PBL 1 - Hypertension and anti-hypertensives

• What anti-hypertensives are indicated in pregnancy associated hypertension?

  Mixed alpha and beta blcokerssuch asLabetalol

  This is due to its dual action of reducing CO and reducing TPR

  Its vasodilatory effects also preserve blood flow to the uterus and placenta reducing the risk of foetal growth isufficiency

  AVOID: ACEI/ARB, renin inhibitors, aldosterone antagonists

  Why?RAAS system plays a crucial role in regulating blood pressure and fluid balance

  Use of ACE inhibitors can contribute to reduced blood flow to the uterus --> inadequate fetal oxygen and nutrient supply -->foetal growth retriction

  They are also associated with the inc risk ofcongenital malformationsetc
• What is verapamil (Diphenylalkylamine Ca2+ channel blocker) contraindicated with in combination therapy?

  Beta blockersas both reduce activity of the heart

  
• What are ACE inhibitors contraindicated with in combination therapy?

  ARBs- similar mechanism of action

  
• What is the usual treatment pathway for hypertension in individuals of black or African Caribbean heritage?

  Same as >55 y/o- treat with CCB first line

  This is because individuals of black family origin have naturally low renin levels due to sodium retention --> ACE inhibitor resistance

  
• What is the usual treatment pathway for hypertension in type 2 diabetics of any age?

  Same as <55 y/o- treat with ACE inhibitor or ARB first line

  
• What is the usual treatment pathway for hypertension <55y/o?

  1st line:ACE inhibitor or ARB

  2nd line (if not controlled):+ CCB or thiazide-like diuretic

  3rd line:+ CCBandthiazide-like diuretic

  4th line:= resistant hypertension

  Seek expert advice

  + Low-dose spirolactulone (if normal blood K+) or alpha blocker or beta blocker if high

  
• What is the usual treatment pathway for hypertension >55y/o?

  1st line:CCB

  2nd line (if not controlled):+ ACE inhibitor or ARB or thiazide-like diuretic

  3rd line:+ ACE inhibitorandthiazide-like diuretic

  4th line:= resistant hypertension

  Seek expert advice

  + Low-dose spirolactulone (if normal blood K+) or alpha blocker or beta blocker if high

  
• Which anti-hypertensives have a risk of rebound hypertension if stopped abruptly?

  Beta blockers and alpha 2 agonists due to inc baseline sympathtic activity
• What are some adverse effects of alpha 2 agonists?

  - Sedation and drowsiness (as depress CNS)

  - Rebound hypertension if stopped abruptly

  Use of alpha 2 agonists --> inc baseline sympathetic actvity

  - Headache - As less vasoconstriction of bvs

  - Nasal congestion

  
• When are alpha 2 agonists indicated

  In pregnancy induced hypertension due to reduced vasoconstriction meaning blood supply to the foetus isn't compromised

  
• Describe the MOA of alpha 2 agonists for reducing hypertension

  Alpha 2 agonists such as methyldopa act on alpha 2 receptors (predominantly found on pre-synaptic nerves) --> reduced NA release --> reduced CO

  Methyldopa --> a-methyldopa by MAO in the body
• What are some adverse effects of alpha blockers?

  - PalpitationsSignificant drop in bp due to vasodilation --> stimulation of baroreceptor reflex --> reflex tachycardia

  Worse in non-selective alpha blockers due to inhibition of presynaptic alpha 2 receptors --> inc NA release

  - First-dose faintingDue to significant drop in bp

  - HeadacheDue to vasodilation

  - Nasal congestionVasodilation in nose --> inc hydrostatic pressure --> mucosal oedema

  
• What types of alpha blockers are there?

  Non-selective

  
  

  Selective alpha 1
• Describe the MOA of alpha blockers. How can they reduce bp?

  Block alpha 1 ARs --> vasodilation --> dec TPR and dec venous return --> dec CO
• What are some adverse effects of beta blockers?

