CVS Pharmacology

Antihypertensive drugs

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 Hypertension
• Hypertension is defined as persistently elevated arterial
blood pressure (BP).
• Hypertension is the most common condition seen in primary
care settings and leads to
Myocardial infarction
Stroke
Heart failure
Renal failure, and death if not detected early and treated
appropriately
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 Categories of BP in Adults

Classification SBP (mm Hg) Vs DBP(mm Hg)

Normal <120 and <80

Elevated 120-129 or <80
Hypertension
Stage 1 130-139 or 80-89
Stage 2 ≥140 or ≥90

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 Hypertensive crisis
- severely elevated blood pressure (BP >180/110 mm Hg).
- can present as hypertensive urgency or emergency.
• Hypertensive urgency
severely elevated BP (≥180/ ≥110 mm Hg ) without
associated organ damage.
• Hypertensive emergency
occur at BP exceeding 180/120 mmHg
 with organ damage (stroke, myocardial infarction, renal
failure, and loss of consciousness).
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 Classification
• Based on etiology, hypertension is classified into
primary and secondary hypertension.
Primary (or essential) hypertension (90-95% pts)
-a single reversible cause cannot be identified
Secondary hypertension (5-10% pts)
-cause can be identified

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 Major mechanisms of secondary hypertension

Cause Major mechanism

Kidney diseases Increased renin release due to decreased

perfusion
Primary aldosteronism Water and salt retention due to increased
levels of aldosterone
Cushing’s syndrome Water and salt retention due to increased
release of corticosteroids
Pheochromocytoma Release of catecholamines from the
tumors of the adrenal chromaffin cells

Drug or alcohol ??????

induced

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 Many risk factors for development of
hypertension
- age
- ethnicity (black)
- family history of hypertension
- genetic factors
- lower education and
socioeconomic status
- greater weight
-lower physical activity
-tobacco use
-psychosocial stressors
-sleep apnea
-dietary factors (dietary fats,
higher sodium intake, lower
potassium intake, and
excessive alcohol intake)
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BP regulation

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 BP regulation…
1) Baroreflexes adjust moment-to-moment blood pressure
Carotid baroreceptors respond to stretch, and their activation
modulate sympathetic discharge.
2) The RAS provides tonic, longer term regulation of blood
pressure.
Decreased renal pressure stimulates renin production and
leads to enhanced levels of angiotensin II (constriction &
aldosterone release).

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 Pathophysiology of hypertension development

• Major pathophysiological mechanisms of hypertension

include:
Activation of the sympathetic nervous system
Activation of the RAAS
Endothelial dysfunction(NO & endothelin)
Oxidative stress (ROS)

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Pathophysiology of hypertension development…

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Non pharmacologic interventions to reduce BP include:

weight loss
sodium restriction
potassium supplementation within the diet
increased physical activity
decreased alcohol intake
decreased saturated fat and total fat

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 Drugs for HTN
Diuretics

Inhibitors of renin angiotensin system

Sympatholytic agents/Sympathoplegics

Vasodilators (Calcium channel blockers &

Direct acting vasodilators)

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 Diuretics
Thiazide diuretics
• The exact mechanism for reduction of arterial BP by diuretics is not
certain.
The initial action of thiazide diuretics decreases extracellular
volume.
• cardiac output returns to pretreatment values, and extracellular
volume returns to almost normal due to compensatory responses
such as activation of the RAS.
However, the antihypertensive effect is maintained during long-term
therapy due to decreased vascular resistance and vasodilator effect.
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 Diuretics…
Thiazide diuretics (primary agents)
Drug Dose
Chlorthalidone 12.5–25 mg once per day
Hydrochlorothiazide 25–50 mg once per day
Indapamide 1.25–2.5 mg once per day
Metolazone 2.5–5 mg once per day

