ANTIHYPERTENSIVE DRUGS

By

Nakalembe Loyce

09/01/2025 Nakalembe Loyce 1

 HYPERTENSION
• Defined as a sustained increase in blood pressure of 140/90 mmHg

or higher

• Most common cardiovascular disease

• Prevalence increases with age (esp 65% of adults age 65 years or older), race,
education, etc

• Principal cause of stroke; a major risk factor for CADd and its

attendant complications, MI and sudden cardiac death

• Major contributor to heart failure, renal insufficiency, and

dissecting aneurysm of the aorta

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 AMERICAN HEART ASSOCIATION CRITERIA FOR
HYPERTENSION IN ADULTS

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 Etiology of hypertension

• Patients in whom no specific cause of hypertension can

be found are said to have essential or primary

hypertension

• Patients with a specific etiology are said to have

secondary hypertension.
• Important to establish the cause coz some are
amenable to definitive surgical treatment: eg Renal artery
constriction, coarctation of the aorta, pheochromocytoma, Cushing’s
disease, and primary aldosteronism
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 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 precapillary

arterioles (peripheral vascular resistance, PVR)

BP = CO × PVR

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Normal Regulation of Blood Pressure

• Maintained by moment-to-moment regulation of CO & and PVR exerted

at 3 anatomic site (fig 1) & the kidney

• Baroreflexes, mediated by autonomic nerves, act in combination with

humoral mechanisms, including the RAAS system, to coordinate

function at these four control sites and to maintain normal BP

• local release of vasoactive substances (e.g NO & endothelin-1) from

vascular endothelium may also be involved in the regulation of vascular

resistance
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Note: All antihypertensive agents act at one or more
of the four anatomic control sites depicted below

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Control of the Heart by the Sympathetic&
Parasympathetic Nerves
• Parasympathetic (Vagal) Stimulation of the Heart. strong vagal
stimulation can decrease the strength of heart muscle contraction by
20 to 30%.
• Strong sympathetic stimulation can ↑se HR & ↑ses force of
heart contraction to as much as double normal, thereby ↑sing
volume of bld pumped & ↑sing the ejection pressure

NOTE: the cardiac output ↑ses during ↑sed sympathetic

stimulation & ↓ses during ↑sed parasympathetic stimulation.

• Changes in output caused by nerve stimulation result both from

changes in HR and from changes in contractile strength of the heart
wch change in response to theNakalembe
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nerve stimulation.
Loyce 8
Regulation of BP by baroreceptor mechanism

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RENAL MECHANISM FOR REGULATION OF BP–LONG-TERM
REGULATION

• Kidneys regulate arterial blood pressure by- regulation of ECF

volume
& Through renin angiotensin mechanism.

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Effect of Potassium & Calcium Ions on Heart
Function
1. Effect of Calcium Ions. An excess of Ca2+ causes effects
almost exactly opposite to those of K+, causing the heart to
go toward spastic contraction

• Deficiency of Ca2+ causes cardiac flaccidity

2. Effect of Potassium Ions. Excess potassium in ECF

causes the heart to become dilated and flaccid & also slows
HR.- ↑se ECF K+ ↓ses RMP

• Large quantities can block conduction of the cardiac

impulse from atria to the Nakalembe
09/01/2025
ventriclesLoyce
through the A-V bundle.
11
 Lethal effects of hypertension
caused mainly in three ways:

1. Excess workload on the heart leads to early heart failure and

coronary heart disease, often causing death as a result of a heart
attack.

2. The high pressure frequently damages a major blood vessel in the

brain, followed by death of major portions of the brain------- cerebral
Infarct/ “stroke.”
Depending on which part of the brain is involved, a stroke can cause paralysis, dementia, blindness, or multiple
other serious brain disorders.

3. High pressure almost always causes injury in the kidneys, producing many areas of
renal destruction and, eventually, kidneyNakalembe
09/01/2025
failure,Loyce
uremia and death 12
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 Difference in Regulation of BP in
hypertensive patients

Same regulatory mxm as in healthy people

HOWEVER:- baroreceptors & the renal blood volume-pressure control

systems appear to be “set” at a higher level of BP

• All antihypertensive drugs act by interfering with these normal

mechanisms
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 Nonpharmacological therapy, or
lifestyle-related changes
• Weight loss (in overweight individuals)

• Restricting sodium intake (to 5–6 g/d)

• Increasing aerobic exercise (>30 min/d)

• Moderating consumption of alcohol (ethanol/day ≤ 20–

30 g in men [two drinks], ≤ 10–20 g in women [one
drink])

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Nonpharmacological therapy, or
lifestyle-related changes
• Smoking cessation

• Increased consumption of fruits, vegetables & low-fat dairy

products

• Renal denervation may be effective in patients with well-defined resistant

hypertension

• Bariatric surgery in grossly overweight individuals may normalize BP and

increase life
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 ANTIHYPERTENSIVE AGENTS
• They produce their effects by interfering with normal
mechanisms of blood pressure regulation.

