CPTP 2.12 BP lowering drugs

Question 1

Main factors that regulate BP

Answer 1

Blood volume; sodium intake and renal excretion

Cardiac output; heart rate and stroke volume

Peripheral resistance

Question 2

Tissue targets for BP lowering

Answer 2

Kidney; regulate blood volume

Heart; alter cardiac output

Arterioles; peripheral resistance

CNS control; centres regulating BP

Sympathetic nerves; release NE

Question 3

Drug therapies for hypertension

Answer 3

ACE inhibitors & Angiotensin II receptor antagonists/ blockers (ARBs); Captopril, Enalapril, Lisinopril
Beta-blockers; Atenolol
CCBs; Nifedipine, Amlodipine
Thiazide diuretics; Bendroflumethiazide
Alpha-blockers; Prazosin, Doxazosin
Centrally acting drugs; Methyldopa

Question 4

ACE inhibitor site of action

Answer 4

• Inhibit conversion of Angiotensin I to Angiotensin II
• Inhibits degradation of bradykinin (which produces vasodilation by release of NO and prostaglandins)
• Reduces aldosterone secretion
• Renal vasodilation

Question 5

Captopril pharmacokinetics

Answer 5

Captopril; well absorbed orally, short-acting, partly metabolised and partly excreted unchaged

Question 6

Enalapril pharmacokinetics

Answer 6

Well absorbed orally

Pro-drug. metabolised to enalaprilat

Question 7

Lisinopril pharmacokinetics

Answer 7

Lysine analogue of enalaprilat

Less well absorbed (30%)

Question 8

ACE inhibitors side effects

Answer 8

Hyperkalaemia
Hypotension
dry cough
renal impairment

Question 9

ARBs mechanism of action

Answer 9

• Inhibit action of endogenous AngII at its receptor
• Vasodilation, decreased SNS activity
• Do not produce cough unlike ACE inhibitors
• AT1 blockers do not block AT2 receptor, which is exposed to high conc Ag - may have beneficial effects
• Used in combination with ACEIs, mostly in heart failure

Question 10

Losartan (ARBs) pharmacokinetics

Answer 10

• 33% absorbed orally
• Short acting
• Competitive antagonist
• Metabolised to an active metabolite which is >10 times more potent than losartan and has a longer half-life
• Once daily dosing adequate

Question 11

Alpha 1 blocker mechanism of action

Answer 11

e. g. Prozosin, doxazosin
- Act on vascular SM
- Vasodilation which leads to fall in BP
- Baroreceptor mediated increased HR occurs
- ‘First dose’ phenomenon - large drop in BP at first but not subsequent doses

Question 12

Beta blockers

mechanism of action?

Answer 12

• decreased HR and decreased rate of spontaneous depolarisation, slow conduction in atria and AVN
• decreased myocardial contractility
• inhibition renin-angiotensin system
• decreased peripheral resistance

Question 13

Beta blocker - propranolol

pharmacokinetics?

Answer 13

• non-selective (act on both B1 and B2)
• Undergoes first-pass hepatic metabolism hence poor oral bioavailability
• Lipid soluble so crosses blood-brain barrier
• Short half life
• not used for management of hypertension or heart failure

Question 14

Beta blocker - atenolol

pharmacokinetics

Answer 14

• cardioselective (B1)
• water soluble. does not cross blood-brain barrier
• 50% absorbed orally
• half-life around 5-8 hours
• eliminated unchanged in urine
• accumulates in renal failure
• used for hypertension and in heart failure with ACEIs

Question 15

Beta blockers

side effects?

Answer 15

• Bronchospasm (action on B2 receptor)
• Heart failure
• Bradyarrhythmias
• Cold extremeties, fatigue
• Sleepiness, vivid dreams

Question 16

CCB mechanism of action

Answer 16

• Block Ca entry into SM and cause vasodilation

- inhibit the slow calcium current in sinus and AVN where there is a Ca dependent upstroke

Question 17

Pharmacokinetics of Nifedipine

Answer 17

• short half-life

Question 18

Pharmacokinetics of Amlodipine

Answer 18

• long half-life allowing once daily dosing
• metabolised in the liver by CYP3A4
• interacts with other drugs which inhibit CYP3A4

Question 19

Side effects of CCBs

Answer 19

Flusing, headach
Oedema - due to increased capillary permeability
Bardycardia and heart block (particularly in combination with beta blocker)
Heart failure (verapamil)
Gingival hyperplasia (dihydropyridines)

Question 20

Thiazide diuretics

mechanisms of action?

Answer 20

e.g. Bendroflumethiazide, Chlortalidone

• Increase excretion of Na, Cl, K and water
• Blocks Na-Cl cotransport mechanism in the distal nephron
• More Na then reaches the distal tubule where some is exchanged by Na-K transport to increase K loss
• BP lowering related to decrease peripheral resistance - unrelated to Na loss

Question 21

Side effects of thiazide diuretics?

Answer 21

Orthostatic hypotension
Gout
Impotence
Diabetes
Hypokalaemia

Question 22

Drug therapies for angina?

Answer 22

Nitrates; GTN
Beta blockers; atenolol
CCBs; Diltiazen, verapamil, nifedipine
Potassium channel activators; Nicorandil

Question 23

Nitrates

mechanisms of action?

Answer 23

• NO donor, releasing NO by reaction of nitrates. Increased cGMP leading to SM relaxation
• Nitrates relax arterial and venous SM
• Venodilation results in decreased ventricular and diastolic pressures with a fall in CO and BP
• Dilation of coronary arteries increase blood supply to the heart
• Redistribution of coronary blood flow to ischaemic myocardium may also occur during nitrate therapy. This leads to increased cardiac oxygen demand

Question 24

Beta blockers

mechanism of action

Answer 24

• Beta blockers counteract effects of catecholamines
• Catecholamines increase myocardial O2 demand during exercise through effects on HR and contractility
• Beta blockers decrease myocardial oxygen demand by decreasing the effects of NE and circulating E
• Angina and exercise tolerance imporved

Question 25

Mechaanisms of action of potassium channel activators

Answer 25

- Potassium channel activator with nitrate component - vasodilation of arterioles and large coronary arteries - venous vasodilation through stimulation of guanylate cylcase

Question 26

side effects of potassium channel activators

Answer 26

headache, flusing myalgia (muscle pain) angioedema