1. Drugs Hypertesnion, heart failure and arryhthmia.pptx

1. Drug therapy of hypertension
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Hypertension
 BP at the beginning of the aorta is generated by the left ventricle.
 This BP varies b/n 120 mmHg during systole and 80 mmHg
during diastole.
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Definitions… Blood Pressure

Hypertension
 Resistance to flow through a vessel depends…
1. On the length of the vessel
2. radius of the vessel, and…
3. On the viscosity of the fluid.
 In the body…
 The length of the blood vessels is essentially fixed.
 Although potentially variable, blood viscosity is also fixed.
 Therefore, when discussing resistance to blood flow in the vascular
system, one usually considers only the radius of the blood vessels.
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Definitions… Resistance

Hypertension
 Blood pressure (BP)… Sometimes referred as arterial blood pressure
 Is the pressure exerted by circulating blood upon the walls of BV
 BP = CO × PVR
 Hypertension is defined as…
 Systolic BP (SBP) ⩾140 mmHg Diastolic BP(DBP) ⩾ 90 mmHg.
 Isolated systolic hypertension (SBP)> 140mmHg and DBP< 90mmHG.
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Definitions
And/or

Hypertension
 Category of stage of hypertension according to the USA Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High BP
 When there is disparity, b/n SBP and DBP, the higher values determines the
severity of the HTN
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Definitions
Category Blood pressure in, mm Hg
Systolic Diastolic
Hypotension ˂90 ˂60
Normal (optimal control) <120 (90-119) And <80 (60-79)
Prehypertension 120-139 or 80-89
Hypertension
 Stage1 140-159 or 90-99
 Stage2 >160 or >100

Hypertension
 Two types
1. Primary (essential) hypertension (90-95%)
 Has no identifiable cause
 Drugs can lower BP but they do not culminate the underlying pathology.
 i.e., not curative
2. Secondary hypertension (5–10%)
 Has identifiable cause
 Possibly by treating the cause directly, some individual can be cured.
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Types of hypertension

Hypertension
 Hypertensive emergency…..
 Is a condition in which elevated BP results in TOD.
 Acute, life threatening with marked ⬆es in BP…> 180/120 mmHg.
 Require immediate (min) BP reduction to prevent or limit TOD
 Primarily involved include…….CNS, CVS, Lung, and the renal system.
 The damages include…
 Hypertensive encephalopathy, intracranial hemorrhage
 Unstable angina, acute MI, pulmonary edema, dissect aortic aneurysm.
 Malignant hypertension and accelerated hypertension are
both hypertensive emergencies, with similar outcomes and
therapies. 8
Definitions

Hypertension
 Hypertensive emergency…..
9
Definitions

Hypertension
 Hypertensive Urgencies
 There is asymptomatic severe HTN ((i.e., systolic BP >220 mm Hg or
diastolic BP >120 mm Hg) ) with no target organ damage.
 The goal is to ↓es BP to ≤160/100 over several hrs to days (not
rapidly; usually 24-48 hours
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Definitions

Hypertension
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Consequences of hypertension
 Cerebrovascular
accident….Stroke…brain attack

Hypertension
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Consequences of hypertension

Hypertension
A. Non-pharmacologic interventions
B. Pharmacologic interventions
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Management of hypertension

Hypertension
1. Weight reduction if overweight:
BMI 18-24 kg/m2,waist circumference <102cm men, <88cm women
 Weight reduction even without Na restriction has been shown to
normalize BP in 75% of overweight pts with mild to moderate HTN.
2. Reduce salt intake:
 Dietary goal in treating HTN is 70–100 mEq of Na/day (1 tsp of table salt)
Don’t forget hidden salts in processed foods…may contain large amounts
of Na.
Can be achieved by not salting food during or after cooking and by
avoiding processed foods that contain large amounts of sodium. 14
A. Non-pharmacologic interventions (Lifestyle changes)

Hypertension
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A. Non-pharmacologic interventions (Lifestyle changes)

Hypertension
3. Moderation of alcohol intake…no more than two drinks per day
 One drink is defined as…
 12 oz (one bottle/can) of 5% beer or wine cooler
 5 ounces of (one glass) of 12% wine
 1.5 oz (one shot) of 80-proof 40% distilled spirits
 Note: All contain 17 g of alcohol
4. Aerobic exercise:
 Reduce resting heart rate and possibly TPR, and
 Also increases HDL levels
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A. Non-pharmacologic interventions (Lifestyle changes)…

Hypertension
5. Smoking cessation: Cigarette smoke is known to reduce blood
flow to various organs and can ⬆es the work of the heart.
6. Relaxation techniques: May reduce heart rate and TPR by
interrupting the sympathetic stress response
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A. Non-pharmacologic interventions (Lifestyle changes)…
7. Dietary recommendations:
 Emphasize fruits, vegetables, low-fat dairy
products, fibre, wholegrains, and protein sources
that are reduced in saturated fats and cholesterol

Hypertension
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1. Diuretics
2. Sympatholytics (mainly Beta blockers)
3. Calcium channel antagonists
4. Angiotensin converting enzyme inhibitors.
5. Angiotensin receptor blockers
6. Vasodilators
Drug classes
B. Pharmacologic Intervention

Hypertension
 Diuretics…
 Are the mainstays of antihypertensive therapy
 Are effective in lowering BP by 10–15 mmHg in most patients
 Alone often provide adequate treatment for mild or moderate HTN.
 In more severe hypertension…
 Diuretics are used in combn with alpha blocker & vasodilator drugs
 Enables to control the tendency of Na+ retention.
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1. Diuretics

Hypertension
1. High efficacy diuretics (inhibitors of Na+-2Cl- co-transport).
 Also called , high ceiling diuretics; loop diuretics
2. Medium efficacy diuretics (inhibitors of Na+-Cl- symport)
3.Weak or adjuvant diuretics
 Carbonic anhydrase inhibitors
 Potassium sparing diuretics
 Luminal Na channel blockers
 Aldosterone antagonists
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Hyperkalemia
Hypokalemia
1. Diuretics

Hypertension
A. Thiazides diuretics -
 Original inhibitors of Na+-Cl- symport were benzothiadiazine
derivatives…hence the name thiazide diuretics.
 Subsequently, drugs that are pharmacologically similar to
thiazide diuretics but are not thiazides were developed and are
called thiazide like diuretics.
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1. Diuretics