• They are classified according to the principal regulatory

site or mechanism on which they act.

• Due to their common MOA, drugs within each category tend

to produce a similar spectrum of toxicities.

• Dietary control of BP e.g. sodium restriction is a relatively

nontoxic therapeutic measure & may even be preventive

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 Categories of antihypertensive agents
Diuretics-lower BP by depleting the body of sodium & reducing
blood volume & perhaps by other mechanisms.

Sympathoplegic agents-lower BP by reducing peripheral

vascular resistance, inhibiting cardiac function & ↑sing venous
pooling in capacitance vessels.

 Direct vasodilators-reduce pressure by relaxing vascular

smooth muscle, thus dilating resistance vessels and—to varying
degrees—↑sing capacitance as well.

Agents that block production or action of angiotensin-

thereby reduce peripheral vascular resistance and (potentially)
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blood volume.
CLASSES OF ANTIHYPERTENSIVE DRUGS

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Sites of action of the major classes of antihypertensive drugs

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 VASODILATORS

Includes

• Oral vasodilators: hydralazine & minoxidil, used

for long-term outpatient therapy of hypertension

• Parenteral vasodilators, nitroprusside, diazoxide,

fenoldopam, used to treat hypertensive emergencies

• Calcium channel blockers-used in both circumstances

• Nitrates-used mainly in angina

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 ACTION OF VASODILATORS
• All vasodilators that used in HTN relax smooth muscle
of arterioles, thereby decreasing systemic vascular
resistance

• Sodium nitroprusside & nitrates also relax veins

• ↓sed arterial resistance & mean arterial BP elicit

compensatory responses, mediated by
baroreceptors & SNS, RAAS

• Hence work best in combination with other

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Mechanisms of action of vasodilators

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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

and SA and AV nodal cells in response to electrical depolarization.

• In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for

contraction, albeit by different mechanisms

• In vascular SM, this leads to relaxation, especially in arterial beds, in cardiac myocytes

to negative inotropic effects.

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CALCIUM CHANNEL BLOCKERS

• MOA in HTN-inhibition of ca2+ influx into arterial smooth muscle cells

Examples:
Phenylalkylamine eg Verapamil

Benzothiazepine: diltiazem

Dihydropyridine family: ( amlodipine, felodipine, isradipine,

nicardipine, nifedipine, nisoldipine, Lercanidipine, nitrendipine )

Clevidipine-newer member, formulated for IV use only

• Are all equally effective in lowering blood pressure,

• Hemodynamic differences may influence the choice of a particular agent

•09/01/2025
Doses used in treating HTN are similarBY to those used in treating angina
NAKALEMBE LOYCE 25
 CALCIUM CHANNEL BLOCKERS

• All CCBs lower BP by relaxing arteriolar SM and decreasing

PVR

• Decrease in PVR evokes a baroreceptor reflex–mediated

sympathetic discharge.

• produce their effects by binding to the α1 subunit of the L-

type voltage-gated Ca2+ channels and reducing Ca2+ flux

through the channel.

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 Differences in effects of CCBs

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• In the case of the dihydropyridines, tachycardia may occur
from the adrenergic stimulation of the SA node; this
response is generally quite modest except when the drug
is administered rapidly.

• Tachycardia is minimal or absent with verapamil and

diltiazem (have direct negative chronotropic effects)

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• Recommended that short-acting oral dihydropyridines not be used for
HTN---RISK OF MI
• Sustained-release CCBs with long half-lives provide smoother blood
pressure control and are more appropriate for treatment of chronic
hypertension

• NOTE: Nifedipine &other dihydropyridine agents are

more selective as vasodilators & have less cardiac
depressant effect than verapamil & diltiazem

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 0ther Clinical uses of CCBs

• Variant angina: dihydropyridines considered first-line treatment

and may be combined with nitrovasodilators

• Also are effective in the treatment of exertional, or exercise-

induced, angina-second choice

• Use of verapamil and diltiazem as antiarrhythmic agents

in supraventricular tachyarrhythmias/atrial fibrillation

• Verapamil also has been used in the prophylaxis of migraine

headaches but second-choice drug.
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Other uses

