Flashcards in L7.3 Drugs used to treat hypertension III Deck (18)
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1
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
- 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
2
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
- Less active than a1 adrenoceptors for vasoconstriction,
- More active at presynaptic a2 adrenoceptors → autoinhibitory feedback → decrease transmitters release
3
Mechanism of a2 agonist
- Stimulates central a2 → decrease SNS from CNS → Decrease CO/TPR/ANGII → Decrease BP
4
a2 SE
- Dreams/nightmares/depression…
- Marked bradycardia
- Postural hypotension
- Clonidine: If suddenly withdrawn → high rebound (related to catecholamine release)
5
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
- Esp in cardiomyocytes for Ca-induced-Ca release from SR
6
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
- Limited by high 1st pass metabolism in gut and liver
7
Mechanism of L-type Ca Channel antagonists
- Inhibit L-type Ca channels
- Decrease Ca entry into vascular SM
- Decrease vascular contractile tone
- Decrease TPR due to arteriolar dilation
- Decrease BP
8
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
- Verapamil > Diltiazem >> Nifedipine
- Nifedipine >> Verapamil > Diltiazem
- 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*
9
Nifedipine SE
- Potnetly drop BP → reflex tachycardia…
- Slow onset & long 1/2 life to avoid baroreflex mediated tachycardia
- Slow onset & long 1/2 life to avoid baroreflex mediated tachycardia
10
Diltiazem SE
- Bradycardia, AV block
11
Verapamil SE
- Bradycardia, AV block, and block P-glycoprotein drug transporter (reduced elimiation of other drugs/toxins)
12
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
- 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
- Selectively coronary, cerebral and renal beds
- Must be combined with b-antagonists & diuretic
13
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)
- Also have hypertrichosis (hair growth on face/arm/back/legs)
14
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
- Metabolised to release NO & CN
- NO causes vasodilatation (Arteries AND veins)
- 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
15
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
- Combination therapy used
- ACE inhibitors/AT1 antagonists → better patients compliance
- Used drugs from different groups with complemntary additive actions
16
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
- Compromise cardiac function
- Hyperkalaemia
- Strong bradycardia & heart block
- Withdrawal → strong hypertensive crisis
17
Overview of contraindications
18
Overview of drugs and their sites of action