Hypertension
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1. Diuretics
• Thiazides
 Chlorothiazide (diuril)
 Hydrochlorothiazide (Hydro-DIURIL)
 Bendroflumethiazide
 Hydroflumethiazide
 Methyclothiazide
 Polythiazide
• Thiazide like
 Chlorthalidone
 Metolazone
 Quinethazone
 Indapamide
A. Thiazides diuretics…

Hypertension
A. Thiazides diuretics -most commonly used…
 Diuresis: Diuretics lower BP primarily by decreasing blood volume
 HCT 12.5- 25 mg/day, P.O. QD
 Lower doses (25–50 mg) exert as much effect as do higher doses.
 Are appropriate for most patients with…
 Mild or moderate hypertension & normal renal and cardiac function.
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1. Diuretics

Hypertension
 Response to Thiazides diuretics…..
 Most pts will respond with a reduction in BP in about 4 wks,
 Some will not achieve max reduction up to 12 wks on a given dose.
 Therefore, doses should not be ⬆ed more often than every 4 to 6
weeks.
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1. Diuretics
A. Thiazides diuretics…

 Combination….is common
1) Have additive effect with other antihypertensive drugs
2) Diuretics also have the advantage of minimizing the retention of
salt & water that is commonly caused by vasodilators & some
sympatholytic (alpha blocker)drugs.
 Omitting or underutilizing a diuretic is a frequent cause of
"resistant hypertension."
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1. Diuretics A. Thiazides diuretics…

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B. High ceiling diuretics
 Drugs:
 Furosemide (lasix)
 Ethacrynic acid
 Bumetanide
 Inhibit Na+2Cl- co transport…
 At the thick ascending limb of loop of henle
 Inhibit reabsorption of 25 % filtered NaCl

B. High ceiling diuretics- diuresis….
Have short duration of action……Single daily dose does’t cause a
significant net loss of Na+ for an entire 24-hour period
 Hence, are necessary in………
A. Severe hypertension
B. In conditions with marked Na retention….
 Multiple drugs with Na-retaining properties (e.g. vasodilators) are used
 In renal insufficiency.
 In cardiac failure or cirrhosis 29
1.Diuretics

C. K sparing diuretics- Degree of diuresis is small…useful both
 To avoid excessive K+ depletion and
 To enhance the natriuretic effects of other diuretics
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1. Diuretics
A. Aldosterone antagonist
 Spironolactone (Aldactone, epilactone)
 Eplerenone
B. Renal Na channel blockers
 Triamterene and
 Amiloride

 In the Rx of HTN, the most common adverse effect of diuretics is…
A. Hypokalemia and alkalosis (except for K-sparing diuretics)
Mild degrees of hypokalemia are tolerated well by many patients,
but…
 Hypokalemia may be hazardous in persons…
 Taking digitalis
 Those who have chronic arrhythmias, or
 Those with acute MI or left ventricular dysfunction.
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1. Toxicity of Diuretics

B. Hyperkalemia
 Produced by K -sparing diuretics particularly in patients with…
 Renal insufficiency or
 Those taking ACEI or ARB
C. Spironolactone (a steroid) is associated with gynecomastia
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D. Others…Diuretics may also cause…
 Magnesium and calcium depletion
 Impair glucose tolerance, and
 Increase serum lipid concentrations.
 Diuretics ↓es uric acid concentrations and may precipitate gout.
 The use of low doses minimizes these adverse metabolic effects…
 Without impairing the antihypertensive action.
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 Potassium is related to insulin release
 Diuretics cause hypokalemia and hence may blunt Insulin
release
 Thiazide diuretics in high doses may worsen glycemic control
 But K supplementation and a combination with ACEIs or
ARBs may prevent hypokalemia.
 Low-dose thiazides can also be used

Hypertension
 Advantages of diuretics
 Effective in elderly and in black people (similar to CCB)
 As compared to ACEI and beta blockers…white and young people
 Can be taken orally
 Less side effects
 Less costly
 Maintain low blood pressure as long as they are taken
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1.Diuretics
Drugs Dose Frequency Cost
Enalapril 5-40 1-2 0.4 cent/tab
HCT 12.5-25 1 0.35/tab

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2. Sympatholytic (adrenergic antagonists)

Hypertension
 Suppress the influence of the SNS
 Five categories of sympatholytic drugs
A. Centrally acting agents: clonidine and methyldopa
B. Ganglionic blocker
C. Adrenergic neuron….. Guanethidine and Reserpine
D. Beta adrenergic blockers
E. Alpha 1 adrenergic blockers
F. Alpha 1 –beta adrenergic blockers: Carvedilol, labetalol
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Hypertension

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Response of the autonomic nervous system and the renin-angiotensin-aldosterone system to a decrease in BP.

 Drugs
 Clonidine and
 Methyldopa
 Guanabenz and Guanfacine
 Mechanism of action
 Site of action: Acts within the brainstem
 Suppress sympathetic out flow to the heart and blood vessels.
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2. Adrenergic antagonists : 1.1. Centrally acting agents:

 Methyl-dopa (aldomet)
1. Competitive inhibitor of DOPA decarboxylase
 Also known as aromatic L-amino acid decarboxylase
 Which converts L-DOPA into dopamine….precursor for NE & subsequently E
 This inhibition results in ↓es dopaminergic and adrenergic NT in the PNS.
 Effect…..↓BP, depression, anxiety, parkinsonism. hyperprolactinemia.
2. Methyl-dopa is converted to Methyl NA (in brain)
 Activates presynaptic α2 receptor in brain→ ↓es sympathetic outflow in CNS
 Decrease BP (↓es CO, Venodilation and Arteriodilation)
 This is also the mechanism of action of clonidine.
40

 Methyldopa…..Pharmacokinetics & Dosage
 Methyldopa enters the brain via an aromatic AA transporter.
 The usual oral dose of methyldopa (250-1000 BID)…..
Clinical Use…..Methyldopa
1.Hypertension (or high BP)…..
 Was widely used in the past
 Its use has declined……..
─⬆ed use of other safer and more tolerable agents such as α-
blockers, β-blockers, & CCB
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 Clinical Use…..Methyldopa
2. Gestational HTN (or pregnancy-induced HTN) &
pre-eclampsia
Is its most common use….due to its relative safety
in pregnancy
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 Clonidine
 MOA: Activates Presynaptic α2 receptor in brain
 This results in …
A. Reduction of cardiac output due to decreased HR
B. Relaxation of capacitance vessels, as well as…..
C. A reduction in peripheral vascular resistance.
43

Hypertension
 Clonidine……clinical use
1. Hypertension
2. Diminishing craving for Narcotics, alcohol and cigarette
smoking.
3. To diminish menopausal hot flushes
4. Attention deficit hyperactivity disorder
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 Clonidine works by blocking chemicals in the
brain that trigger SNS activity.
 This reduces uncomfortable symptoms of opioid
detoxification*, such as sweating, hot flashes,
watery eyes and restlessness.

