1

ANTI-HYPERTENSIVE DRUGS
LUKE LUNDAU BIETE
DipPharm, BPharm, MclinPharm
Overview 2

 The normal physiological function of the body requires blood

circulation

 This is vital in enhancing the subsequent circulation of oxygen and

other nutrients to the rest of the body

 This circulation is supposed to be done at a certain blood pressure

(BP)

 Currently the pressure from 110/70mmHg and the upper limit of less
than 140/90mmHg being the acceptable normal
Definition of Hypertension 3
 Hypertension is a common chronic disease which involves a
persistent elevated arterial blood pressure(BP) of more that
140/90mmHg

 The targeted BP is 140/90mmHg though 130/80mmHg is currently the

target in those with Cardiovascular conditions and diabetes

 For each 20mmHg systolic or 10mmHg diastolic BP increase, there is

a 2 fold increase in risk of Cardiovascular diseases

 Increasing awareness and diagnosis of hypertension, and improving

control of BP with appropriate treatment, are considered critical
public health initiatives to reduce CV morbidity and mortality
Types of hypertension (ETIOLOGY)
4
Essential or primary hypertension
 Forms 90% of hypertension of the cases n most patients, hypertension
results from an unknown pathophysiologic etiology

 This form of hypertension cannot be cured, but it can be controlled

Non essential or secondary hypertension)

 A small percentage (10%) of patients have a specific cause of their
hypertension

 There are many potential secondary causes that are either concurrent
medical conditions or are endogenously induced

 If the cause can be identified, hypertension in these patients has the

potential to be cured
Factors controlling BP 5

 Multiple factors that control BP are potential contributing component;

i. Humoral - can either be the renin–angiotensin–aldosterone system
[RAAS]) or vasodepressor mechanism
ii. Abnormal neuronal mechanisms
iii. Defects in peripheral auto regulation
iv. Disturbances in sodium, calcium, and natriuretic hormones
 Many of these factors are cumulatively affected by the multifaceted
RAAS, which ultimately regulates arterial BP
 It is probable that none of these factors is solely responsible for essential
hypertension
 However, most anti-hypertensives specifically target these mechanisms
and components of the RAAS
 6
Secondary causes of Hypertension

 The following are notable secondary causes of hypertension;

1. Diseases

2. Drugs
- Prescription drugs
- Street drugs and other natural products

3. Food substances
 7
Diseases as causes of hypertension
 Chronic kidney disease
 Cushing’s syndrome
 Coarctation of the aorta
 Obstructive sleep apnea
 Parathyroid disease
 Pheochromocytoma
 Primary aldosteronism
 Renovascular disease
 Thyroid disease
Drugs that can cause hypertension 8
Street drugs and other
Prescription drugs natural products
 Adreneal steroids e.g prednisolone,  Cocaine and cocaine withdrawal
fludrocortisone, triamcinolone Ephedra alkaloids (e.g., Ma-huang),
 Amphetamines or anorexiants
 “herbal ecstasy,” other
 Decongestants phenylephrine, phenylpropanolamine analogsa
pseudoephedrine Nicotine withdrawal
 NSAIDs e.g. ibuprofen, diclofenac,  Anabolic steroids
Valecoxibetc
 Narcotic withdrawal
 Methylphenidate
Others:
 Phencyclidine
 Bromocriptine, clozapine
 Ketamine
 Beta blockers or or centrally acting
alpha agonists  Ergotamine and other ergot-
 Beta blockers without alpha containing herbal products
blockers first when treating  St. John’s wort
pheochromocytomawhen stopped
abruptly when
 9

Food substances that can cause hypertension

 Sodium
 Ethanol
 Licorice
 Tyramine-containing foods if taking a monoamine oxidase inhibitor
 10

Blood pressure as a mathematical product

 Blood pressure = cardiac output x Peripheral resistance

 Cardiac output relates to blood volume while peripheral resistance

is the resistance or friction the blood has to go against as it moves
along the blood vessel

 Elevated blood pressure can result from increased cardiac output

and or increased total peripheral resistance
 11

Stages of hypertension
Complications of hypertension 12
 When not well controlled hypertension can cause a number of
complications that can be life threatening

 Be low are the major four hypertensive complications;

i. Congestive cardiac failure
ii. Renal failure
iii. Hypertensive retinopathy
iv. Stroke

NB:
Other cardiovascular complications have also been known to occur as
complications
Treatment of hypertension 13

Goals o treatment

i. Reduce mortality and morbidity associated to hypertension

ii. Improve quality of life of patients
iii. Prevent end organ damage e.g., CV events, heart failure, and kidney
disease)

