Anti-Hypertensive Drugs

Hypertension: Classification
Joint National Committee criteria: 7TH JNC

Normal BP: <120 / <80 mmHg Pre-hypertension: 120139/ 8089 mmHg Stage 1 hypertension: 140159 / 9099 mmHg Stage 2 hypertension: >160 / >100 mmHg
B.P. is measured three times at standard conditions to confirm the diagnosis.
Reference; Hypertension 2003;42:1206
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Drugs Used in Hypertension

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Classification of Antihypertensive Drugs

1. 2. 3. 4. 5. Thiazide and Related Diuretics Calcium Channel Blockers (CCBs) Beta-Adrenergic Receptor Blockers (BARBs) Alpha-Adrenergic Receptor Blockers (AARBs) Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers (ACEIs & ARBs) 6. Direct Vasodilators 7. Centrally Acting Drugs
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Regulation of blood pressure (long-term)

SVC Brain, head and neck

Essential components of CVS 1. The heart 2. The blood volume 3. Arterial and venous tone

IVC

BP = CO x PR
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Blood Pressure (BP) = Cardiac Output (CO) x Peripheral Resistance (PR)

CO = stroke volume (SV) x heart rate(HR) CO = the amount of blood pumped out of the heart (each ventricle) per minute (5 litres/minute in an adult) PR = Peripheral resistance (resistance of the blood vessels; arterioles) PR is low in large vessels/vasodilatation PR is high in smaller vessels/vasoconstriction
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How do antihypertensive DRUGs act to normalise blood pressure

Mechanisms of action of antihypertensives

1. Diuretics: thiazides 2 mechanisms

1. Promote loss of sodium and water (diuresis) in kidney lowers CO and blood volume 2. Vasodilatation (PR) by direct action on vascular smooth muscle.
CO x PR = BP
(Limited Efficacy lower BP by 1015 mm Hg in most patients)

Thiazide diuretics inhibit the Na+-Cl symporter in DCT

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2. CCBs
Calcium entry is blocked in Vascular smooth muscle cells Myocardial cells Cells in cardiac conducting system This results in Coronary and Systemic Vasodilation (PR) Reduced contractility of heart (CO) Reduced conduction velocity in heart
CO x PR = BP
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3. Beta-Adrenergic Receptor Blockers

BARBs Reduce heart rate (HR) Reduce contractility of heart (SV) CO Reduce RAS activity reduce angiotensin II and aldosterone

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3. Beta-Adrenergic Receptor Blockers

Selectively block the beta adrenergic effects of norepinephrine and epinephrine They may be pure antagonists or partial agonists

1 receptors are found in cardiac muscle and the conducting system of the heart (Purkinje system) and the kidneys 2 receptors are found in the bronchial smooth muscle, vascular smooth muscle and skeletal muscle.
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3. Beta-Adrenergic Receptor Blockers

Results in reduced sympathetic drive
Effects: Delayed AV node conduction; heart rate Reduced myocardial contractility and oxygen consumption Reduced Renin secretion from the Juxtaglomerular apparatus of the renal cortex

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4. Alpha-Adrenergic Receptor Blockers (AARBs) Stimulation of 1adrenergic receptor causes vasoconstriction. Blockade of 1adrenergic receptor causes vasodilatation (PR)

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Over activated renin angiotensin system (RAS)

Angiotensinogen (liver)
Angiotensin I (inactive)
ACE Renin (From JGA of kidneys) Angiotensin II (in lungs)

Production of Aldosterone (adrenal cortex (Na+ retention) Increases blood volume CO

Acts as a potent vasoconstrictor and

PR

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5. Angiotensin Converting Enzyme Inhibitors (ACEI)

Mechanism of Action
Angiotensinogen (liver)

Angiotensin I (inactive)
ACEI Renin (From JGA of kidneys) Angiotensin II (in lungs)