Hypertension
 Clonidine……Pharmacokinetics & Dosage
 Clonidine……To maintain smooth BP control……..
 Oral clonidine must be given BID or as a patch…….Because….
 Have a relatively short half-life and……..
 Its effect is directly related to blood concentration
 Dose…….0.1mg BID
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Hypertension
 Guanabenz and guanfacine:
 MOA: Activates Presynaptic α2 R in brain (similar to clonidine)
 They do not appear to offer any advantages over clonidine and
are rarely used
46

Hypertension
 Guanfacine…other use…Attention deficit hyperactivity disorder.
 Is a highly selective agonist of the α2A adrenergic receptor
 Guanfacine availability is significantly affected by the CYP3A4
and CYP3A5 enzymes,
 Medications that inhibit or induce those enzymes change the
amount of guanfacine in circulation and thus its efficacy and
adverse effects
47

Hypertension
 Side effect
 Sedation that is largely transient.
 Dryness of the mouth.
 Methyldopa causes
 Hemolytic (positive Coombs test, due to auto antibodies,) and
 Hepatoxicity (sometimes related to fever)
 M.dopa, Clonidine…severe rebound HPN if abruptly discontinued*
 Lactation….with ⬆ed prolactin secretion……..occur both in men
and in women
 Mediated by inhibition of dopaminergic in the hypothalamus
48

 Side effect
 Clonidine…severe rebound HPN if abruptly discontinued*
Dosage forms
Clonidine
 Oral: 0.1, 0.2, 0.3 mg tablets
 Transdermal: patches that release 0.1, 0.2, 0.3 mg/24 h
Methyldopa
 Oral: 250, 500 mg tablets
 Parenteral: 50 mg/mL for injection
49

Hypertension
 Are no longer available clinically……..
 Because of intolerable toxicities related to their primary action
 Can competitively block nicotinic Rs on postganglionic neurons in
both sympathetic & parasympathetic ganglia.
 In addition, these drugs may directly block the nicotinic Ach
channel, in the same fashion as neuromuscular nicotinic blockers
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2. Adrenergic antagonists : 1.2. Ganglion-blocking agents

Hypertension
 Site of action…Sympathetic nerve terminals
 Drugs :
1. Guanethidine  inhibits release of NE
 Guanethidine is too polar to enter the CNS.
 As a result, this drug has none of the central effects seen with other agents
 Guanadrel is a guanethidine-like drug that is available in the USA
 Bethanidine and debrisoquin, not available for use in the USA, are similar.
2. Reserpine  causes NE depletion
 By interfering with the vesicular membrane-associated transporter (VMAT)
 Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina
 At present, it is rarely used owing to its adverse effects.
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2. Adrenergic antagonists : 1.3. Adrenergic neuron blockers

Hypertension
 Site of action…Sympathetic nerve terminals
52

Hypertension
 Guanadrel…Oral: 10, 25 mg tablets
 Guanethidine…Oral: 10, 25 mg tablets
 Reserpine…Oral: 0.1, 0.25 mg tablets
53

Hypertension
 Other clinical use
 Guanadrel and Guanethidine can be used in Hyperthyroidism…
 To ameliorate the exophthalmia, eye drops, act by relaxing the
sympathetically innervated smooth muscle that causes eyelid
retraction
54

Hypertension
 Most of the unwanted effects result from actions on the…
1. Brain leading to:
 Orthostatic hypotension…..from ⬇ed sympathetic tone to veins
 Sedation, lassitude, nightmares, & severe mental depression
2. GIT
 Reserpine often produces mild diarrhea and GI cramps and
increases Gastric acid secretion.
55

 Drugs
 Propranolol
 Timolol
 Esmolol
 Metoprolol
 Atenolol
 Acebutolol etc.
 Most widely used drugs
56
1.4. Beta adrenergic blockers

 Mechanism of action……..Block β-1 and β-2 receptor
 Other actions…….Some have local anesthetic activity
 Is the result of typical local anesthetic blockade of Na
channels
 But, is not important for systemic administration of these
drugs….
 Since the concentration in plasma usually achieved by these
routes is too low for the anesthetic effects to be evident.
57
2. Adrenergic Antagonists:

 Category
A. Selective β-1
 Betaxolol, Bisoprolol, Metoprolol, Esmolol, Atenolol,
Acetbutolol
 Celiprolol, Nebivolol
B. Partial agonists…..
 Pindolol, Nadolol, Acebutolol,, ……
 Celiprolol, Penbutolol, Carteolol
C. α-1, β adrenergic blockers.... Carvedilol, Labetalol, Nebivolol
58

Hypertension
59
2. Adrenergic Antagonists: 1.4. Beta adrenergic blockers

 Have at least three useful actions in hypertension
a) Blockade of cardiac β-1 receptors → ↓es HR & contractility
b) Suppress reflex tachycardia caused by vasodilators
c) Blockade of β-1 receptors on juxtaglomerualr cells of the
kidney
 Means reduction of renin release →
 Reducing angiotensin II mediated vasoconstriction and
aldosterone volume expansion
60

 β-receptor blockers are highly preferred drugs for…
 Hypertensive patients with conditions such as…
 Ischemic heart disease
 Myocardial infarction , or
 Congestive heart failure.
 Migraine
61

Hypertension
 Dosage
 Atenolol………………………….25-100mg P.O……QD
 Metoprolol succinate...........25-100 PO.............QD
 Propranolol..............................40-160 PO..............BID/TID
 Carvedilol.................................12.5-50 PO.............BID
62

