Antihypertensives

Dr. Lucy Clunes

1
 Propranolol / Metoprolol / Atenolol / Pindolol

• Used only as add-on therapy to first line agents in

primary prevention patients
• First-line therapy only for patients with coronary
artery disease, heart failure or post-MI

2
 Propranolol / Metoprolol / Atenolol / Pindolol

• Propranolol
Non-selective b1 & b2 receptor antagonist

• Metoprolol & atenolol (most widely used)

Selective b1 receptor antagonists
• Pindolol
Non-selective b1 & b2 partial agonist with intrinsic
sympathomimetic activity (preferred b-blocker in
pregnancy)

3
MOA
• Reduce BP by cardiac output, contractility & heart rate

• Blunt sympathetic reflex with exercise

• Inhibit both release of norepinephrine and renin (b1 R) (→

decrease in angiotensin II & aldosterone secretion)

Pharmacokinetics
• May take several weeks to develop full effects

4
• Bradycardia, CNS effects (fatigue, lethargy, insomnia,
hallucinations), hypotension, decreased libido &
impotence

• Disturb lipid metabolism ( HDL & TAGs)

• Hypoglycemia (via b2 blockade)

• Drug withdrawal (abrupt withdrawal may induce angina,

MI or sudden death in patients with heart disease) →
taper off dose in these patients

• Non-selective b-blockers are contraindicated in

asthmatics and COPD patients 5
 Prazosin / Doxazosin

• Competitively block a1-adrenoceptors

• peripheral vascular resistance & arterial BP by
relaxing both arterial & venous smooth muscle
• Cause minimal changes in cardiac output, renal blood
flow & GFR → no long-term tachycardia
• Na+ & H20 retention does occur
• Effective in lowering BP but more adverse effects
than other antihypertensives

6
• Hypertension (due to side-effect profile, development
of tolerance & advent of safer antihypertensives, a-
blockers are seldom used in treatment of essential
hypertension)

• Reserved as alternative agents for unique situations, such

as men with benign prostatic hyperplasia

• Have been used in heart failure (but not commonly)

7
• Orthostatic hypotension (which may lead to syncope)
upon first-dose or large increases in dose
• Concomitant use of a b-blocker may be necessary to blunt
short-term effect of reflex tachycardia
• Dizziness, drowsiness, headache, lack of energy, nausea,
and palpitations,
• Doxazosin shown to rate of congestive HF

8
 Labetalol

• Oral & parenteral admin.

• Used in hypertension management (safe in pregnancy)
• IV labetalol = rapid reduction in BP → useful in
hypertensive emergencies

Advantages
• in BP associated with a1-blockade is not
associated with reflex increase in HR or cardiac
output
9
• Orthostatic hypotension may be a problem (first use or
high doses)

10
 Clonidine

• Reduces sympathetic outflow by acting on presynaptic a2

adrenergic autoreceptors
• Resultant decrease in peripheral vascular resistance &
cardiac output → BP
• DOES NOT renal blood flow or GFR

• Used in hypertension management, including

hypertensive crises (other drugs with fewer side effects
are now generally preferred)

11
 Clonidine

• Drowsiness, dry mouth, dizziness, headache & sexual

dysfunction occur commonly

• Rebound hypertension may occur following abrupt

withdrawal (avoid concomitant use with b-blockers)

12
 Methyldopa

• a2-agonist converted to a-methyldopamine and a-

methylnorepinephrine centrally to diminish sympathetic
outflow in CNS
•→ peripheral resistance & BP (cardiac output NOT )
• DOES NOT renal blood flow or GFR

• Usually treatment of choice for pregnancy-induced

hypertension
• Used in hypertension management (other drugs with
fewer side effects are now generally preferred)
13
 Methyldopa

• Sedation, drowsiness, dizziness, nausea, headache,

weakness, fatigue, sexual dysfunction

• Nightmares, mental depression, vertigo (infrequent)

• Development of positive Coombs test (10-20% patients

on long-term treatment (>1 year)). Can result in hemolytic
anemia, hepatitis & drug fever

14
 Hydralazine / Minoxidil

• Not used as first-line antihypertensives

• Direct acting smooth muscle relaxants

• Produce reflex tachycardia, increase plasma renin → Na+

& H20 retention

• Major side effects can be blocked if combined with diuretic

& b-blocker

15
 Hydralazine

• Can be given oral or IV

• Acts mainly on arterioles

• Used to treat pregnancy induced hypertension / pre-

eclampsia

• Used in management of hypertension as last-line therapy

16
 Hydralazine

• Fluid retention & reflex tachycardia are common

• Reversible lupus-like syndrome

• Headache, nausea, sweating, flushing

• Usually administered with b-blocker & thiazide

17
 Minoxidil

• Causes direct peripheral vasodilatation of arterioles

• Oral treatment for severe-malignant hypertension

(refractory to other treatments)

18
 Minoxidil

• Reflex tachycardia & fluid retention may be severe

(combine with loop diuretic & b-blocker)

• Causes hypertrichosis (also used topically to treat

male pattern baldness)

19
• An increase in blood pressure in the pulmonary
artery, pulmonary vein or pulmonary capillaries

Treatments
• Prostaglandins (epoprostenol)
• Inhibitors of endothelin synthesis and action
(bosentan)
• Vasodilators (sildenafil)
20
• Synthetic PGI2

• Lowers peripheral, pulmonary, and coronary resistance

• Given via continuous infusion

• Adverse effects include flushing, headache, jaw pain,

diarrhea and arthralgias

21
• Nonselective endothelin receptor blocker

• Blocks both the initial transient depressor (ETA) and the

prolonged pressor (ETB) responses to endothelin

• Pregnancy category X

22
• Inhibitor of phosphodiesterase 5 (PDE5)

