1. Dr Laith M Abbas Al-Huseini M.B.Ch.B, M.Sc., M.Res., Ph.D.
Antihypertensives
Dr Laith M Abbas Al-Huseini
M.B.Ch.B, M.Sc., M.Res., Ph.D.

2. Hypertension What is normal blood pressure? Normal: <139/89 mmHg
Mild HT: /90-99 mmHg
Moderate HT: / mmHg
Severe HT: >180/110 mmHg
British Hypertension Society

3. Blood pressure (BP) depends on:
- peripheral vascular resistance (PVR)
- blood volume
- cardiac output
Pressure = flow x resistance
BP = CO x PVR

4. In theory, drugs could act on:
heart - to alter CO
blood vessels - to alter PVR
kidney - to regulate blood volume
nerves - to affect blood vessels or heart
Blood vessels:
smooth muscle - controls PVR
endothelial cells - affect muscle tone - single layer

5. Aetiology Primary (Essential) hypertension Secondary causes:
Renal disease: chronic glomerulonephritis and pyelonephritis, polycystic disease, renal artery stenosis
Endocrine disease: Cushing’s syndrome, Conn’s syndrome, phaeochromocytoma, acromegaly
Drugs: NSAIDS, COCP, steroids
Coarctation of the aorta
Pre-eclampsia/hypertension in pregnancy

6. Antihypertensive Drug Classes
Diuretics, which lower blood pressure by depleting the body of Na+ and reducing blood volume and perhaps by other mechanisms.
2. Sympatholytic agents, which lower blood pressure by
reducing PVR, inhibiting cardiac function, and increasing venous pooling in capacitance vessels.
(The latter two effects reduce cardiac output.)
These agents are further subdivided according to their
putative sites of action in the sympathetic reflex arc.
3. Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well.
4. Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume.

7. Sites of action of the major classes of antihypertensive drugs

8. THIAZIDES
Mechanism – inhibits absorption of sodium in distal convoluted tubule and water lost with sodium
major effect is with vasodilatation not diuresis
ADME – well absorbed orally
causes diuresis in about 1-2 hours, lasts for 12
relatively flat dose-response curve
ADRs - hypokalaemia, hyponatraemia, hyperuricaemia, hypercalcaemia, impaired glucose tolerance, erectile dysfunction, rash

9. THIAZIDES Example - bendroflumethiazide
Other indications - cardiac failure
Contraindications - gout
- allergy
- renal disease

10. THIAZIDES Drug interactions – digoxin loop diuretics steroids NSAIDs
Disease interactions - renal failure

11. BETA-BLOCKERS
Examples – non-selective: propranolol vs selective atenolol or metoprolol
Other indications – angina, heart failure, thyrotoxicosis, anxiety, tremor
Contraindications - asthma, PVD, (heart failure)

12. BETA-BLOCKERS
Mechanism – competitively block β-adrenoceptors in the heart and reduce production of cyclic AMP generated by catecholamines, mostly β1
selective vs non-selective
exact mechanism of BP lowering unknown
ADME – propranolol: non-selective, lipid sol, extensive first pass metabolism
atenolol: selective β1, water sol, poor absorption, renal excretion
metoprolol: selective β1, lipid sol

13. BETA-BLOCKERS
ADRS – bradycardia (and heart block), bronchospasm, peripheral vasoconstriction: cold extremities, fatigue, vivid dreams, diabetes
Drug interactions – verapamil
salbutamol
NB: Upregulation of number and sensitivity of receptors with treatment. Sudden withdrawal can be dangerous, especially in setting of IHD

14. BETA - BLOCKERS Examples - propranolol (non selective, lipid sol)
atenolol (selective, water sol)
Other indications - angina
thyrotoxicosis
anxiety
tremor
heart failure

15. ALPHA-BLOCKERS Other indications – prostatic hypertrophy
Examples – Prazosin, terazosin, doxazosin, phenoxybenzamine and phentolamine
Other indications – prostatic hypertrophy
Contraindications - hypersensitivity

16. ALPHA-BLOCKERS Mechanism – vasodilation blockade of α1 receptors
peripheral blood vessels
ADME – slowly absorbed
extensively metabolised
long-half life

17. ALPHA-BLOCKERS ADRs – first dose hypotension
orthostatic/postural hypotension
dizziness
urinary incontinence in women
Drug interactions – beta-blockers and thiazides
NB. May not lower mortality despite lowering blood pressure.

18. ACE Inhibitors
Examples – captorpril, enalapril, lisinopril, ramipril, perindopril, trandalopril
Other indications – heart failure and diabetic nephropathy
Contraindications – hypersensitivity, pregnancy, bilateral renal artery stenosis

19. ACE Inhibitors Mechanism –
selective inhibitor of ACE which converts AI to AII
prevents vasoconstrictor effects
decreases aldosterone production
ACE also inactivates bradykinin
lowers BP by reducing peripheral resistance
more effective if salt-deplete

20. ACE Inhibitors
ADME –
some as inactive precursor: enalapril example of pro-drug converted to active enalaprilat, excreted by kidneys
captopril mainly metabolised
variable half-life/duration of effect