  - Bronchoconstriction (in asthmatics)

  - Cold extremities - Due to reduced vasodilatory effects NA --> unopposed alpha-adrenergic activity --> vasoconstriction

  - Sexual dysfunction - Hypoglycaemia - Due to less glucagon release (beta 2 receptors found on alpha cells)

  - Insomnia - Can interfere with the sleep-wake cycle

  
• When are mixed alpha and beta blockers used? Why?

  Mixed alpha and beta blockers, such as labetalol, are sometimes used in the management of pregnancy - induced hypertension (PIH) or preeclampsia

  This is due to its dual action of reducing CO and reducing TPR

  Its vasodilatory effects also preserve blood flow to the uterus and placenta reducing the risk of foetal growth isufficiency

  
• What types of beta blockers are there?

  Non-selective beta(P-->Z)

  Selective B1(A-->P)

  Mixed alphas and beta
• When are selective B1 blockers used over non-selective?

  In patients with COPD and asthmatics due to the bronchial smooth muscle being rich in beta 2 receptors
• Describe the MOA of beta blockers. How can they reduce bp?

  Inhibit Na/adrenaline from binding to the beta-ARs by competing for the same binding site of the GPCR --> reduced HR and SV --> reduced CO

  
  

  They also reduce renin release from the granular cells of the kidney --> reduced angiotensin 2

  
  

  Finally they dec sympathetic outflow by blocking the presynaptic beta 2 receptor --> dec NA release
• Which drugs have the suffix "-olol"

  Beta blockers
• What are some adverse effects of potassium-sparing diuretics?

  - Hyperkalaemia Due to dec K+ secretion

  - Gynecomastia Due to its anti-androgenic effects - dependent on dose

  - Gastric upset Due to imbalance of Na+ and K+ --> dysfunction of GI

  - Lethargy

  
• Describe the MOA of aldosterone antagonists (potassium-sparing diuretics)

  Competes with aldosterone for binding to mineralocorticoid receptors (MR) in the ASDN and block it --> reduced Na+ reabsorption and K+ secretion

  
• What are some adverse effects of loop diuretics?

  - Hypokalaemia : Block NKCC2 channel --> inc K+ excretion along with Na+ and Cl-

  - Hyperuricemia --> goutThe increased sodium delivery to the distal tubules enhances the exchange of sodium for uric acid --> inc reabsorption of uric acid

  - Hypomagnesemia

  - Ototoxicity(toxic effects to the ear)
• Describe the MOA of loop diuretics

  InhibittheNKCC2 transporterin the ascending loop of Henle --> dec reabsorption of Na+ and Cl- --> dec water reabsorption

  Also

  Inc prod of prostaglandins --> vasodilation --> inc GFR --> inc Na and water excretion

  THIS MEANS THEY CAN'T BE USED WITH NSAIDS!

  
• What are some adverse effects of thiazide diuretics?

  - Hyperurecemia--> gout (elevated level of uric acid in the blood)

  Primarily work by inhibiting the reabsorption of sodium and chloride in the DCT --> increased sodium and water excretion

  The increased sodium delivery to the distal tubules enhances the exchange of sodium for uric acid --> inc reabsorption of uric acid

  Simultaneously, they competitvely inhibit the urate transporters in the renal tubules --> dec uric acid clearance

  - Hypokalaemia

  Inc loss of water --> inc loss of K+ due to solvent drag

  Also

  The inc delivery of Na+ to the collecting ducts --> inc action of ENaC channels --> inc secretion of K+

  Worsened by it causing a direct inc in aldosterone...

  - Hypomagnesemia

  - Hypercalcemia

  - Hyperglycemia
• Describe the MOA of thiazide diuretics

  Inhibit apical Na+Cl- transporters in the DCT--> dec reabsorption of Na+ and Cl- --> dec water reabsorption --> dec blood volume

  Also have an additional vasodilatory mechanism

  
• How do thiazide type and thiazide-like thiazide diuretics differ?

  Chemical structure and potency- thiazide type are more potent and have a longer duration of action BUT have a more significant effect on electrolyte balance
• What other types of diuretic are there?

