L7.3 Drugs used to treat hypertension III

Question 1

a2 agonists

Answer 1

• Clonidine
• a-methyl dopa
  
  • ​Prodrug which is converted to a-methyl NA (the a2 agonist)
  • Stored in secretory vesicles of adrenergic neurons (substituting NA in vesicles)
  • When SNS stimulates, a-Me NA is released instead of NA

Question 2

Effects of a2 agonist in the periphery and CNS

Answer 2

• In the periphery:
  
  • Less active than a1 adrenoceptors for vasoconstriction,
• In CNS:
  
  • More active at presynaptic a2 adrenoceptors → autoinhibitory feedback → decrease transmitters release
• Actively transported into the brain - acts in medulla
• Mainly used for hypertension in pregnancy

Question 3

Mechanism of a2 agonist

Answer 3

• Stimulates central a2 → decrease SNS from CNS → Decrease CO/TPR/ANGII → Decrease BP

Question 4

a2 SE

Answer 4

• Dreams/nightmares/depression…
• Marked bradycardia
• Postural hypotension
• Clonidine: If suddenly withdrawn → high rebound (related to catecholamine release)

Question 5

Importance of Ca in cardiac function

Answer 5

• Ca influx via L-type channels important → for vasculcar tone and cardiac contractility
  
  • Esp in cardiomyocytes for Ca-induced-Ca release from SR
• Vascular smooth muscles cells dependent on intracellular Ca concentration
• BP is increased due to increase TPR (afterload) → antagonists act to decrease contractile tone

Question 6

L-type Ca channel antagonists

Answer 6

• Verapamil, diltiazem, nifedipine
• Relax arterial SM → decrease TPR
• Has minimal effect of Ca entry into veins → NO effect on PRELOAD
• Little effect on skeletal muscle (Have SR Ca pools)
• Oral bioavailability
  
  • Limited by high 1st pass metabolism in gut and liver

Question 7

Mechanism of L-type Ca Channel antagonists

Answer 7

1. Inhibit L-type Ca channels
2. Decrease Ca entry into vascular SM
3. Decrease vascular contractile tone
4. Decrease TPR due to arteriolar dilation
5. Decrease BP

Question 8

Site specificity of L-type Ca antagonists

Answer 8

• Myocardium & nodal/conducting tissues:
  
  • Verapamil > Diltiazem >> Nifedipine
• Arterial SM:
  
  • Nifedipine >> Verapamil > Diltiazem
• Bind to distinct sites:
  
  • allosteric sites: no direct competition
  • A1 pore forming sites

*Nifedipine more potent in BV to decrease TPR; Diltiazem and verapamil more potent for other CV sites*

Question 9

Nifedipine SE

Answer 9

• Potnetly drop BP → reflex tachycardia…
  
  • Slow onset & long 1/2 life to avoid baroreflex mediated tachycardia

Question 10

Diltiazem SE

Answer 10

• Bradycardia, AV block

Question 11

Verapamil SE

Answer 11

• Bradycardia, AV block, and block P-glycoprotein drug transporter (reduced elimiation of other drugs/toxins)

Question 12

Vasodilator agonists - Hydralazine

Answer 12

• Used when there is very high BP, not 1st line antihypertensive drug
  
  • E.g. pregnant women with preeclampsia
  • Caution with elderly & patients with coronary artery disease
    
    • Reflex may exacerbate angina pectoris → causing MI due to reflex tachycardia
• Relaxation of arteriolar SM BUT NOT venous SM
  
  • Selectively coronary, cerebral and renal beds
• Molecular mech is unclear
• Causes powerful baroreflex
  
  • Must be combined with b-antagonists & diuretic

Question 13

Vasodilator agonists - Minoxidil

Answer 13

• Used in emergency hypertension as well
• Promotes K efflux in SM → hyperpolarise it, resistance to further depol
• Arteriolar vasodilation and little effect on veins
• Used with b antagonist & diuretic
• SE similar to hydralazine
  
  • Also have hypertrichosis (hair growth on face/arm/back/legs)

Question 14

Vasodilator - sodium nitroprusside

Answer 14

• Nitrate compound, Directly acting vasodilator
• Used iv in hyeprtensive emergencies
• Mech:
  
  • Metabolised to release NO & CN
  • NO causes vasodilatation (Arteries AND veins)
• SE:
  
  • Nausea/headache/tachycardia
  • Toxic effect of CN buildup (therefore not used as long-term therapy)
    
    • CN metabolised in liver → excreted by kidney → toxicity in prolonged admin

Question 15

Effectiveness of combination therapy

Answer 15

• 50% of patients will not respond to adequately to monotherapy
  
  • Combination therapy used
• Some drugs for monotherapy (montherapy is usually initial choice)
  
  • ACE inhibitors/AT1 antagonists → better patients compliance
• Usually treated with combination
  
  • Used drugs from different groups with complemntary additive actions

Question 16

Combinations to avoid

Answer 16

• Verapamil/diltiazem & b antagonists
  
  • Compromise cardiac function
• ACEi & K sparing diuretics
  
  • Hyperkalaemia
• B antagonists & clonidine/methyldopa
  
  • Strong bradycardia & heart block
  • Withdrawal → strong hypertensive crisis

Question 17

Overview of contraindications

Answer 17

Question 18

Overview of drugs and their sites of action

Answer 18