21. ACE Inhibitors ADRs – hypotension renal failure hyperkalaemia
dry cough (bradykinin)
angioneurotic oedema
rash

22. ACE Inhibitors
Drug interactions – diuretics, especially potassium-sparing diuretics, lithium (increased levels)
Disease interactions - RAS renal failure

23. Angiotensin Receptor Blockers
Mechanism – blockade of AII receptor itself (rather than AII production)
reserve drugs for patients with cough due to ACEI because do not affect bradykinin
ADME – losartan (short acting)
valsartan (longer acting)
ADRs – similar to ACEI

24. Angiotensin Receptor Blockers
Examples – losartan, valsartan, irbesartan, candesartan
Other indications – similar to ACEI
Contraindications - similar to ACEI

25. CALCIUM CHANNEL BLOCKERS
Two types:
Dihydropyridines (eg. nifedipine)
Phenylalkylamines (eg. verapamil)

26. DIHYDROPYRIDINE CCBs Examples – nifedipine, amlodipine, felodipine
Other indications – angina, Raynaud’s
Contraindications - hypersensitivity

27. DIHYDROPYRIDINE CCBs Mechanism
competitive blockade of voltage gated slow calcium channels
calcium essential for interaction between actin and myosin in muscle
reduce calcium entry
vasodilatation
negatively inotropic
no effect on skeletal muscle (less Ca dependent)

28. DIHYDROPYRIDINE CCBs Lower blood pressure and afterload
Short acting drugs such as nifedipine cause reflex tachycardia
Amlodipine is long acting
ADME – well absorbed orally
amlodpine no significant FPM
all extensively metabolised
FPM (first pass metabolism)

29. DIHYDROPYRIDINE CCBs ADRs – facial flushing (nif vs amlod)
ankle swelling, gum hypertrophy
headache
dizziness
Drug interactions – beta-blockers if heart failure

30. PHENYLALKYLAMINE CCBs
Mechanism – slows the heart, slowing conduction through av node (action potential very Ca dependent)
negatively inotropic
verapamil has less an effect on blood vessels than diltiazem
ADME – extensive FPM, given orally or iv

31. PHENYLALKYLAMINE CCBs
Examples – verapamil (cardiac)
diltiazem (peripheral)
Other indications - SVTs, angina
Contraindications - bradycardia
heart block
heart failure

32. PHENYLALKYLAMINE CCBs
ADRs - heartblock/bradycardia
constipation
less headache
flushing/oedema uncommon
Drug interactions – digoxin, beta- blockers, enzyme inducers

33. CENTRALLY ACTING DRUGS
Examples - methyldopa (rare now, only in pregnancy)
moxonidine
Guanabenz and guanfacine
Methyldopa - false neurotransmitter
- stimulation of central α adrenoceptors
- tiredness
- depression (dose)
- haemolytic anaemia

34. Moxonidine Mechanism of action - imidazoline I receptor antagonist
ADRs - dry mouth, headache, fatigue, nausea, sleep disturbance
Contraindications - angioedema, heart block, severe heart failure, pregnancy
The central control of sympathetically mediated vasoconstriction is believed to involve α2 adrenoceptors and also another class of receptor, termed the imidazoline I1 receptor, present in the brain stem in the rostral ventrolateral medulla.

35. OTHER DRUGS RESERPINE CLONIDINE GANGLION BLOCKERS
ADRENERGIC NEURONE BLOCKERS
MINOXIDIL (vasdodliator, causes fluid retention and tachycardia, male pattern hair growth)
SODIUM NITROPRUSSIDE

36. MANAGEMENT OF HYPERTENSIVE EMERGENCIES
Parenteral antihypertensive medications are used to lower BP rapidly (within a few hours).
As soon as reasonable blood pressure control is achieved, oral antihypertensive therapy should be substituted because this allows smoother long-term management of hypertension.
The goal of treatment in the first few hours or days is not complete normalization of blood pressure because chronic hypertension is associated with auto-regulatory changes in cerebral blood flow.
The parenteral drugs used to treat hypertensive emergencies include sodium nitroprusside, nitroglycerin, labetalol, calcium channel blockers, fenoldopam (selective dopamine D1 receptor agonist), and hydralazine.
Esmolol is often used to manage intraoperative and postoperative hypertension.
Diuretics such as furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators.

37. How to use them Use one drug if you can.
Start with a low dose and build up to maximum (BNF).
Monitor response, and look for ADRs.
Add a second drug if you need to.
Add a third drug if you need to.
Remember that failure to respond might equal non-compliance.

38. Endothelial Cells Release:
Vasodilators
- prostacyclin (PGI2)
- EDRF - endothelium-derived relaxing factor
= nitric oxide
- EDHF - endothelium-derived hyperpolarising factor
= ? K+, epoxyeicosatrienoic acid ? Vasoconstrictors
- EDCFs - endothelium-derived contracting factors, rapid onset, short duration (TxA2, PGH2, superoxide ?)
- Angiotensin ll
- Endothelin - slower onset, longer duration

39. Endothelins ET-1, ET-2, ET-3 - 21 amino acids
ET-1 most common in endothelial cells
Two subtypes of endothelin receptors
- ETA ETB
In hypertension:
- Reduced basal and stimulated NO production
- Increased endothelin??