Calcium channel blockers and nitrates Flashcards
Learning outcomes
- Describe the proposed mechanism of action of calcium channel modulators and their effects on cardiac and smooth muscle cells
- Distinguish between the different pharmacodynamic effects of dihydropyridine and non-dihydropyridine calcium channel modulators and their clinical indications, with particular reference to angina pectoris and systemic hypertension
- Identify the known contraindications and drug interactions that must be considered when prescribing calcium channel modulators
- Describe the clinical pharmacology of organic nitrates and their use in prophylaxis and relief of stable angina pectoris
- Explain how the properties of organic nitrates benefit the treatment of heart failure
- Briefly discuss the clinical pharmacology of other anti-angina drugs, namely nicorandil and ivabradine
Smooth muscle- excitation/contraction coupling
- Has spontaneous electrical and mechanical activity
- Activity can be phasic or tonic (Tonic firing refers to a sustained response, which activates during the course of the stimulus; while phasic firing refers to a transient response with one or few action potentials at the onset of stimulus followed by accommodation)
- Activity is modified by circulating hormones and neurotransmitters
- Contraction velocity is less than skeletal muscle
- Smooth muscle can maintain prolonged contractions at less energy cost of other muscle types
- Smooth muscle -no troponin
- Calmodulin important
- Cellular junctions transmit force and electrical activity
- Syncitium (like heart)
Calcium channel antagonists
Calcium channel antagonists Examples 1.Dihydropyridines •Nifedipine •Amlodipine •Lercanidipine
- Diltiazem (benzothiazepines)
- Verapamil (phenylalkylamines) (2 and 3 rate limiting)
New dihydropyridine calcium antagonists are similar to nifedipine but may:
- Be longer acting
- Have fewer adverse effects?
(a) Cardiac depression
(b) Vasodilator effects (ankle oedema)
•Calcium antagonists block the entry of calcium through the calcium channel in vascular smooth muscle and myocardium•Less calcium is available for the contractile apparatus causing:–Vasodilatation–Negative inotropic effect
New dihydropyridine calcium antagonists
New dihydropyridine calcium antagonists are similar to nifedipine but may: 1.Be longer acting 2.Have fewer adverse effects? (a)Cardiac depression (b)Vasodilator effects (ankle oedema) NIFED AMLOD LACID LERCANID\_\_\_\_\_\_\_\_\_\_\_\_IPINE –dihydropyridine, calcium antagonists
•Calcium antagonists block the entry of calcium through the calcium channel in vascular smooth muscle and myocardium•Less calcium is available for the contractile apparatus causing:
–Vasodilatation
–Negative inotropic effect
Differences in effect by amlodipine vs verapamil/ dilitazem
Amlodipine/dihydropyridines (Depolarised L-type Ca Channels)
Decreased intracellular Ca2+ > smooth muscle cell relaxes (vasodilation)
Verapamil / Diltiazem (Hyperpolarised L-type Ca Channels)
Decrease intracellular Ca2+ > cardiac muscle cell relaxes
Selectivity and clinical indications of dihydropyridines/ dilitiazem and verapamil
- Dihydropyridines favour depolarised closed Ca++channels most commonly found in the vascular smooth muscle cells
- Diltiazem and Verapamil favour the hyperpolarised Ca++channels more commonly found in cardiac muscle cells
Contraindications
Contraindications
Amlodipine-Aortic stenosis
-Severe myocardial depression
Diltiazem-Myocardial depression
-Impaired cardiac conduction
Verapamil-Sick sinus syndrome
- Impaired cardiac conduction
- Combinations with large doses of beta blockers or digoxin
Minor and major adverse effects/ interactions
Amlodipine
- Headache
- Flushing
- Tachycardia
- Peripheral oedema
Verapamil-As Above, but less marked oedema
Diltiazem -tend to cause bradycardia
-Constipation especially in the elderly
Major adverse effects
Amlodipine-Rare but can cause heart failure in patients with poor left ventricular function
Diltiazem-May cause heart block in ‘at risk’ patients and those on digoxin and beta blockers
Verapamil- As above, especially if given intravenously
Chest pain in angina may increase –Steal effect
Interactions: Verapamil and diltiazem can cause an increase in digoxin levels
Enhance effects of verapamil by (a)Digoxin
(a)Beta blockers
Calcium channel antagonist- summary
- 3 main groups
- Block L-type Ca++channels
- Dihydropyridines mainly vasodilator effects so main use is hypertension
- Diltiazem and verapamil have rate-limiting activity so may be used more for anti-anginal or anti-arrhythmic
- Potential for negative inotrope effect so avoid in heart failure
History of nitrates
History of Organic Nitrates
•Lauder Brunton –Scottish Physician 1867
•Angina reduced by bleeding ?due to lowering blood pressure
•Amyl nitrate –decreased blood pressure
•Amyl nitrate inhalation –improved angina
•More stable -Glyceryl trinitrate (GTN) developed
•Longer duration organic nitrates developed
Nitrates
Nitrates
•Glyceryl Trinitrate(GTN)
•Isosorbide mononitrate(ISMN)
•Isosorbide dinitrate(ISDN)
- Nitrates bind to receptor in vascular smooth muscle
- A NO group is formed which stimulates guanylate cyclase to produce cyclic GMP
- Calcium entry is inhibited or calcium exit enhanced and vasodilatation occurs
- Process requires SH groups. Tolerance is thought to be due to depletion of SH group
Tissue Characteristics: Receptor –response coupling
there are different types of coupling
this can affect the extent of amplification of the initial signal and size of response
agonist > agonist-receptor complex
signal transduction mechanism (amplification:
-chemical gating of ion channels
-activation of G-proteins linked to ion channels or enzymes
-direct activation of enzymes
-regulation of gene transcription)> size of cell or tissue response
Pharmacodynamics (what drug does to body)
•Dilate arteries and veins. Veins»_space; arteries
•Venous dilatation results in reduction of preload which can reduce cardiac work in angina and relieve symptoms in heart failure
Oxygen demand is thus reduced
•Dilate normal coronary arteries and reduce coronary artery spasm
•Redistribute blood from epicardial to endocardial regions
Preparations of nitrates and pharmacokinetics of Sublingual GTN
Preparations •Sublingual / buccal -glyceryl trinitrate (GTN) •Glyceryl trinitrate (GTN) patches •GTN intravenous infusion •Isosorbide dinitrate •Isosorbide mononitrate
Sublingual GTN •Poor oral bioavailability* •Good buccalabsorption •Rapid effect (< 2 mins) •Ideal for acute prophylaxis and diagnosis of angina •Short acting (T½= 7 mins
Pharmacokinetics(what body does to drug) of isosorbine mono/dinitrate and nitrate patches
Nitrate patches
•Absorption variable and is dependent on skin area in contact
•Sustained effect or no effect
•Tolerance is a major problem for preparations which have 24 hr duration of effect
•Care when defibrillating
Isosorbide dinitrate •Satisfactory gut absorption •Relatively large first pass effect •T½= 2-4 hr. Duration of effect 4-6 hr Isosorbide mononitrate –same as dinitrate but oral bioavailability is better due to reduced liver metabolism during first pass