 Reducing risk remains the primary purpose of hypertension therapy and

the specific choice of drug therapy is significantly influenced by
evidence demonstrating such risk reduction
 14

Benefits of controlling BP

 40% decrease in stroke

 25% decrease in myocardial infarction
 50% decrease in heart failure
Approaches to treatment 15
 After a definitive diagnosis of hypertension is made, most patients
should be placed on both lifestyle modifications and drug therapy
concurrently

 Lifestyle modification alone is considered appropriate therapy for

patients with prehypertension

 However, lifestyle modifications alone are not considered adequate

for patients with hypertension and additional CV risk factors

 These patients have BP goals of less than 130/80 mm Hg (e.g.,

diabetes, coronary artery disease, chronic kidney disease) or less
than 120/80 mm Hg i.e. left ventricular dysfunction)
Non Pharmacological treatment of hypertension 16
Modification Recommendation
Weight loss Maintain normal body weight (body mass
index 18.5–24.9 kg/m2 )
DASH(Dietary Consume a diet rich in fruits, vegetables, and low-
approaches to stop fat dairy products with a reduced content of
Hypertension) saturated and total fat

Reduced salt intake Reduce daily dietary sodium intake as much as

possible, ideally to ≈65 mmol/day (1.5 g/day
sodium, or 3.8 g/day sodium chloride)

Physical activity Regular aerobic physical activity (at least 30

min/day, most days of the week)

Moderation of alcohol Limit consumption to ≤2 drinks/day in men and ≤1

intake drink/day in women and lighter-weight persons
Types of anti-hypertensive drugs 17
 The following groups of drugs are used in hypertension;
 Diuretics
- Thiazides diuretics
- Loop diuretics
- Potassium sparing diuretics
- Osmotic diuretics
- Carbonic anyhydrase inhibitors
 Angiotensin converting enzyme inhibitors (ACE-Is)
 Angiotensin receptor blockers (ARBs)
 Calcium channel blockers
 Beta blockers
 Alpha receptor blockers
 Centrally acting drugs
 18

DIURECTICS
Mechanism of Action and Sites 19

 Diuretics are drugs that slow down the absorption of salts and fluids in
the kidney tubules, thereby increasing the volume of fluid excreted by
the urinary system

 These drugs accelerate the flow of urine

 Their effect is based on the ability to inhibit the reabsorption of

electrolytes by the kidneys

 Enhanced elimination of electrolytes is accompanied by an increase in

the volume of fluid excreted from the body through osmotic pressure

 All this achieved at different sites of the nephron i.e. the proximal
convoluted tubule, ascending loop of henle, distal convoluted tubule
and the collecting duct
Different sites of diuretic actions
20
Loop diuretics
 Examples – Furosemide, Torasemide, Bumetanide, Ethacrynic acid 21
 Site of Action
- Ascending loop of henle where they inhibit the protein or enzyme Na+/K+/2Cl–
transporter and thus preventing absorption of the said ions, with water following by
osmosis
- Also work by a secondary mechanism namely; dilatation of capacitance veins, an
effect which reduces preload and enhances the contractile ability of cardiac muscle

Indications
 Hypertension
 Congested cardiac failure
 Pulmonary edema
 Liver renal dysfunction – treating fluid build up associated with these conditions
(Ascites)

Side effects
 Hypotension, hypokalemia, hypocalcemia, dehydration, hyperglycemia, electrolyte
loss, dizziness, faintness, elevated serum creatinine concentration, ototoxicity,
nephrotoxicity
Contraindications of loop diuretics 22
 Dehydration or severe hypovolemia
 Patients taking aminoglycosides like gentamycin, amikacin and the
like due to the increase risk of ototoxicity and nephrotoxicity
 Hepatic encephalopathy where hypokalemia can worsen coma
 Patients with gout as reduces the excretion of uric acid when taken
for a long time
 Recommended to be taken early in the day to avoid nocturia
which can affect the quality of sleep
 Pregnancy – belong to category C and thus risk cannot be ruled out
 Combination with ACE inhibitors and NSAIDs – leads to triple
whammy effect and hence heightening risk of kidney failure
 Patients with know history of sulfa allergies except ethacrynic acid
which is a not a sulfa drug
Thiazide diuretics
23
Examples
 Hydrichlorothiazide, bendroflumethiazide, indapamide, metalazone

Site of action
 Distal convoluted tubule

Indication
 First line treatment of hypertension

Side effects
 Hypovolemia, hypokalemia, metabolic alkalosis, hyperuricemia,
hypercalcemia, glucose intolerance
Potassium sparing diuretics
24
Examples
 Spironolactone, Eplerenone, Amloride, Triamterene