 Chlorthalidone preferred based on prolonged t1/2 & proven

trial reduction of CVD.
 Indapamide has direct vasodilator and less metabolic side
effects, can be used as an antihypertensive in DM ?????.
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 Need monitoring of electrolytes and caution in DM and gout.
 Diuretics…
Loop diuretics
less effective than thiazides in patients with normal renal
function.
most likely related to the short duration of action
the strong initial diuretic effect is followed by a rebound
mediated activation of the RAS.
when a loop diuretic is given twice daily, the acute diuresis
can be excessive and lead to more side effects than occur
with a slower-acting, milder thiazide diuretic.
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 Diuretics…
Loop diuretics (secondary agents)
Drug Dose
Bumetanide 0.5–2 mg BID
Furosemide 20–80 mg BID
Torsemide 5–10, mg once/day

 Preferred diuretics in patients with symptomatic HF.

 Preferred over thiazides in patients with moderate-
to-severe CKD (e.g., GFR <30 mL/min)
 Common ADR; Hyponatremia, hypocalcemia,
hypokalemia, hypotension….. 17
 Diuretics…
K sparing diuretics (secondary agents)
Drug Dose
Amiloride 5–10mg once/day or BID
Triamterene 50–100 once/day or BID

 Combination therapy of potassium sparing diuretic with a thiazide

can be considered in patients with hypokalemia on thiazide
monotherapy
 Avoid in patients with significant CKD (e.g., GFR <45 mL/min)

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 Diuretics…
K sparing diuretics (secondary agents)
Drug Dose (mg per day)
Eplerenone 50–100 mg once/day or BID
Spironolactone 25–100mg BID

 Preferred agents in primary aldosteronism and resistant

hypertension
 Common used as an add-on therapy in resistant hypertension
 Avoid use with significant renal dysfunction
 Common ADR; hyperkalemia, gynecomastia and impotency
(more common in spironolactone) 19
Inhibitors of the renin-angiotensin system
(RAAS Targeting Drugs)

ACE Inhibitors
AT1 Receptor Blockers
Direct Renin Inhibitors

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Drug targeting RAAS Pathway

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 ACE Inhibitors

- ACE inhibitors are a first-line option

- Slow the development & progression of
• diabetic glomerulopathy
• other forms of CKD, such as glomerulosclerosis, which
could coexists with hypertension
- Patients with systolic dysfunction & IHD are candidates
- The endocrine consequences of inhibiting the biosynthesis of
AngII are of importance in a number of facets of hypertension
treatment.
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 ACE Inhibitors…
- The ACE inhibitors lower BP by reducing PVR without
reflexively increasing CO, HR, or contractility.
- Vasodilation of both arterioles and veins occurs as a result of
decreased vasoconstriction (from diminished levels of
angiotensin II) and enhanced vasodilation (from increased
bradykinin).
- also decrease the secretion of aldosterone, resulting in
decreased sodium and water retention.

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 ACE Inhibitors…
• Following the initial dose of an ACE inhibitor, there may
be a considerable fall in BP in some patients
• this response to the initial dose is a function of plasma
renin activity prior to treatment.
• The potential for a large initial drop in BP is the reason for
using a low dose to initiate therapy.
• GFR declines in patients receiving ACE inhibitors because
of inhibition of angiotensin II vasoconstriction on efferent
arterioles (increased serum creatinine). 24
 ACE Inhibitors…
Drug Dose (mg per day) Frequency
Benazepril 10-40 1 or 2
Captopril 12.5-50 2 or 3
Enalapril 5-40 1 or 2
Fosinopril 10–40 1
Lisinopril 10–40 1
Moexipril 7.5–30 1 or 2
Perindopril 4–16 1
Quinapril 10–80 1 or 2
Ramipril 2.5–20 1 or 2
Trandolapril 1–4 1

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 AT1 Receptor Blockers
• Same effect with ACE inhibiters
- By antagonizing the effects of AngII, these agents relax smooth
muscle and thereby promote vasodilation, increase renal salt and
water excretion, reduce plasma volume, and decrease cellular
hypertrophy.
- ACE inhibitors and ARBs increase the risk of hyperkalemia in
CKD and with supplemental K+ or K+-sparing drugs.
- ACE inhibitors and ARBs: avoid in pregnancy
- May cause acute renal failure in patients with severe bilateral
renal artery stenosis.
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 AT1 Receptor Blockers…
• The AT1 receptor blockers have a sufficient 24-h effect at
once-daily dosing (except losartan).