  Thiazide-like thiazide diuretics

  Loop diuretics

  Aldosterone antagonists(potassium-sparing diuretics)
• Which drugs have the suffix "-thiazide"?

  Thiazide type thiazide diureticse.g. bendroflumethiazide
• What are some adverse effects of Ca2+ channel blockers?

  - Constipation : Block Ca2+ channels in all smoth muscle, not just VSMCs --> reduced peristalsis

  - Headaches (due to vasodilation)

  - Ankle oedema : CCBs --> dec venous tone --> inc venous capacitance --> inc pressure in veins --> inc filtration

  Vasodilation --> reflex sympathetic activation --> inc sodium and water retention --> inc blood volume --> inc hydrostatic pressure

  - Fatigue

  - Gingival enlargement (abnormal increase in the size of the gums) due to associated inc in fibroblast activity

  
• What other types of Ca2+ chennel blockers are there? What are they used for?

  -Diphenylalkylaminesi.e verapamil

  This affects both the calcium channels in the heart (cardiac calcium channels) and those in the smooth muscle cells of blood vessels compared to dihydropyridines which primarily target vascular calcium channels

  By acting of cardiac calcium channels too, they are able to dec HR and conduction velocity --> reduction in workload of the heart and a dec in oxygen demand as well as dec in CO, reducing bp

  This makes it a good medication for conditions such asangina(able to dilate the coronary arteries too), atrial fibrillation etc

  - Benzothiazepinese.g. diltiazem

  Has immediate action meaning they are used for SVT (able to slow down AV nodal conduction), acute management of angina, atrial fibrillation and hypertensive emergencies
• Describe the MOA of dihydropyridine Ca2+ channel blockers

  Cause vasodilation by inhibiting calcium channels primarily inVSMCs--> reduced TPR --> reduced bp

  Vasodilation --> inc Na+ excretion (means additional diuretic isn't required)

  Have limited effect on cardiac Ca2+ channels
• Which drugs have the suffix "-pine"?

  Dihydropyridine Ca2+ channel blockers- most commonly used Ca2+ channel blockers for hypertension

  1st gen and 2nd gen

  2nd gens such as amlodipine are often preferred due to their longer duration of action and reduced likelihood of reflex tachycardia compared to some first-generation dihydropyridines like short-acting nifedipine
• When are ARBs contraindicated?

  Bilateral renal artery stenosis, pregnancy and hyperkalaemia(same reasons as ACE inhibitors)
• What are some adverse effects of ARBs?

  Taste disturbance

  Headache

  NO COUGH(removal of bradykinins by ACE undisturbed)

  
• Describe the MOA of angiotensin receptor blockers (ARBs)

  Specifically block the angiotensin 2 type 1 (AT1) receptor --> dec aldosterone production and inc AT2 receptor action --> vasodilation, inc Na+ excretion etc

  
• Which drugs have the suffix "-sartan"?

  Angiotensin receptor blockers (ARBs)
• Why are ACE inhibitors contraindicated during pregnancy?

  RAAS system plays a crucial role in regulating blood pressure and fluid balance

  Use of ACE inhibitors can contribute to reduced blood flow to the uterus --> inadequate fetal oxygen and nutrient supply -->foetal growth retriction

  They are also associated with the inc risk ofcongenital malformationsetc

  
• Why are ACE inhibitors contraindicated in patients with severe bilateral renal artery stenosis?

  Due to the potential risk of renal failure

  Renal artery stenosis --> reduced perfusion of the kidneys --> reduced GFR and potential ischaemic damage

  In individuals with bilateral renal artery stenosis, the kidneys may be particularly dependent on the effects of angiotensin 2 to maintain their blood flow - constricts efferent more so GFR is maintained

  Reduced angiotensin 2 --> vasodilation of the efferent arterioles in the kidneys --> reduced pressure and filtration -->AKI

  
• When are ACE inhibitors contraindicated?

  In patients withsevere bilateral renal artery stenosisand inpregnancyor in patients with hyperkalaemia (due to reduction in aldosterone production)