Hypertension
 Atenolol
 Oral: 25, 50, 100 mg tablets
 Parenteral: 0.5 mg/mL for injection
 Metoprolol
 Oral: 50, 100 mg tablets
 Oral extended-release: 25, 50, 100, 200 mg tablets
63

Hypertension
 Propranolol
 Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8 mg/mL oral solution;
 Oral sustained-release : 60, 80, 120, 160 mg capsules
 Parenteral: 1 mg/ml for injection
 Labetalol
 Timolol
64

Hypertension
 Propranolol………….
 Was the 1st β blocker shown to be effective in HTN and IHD
 Largely replaced by cardioselective β blockers such as
metoprolol and atenolol.
 Can be administered BID, & slow-release preparations are
available.
65
Propranolol

Hypertension
 Metoprolol and atenolol…………
 Are cardioselective……are the most widely used in the RX of HTN.
 Metoprolol is……….
 Approximately equipotent to propranolol in inhibiting
stimulation of β1 adrenoceptors such as those in the heart…….
 But 50-100-fold less potent than propranolol in blocking β2 R.
66
Metoprolol & Atenolol

Hypertension
 Metoprolol and atenolol…………
 Relative cardioselectivity may be advantageous in treating
hypertensive patients…….
 Who also suffer from asthma, diabetes, or PVD
67

Hypertension
 Metoprolol…………….
 Extensively metabolized by CYP2D6 with high 1st pass metabolism.
 The drug has a relatively short t1/2 of 4-6 hrs……
 But the extended-release preparation can be dosed once daily
 Metoprolol succinate...........25-100 mg/d PO.............QD
68

 Pindolol, acebutolol, and penbutolol…………..
 Are partial agonists…some intrinsic sympathomimetic activity.
 Pindolol………….10 mg/d
 Acebutolol…........ 400 mg/d
 Penbutolol………..20 mg.
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Pindolol, Acebutolol, & Penbutolol

Hypertension
 Atenolol…………….
 Excreted 1o in the urine with a t1/2 of 6 hrs…usually dosed QD
 The usual dosage is 25–100 mg/d.
 Atenolol and metoprolol…… Studies……. Atenolol less effective…..
 Than metoprolol in preventing the complications of HTN.
 A possible reason….QD dosing doesn't maintain adequate
blood levels of atenolol.
70

Hypertension
 Nadolol and Carteolol………..Nonselective β-receptor
antagonists…
 Betaxolol and Bisoprolol………Are β1 -selective blockers
 Have long t1/2…….dosed once daily.
 Nadolol is usually begun at a dosage of 40 mg/d
 Carteolol at 2.5 mg/d
 Betaxolol at 10 mg/d, and
 Bisoprolol at 5 mg/d.
71
 Nadolol, Carteolol, Betaxolol, & Bisoprolol

 Labetalol, Carvedilol, & Nebivolol…………………
 Have both β-blocking & α blockade (vasodilating effects).
 Labetalol……. Because of its combined α- and β-blocking
activity……
 Labetalol is useful in treating the……
A. HTN of pheochromocytoma and
B. Hypertensive emergencies
C. Rebound hypertension
 α & β-blocking activities of labetalol may be beneficial in a
hyperadrenergic state ff abrupt withdrawal of β-blockers.
72

 Drugs
 Prazocin
 Terazocin
 Tamsulocin
 Doxazosin
 MOA
 Prevent stimulation of α1 receptors on arteries and veins →
vasodilation→ reduces PR
73
1.5. Alpha 1 adrenergic blockers
Phentolamine and
Phenoxybenzamine

 Long-term Rx with these α blockers……..
 Causes relatively little postural hypotension……………..
 Develops in some pts shortly after the 1st dose is absorbed.
 Hence, the 1st dose should be small & be administered at bedtime.
 Although the MZM of this 1st -dose phenomenon is not clear, it occurs
more commonly in pts who are salt- and volume-depleted.
74
2. Adrenergic antagonists : 1.5. Alpha 1 adrenergic blockers

 Terazosin…..can often be given once daily, with doses of 5-20 mg/d.
 Doxazosin…….. is usually given once daily starting at 1-4 mg/d
75

 Side effects
A. Orthostatic hypotension……
 Also known as postural hypotension is the major adverse effect.
 Occurs when a person's BP falls when suddenly standing up from a lying or
sitting position.
 It is defined as a fall in SBP of at least 20 mm Hg or DBP of at least 10 mm
Hg when a person assumes a standing position
 As a result, blood pools in the blood vessels of the legs for a longer period
and less is returned to the heart, thereby leading to a reduced CO.
76

Hypertension
 Side effects
B. Reflex tachycardia
 These agents can produce reflex tachycardia when lowering BP
 But the reflex tachycardia is less than do nonselective α
antagonists such as phentolamine.
 α1-receptor selectivity allows NE to exert unopposed (–Ve)
feedback (mediated by presynaptic α2 Rs) on its own release
77

Hypertension
 Side effects
 α1-blockers……….
 ↓es BP by dilating both resistance & capacitance vessels.
 Retention of salt & water occurs when these drugs are
administered without a diuretic.
 The drugs are more effective when used in combination with
other agents, such as a β blocker & a diuretic, than when used
alone.
78

Hypertension
 Clinical Use
 Hypertension
 Owing to their beneficial effects in men with BPH symptoms,
these drugs are used 10 in men with concurrent HTN and BPH.
79

Hypertension
 Drugs:
 Carvedilol
 Labetalol
 Nebivolol
 Lowering of BP results from a combination of actions
 Side effects
 Like other non-selective β-blockers
 Exacerbates bradycardia
 AV block
 Asthma 80
2. Adrenergic antagonists :1.6. Alpha 1 –beta adrenergic blockers:

 Lipid profile disturbance
 The chronic use ↑es VLDL and ↓es
HDL cholesterol……risk of CV disease
 Occur with both selective and
nonselective β blockers
 Less likely with β blockers with
intrinsic sympathomimetic activity
81
2. β- Adrenergic Blocking Agents:
 Side effects of β-blockers
 Exacerbates bradycardia
 AV block
 Fatigue
 Insomnia
 Erectile dysfunction
 Impaired exercise
tolerance