• The full effect of AT1 receptor blockers on BP typically is not

observed until about 4 weeks after the initiation of therapy.

• If BP is not controlled by an AT1 receptor blocker alone, a

second drug acting by a different mechanism (e.g., a diuretic
or Ca2+ channel blocker) may be added.

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 AT1 Receptor Blockers…
Drug Dose (mg per day) Frequency
Azilsartan 40–80 1
Candesartan 8–32 1
Eprosartan 600–800 1 or 2
Irbesartan 150–300 1
Losartan 50–100 1 or 2
Olmesartan 20–40 1
Telmisartan 20–80 1
Valsartan 80–320 1

Do not use if history of angioedema with ARBs.

Patients with a history of angioedema with an ACEI can receive an
ARB beginning 6 weeks after ACEI discontinued.

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 Direct Renin Inhibitors
• Aliskiren, the first orally effective direct renin inhibitor is
FDA-approved for the treatment of hypertension.
• Given the unclear effectiveness and safety of aliskiren
monotherapy, the place of this drug in the treatment of
hypertension remains clouded.
• ACE, ARBs and direct renin inhibitors should not be used in
combination.
• Aliskiren (150-300mg/day, once/day; very long acting)

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Sympatholytic Agents/Sympathoplegics

Centrally acting sympatholytic drugs

Ganglionic nicotinic receptor blockers

Adrenergic neuronal blocking drugs

Drugs on post sympathetic receptors /

adrenergic receptor blockers

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The sympathetic flow and drug targeting

????

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The sympathetic flow and drug targeting….

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 Centrally Acting Sympatholytic Drugs

Methyldopa

Clonidine

Guanfacine

Guanabenz

Generally reserved as last-line due to significant CNS adverse

effects, especially in older adults.

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 Methyldopa
- The effect of α methyl dopa is due to its conversion to α
methyl norepinephrine (α methyl dopa is a prodrug and
converted to its active metabolite in the brain).
- Stimulate α2 adrenergic receptors  NE release
- current use largely to treatment of hypertension in pregnancy,
250 mg twice daily.
- t1/2 2 h, but has long duration of action

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 Clonidine
- Clonidine directly activate α2 receptors
- When administered by i.v. route, it initially leads to rapid rise in
BP followed by prolonged fall.
- The initial rise is due to the activation of vascular post-synaptic
α2B receptors by high concentration of clonidine.
- Oral dose is slowly absorbed and such high concentrations are
not attained, so orally it results only in antihypertensive effects

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 Clonidine…
- has been used in hypertensive patients for the diagnosis of
pheochromocytoma
- effective in reducing early morning hypertension in patients
treated with standard antihypertensives
- It does not decrease RBF or glomerular filtration (useful in the
treatment of HTN complicated by renal disease)
- available as a transdermal patch (weekly dosing).
- moxonidine and rilmenidine are congeners of clonidine with
longer half lives (central α2 selective).

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 β‐blockers
Group of β‐blockers Member

Non cardio selective β‐ Propranolol, Nadolol, Pindolol*,

blockers
Selective β1‐blockers
3rd generation β‐blockers
(possess other novel activities)
Penbutolol*,
Acebutolol*, Atenolol, Betaxolol,
Bisoprolol, Esmolol, Metoprolol
Carvedilol, Labetalol, Nebivolol

* Contain intrinsic sympathetic activity

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Effects of β‐blockers on the cardiovascular
system

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 MOA of B-blockers as antihypertensive
drugs include
- Inhibition of cardiac b1 receptors leading to  cardiac output.

-  in renin due to inhibition of b1 receptors in JG cells of the

kidney.
- Inhibition of central and peripheral sympathetic outflow due to

the inhibition of presynaptic stimulatory b1 receptors on

adrenergic neurons.
-  vasodilatory prostacyclin synthesis in the vascular beds.