Production of Aldosterone (Na + retention) increases blood volume

Aldosterone block = CO

Acts as a potent vasoconstrictor

AII block = PR

High blood pressure

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5. ACEIs and ARBs

Prevent vasoconstriction by Inhibiting angiotensin II production/receptors reduce PR Reduced aldosterone production reduced salt and water retention (CO)

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6. Direct Vasodilators
Act directly and causes arteriolar smooth muscle relaxation vasodilatation reduced PR fall in BP

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7. Centrally acting drugs

Acts on the brain and sympathetic outflow Methyldopa act by its metabolite, -methyl-noradrenaline (regarded as a false neurotransmitter) which stimulates pre-synaptic 2-adrenergic receptors
Feedback reduction of central sympathetic outflow lowers BP

Clonidine acts directly on 2 receptors, & causes rebound hypertension on abrupt withdrawal.
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7. Centrally acting drugs

Methyldopa Persistent inhibition of sympathetic outflow:
No stimulation of peripheral 1 receptors in blood vessels = PR No stimulation of 1 receptors in heart = CO Normalisation of blood pressure

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Fill the Table

Anti hypertensive drug class
1. Thiazides

Mechanism of Action
Reduced blood volume and arteriolar dilatation {CO x PR = BP}

2. 3. 4. 5. 6. 7.
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Sites of drug action

Heart rate contractility

Beta1 blockers

Thiazides and related diuretics

Vasodilators

Centrally acting drugs Thiazides and related Diuretics

Calcium channel blockers

Alpha1 blockers

Beta 1 blockers
ACEI ARB

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Pharmacology of Thiazide Diuretics

Examples: Hydrochlorothiazide Bendrofluazide, chlorthalidone, indapamide) (Metolazone profound diuresis)

Indications: hypertension, oedema Recommended as first line therapy in moderate hypertension. Good compliance with once a day therapy, given orally every morning.
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Hydrochlorothiazide: Adverse Effects

serum K+ (Hypokalaemia) serum Na+ (Hyponatraemia) serum Cl-, serum Mg++
Serum levels of glucose, lipids, calcium and uric acid hyperglycemia, hyperlipidaemia, hypercalcaemia, hyperuricaemia Side effects are less with low dose.

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Thiazides
Prescribing in special situations
Avoid in pregnancy; impaired placental perfusion Breast feeding; the amount in milk is too small Liver disease; hypokalemia may precipitate coma.

Renal disease; ineffective when eGFR is <30mL/minute

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Calcium Channel Blockers.

Relaxes vascular smooth muscle dilates coronary and peripheral arteries Dihydropyridine: Nifedipine, amlodipine less effect on the myocardium No antiarrhythmic activity Non-dihydropyridine: verapamil, diltiazem Greater effect on the myocardium (negative ionotropic) Have antiarrhythmic properties (negative chronotropic)
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Calcium Channel Blockers.

Indications
1.Hypertension 2.Ischemic heart disease: angina 3.Cardiac Arrhythmia (verapamil, diltiazem)
Important: Long acting Nifedipine to be used e.g. Nifedipine SR (sustained release) Short acting Nifedipine should not be used since it may worsen ischemic heart disease as a result of reflex tachycardia.
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Calcium Channel Blockers.

Adverse effects
Gum hypertrophy, Ankle oedema
Verapamil: constipation

Precautions: Avoid in pregnancy if other drugs are available.

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Beta-adrenergic receptor blockers

Classification 1. Lipid soluble / water soluble

2. Cardio selective / non-cardio selective

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Lipid soluble beta blockers

Readily cross cell membranes

Have high volume of distribution Readily enter the CNS, concentration about 20 times higher than the those of water soluble drugs High first pass metabolism in the liver Example: propranolol

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Water soluble beta blockers

Less liver metabolism

Have more predictable plasma concentrations Excreted unchanged by the kidneys Should be best avoided in renal disease Less penetration to CNS, hence less CNS side effects such as nightmares
Example: atenolol
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Beta adrenergic receptor blockers Cardio selective (1) blockers Examples: Atenolol Metoprolol Acebutalol Predominant effect on 1 receptors in the heart = cardio selective