• Nimodipine has been approved for use in patients with

neurological deficits secondary to cerebral vasospasm
after the rupture of a congenital intracranial aneurysm

• Nifedipine, diltiazem, amlodipine, and felodipine appear

to provide symptomatic relief in Raynaud disease

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 CALCIUM CHANNEL BLOCKERS
• Immediate-release nifedipine and short-acting dihydropyridines can

cause tachycardia and hypotension and trigger angina

• • Diltiazem and verapamil can ↓ heart rate and AV conduction;

should not be used with β blockers

• CYP3A4-mediated drug interactions with verapamil and diltiazem •

• Other unwanted effects: peripheral edema (dihydropyridines),

constipation (verapamil)
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SODIUM NITROPRUSSIDE-complex of iron, cyanide groups, & a
nitroso moiety.

• Unstable molecule that decomposes under strongly alkaline

conditions or when exposed to light (need for protection)

• Powerful parenterally admin vasodilator (y continuous

intravenous infusion)

• Used in treating hypertensive emergencies as well as

severe heart failure

• Nitrovasodilator that acts by releasing NO

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structure MOA

• NO released activates the guanylyl cyclase–

cyclic guanosine monophosphate–protein

kinase G pathway, leading to vasodilation,

mimicking the production of NO by vascular

endothelial cells, which is impaired in many

hypertensive patients.

• Hence ↑sed intracellular cGMP, which

relaxes vascular smooth muscle

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 Sodium nitroprusside
• Dilates both arterial & venous vessels, resulting in reduced
peripheral vascular resistance & venous return

PK
onset of action is within 30 sec

peak hypotensive effect occurs within 2 min, Effect

disappears within 3 min when infusion is stopped.
Available in vials that contain 50 mg.

Vial contents dissolved in 2–3 mL of 5% dextrose in water.

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 CLINICAL INDICATIONS
• Used primarily to treat hypertensive emergencies

• Also can be used in situations when short-term reduction of cardiac preload

or afterload is desired.

• Has been used to lower BP during acute aortic dissection (CO-admin with β
blocker)

• Improve cardiac output in congestive heart failure, especially in hypertensive

patients with pulmonary edema that does not respond to other treatment

• Decrease myocardial O2 demand after acute MI.

• Used to induce controlled hypotension during anesthesia to reduce bleeding

in surgical procedures.
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pk
• Recommended dose: infusion of 0.25–1.5 μg/kg/min

• Metabolism

Reduction, which is followed by the release of cyanide

and then NO. Cyanide is metabolized by hepatic

rhodanase to form thiocyanate

• Thiocyanate eliminated almost entirely in the urine

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Toxicity

• Excessive BP lowering

• most serious-related to accumulation of cyanide

 -Toxic accumulation of cyanide leading to severe lactic acidosis

usually occurs when drug is infused at a rate greater than 5 μg/kg/min

 Can also occur in some patients receiving doses on the order of 2

μg/kg/min for a prolonged period

 Prevention: concomitant administration of sodium thiosulfate can

prevent CN- toxicity

• metabolic acidosis, arrhythmias, excessive hypotension, & death

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 HYDRALAZINE
• Not first choice in treating HTN

• Was used infrequently because of tachycardia and tachyphylaxis.

Its vasodilation is associated with powerful SNS stimulation- due to

baroreceptor-mediated reflexes
Resulting in ↑sed HR & contractility, ↑sed plasma renin activity,&
fluid retention
 These effects tend to counteract the drugs’ antihypertensive effect

• Was combined with sympatholytic agents & diuretics with

greater therapeutic success.

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 Mechanism of action
• Directly relaxes arteriolar SM with little effect on venous SM
• Mechanisms mediating this action are not clear
• May ultimately involve a reduction in intracellular Ca2+
concentrations
Potential 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
Activation of an arachidonic acid, COX, and prostacyclin pathway that
would explain sensitivity to NSAIDs
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 HYDRALAZINE
• Metabolized by NAT2.

