Drugs & Disease A/B
Pharmacology &
5BBM0212/3
Therapeutics
2024/25
School of Treatment of hypertension
Bioscience
Education
Dr Dibesh Thapa
Cardiovascular Disease Continuum
Risk Vascular
Hypertension Stroke
factors dysfunction
Atherosclerosis Thrombosis
Acute Heart
Angina
MI failure
Arrhythmias and
sudden cardiac death
Learning outcomes
By the end of the lecture, you should be able to
- Describe hypertension and explain why it is important to treat it.
- Explain why hypertension is the main risk factor for cardiovascular diseases.
- Describe how blood pressure is regulated.
- Explain different classes of drugs (pharmacology) available for the treatment of hypertension.
Hypertension
120/80
mmHg
140/90
mmHg
Servier Medical Art
Systolic (mmHg) Diastolic (mmHg)
Normal <120 <80
Pre-hypertension 120-129 80
Stage 1 hypertension 130-139 80-89
Stage 2 hypertension 140-180 90-120
Hypertensive crisis >180 >120
Hypertension
Primary hypertension: 90-95%, no apparent cause Secondary hypertension: caused by an underlying conditions
- Ageing
- Obesity - chronic kidney disease
- high salt diet - diabetes
- lack of exercise - primary aldosteronism
- family history - pheochromocytoma.
- Smoking
- Drinking
According to WHO, an estimate 1.28 billion adults aged 30-79 worldwide have hypertension.
About 46% of adults with hypertension are unaware they have the condition, i.e. silent killer.
Hypertension is a major cause of premature death worldwide.
As of July 2024,
COVID-19 caused 7.1
million deaths (WHO).
Why is high blood pressure dangerous?
Cardiovascular Disease Continuum
Risk Vascular
Hypertension Stroke
factors dysfunction
Atherosclerosis Thrombosis
Acute Heart
Angina
MI failure
Arrhythmias and
sudden cardiac death
Pathophysiology of hypertension
➢ High blood pressure damages the inner lining of the blood vessels (endothelium), i.e. vascular damage can release
inflammatory mediators, promote atherosclerosis, thrombus formation, and dysregulate autoregulation.
Accompanied by inward eutrophic remodelling.
normotensive hypertensive
Martinez-Quinones, Am J Hypertens., 2018
Pathophysiology of hypertension
➢ High pressure in microcirculation can damage organ such as brain, eye and kidney.
➢ Cardiac damage, brain damage, renal damage, retinal damage.
Pathophysiology of hypertension
➢ High blood pressure forces the heart to work harder. Increased afterload which can cause cardiac hypertrophy,
stiffening and heart failure.
Greater force to work against…
Mayoclinic.org
Blurred/loss
of vision
Stroke
Heart attack
Heart failure
Kidney
damage
Sexual dysfunction
Bone loss
Headache/confusion
Vascular damage/dysfunction (atherosclerosis)
Peripheral artery disease
Aneurysm
- Hypertension is the leading
contributor to all cause
mortality and disability
worldwide. (Forouzanfar et al,
Lancet, 2015)
- Lowering systolic blood
pressure by 10mmHg is
associated with a reduction in
CVD event rate by 29% (Bundy
et al, JAMA Cardiol, 2017).
Oparil et al, Nat Rev Dis Primers, 2018
Lower your
blood
pressure!!!
How is blood pressure regulated?
BP = CO X TRP
Blood
Pressure
Cardiac Total peripheral
Output resistance
Blood volume Vessel diameter
Vessel length
Blood viscosity
pressure = flow x resistance
BP = CO x TPR
BP is
generated by TPRtotal = R1 + R2 + R 3
LV contraction
Pressure falls steeply across segments of high resistance
TPRtotal = R1 + R2 + R
3
R2 increases in hypertension. So, pressure must rise (BP = CO x TPR)
(BP = CO x TPR)
Blood
Pressure
Cardiac Total peripheral
Output resistance
In hypertension, blood
volume goes up or/and
resistance goes up
Blood
Pressure
Lumen
Cardiac Total peripheral
diameter /
Output resistance
arterial stiffness
Heart Stroke
Preload
rate volume ANS
Cardiac Venous tone /
Kidney / RAAS
ANS Blood volume
contractility
Baroreceptors
Autonomic
BP RAAS
Nervous System
Baroreceptors
Sensory mechanoreceptors that sense the change in blood pressure and alter the total vascular resistance or
cardiac output to maintain the homeostatic blood pressure. Located in the walls of aortic arch and carotid sinuses.