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2. β- Adrenergic Blocking Agents
 Contraindication
 Bronchospastic conditions (like Asthma)
 Severe bradycardia
 AV blockade and
 Severe unstable LVF
Hypertension

Pharmacology of ANS
 Antidotes….Therapies include:
 Β-agonists
 Glucagon
 PDE Inhibitors (Amrinone)
 Insulin
83
4. Adrenergic antagonists… 4.3. β- Adrenergic Blocking Agents

Pharmacology of ANS
 High-dose glucagon is considered the first-line antidote.
 Glucagon increases heart rate and myocardial contractility, and…
 Improves atrioventricular conduction.
 Insulin…………….
 High-dose insulin with supplemental dextrose & Potassium
therapy (HDIDK) is reserved for refractory cases.
 Insulin…have a positive inotropic effects
84

Pharmacology of ANS
 Glucagon…
 Increases HR and myocardial contractility, and
 Improves AV conduction.
Glucagon binds to glucagon receptor found on
cardiac myocytes and stimulates AC via G proteins.
85

86
3. Direct acting vasodilators

Hypertension
• Drugs
• Oral vasodilators
• Hydralazine
• Diazoxide
• Minoxidil
• Parenteral vasodilators
• Hydralazine first line drug for Hypertensive Emergencies
• Diazoxide
• Sodium Nitroprusside
• Fenoldopam
87
Managementofhypertension
3. Direct acting vasodilators  Used for long-term outpatient therapy of HTN
 Are used to treat hypertensive emergencies

Hypertension
 Minoxidil
 Oral: 2.5, 10 mg tablets
 Topical (Rogaine): 2% lotion
 Nitroprusside
 Parenteral: 50 mg/vial
 Fenoldopam
Parenteral: 10 mg/mL for IV
88
Management of hypertension …..3. Direct acting vasodilators
 Hydralazine
 Oral: 10, 25, 50, 100 mg tablets
 Diazoxide
 Oral (Proglycem):
 50 mg capsule
 50mg/ml PO suspension (for
insulinoma)
 Parenteral: 15 mg/mL ampule
 Dosage forms

Hypertension
 All Relax smooth muscle of arterioles… ↓ing vascular resistance.
 Sodium nitroprusside and the nitrates also relax veins.
89
Management of HTN

Hypertension
90
Management of HTN

Hypertension
 Decreased arterial resistance & hence, decreased mean BP……
 Elicit compensatory responses…Mediated by…
 Baroreceptors and
 The sympathetic nervous system as well as
 Renin, angiotensin, and aldosterone
 B/se sympathetic reflexes are intact…Vasodilator therapy doesn’t…
 Cause orthostatic hypotension or
 Sexual dysfunction. 91

Hypertension
 Vasodilators work best in combination with…
 Other antihypertensive drugs that oppose the compensatory
cardiovascular responses.
 As a group, if a drug blocks…
 Only Veins…can cause orthostatic hypotension
 Artery…decrease in TPR...leading to reflex tachycardia
 Hydralazine
Because of preferential dilation of arterioles over veins……postural
hypotension is not a common problem
92

Hypertension
 Hydralazine…………….Pharmacokinetics & Dosage
 Hydralazine is…..
 Rapidly metabolized during the first pass….bioavailability is low (25%)
 Variable among individuals.
 It is metabolized in part by acetylation at a rate that appears to be
bimodally distributed in the population
 As a consequence, rapid acetylators have greater 1st -pass metabolism…..
lower blood levels, and less antihypertensive benefit from a given dose than
do slow acetylators.
93
 Tablet, 10, 25, 50, 100 mg
 Injection, 20 mg /ml in 1 ml ampoule

Hypertension
I. Hydralazine:
A. First line drug for Hypertensive Emergencies
 Dilates arterioles but not veins.
 5-10mg IV every 20-30 min (with maximum dose of 20 mg)
B. Hydralazine is the first line drug for hypertensive pregnant women.
 5 -10mg IV every 20 minutes whenever the diastolic BP> 110 mmHg.
94
 Tablet, 10, 25, 50, 100 mg
 Injection, 20 mg /ml in 1 ml ampoule

Hypertension
 Adverse effects:
 Mots common AEs after the use of hydralazine are:
1. Extensions of the pharmacological effects of the drug
 Headache, nausea, flushing, hypotension, palpitations, tachycardia,
 Dizziness, and angina pectoris and Myocardial ischemia
95

Hypertension
 Adverse effects:
2. The 2nd type of adverse effect is caused by
immunological reactions….
 Lupus syndrome…most common.
 Usually occurs after at least 6 mths of Rx
96
 Hydralazine also can produce a pyridoxine-responsive polyneuropathy.
 The MZM appears to be related to the ability of hydralazine to combine with
pyridoxine to form a hydrazone.

Hypertension
II.Minoxidil
 Minoxidil is a prodrug…….
 Is converted by sulfation via the sulfotransferase enzyme to its
active form, minoxidil sulfate.
 Is Orally active vasodilator
 By opening K+ channels in smooth muscle…permitting K+ efflux…
 Increased K permeability stabilizes the membrane at its resting
potential & makes contraction less likely. 97

Hypertension
II. Minoxidil
 Minoxidil
 Produces arteriolar vasodilation…..essentially no effect on the
capacitance vessels;
 The drug resembles hydralazine and diazoxide in this regard.
98

Hypertension
II. Minoxidil
 Its use is associated with reflex sympathetic stimulation and
Na+& fluid retention (Even more than with hydralazine)
 Hence, Minoxidil must be used in combination with a β-blocker
and a loop diuretic.
99

Hypertension
II. Minoxidil…….Side Effects
 Are divided into 3 major categories:
 Fluid and salt retention
 Cardiovascular effects : Tachycardia, palpitations, angina
 Hypertrichosis…
 Particularly bothersome in women, are relatively common
 Topical minoxidil (as Rogaine) is used as a stimulant to hair
growth for correction of baldness. 100

Hypertension
II. Minoxidil…….Clinical use
1. Hypertension
2. Treat hair loss
 The MZM of promoting hair growth is not fully understood.
 Hypothetically, by widening BV and opening K+ channels, it allows more
oxygen, blood, and nutrients to the follicles.
 About 40% of men experience hair regrowth after 3–6 months
 It must be used indefinitely for continued support of existing hair follicles
101

