L7.3 Drugs used to treat hypertension III Flashcards Preview

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Flashcards in L7.3 Drugs used to treat hypertension III Deck (18)
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a2 agonists

  • 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


Effects of a2 agonist in the periphery and CNS

  • 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


Mechanism of a2 agonist

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


a2 SE 

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  • Clonidine: If suddenly withdrawn → high rebound (related to catecholamine release)


Importance of Ca in cardiac function 

  • 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


L-type Ca channel antagonists

  • 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


Mechanism of L-type Ca Channel antagonists

  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


Site specificity of L-type Ca antagonists

  • 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*


Nifedipine SE

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


Diltiazem SE

  • Bradycardia, AV block


Verapamil SE

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


Vasodilator agonists - Hydralazine

  • 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


Vasodilator agonists - Minoxidil

  • 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)


Vasodilator - sodium nitroprusside

  • 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


Effectiveness of combination therapy

  • 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


Combinations to avoid

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


Overview of contraindications


Overview of drugs and their sites of action