With hypertension, the baroreceptors reset to the new high blood pressure, as a result it maintains that high
blood pressure instead of reducing it.
Autonomic Nervous System (ANS)
Sympathetic NS Parasympathetic NS
- flight/fight response
- rest/digest or feed/breed system
- usually excitatory response
- usually inhibitory response
- adrenergic receptor at target tissue
- muscarinic receptor at target tissue
(exception)
- acetylcholine main neurotransmitter
- noradrenaline main neurotransmitter
- Decrease heart rate
- Increase heart rate, contractility, and
- Decrease blood pressure
vasoconstriction
- Increase blood pressure
Servier Medical Art
RAAS – Renin Angiotensin Aldosterone System
Blood (BP = CO x TPR)
pressure
Low blood Low Na+
volume Juxtaglomerular Macula densa
cells
SNS
Renin ACE H20
ADH Collecting duct reabsorption
Angiotensinogen Ang I Ang II
Aldosterone Na+
DCT & reabsorption
Collecting
duct
Treatment of hypertension
- Lifestyle changes (diet and exercise)
- Pharmacological treatment (Drugs)
Lifestyle changes
Diet, blood pressure and cardiovascular diseases
Evidence to support relationship between diet and reduced blood pressure and CVD
DASH diet Mediterranean diet
(Dietary Approaches to Stop Hypertension)
Pharmacological treatment
Until 1950, there was
no effective treatment
for hypertension.
Lower your
blood
pressure!!!
Treatment of hypertension
Medications (drugs) will affect one
or more of these pathways…….
Drugs
First line of treatments (AACD)
- ACE inhibitors (ends in pril, e.g. enalapril, lisinopril, ramipril)
- Angiotensin II blockers (ends in sartan, e.g. candesartan, irbesartan, losartan)
- Calcium channel blockers (dihydropyridine blockers end in dipine, e.g. amlodipine, felodipine, nifedipine)
- Diuretics (indapamide, bendroflumethiazide)
Other classes of treatments
- Beta blockers (ends in lol, e.g. atenolol, bisoprolol)
- Alpha blockers (many side effects, so not popular)
- Renin antagonists
- Aldosterone antagonists
ACE Inhibitors
- Blocks angiotensin converting enzymes, inhibits production of Ang II
- Relaxes blood vessel to decrease TPR and BP.
- First line of treatment for people aged <55 years (young people tend
to have more renin)
- Shown to improve glucose metabolism, thus preferrable in younger
patient and type II diabetic patients
- Generally well tolerated but side effects include hyperkalaemia,
cough and angioedema which can be life threatening and is
substantially increased in black individuals, hence they are given
CCBS.
- Not recommended during pregnancy
Enalapril has 30,000 times greater affinity
- enalapril, lisinopril, ramipril for ACE compared to Ang I !!!
Angiotensinogen
Bradykinin 1-5 Renin
(inactive) ACE-I
Ang I
ACE
Cough & Bradykinin
angioedema Ang II
Increased NO
(Vasodilation)
AT1 AT2
Vasoconstriction Vasodilation
Sympathetic Natriuresis
activation
Increase Na & H2O
retention
Angiotensin II receptor blocker (ARBs)
- Angiotensin II receptor antagonist, thus blocks the activity of Ang II.
- Blocks the ANG II receptor in heart, blood vessels and kidneys.
- Relaxes blood vessel to decrease TPR and BP.
- Interchanged with ACE inhibitors as first line of treatment for
people aged <55 years.
- ARBs preferred in patients with persistent dry cough side effect
caused by ACE inhibitors.