Important (the selectivity is not 100%)

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Beta adrenergic receptor blockers

Non-cardio selective

blockers;

block 1 receptors in the heart and kidneys block 2 receptors in the bronchial smooth muscle, vascular smooth muscle and skeletal muscle. e.g. Propranolol
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Beta adrenergic receptor blockers

Indications for Cardiovascular diseases 1.Hypertension, angina pectoris 2.Myocardial infarction (Tx & secondary prevention) 3.Cardiac arrhythmia 4.Heart failure (low dose used as an additional agent) Other Indications 1.Anxiety & thyrotoxicosis (adrenergic over activity) 2.Benign essential tremors 3.Prevention of migraine 4.Treatment of glaucoma with eye drops
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Beta adrenergic receptor blockers

Adverse effects tiredness, bradycardia and heart block, cold extremities, worsening of Raynauds disease. Caution avoid sudden withdrawal may block symptoms of hypoglycemia in diabetes Contraindications bronchial asthma, 2nd or 3rd degree heart block ( both selective and non selective beta blockers) Pregnancy; intrauterine growth retardation
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Alpha adrenergic receptor blockers

Prazosin, Doxazosin ( long acting ) Mechanism of action is by blocking 1 receptors. What is the effect of 1-receptor stimulation? 1 blockers cause vasodilatation and PR. BP = CO X PR reduction in B.P Side effects Hypotension particularly with the first dose urinary frequency may occur due to , 1 blockade (1 stimulation causes contraction of sphincters) First dose hypotension is less with doxazosin
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Alpha adrenergic receptor blockers

Take the first dose at bed time and Start with the lowest possible dose. Other side effects include o Postural hypotension. o Palpitations o Headache Other uses of prazosin: In benign prostate enlargement, there is hesitancy in passing urine. Explain how prazosin would help
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ACEI
Captopril, Enalapril : Side effects
First dose hypotension (Caution) Give the first dose, a low dose at bed time to minimize the 1st dose hypotension. Elderly need to be supervised/admitted to hospital Hyperkalaemia ( serum K+ ) Angio-oedema & Dry cough (persistent and troublesome) For side effect, Consult doctor, choose ARB or a different class of drug. 38

ACEI
Indications Hypertension, Heart failure, Diabetes with proteinuria to reduce worsening of proteinuria. Contraindications pregnancy following allergic reactions, e.g. angioedema.
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Angiotensin II Receptor Blockers Losartan

Similar efficacy as ACEIs as an antihypertensive.

Lower incidence of dry cough (no effect on bradykinin metabolism)

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Vasodilator Antihypertensives
Hydralazine, Diazoxide, Sodium nitroprusside, Minoxidil.
Hydralazine HCl Used in moderate to severe hypertension. Hypertensive emergencies. Recommended in pregnancy - oral / IV Side effects Tachycardia, Hypotension, Fluid retention, Headache Drug induced S.L.E. (systemic lupus erythematosus)
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Methyldopa
Methyldopa is not commonly used as first line treatment because of many side effects and the high cost.

Indications: Hypertension in pregnancy H/T due to renal disease, resistant hypertension, Side Effects Dry mouth, Depression, Diarrhoea Sedation (sleepiness), Rashes, Haemolytic anaemia Liver damage, Impaired male sexual function Contraindicated if h/o depression and in active liver dis.
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Match the adverse effects

Antihypertensive verapamil Atenolol Nifedipine Captopril Methyldopa Adverse effect Hypokalemia 1ST dose hypotension Constipation Bradycardia Headache

Prazosin Thiazides vasodilators

Persistent dry cough Depression Gum hypertrophy

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Site of action of the major classes of antihypertensive drugs

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Classification of Antihypertensive Drugs

1. 2. 3. 4. 5. Thiazide and Related Diuretics Calcium Channel Blockers (CCBs) Beta-Adrenergic Receptor Blockers (BARBs) Alpha-Adrenergic Receptor Blockers (AARBs) Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers (ACEIs & ARBs) 6. Direct Vasodilators 7. Centrally Acting Drugs
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Thank you