• Admin of therapeutic doses of hydralazine to a slow acetylator

can result in extreme hypotension and tachycardia

Adverse effects: headache, nausea, flushing, hypotension,

palpitations, tachycardia, dizziness, and angina pectoris

• Lupus syndrome at high (Don’t exceed 200 mg/d)

• Pyridoxine-responsive polyneuropathy (ABOVE 200mg/d)

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 Therapeutic uses

• In a combination pill containing isosorbide dinitrate

(BiDil) in heart failure

• useful in hypertensive emergencies, especially

preeclampsia, in pregnant women

• RECOMMENDED DOSE: orally 25–100 mg twice daily

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Potassium channel openers
1. MINOXIDIL

• not active in vitro but metabolized by hepatic

sulfotransferase to the active molecule, minoxidil N-O
sulfate

MOA: Minoxidil sulfate activates the ATP-modulated K+

channel permitting K+ efflux, and causes hyperpolarization
and relaxation of smooth muscle

• Very efficacious orally active vasodilator (dilates arterioles

but not veins)
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 MINOXIDIL cont’d
• Has greater potential antihypertensive effect HENCE

 Should replace hydralazine when maximal doses of

the latter are not effective or in patients with renal

failure and severe hypertension, who do not respond

well to hydralazine.

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PK
• MOST eliminated as a glucuronide; about 20% is excreted unchanged

in urine

• Plasma t 1/2 of 3–4 h

• Duration of action is 24 h & occasionally even longer

• usually administered either once or twice a day, some patients may

require more frequent dosing for adequate control of BP.

• Initial daily dose of minoxidil may be as little as 1.25 mg, can be

increased gradually to 40 mg in one or two daily doses

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Toxicity

• Associated with fluid and salt retention, cardiovascular effects, and

hypertrichosis.

• Tachycardia, palpitations, angina & edema observed when doses of β

blockers and diuretics are inadequate.

• Headache, sweating

• hypertrichosis (excessive hair growth over & above the normal for

the age, sex & race)-bothersome in women, occurs on the face, back,
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• NOTE: Topical minoxidil (as Rogaine) is used as a

stimulant to hair growth for treatment of male

pattern baldness and hair thinning and loss on the top

of the head in women

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 CAUTION
• Should never be used alone

• must be given concurrently with:-

 a diuretic to avoid fluid and salt retention

secondary to reduced renal perfusion pressure and to reflex stimulation of

renal tubular α adrenergic receptors (also seen with diazoxide and
hydralazine)

 a sympatholytic drug (e.g., β blocker) to control reflex cardiovascular

effects same as in hydralazine admin

An inhibitor of the RAS to prevent remodeling effects on the heart.

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 2. DIAZOXIDE ( an arteriolar dilator)

• Effective & relatively long-acting

• Parenterally administered

• Occasionally used to treat hypertensive emergencies.

• Fell out of favor at least in part due to the risk of marked

falls in BP when large bolus doses of the drug were used.

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MOA: prevents vascular SM contraction by opening
potassium channels and stabilizing the membrane
potential at the resting level

• Injection of diazoxide results in a rapid fall in systemic

vascular resistance & mean arterial BP

09/01/2025 Nakalembe Loyce 50

PK

• Chemically similar to the thiazide diuretics but no diuretic activity.

• Bound extensively to serum albumin and to vascular tissue

• half-life is approx. 24 hrs

• BP-lowering effect after a rapid injection is established within 5

minutes and lasts for 4–12 hrs

TOXICITY

• Excessive hypotension, resulting from the recommendation to use

a fixed dose of 300 mg in all patients.

• This results in stroke and myocardial infarction.

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NOTE: The reflex sympathetic response can provoke angina, ECG
evidence of ischemia, & cardiac failure in patients with ischemic
heart disease,hence should be avoided in this situation.

• Diazoxide inhibits insulin release from the pancreas (probably by

opening potassium channels in the beta cell membrane) and is
used to treat hypoglycemia secondary to insulinoma.

• Occasionally, hyperglycemia complicates diazoxide use,

particularly in persons with renal insufficiency.

• causes renal salt & water retention but rare since drug is used
for short periods.
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FENOLDOPAM-peripheral arteriolar dilator

• For hypertensive emergencies & postoperative hypertension

• MOA: acts primarily as an agonist of dopamine D 1

receptors, resulting in dilation of peripheral arteries &
natriuresis

• Major toxicities: reflex tachycardia, headache, flushing

• ↑ses intraocular pressure, avoid in patients with glaucoma

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ANTIHYPERTENSIVE AGENTS PREFERRED IN SPECIFIC
PATIENT POPULATIONS

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 Resistant hypertension
• Occurs when some patients with HTN fail to respond to
recommended antihypertensive treatments
CAUSES
• Many patients require two, three, or four appropriately
selected drugs used at optimal doses.
• Non-adherence
• Use of multiple drugs in the same therapeutic class that
act by the same mechanism
• Excess salt intake and the tendency of some
antihypertensive drugs, especially vasodilators, to promote
salt retention
• Drug-interactions
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