Site of action
 Collecting duct or later part of the distal convoluted tubule

Indication
 Congestive cardiac failure
 Hypertension

Side effects
 Hyperkalemia
 25

ANGIOTENSIN CONVERTING
ENZYME INHIBITORS (ACE-Is)
Examples 26
 Enapril, Ramipril, Lisinopril, Perindopril, Captopril, Fosinopri

Mechanism of action
 They work by inhibiting the enzyme, angiotensin-converting
enzyme (ACE), an enzyme responsible for converting angiotensin I
to angiotensin II
 Angiotensin II is a potent vasoconstrictor and blocking its formation
helps of peripheral resistance
 Furthermore, by blocking ACE, these drugs prevent aldosterone
release from the adrenal cortex and eliminate sodium ions (along
with water) from the kidneys
 These two cumulative effects serve to reduce blood volume and
blood pressure.
Indications 27
 Hypertension - ACE inhibitors reduce the risk of serious cardiovascular
events, such as heart attack and stroke. They may be used first or second-
line, usually in combination with another drug

 Iscaemic heart disease – Reduce risk of cardiovascular events and stroke

 Chronic cardiac failure – symptomatic relief and overall prognosis

 Diabetic nephropathy – prevent nephropathy from progressing in

diabetic patients . Also used for chronic kidney disease to reduce
proteinuria

NB
 They are the best choice in hypertensive patients with diabetes co-
morbidity
 28
Side effects
 Hypotension – first-dose hypotension is prevalent with ACE inhibitors
 Persistent, dry cough – due to pulmonary kinin accumulation
 Hyperkalemia – ACE inhibitors promote potassium retention
 Angioedema – the drug should be stopped immediately if this occurs
 Other – fatigue, nausea, dizziness, headache

NB:
 Because ACE inhibitors cause hyperkalemia, patients should not be
prescribed other potassium-elevating drugs or supplements
 29

ANGIOTENSIN II RECEPTOR
BLOCKERS (ARBs)
 30
Examples
- Candesartan
- Irbesartan
- Losartan
- Telmisartan
 Mechanism of Action
 Angiotensin-receptor blockers have a similar mechanism of action
to ACE inhibitors.
 Whereas ACE inhibitors block the conversion of angiotensin I into
angiotensin II, ARBs work by blocking the action of angiotensin II at
the AT1 receptor. Because angiotensin II promotes aldosterone
secretion and acts as a vasoconstrictor, its blockage reduces
peripheral vascular resistance and lowers blood pressure.
 31
Side effects of ARBs

 Hypotension
 Hyperkalemia
 Renal failure (as with ACE inhibitors)
 Cough – though less likely than with an ACE inhibitor

 Due to the risk of hyperkalemia, other potassium-elevating drugs should

not be prescribed including potassium supplements, potassium-sparing
diuretics

 As with ACE inhibitors, taking ARBs with NSAIDs increases the risk of renal
failure
 32

CALCIUM CHANNEL BLOCKERS

(CCBs)
 33
Types of Calcium Channel blockers

Dihydropyridines Non - dydropyridines

 Amlodipine Diphenyl alkylamines

 Nifedipine (safe in gestational  Verapamil
hypertension!)
 Felodipine
Benzothiazepines
 Nimodipine
 Diltiazem

Dihydropyridines have greater selectivity for the vasculature in contrast to non-

dihydropyridines which have greater selectivity for the heart
Mechanism of action of CCBs 34

 Calcium channel blockers reduce calcium entry into vascular and

cardiac cells

 This leads to reduced intracellular calcium concentration which, in turn,

causes relaxation and vasodilation in arterial smooth muscle

 Calcium channel blockers also reduce myocardial contractility in the

heart and suppress cardiac conduction at the AV node

 Reduced cardiac rate, contractility and afterload lower myocardial

oxygen demand and thus preventing angina
Indications of CCBs 35
 Hypertension (Forms part of the first line agents)
 Angina pectoris
 Nifedipine is also used as a tocolytic agent

Side effects of CCBs

 Flushing, headache, ankle swelling, palpitations, light headedness, shortness
of breath, constipation (most common with verapamil), gingival
hyperplasia (gum overgrowth)

NB:
 CCBs especially non dihydropyridines should not be combined with beta-
blockers except under specialist supervision as both drug classes are
negatively inotropic and negatively chronotropic