Slide for Self learning and self assessment follows

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Q&A Normal blood pressure

Select the correct answers; give reasons
Blood pressure
is age related. is usually less than 120/80 mmHg in a young adult. rises with age. systolic blood pressure increases with exercise rises when standing from the sitting position decreases with sympathetic stimulation
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Activity Case scenario 1

60 year old Mr. SS found he was unable to lift his right arm, he had weakness of his right leg, and unable to speak while he was gardening. Soon he became unconscious. He was rushed to the Emergency department. He has been on antihypertensive drugs for the past 2 years. Discuss the following
1.The possible clinical problem? 2.The possible cause of the clinical problem? 3.How can we prevent this clinical problem?

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Why should we treat high blood pressure?

1. To prevent a stroke: acute cerebrovascular disease caused by thrombosis embolism and haemorrhage (bleeding).

Hemiplegia (paralysis of one side of the body) may occur as a result of a stroke. Acute cerebrovascular disease is a medical emergency
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Cerebral thrombosis

Cerebral hemorrhage
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Cerebral embolism

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HEMIPLEGIA

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Activity

Case scenario 2
Mrs. Rs is 60 years, one morning she woke up with severe breathlessness, cough and white frothy sputum. Her hands and feet were cold.
She has been a diabetic for 10 years on treatment, has not gone for clinic follow up and not checked her blood pressure for about an year. She was rushed to the Emergency department. Discuss the following.
The possible clinical problem? The possible cause of the clinical problem? How can we prevent this clinical problem?

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Why should we treat high blood pressure?

2. To prevent acute left ventricular failure (LVF) Acute LVF is a medical emergency
Left ventricle fails to pump out blood effectively (reduced cardiac output) reduced tissue perfusion (cold hands and feet) fluid seeps into lungs due to back pressure Severe breathlessness (dyspnoea)

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Case scenario 3
Mr. SS 60 years, noticed swelling of face when he wakes up in the morning. His appetite has been poor over the last 1 month. He was feeling tired at work as a company executive in a private firm. He complained of blurred vision as well. Mr. SS was diagnosed to have hypertension 10 years ago, during a routine medical examination. Although he was prescribed an antihypertensive he could not adhere to treatment. He failed to report for follow up as he had no symptoms.
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Why should we treat high blood pressure?

3. To prevent renal impairment
(increased blood pressure if untreated will lead to chronic kidney disease.) 4. To prevent visual impairment.
Retinal hemorrhages

5. To prevent atherosclerosis and coronary heart disease.

6. To improve quality of life.
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Activity Modifiable risk factors for hypertension

Select the correct answers; discuss with a colleague
Obesity Smoking Sedentary life Family history Stress Age Increased alcohol consumption Increased intake of salt
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Management of hypertension; Non pharmacological methods Q &A Reduce weight and BMI up to the ideal
weight for the height. What are the BMI cutoff values? (normal/overweight/obesity) Reduce salt intake (avoid added salt). How much salt is recommended? Reduce alcohol. What is the recommendation? Quit smoking. Why not reduce? Regular exercise. What is the recommendation? Reduce stress. What methods are available? Reduce fat intake. What fats to be reduced?
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Non-pharmacological methods
Who should practice the non-pharmacological methods? Select the correct answer/s Those with Stage 1 hypertension Stage 2 hypertension pre hypertension normal blood pressure

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Targets for control of hypertension

If no complications; BP = <140/<90 mmHg usually. In diabetes and those with target organ damage/ complications;(heart, brain ,kidneys)

BP = <130/<80mmHg

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Education of the patient; on what aspects?

Complications of poorly controlled hypertension
The importance of taking treatment without missing a single dose, how to minimise adverse effects eg.1st dose hypotension

Strategies to improve adherence to therapy(use of a pill box, fix medication with the time/meals) There are no symptoms of high BP unless the patient has severe hypertension. Regular BP measurement and review of medication.
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A pill box

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Thank you

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