- Generally well tolerated but side effects include dizziness, headache
and fatigue.
- Not recommended during pregnancy.
- Irbesartan, valsartan, losartan and candesartan
Angiotensinogen
Bradykinin 1-5 Renin
(inactive)
Ang I
ACE
Cough & Bradykinin
angioedema Ang II
ARB
Increased NO
(Vasodilation)
AT1 AT2
Vasoconstriction
Sympathetic
Vasodilation
activation
Increase Na & H2O Natriuresis
retention
Calcium channel blockers (CCBs)
- Dihydropyridine calcium channel blockers elicit vasodilation by
blocking vascular smooth muscle L-type calcium channels.
- Prevents calcium entry into cells which prevents vasoconstriction
and facilitates vasodilation, which drops blood pressure.
- Non-dihydropyridine calcium channel blockers such as verapamil also
inhibits cardiac calcium channels which can reduce heart rate and
cardiac contractility.
- First line of treatment for white patients >55 years age, black
patients of any age (unless they are diabetic).
- Side effects include peripheral oedema, tachycardia, flushing,
headache. Constipation, negative ionotropic and chronotropic effect
with non-selective CCBs.
- Amlodipine, felodipine, nifedipine, verapamil, diltiazem
Dihydropyridines Non-dihydropyridines
- Amlodipine, felodipine, nifedipine - Verapamil, diltiazem
- Affects smooth muscle cells in - Greater effect on cardiac cells
vascular beds
- Antidysrhythmic properties (slows AV
- Peripheral vasodilation, reduce TPR. conduction), also has negative
inotropic effect
Vascular Smooth muscle contraction
Cardiovascular physiology concepts
Diuretics
- Diuretics promotes diuresis and natriuresis to reduce blood pressure.
- Increase water and salt excretion by kidney reduces blood volume, cardiac
output and BP.
- Thiazides, loop diuretics, potassium sparring diuretics, carbonic anhydrase
inhibitors
- First line of treatment in black individuals alongside calcium channel blockers.
Its added if ACE inhibitors/ARBs do not result in desired drop in BP. Not
recommended during pregnancy
- It can worsen glucose metabolism so not given to diabetics.
- Major side effects include hypokalaemia and hyponatraemia and both can be
life threatening. Hypokalaemia can cause arrhythmias and muscle weakness.
Hyponatraemia can cause confusion, seizures and coma.
- Furosemide, Hydrochlorothiazide, chlorthalidone, metolazone
Drug class Action Effect
Thiazide (thiazide-type Inhibits Na+Cl- transporter in distal Promotes natriuresis
diuretics / thiazide–like convoluted tubule
diuretics)
Loop diuretics Inhibits Na+K+Cl- cotransporter in ascending Promotes natriuresis
loop of henle.
Potassium sparing Inhibit Na+K+ exchange in collecting duct. Promotes natriuresis
diuretics Blocks aldosterone receptor. without causing
potassium loss.
Carbonic anhydrase Inhibits reabsorption of HCO3-distal which Promotes natriuresis
inhibitors results in decreased activity of apical Na+H+
exchanger
Osmotic diuretics Increases osmolarity of blood, increases Promotes increased
blood flow to kidney to increase water water excretion and
excretion from PCT and descending loop of natriuresis.
henle.
C3 = Na+ Cl- cotransporter
P = Na+ / K+ pump hydrochlorothiazide
Rang & Dale Pharmacology, 10th ed.
C1 = Na+ K+ Cl- cotransporter Furosemide
P = Na+ / K+ pump
Rang & Dale Pharmacology, 10th ed.
P = Na+ / K+ pump
Amiloride
Rang & Dale Pharmacology, 10th ed.
Beta blockers
- Beta blockers block beta adrenergic receptors.
- The selective β1 blockers block the receptors in the heart to reduce cardiac
output and heart rate.
- Additionally β1 receptor inhibits renin release in the kidney and inhibit SNS
activity.
