L7.3 Drugs used to treat hypertension III Flashcards Preview

• 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

• 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

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

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• Clonidine: If suddenly withdrawn → high rebound (related to catecholamine release)

• 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

• 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

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

• 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*

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

• Bradycardia, AV block

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

• 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

• 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)

• 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

• 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

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