Hypertension
III. Diazoxide
 Diazoxide
 Arteriolar dilator
 Relatively long-acting
 Parenterally and orally administered
102

Hypertension
III. Diazoxide
 Mechanism of action…
 Prevents vascular smooth muscle contraction by opening K channels and
stabilizing the membrane potential at the resting level.
 The most significant toxicity has been excessive hypotension
103

Hypertension
III. Diazoxide
 Indication
A. Occasionally used to treat hypertensive emergencies.
B. Diazoxide inhibits insulin release from the pancreas…..
 Probably by opening K channels in the β-cell membrane and….
 Used to treat hypoglycemia 20 to insulinoma (a tumor producing insulin)
 This MOA is the mirror opposite of that of sulfonylureas
 Therefore, this medicine is not given to non-insulin dependent diabetic pts.
104

Hypertension
IV. Sodium Nitroprusside
 Powerful parenterally administered……….vasodilator
 Used in
A. Rx of hypertensive emergencies (since has rapid onset of action)
B. Severe heart failure (Affects preload and afterload. ).
 Nitroprusside dilates both arterial and venous vessels
 Results in reduced peripheral vascular resistance & venous return.
105

Hypertension
 MOA
 Sodium nitroprusside activates of guanylyl cyclase…
 Either via release of NO or By direct stimulation of the enzyme.
 The result is increased IC cGMP, which relaxes vascular smooth muscle
106

Hypertension
 Side effects
 Low blood pressure & cyanide toxicity
 Methemoglobinemia
107

Hypertension
V. Fenoldopam
 Fenoldopam is a peripheral arteriolar dilator
 Is used for….
 Hypertensive emergencies
 Postoperative hypertension
 The drug is administered by continuous IV infusion
 Fenoldopam…..
 Has a rapid onset of action (4 minutes) and…………
 Short duration of action (< 10 min) & a linear dose response r/ship
108

Hypertension
V. Fenoldopam
 MOA
 It acts primarily as an agonist of dopamine D1 receptors
 Unlike dopamine, fenoldopam lacks agonistic action at α- and β-
adrenoceptors
109

Hypertension
V. Fenoldopam
 MOA
 Dopamine D1 receptors are primarily post-junctional
 They mediate….Arterial dilatation notably…..vascular beds of…
A. Kidney (more effect)
B. Mesenteric
C. Coronary and cerebral vascular beds and………………..
D. Peripheral arteries.
 Results in dilation of peripheral arteries and natriuresis. 110

Hypertension
V. Fenoldopam
 MOA
111

Hypertension
V. Fenoldopam
 Fenoldopam…
 Unlike other parenteral antihypertensive agents…
 Maintains or increases renal perfusion while it lowers BP
 May be particularly beneficial in patients with renal insufficiency.
 Comparative clinical trials have demonstrated that….
 The efficacy of IV infused fenoldopam is similar to that of sodium
nitroprusside in reducing BP in hypertensive emergencies 112

Hypertension
V. Fenoldopam
 As with other direct vasodilators, the major toxicities are…
 Reflex tachycardia
 Headache, and
 Flushing
113

Hypertension
 Figure 3-13:
 Compensatory responses to vasodilators
 Basis for combination therapy with…
 Blockers
 Diuretics.
1. Effect blocked by diuretics.
2. Effect blocked by blockers.
114

Hypertension
 Two sub class
115
4. Calcium channel blockers
 Non-dihydropyridines
 Diltiazem
 Verapamil
 Dihydropyridines
 Non-dihydropyridines
Dihydropyridines
 Amlodipine
 Felodipine
 Isradipine
 Nicardipine
 Nifedipine
 Nisoldipine
 Clevidipine (IV use only)

Hypertension
 In response to electrical depolarization…
 Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the
entry of extracellular Ca2+ into…
 Smooth muscle and
 Cardiac myocytes and
 Sinoatrial (SA) and
 Atrioventricular (AV) nodal cells
116
Ca2+ is a trigger for contraction

Hypertension
 Calcium channel blockers…
 Are all equally effective in lowering blood pressure
 Have Hemodynamic differences among them
 May influence the choice of a particular agent
 Nifedipine and the other dihydropyridine agents are…
 More selective as vasodilators and
 Have less cardiac depressant effect than verapamil & diltiazem.
 Reflex sympathetic activation with slight tachycardia maintains or increases
cardiac output in most patients given dihydropyridines. 117
 Verapamil has…
 The greatest depressant effect on the heart &
 May decrease HR and CO.
 Diltiazem has intermediate actions.

Hypertension
 Clinical uses
1. Hypertension
2. CAD
3. Arrhythmia (Verapamil)
4. Tocolytic (Nifedipine)
5. Raynaud syndrome ( Raynaud's phenomenon)
 Is a medical condition in which spasm of arteries cause
episodes of reduced blood flow
6. Migraine : Prophylaxis (Verapamil)
118
Raynaud's phenomenon

 The choice of a particular CCB should be made with
knowledge of its…
1. Specific potential adverse effects as well as
2. Its pharmacologic properties
119
Hypertension

1. Nifedipine…
 Does not decrease AV conduction and hence, in the presence of
AV conduction abnormalities…….
 Nifedipine can be used more safely than verapamil or diltiazem
120
The choice of a particular CCB…
Hypertension

2. A combination of verapamil or diltiazem with β-blockers…
 May produce AV block and depression of ventricular function.
3. In the presence of overt heart failure…
 All CCBs can worsen failure as a result of their –ve inotropic
effect.
121
Hypertension

4. In patients with relatively low BP (hypotension)…
 Dihydropyridines can cause further deleterious lowering of BP.
 But, Verapamil and diltiazem…
 Produce less hypotension and
 May be better tolerated in these circumstances.
122
Hypertension

5. In pts with a history of atrial tachycardia, flutter, and fibrillation…
 Verapamil & diltiazem provide a distinct advantage because of…
 Their antiarrhythmic effects.
6. In the pt receiving digitalis, verapamil should be used with caution…
 B/se it may ↑ digoxin blood levels b/se Verapamil inhibits CYP3A4
123
Hypertension