- Bisoprolol, nebivolol, carvedilol, atenolol, propranolol
Beta blockers
- Once a first line of treatment for hypertension but ASCOT trial in 2005 showed they are not as effective in
reducing cardiovascular events.
- Beta blockers are inferior to other first line antihypertensives in reducing CVD morbidity and mortality.
- They are effective following myocardial infarction and in patients with heart failure with reduced left ventricular
ejection fraction.
- Beta blockers can cause bronchial obstruction in asthmatic patients and should not be given together with non-
dihydropyridine calcium channel blockers that lower SA node or AV conduction.
- Generally well tolerated but may cause cold hands/feet in older people, fatigue and erectile dysfunction in some
men.
ASCOT trial (2005)
Fatal & non-fatal stroke Cardiovascular
Cardiovascular events
events
Fatal & non-fatal stroke
Cardiovascular mortality All-cause mortality
Alpha blockers
- Noradrenaline, released from sympathetic nerve fibres in blood vessels,
causes vasoconstriction by binding to α1-receptors on vascular smooth
muscle cells. Using alpha blockers to block these receptors causes
vasodilatation, decrease in TPR and BP.
- Mainly used in combination with other anti-hypertensive agents, these are
4th line drugs. They effectively lower blood pressure, but their adverse
effects limit their use.
- Adverse effects: Orthostatic hypotension, esp. on first dosing, ankle
oedema, drowsiness
- Contraindicated in mild heart failure, pre-existing orthostatic hypotension
- Indicated in hyperlipidaemia, benign prostatic hyperplasia
- Doxazosin, prazosin
Vascular Smooth muscle contraction
Alpha blockers
Cardiovascular physiology concepts
Renin inhibitor
- Blocks the activity of renin. Inhibits production of Ang I from
angiotensinogen. Significant because it blocks the RAAS at the start of the
activation point (Remedies Ace escape!)
- Decreases Ang II level which promotes vasodilation, promotes natriuresis,
reduces sympathetic activity and fall in blood pressure.
- Aliskiren is the only renin inhibitor.
- Only used when first line drugs do not produce effective drop in BP. Does
not have a great effect on reducing mortality and major cardiovascular
events.
- Adverse effects: angioedema, hyperkalaemia, headache, cough
- Contraindicated in pregnancy and diabetes.
RAAS – Renin Angiotensin Aldosterone System
Blood
pressure
Low blood Low Na+
volume Juxtaglomerular Macula densa
cells
SNS
Renin ACE H20
ADH DCT & collecting reabsorption
duct
Angiotensinogen Ang I Ang II
Aldosterone Na+
DCT reabsorption
Ram, J Clin Hypertens., 2007
Villamil et al, J Hypertens, 2007
Mineralocorticoid receptor antagonists
- Aldosterone antagonist, blocks the action of aldosterone at
mineralocorticoid receptor.
- Decreases sodium reabsorption, causes natriuresis, reduces blood volume
and decreases blood pressure.
- Given in combination therapy with first line treatments.
- Adverse effects: Cough, dizziness, hyperkalaemia, diarrhoea
- Spironolactone, eplerenone, finerenone,
- Especially effective in resistant hypertension.
Resistant hypertension
- Resistant hypertension is when BP persists over 140/90 PATHWAY-2 TRIAL
mmHg with 3 or more first line anti-hypertensive
medications (including diuretics) at maximum
tolerated doses.
- Secondary hypertension needs to be ruled out.
- The most common reason is poor adherence to
prescribed medications.
- Spironolactone is the most effective 4th medication to
treat resistant hypertension (more than alpha or beta
blockers). Adverse effects: hyperkalaemia
- Transcatheter renal denervation and baroreflex
activation therapy used in severe resistant
hypertension in some countries.
Williams et al, Lancet, 2015
Learning outcomes
By the end of the lecture, you should be able to
- Describe hypertension and explain why it is important to treat it.
- Explain why hypertension is the main risk factor for cardiovascular
diseases.
- Describe how blood pressure is regulated.
- Explain different classes of drugs (pharmacology) available for the
treatment of hypertension.
Lower your blood
pressure!!!