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Beta blockers…

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Beta blockers…

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 Therapeutic use in HTN
- Beta blockers are not recommended as first-line agents unless
the patient has IHD or HF
- Bisoprolol, carvedilol and metoprolol succinate preferred in
patients with HFrEF.
- Vasodilating β blockers (e.g., carvedilol, nebivolol) may be
preferred in patients with peripheral artery disease.
- Generally avoid BBs with ISA (Acebutolol, penbutolol &
pindolol), especially in patients with IHD or HF

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 Therapeutic use in HTN…
- Provide effective therapy for all grades of hypertension
- can be combined with diuretics for additive effects
- The combination of a β blocker, a diuretic, and a vasodilator
is effective for patients who require a 3rd antihypertensive
drug.
- lesser antihypertensive response for elderly and African
Americans.

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 Adverse Effects
The four major mechanisms for b-blocker side effects
- Smooth muscle spasm (bronchospasm and cold extremities)
- Cardiac therapeutic actions (bradycardia, heart block, excess
negative inotropic effect)
- CNS penetration (insomnia, depression, fatigue)
- Metabolic side effects (TGs, HDL).
Quality of life: weight gain, DM precipitation & erectile
dysfunction, fatigue (work)
Caution: abrupt withdrawal & type 1 DM pts.

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 Selective α1 Blockers
Prazosin, Terazosin, Doxazosin, Alfuzosin
- These drugs are the treatment of choice for patient with
hypertension and benign prostate hyperplasia (BPH).
- not recommended as monotherapy for hypertensive patients
- Monotherapy for hypertension increases the risk for
developing CHF.
- α1 blockers are not the drugs of choice in patients with
pheochromocytoma.

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 α1 Blockers…
- These drugs do not impair the metabolism, thus can be safely
used in patients with diabetes (no change in blood glucose),
coronary artery disease (improves lipid levels) and gout (do not
affect uric acid).
- Cause retention of fluid and reflex tachycardia (used in
combination with diuretics, β blockers)
- Major adverse effect of alpha blockers is first dose hypotension
(postural hypotension occurring at the start of treatment or on
dose escalation, less common in tamsulosin).

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 Calcium channel blockers
• Voltage-gated Ca2+ channels (L-type or slow channels) mediate
the entry of extracellular Ca2+ into
Smooth muscle and cardiac myocytes
SA and AV nodal cells in response to electrical
depolarization.

• CCBs “block” the entry of calcium through the calcium

channel in both smooth muscle and myocardium, so that less
calcium is available to the contractile apparatus.

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 Classification
Dihydropyridine CCBs:
- Amlodipine
- Clevidipine
- Felodipine
- Isradipine
- Nicardipine
- Nifedipine
- Nisoldipine
- Nimodipine… hemorrhagic stroke
Nondihydropyridine CCBs
- Verapamil: Phenylalkylamine
- Diltiazem: Benzothiazepine

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 Pharmacological Actions
Vascular Tissue
- All Ca2+ channel antagonists relax arterial smooth muscle
and thereby decrease arterial resistance, BP, and cardiac
afterload.
- Ca2+ channel blockers do not affect cardiac preload
significantly when given at normal doses in patients.
Heart
- decreased activity of the heart (decrease heart rate, AV
conduction and contractility).
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 Comparative CV effects of CCBs

Drug Blood BP Heart rate

vessel Direct Reflex Net effect
effect effect
Verapamil vasodilation ↓ ↓↓↓ ↑ ↓↓
Diltiazem vasodilation ↓ ↓↓ ↑ ↓
DHPs vasodilation ↓ No effect ↑ ↑

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 Clinical uses
Cardiovascular Diseases
- Hypertension
- Stable angina
- Acute coronary syndromes
- Supraventricular arrhythmias, rate control in AF or flutter

Non-cardiovascular Diseases
- symptom relief of Raynaud’s disease
- prevention of migraine headache
- prevention of preterm labor
- treatment of Peyronie’s disease
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 Calcium channel blockers for HTN
- as monotherapy and in combination with others
- suitable for elderly patients, patients with low renin hypertension,
patients with diseases like asthma, migraine or peripheral vascular
disease and in cases of isolated systolic hypertension.
- Immediate-release nifedipine can increase the risk of angina
(increases cardiac work due to increase in heart rate)
- Verapamil and diltiazem also have short half-lives, more cardiac
side effects, and a high drug interaction potential (verapamil >
diltiazem) and are therefore not first-line antihypertensives.