 Taken together, this can lead to heart failure, bradycardia and asystole
 36

BETA BLOCKERS
Examples 37
 Acebutelol
 Metoprolol
 Bisoprolol
 Labetalol (safe in gestational hypertension)
 Nebivolol
 Propanolol
 Timolol
 Betaxolol
 Carvedilol

Mechanism of action
 reduce renin secretion from the kidney – an effect ordinarily mediated by beta-
1 receptors.
 Direct blockage of the beta 1 receptors reduce the heart rate and contractility
Specific properties 38
 Compairing the drugs; propranolol, nadolol, pindolol and timolol some
specific properties are found with individual drugs

 Pindolol is found to have intrinsic sympathomimetic activity or partial

agonist activity which enables it to exert a weak agonist effect on β –
adrenoceptors

 Although propranolol and pindolol have membrane stabilizing effects

(Local anesthetic activity), nadolol and timolol do not

 This membrane stabilizing activity causes the blockage of sodium

channels in nerves and heart tissue thereby, slowing conduction velocity

 Propranolol the first β-blocker approved (Prototype) for clinical use is

distinguished by it high lipid solubility and CNS penetration and hence a
higher incidence of side effects such as headache, psychosis, nightmares,
sleep disturbances, vertigo, visual disturbance
Indications Non selective β-blockers
Pindolol 39
 Approved for hypertension treatment

Propranolol
 Treatment of hypertension, angina pectoris and cardiac arrhythmias
 Prevention of migraine headaches and as adjunctive therapy in treatment of acute
thyrotoxicosis, acute myocardial function and pheochromocytoma

Nadolol
 Treatment of hypertension, angina pectoris and prevention of migraine headache

Timolol
 Administered orally for treatment of hypertension, to reduce risk of death in patients
with acute myocardial infarction and prevention of migraine headache

 Ocular topical application for treatment of glaucoma and is suitable because it

does not have local anesthetic effect and hence cannot anesthetize the cornea
when instilled into the eye
Selective β1-blockers
40
 These have a greater affinity for β1 than for β2 adrenoceptors and because
β1 are primarily located in the cardiac tissue, β1-blockers are also known as
cardio selective β-blockers

 Examples are acebutolol, atenolol, esmolol and metoprolol

 Comparing with non selective β-blockers, selective β1-blockers produce less

bronchoconstriction and other mediated effects

 Their selectivity for β1 adrenoceptors is not absolute and therefore,

blockade of β2 - receptors increases with dose and hence β1 should be used
with caution in patients with asthma

NB: with the last point in mind, it is important to appreciate that cardio
selectivity is not the same as cardio specificity
Specific properties and indications for selective β1-blockers 41
Acebutolol
 Administered orally for treatment of hypertension and cardiac arrhythmias

Atenolol
 Shows less variability in its oral absorption than do other β – blockers and is
largely excreted unchanged in the urine and has lower lipid solubility
 Administered orally for treatment of hypertension, angina pectoris and
acute myocardial infaction

Esmolol
 Has shorter half life compared to others β – blockers and is administered
intravenously for treatment of hypertension and acute supraventricular
tachycardia when these occur during surgery
Metoprolol 42
 Used to treat hypertension, angina pectoris and acute myocardial
infarction

 Administered orally or parenterally and is extensively metabolized by

CYP450 enzymes before undergoing renal excretion

Other β1- selective antagonists

 These include bisoprolol and betaxolol

 Both of these drugs are administered orally for treatment of hypertension

 Topical application of betaxolol also reduces aqueous humour secretion

while producing negligible systemic β-adrenoceptors and hence it is used in
treatment of chronic open angle glaucoma
 and β – Adrenoceptor Antagonists
43
 These block both and β adrenoceptors and they include carvedilol and
labetalol

Carvedilol
 Carvedilol blocks β1, β2 and 1 adrenoceptors and also possesses
antioxidant activity
 Each of these properties offer the cardioprotective effect

Antioxidant effects of carvedilol

 Inhibition of lipid peroxidation in myocardial membranes
 Scavenging of free radicals
 Prevention of neutrophil release of O2
 Additionally carvedilol has antiapoptotic effect which helps prevent
myocyte death and reduce infarct size in persons with myocardial
ischaemia
Indications of carvedilol 44
 Carvedilol is therefore referred to as third generation β-blockers and
neurohumoral antagonists and its value in treating myocardial
infarction has been established

 Carvedilol is used in management of hypertension

Labetalol
 This is a non selective β blocker and selective 1 blocker that is
primarily used in the treatment of hypertension

 Labetalol decreases heart rate and cardiac output as a result of β1-

adrenoceptor blockade and it reduces peripheral vascular
resistance as a result of 1-adrenoceptor blockade