, and when in solution, it should be protected from light
Nitroprusside is light sensitive, and when in solution, it should be protected from light