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 List of CCBs for Hypertension
Amlodipine
Nifedipine (extended release)
Felodipine (extended release)
Nisoldipine (extended release)
Isradipine
Nicardipine (oral, iv)
Clevidipine (iv)
Diltiazem (extended release)
Verapamil
Verapamil (extended‐release capsules)

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 Calcium channel blockers…
Also available in combination with others
• Two drug combinations include the following:
CCB + Diuretic
 CCB + ACE inhibitor
CCB + ARB
CCB + Direct renin inhibitor (aliskiren)
• Three drug combinations include the following:
CCB + Diuretic + ACE inhibitor
CCB + Diuretic + ARB
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 Direct acting Vasodilators

Hydralazine

KATP Channel Openers: Minoxidil, Diazoxide

Sodium Nitroprusside

Direct-acting vasodilators are associated with sodium and

water retention and must be used with a diuretic and beta-
blocker.

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 Hydralazine
• Hydralazine directly relaxes arteriolar smooth muscle with
little effect on venous smooth muscle.
• Proposed mechanisms include
- inhibition of inositol trisphosphate–induced release of Ca2+
from intracellular storage sites
- opening of high-conductance Ca2+-activated K+ channels in
smooth muscle cells and
- activation of an arachidonic acid, COX, and prostacyclin
pathways
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 Hydralazine…
ADME

-Well absorbed via the GI tract.

-N-acetylated in the bowel and the liver (polymorphism)

-elimination is principally a function of hepatic blood flow

than the rate of acetylation.

- Although its t1/2 in plasma is about 1 h, the hypotensive effect

of hydralazine can last as long as 12 h, no clear explanation.

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 Hydralazine…
Clinical uses
- No longer a first-line drug for hypertension
- is approved for treating hypertensive crises accompanying
acute glomerular nephritis or eclampsia.
- Hydralazine elicits the baroreceptor reflex, necessitating
coadministration with a diuretic to counteract sodium and
water retention and a β-blocker to prevent tachycardia.
- Heart failure in African Americans (FDC with ISDN)

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 Hydralazine…
Adverse effects:
- headache, nausea, flushing, hypotension, palpitations,
tachycardia, dizziness, and angina pectoris.
- use cautiously in patients with CAD & elderly
- lupus syndrome at high doses
- because of preferential dilation of arterioles over veins,
postural hypotension is not a common problem
- can produce a pyridoxine-responsive polyneuropathy

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 HTN & compelling indications
Concomitant condition Drugs preferred Drugs to be
avoided
Angina (CAD) β blocker, CCB Vasodilators
Diabetes & Hyperlipidemia ACEI, ARB, CCB, α β blocker, Diuretics
blocker
Elderly & Isolated systolic HTN Diuretics, CCB
Low renin hypertension Diuretics, CCB
High renin hypertension ACEI, ARB, β blocker
Asthma CCB, Diuretics, ACEI, β blocker
ARB
CHF ACEI, Diuretics CCB
CKD ACEI, ARB
Post MI β blocker, ACEI
BPH α blocker
Peripheral vascular disease CCB, α blocker β blocker
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 Special populations
Older People: Diuretics, ACE inhibitors & ARBs
Preeclampsia & Eclampsia: IV hydralazine is most
commonly used; IV labetalol is also effective.
Chronic hypertension during pregnancy
- Methyldopa
- β-Blockers (other than atenolol), labetalol and CCBs
African Americans: Thiazides and CCBs

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End

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