Hypertension
 Compared with other classes of antihypertensive agents…
 There is a greater frequency of achieving BP control with CCB as
monotherapy in elderly subjects and in African-Americans.
 This are population groups in which the low renin status is
more prevalent.
124

Hypertension
 Dose
 Verapamil………
 Extended release: Initial: 180mg – 480mg/day
 Immediate release Initial: 80-160 mg, P.O., TID
 Amlodipine, 5-10mg/day P.O.
 Felodipine, 2.5-10mg/day P.O.
 Nifedipine slow release, 20-180mg/day P.O.
125

Hypertension
 Dihydropyridines:
 Most are due to excessive vasodilation. Symptoms include…
 Dizziness, hypotension, headache, flushing, Nausea
 Its effects on smooth muscle produce a extra-cardiac effects……
 E.g. In GIT can cause constipation
 Non-dihydropyridines
Bradycardia (due to AV block)…can be treated with Atropine or β-
stimulants.
126
4. Calcium channel blockers  Side Effects

Hypertension
 Verapamil interacts with drugs In two ways;
1. Verapamil Inhibits CYP3A4….
 Increase concentrations , digoxin, lovastatin, simvastatin
 The use of verapamil to treat digitalis toxicity is thus contraindicated.
2. Verapamil blocks the P-gp drug transporter.
 Both the renal & hepatic disposition of digoxin occurs via this
transporter.
127
4. Calcium channel blockers  Drug interaction

Hypertension
 Antidotes
 Traditionally, antidotes for CCB overdose have included…
 Calcium, glucagon, adrenergic drugs, and amrinone.
 For cases of CCB poisoning where cardiotoxicity is evident, first-
line therapy is a combination of calcium and epinephrine;
128

Hypertension
 The following are important regulator of
CVS function.
 Renin (= Latin ren "kidney“)
 Angiotensin (Angio…prefix… blood or
lymph vessel)
 Aldosterone
129
5. Inhibitors of angiotensin

Hypertension
 The juxtaglomerular cells (JG cells, or granular cells)…..
 Are cells that synthesize, store, and secrete the enzyme renin.
 Are specialized smooth muscle cells in the walls of the afferent &
efferent arterioles
130
…….

Hypertension
 Juxtaglomerular cells secrete renin in response to…….
A. A drop in pressure detected by stretch receptors in the vascular walls, or
B. ↓ed in systemic BP….manifested as a lower renal perfusion pressure.
C. When stimulated by macula densa cells.
 Macula densa cells are located in the DCT
 When they detect a drop in Na in DCT, macula densa cells release
prostaglandins, which triggers JG cells to release renin
D. JG cells harbor β1 adrenergic receptors.
 When stimulated by SNS, these receptors induce the secretion of renin.
131
…….

Hypertension
 Angiotensin II is an important regulator of cardiovascular function.
133
5. inhibitors of angiotensin
 Renin release from the JG cells is
stimulated by…
 Reduced renal arterial pressure
 Sympathetic neural stimulation,
 Reduced sodium delivery or
 Increased sodium conce. at the DCT
 Renin……Angiotensinogen
 Decapeptide angiotensin I.
 Octapeptide angiotensin II
vasoconstrictor

134
Hypertension

136
Angiotensin I
Angiotensinogen
(Liver)
AT1 AT2
Angiotensin II
ACE
inhibitor
Valsartan
AT1 receptor blocker
Renin
inhibitor
Bradykinin
Peptides
Chymase
Local Ang II synthesis is independent of ACE
Several pathways of Ang II
generation
de Gasparo et al. Pharmacol Rev 2000; 52:415
Message: ACE inhibitors do not block the conversion of Ang I to Ang II by alternative enzymes
prominent in heart tissue, such as chymase.
(heart tissue)

 Vasoconstriction
 Aldosterone secretion
 Increased sympathetic tone
 Vascular proliferation
 Cardiac myocyte proliferation
 Vasodilation
 Anti-proliferation
 Apoptosis
AT1 AT2
Angiotensin II
Different roles of AT1 and AT2 receptors
de Gasparo et al. Pharmacol Rev 2000; 52:415

138
GFR (renal vasoconstrction)
Proteinuria
Aldosterone release
Glomerular sclerosis
Angiotensin-II plays a central role in
organ damage
A-II AT1
receptor
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial hypertrophy
LV hypertrophy
Fibrosis
Remodelling
Apoptosis
Stroke
DEATH
*Preclinical data
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Hypertension
Heart failure
MI
Renal failure

Hypertension
 3 classes of drugs act specifically on the RAAS
1. ACE inhibitors
2. Angiotensin Receptor Blockers
3. Aliskiren, an orally active renin antagonist
140
 Other group of drugs…
 The aldosterone Rs inhibitors (eg, spironolactone)
 In addition, β-blockers, can reduce renin secretion.

Hypertension
 Inhibits Angiotensin converting enzyme… Reduce levels of angiotensin II
 Drugs
 Captopril
 Enalapril
 Lisinopril
 Quinapril
 Benazepril
 Fosinopril
 Moexipril
141
5.1. Angiotensin converting enzyme inhibitors

Hypertension
 The hypotensive activity results from
1. An inhibitory action on the RAS &
2. A stimulating action on the KKS.
 The latter MZM has been
demonstrated by…
142
5. ACEI
 Showing that a bradykinin receptor antagonist, icatibant, blunts
the blood pressure-lowering effect of captopril.