• Increased cGMP → smooth muscle relaxation

• Adverse Effects: headache, flushing, dyspepsia,

cyanopsia

• Contraindications: Nitrates

23
 Comorbid First-line Treatments Second-line
Condition Treatments
None ACEI or ARB, CCB or thiazide b-blockers, aldosterone
diuretic antagonists
Chronic or Acute b-blocker + ACEI or ARB Thiazide diuretic (BP
CAD control), CCB (ischemia
control)
Chronic Kidney ACEI or ARB CCB or thiazide
Disease
Diabetes Mellitus ACEI or ARB CCB or thiazide
Heart Failure ACEI or ARB + thiazide (or Aldosterone antagonist
loop) diuretic + b-blocker (if severe),
hydralazine/isosorbide
dinitrate ( if black)

24
 Comorbid First-line Treatments Second-line
Condition Treatments
Myocardial b-blocker then add ACEI / ARB Aldosterone antagonist
Infarction
Prior Ischemic ACEI or ARB CCB or thiazide
Stroke

25
26
By the end of this session the student should be able
to:
• Principal problems caused by excessive hypertension &
symptoms.

• Terms ‘hypertensive urgency’ & ‘hypertensive

emergency’.

• Basic outlines of the diagnostic and therapeutic approach.

• Objectives of management and typical drugs used.

27
• Clinical symptoms characterized by severe (typically
acute) elevations in BP (generally diastolic BP
>120mmHg) → vascular injury & organ damage

• Divided into two general categories:

• Hypertensive Emergencies
• Hypertensive Urgencies

28
• Severe hypertension with signs of damage to target
organs (brain, CV system, kidneys)

• Immediate BP reduction is required with IV drugs

29
• Very high BP without target-organ damage. Acute
complications unlikely so immediate BP reduction not
required

• Patients should be started on 2-drug oral combination &

close evaluation continued on an outpatient basis

30
• DBP > 150 mmHg (with SBP > 210 mmHg) in otherwise
healthy person,
or,
• DBP > 120 mmHg in individuals with pre-existing
complications (eg, cerebral hemorrhage, aortic stenosis)

Therapeutic goal
• Progressive reduction of blood pressure using IV
drugs 31
• Essential hypertension
• Renal parenchymal disease
• Renovascular disease
• Pregnancy (eclampsia)
• Endocrine, eg. Pheocromocytoma, Cushing’s, renin-
producing tumors
• Drugs eg, cocaine, crack, sympathomimetics,
amphetamines, MAO-inhibitors, tyramine
32
• Drug withdrawal eg, clonidine, nifedipine etc.
• CNS disorders eg, injury, stroke, tumor
• Autonomic hyperreactivity

33
• Admission to ICU, drugs applied by IV line

• Arterial line to measure BP

• BP should be progressively reduced using a short-acting

titratable IV drug

• Avoid abrupt decreases in BP, can lead to MI, stroke or

visual changes

34
(a) Lower BP by no more than 25 % (within min – 1 h).
Appropriate goal is 100-110 mmHg (DBP)

(b) If stable, followed by further reduction towards goal

of 160/100 mmHg (SBP/DBP) within 2-6 h and
gradual reduction to normal over next 8-24 h

35
A variety of parenteral antihypertensive
drugs are available for use. Few studies
have compared these agents with one
another, and all are tolerated reasonably
well. The drug of choice is often dictated
by the type of hypertensive emergency.

36
• Sodium nitroprusside
• Labetalol
• Fenoldopam
• Nicardipine
• Nitroglycerin
• Diazoxide
• Phentolamine
• Esmolol
• Hydralazine 37
• Always given IV (poisonous if given orally)

• t1/2 = 1-2 min → requires continuous infusion

• Prompt vasodilation & reflex tachycardia

• Causes peripheral vasodilation by direct effects on

arterial & venous smooth muscle

38
Adverse effects
• Hypotension (overdose), goose bumps, abdominal
cramping, nausea, vomiting, headache
• Cyanide toxicity (rare)
Nitroprusside metabolism → cyanide ion
Can be treated with sodium thiosulfate infusion →
nontoxic thiocyanate

39
• Combined a and b blocker
• IV bolus or infusion for hypertensive emergency
• t1/2 = 3-6 h
• DOES NOT cause reflex tachycardia

Contraindications
Asthma, COPD, patients with 2nd or 3rd-degree AV
block or bradycardia

40
• Peripheral dopamine-1 (D1) receptor agonist
• Evokes arteriolar dilation
• IV infusion for hypertensive emergency
• t1/2 = 30 min
• Maintains or increases renal perfusion as lowers BP
• Promotes naturesis
• Safe to use in all hypertensive emergencies (particularly
beneficial in patients with renal insufficiency)
Contraindications
Glaucoma 41
• Calcium-channel blocker
• IV infusion for hypertensive emergency
• t1/2 = 30 min
• Evokes reflex tachycardia

42
• Vasodilator (more effect on veins than arteries)
• Drug of choice for hypertensive emergencies in
patients with cardiac ischemia or angina, or after
cardiac bypass surgery
• t1/2 = 2-5 min
• Hypotension = most serious side effect

43
• Arteriolar dilator
• Prevents vascular smooth muscle contraction by opening
K+ channels and stabilizing membrane potential
• t1/2 = ~ 24 h

Adverse Effects
Hypotension, reflex tachycardia, Na+ & H20
retention
• Inhibits insulin release and can be used to treat
hypoglycemia secondary to insulinoma

44
Phentolamine
Drug of choice for patients with catecholamine-
related emergencies

Esmolol
Often used for aortic dissection or postoperative
hypertension

Hydralazine
Drug of choice in treating hypertensive emergencies
in pregnancy related to eclampsia
45