Hypertension
 Angiotensin converting enzyme inhibitors
 All are pro-drugs
 Are converted to the active agents by hydrolysis, primarily in the
liver.
 E.g. Enalapril is an oral pro-drug that is…
 Converted by hydrolysis to a converting enzyme inhibitor, enalaprilat,
 Enalaprilat itself is available only for IV use
 Lisinopril is a lysine derivative of enalaprilat
143
5. Angiotensin converting enzyme inhibitors

Hypertension
 The ACEI appear to confer a special advantage In the Rx …
1. Of patients with diabetes……..slowing the dev’t & progression of
diabetic glomerulopathy.
 Also effective in slowing the progression of other forms of
chronic renal disease, such as glomerulosclerosis,
 An ACE inhibitor is the preferred initial agent in these patients
144

Hypertension
 These benefits probably result from…
 With ⬇ed glomerular efferent arteriolar resistance… decrease
intrarenal hemodynamics (prevent build up of BP in the glomerulus), and
 This reduction of intraglomerular capillary pressure prevents the
damage that the BP causes on the glomerulus which otherwise would
have led to proteinuria etc.
 Problem: the decrease in intrarenal hemodynamics can cause a
decrease in GFR and hence acute renal failure
145

Hypertension
2. Patients with hypertension and ischemic heart disease…
 Are……candidates for treatment with ACE inhibitors
 ACEI in the immediate post-MI period has been shown to improve
ventricular function and reduce morbidity and mortality
146

Hypertension
 Response to ACE inhibitors
 Young and middle-aged Caucasian pts have a higher probability
 Elderly African-American patients as a group are more resistant
to the hypotensive effect of these drugs.
 This are population groups in which the low renin status is
more prevalent.
147

Hypertension
 Pharmacokinetics & Dosage
 Dosing
 Most ACE inhibitors are approved for once-daily dosing
 But, significant fraction of pts have a response that lasts for < 24 hrs.
 These pts may require twice-daily dosing for adequate control of BP
 Enalapril….t1/2…11 hours…..are 2.5mg-10mg P.O., BID
 Lisinopril t1/2….12 hours…5-20mg P.O., daily
 Captopril, t1/2…2 hours……6.25-25mg P.O., TID
148

Hypertension
 Pharmacokinetics & Dosage
 All of the ACEI….except fosinopril and moexipril….
 Are eliminated primarily by the kidneys
 Doses of these drugs should be ↓ed in pts with renal insufficiency.
149

Hypertension
 Side Effects
I. Angiotensin/Aldosterone suppression
 Acute renal failure (use balancing dose*)
 But, Recovery of renal function occurs
without sequelae
 Hyperkalemia
 Hypotension
150
II. Bradykinin increase
A. Cough
 20% of patients
 Non-productive
 Due to bradykinin: bronchoconstriction
 Consider change to ARB
B. Angioedema
 Rare event
 Lips swelling, difficulty swallowing
 Do not start ACE if hx of angioedema
 Discontinue ACE
 May change to ARB (lower risk)
III. Neutropenia…rare but serious

Hypertension
151

Hypertension
III. Contraindications
 Angioedemia
 Pregnancy: Pregnancy Category D (Captopril)
 CI during the 2nd & 3rd trimesters b/se of clear evidence of risk to the fetus
 Fetal hypotension
 Renal failure
 Teratogenic risk (fetal malformations) or death.
152

Hypertension
 Drug-drug interactions:
1. K supplements or K-sparing diuretics……can result in
hyperkalemia.
2. Nonsteroidal anti-inflammatory drugs
 Impair the hypotensive effects of ACEI by blocking bradykinin-
mediated vasodilation, which is at least in part, PG mediated.
 Since food reduces the oral bioavailability of captopril by 25% to
30%, the drug should be given 1 hour before meals. 153

Hypertension
 Captopril ….Oral: 12.5, 25, 50, 100 mg tablets
 Fosinopril …Oral: 10, 20, 40 mg tablets
 Moexipril …Oral: 7.5, 15 mg tablet
 Lisinopril…Oral: 2.5, 5, 10, 20, 40 mg tablets
 Enalapril
 Oral: 2.5, 5, 10, 20,40 mg tablets
 Parenteral: 1.25 mg/mL for injection
154

Hypertension
 Drugs :
155
5.2. Angiotensin Receptor Blockers
1 Candesartan Oral: 4, 8, 16, 32 mg tablets
2. Valsartan Oral: 40, 80, 160, 320 mg tablet
3. Losartan Oral: 25, 50, 100 mg tablets
4. Eprosartan Oral: 600 mg tablets
5. Irbesartan Oral: 75, 150, 300 mg tablets
6. Azilsartan Oral: 40, 80 mg tablets
7. Telmisartan Oral: 20, 40, 80 mg tablets
8. Olmesartan Oral: 5, 20, 40 mg tablets

Hypertension
 Difference ARB from from ACEI
1. No effect on bradykinin Metabolism…more selective blockers of
angiotensin effects
2. Potential for more complete inhibition of angiotensin action
 There are enzymes other than ACE that are capable of
generating angiotensin II (chymase from heart)
 ARB provide benefits similar to those of ACE inhibitors in pts with…
 Heart failure and
 Chronic kidney disease 156

Hypertension
 Difference from ACEI
157

Hypertension
 Side Effects
Lowest incidence of side effects
 Hyperkalemia
 Hypotension
 Acute Renal Failure
158
Hyperkalemia
 Due to decreased aldosterone
 Risk factors:
 CKD, potassium sparing diuretics,
 Aldosterone antagonists , NSAIDs
 Digoxin, tumor lysis, Diuretics
 Metabolic Acidosis
 Monitor K+ within 2-4 weeks of
initiation or dose changes

Hypertension
 Angioedema
 Rare event
 NOT a contraindication
159
ARB: Contraindications
 Pregnancy
 Bilateral renal artery stenosis

Anti-hypertensive
160
Figure. Sites of action of the major classes of antihypertensive drugs

Hypertension
 Treatment of Hypertensive Emergencies….
 Parenteral medications are used to lower BP rapidly (within a
few min to hrs)
 As soon as reasonable BP control is achieved, oral therapy should
be substituted……. because
 This allows smoother long-term management of hypertension.
161
Treatment of Hypertensive Emergencies

Hypertension
 The goal of treatment in the first few hours or days…..
 Is not complete normalization of BP because……..
 Chronic HTN is associated with autoregulatory changes in
cerebral blood flow.
 Thus, rapid normalization of BP may lead to cerebral
hypoperfusion and brain injury.
162

Hypertension
 Rather, BP should be lowered by about 25%......
 Maintaining diastolic BP at no less than 100–110 mm Hg.
 Subsequently, BP can be reduced to normal levels using oral
medications over several weeks.
163

Hypertension
 The drug most commonly used to Rx hypertensive emergencies is….
 The vasodilator sodium nitroprusside.
 Other parenteral drugs that may be effective include……….
 Fenoldopam, NG, labetalol, CCB, diazoxide, and hydralazine.
 Diuretics such as furosemide are…….
 Administered to prevent the volume expansion that typically
occurs during administration of powerful vasodilators
164

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