Download Calcium channel blockers/antagonists

CALCIUM CHANNEL
BLOCKERS/ANTAGONISTS
February 2017
History
• The term “calcium antagonists” was 1st
coined by Fleckenstein & colleagues in
1969.
• Investigating vasodilator effects of
prenylamine and verapamil
• Observed that they have a negative
inotropic effect on the heart
• Showed that the –ve inotropic effect can
be antagonized by calcium
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• The term ‘calcium antagonist’ is used for
drugs that block cellular entry of Ca+2
through calcium channels rather than its
intracellular actions.(refer to How drugs act: cellular
aspects-excitation, contraction and secretion)
• Some authors use the term ‘Ca+2 entry
blockers’ to make this distinction clearer.
• Therapeutically important calcium
antagonists act on L-type channels.
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Classification of Ca+2
antagonists
1) Phenylalkylamines:
• Verapamil, desmethoxyverapamil,
tiapamil, anipamil, gallopamil, ronipamil,
devapamil, terodilin
2) Benzothiazepines:
• Diltiazem, fostedil
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Classification of Ca+2
antagonists …
3) Dihydropiridines:
• Nifedipine, nitrendipine, nimodipine,
niludipine, niguldipine, nicardipine,
nisoldipine, amlodipine, felodipine,
isradipine, ryosidine, lacidipine
Piperazines:
• Cinnarizine, lidoflazine, flunarizine
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Membrane effects of
antagonists
+2
Ca
• Free Ca+2 in the cytosol regulates a
number of cellular functions
• The intracellular pools of Ca+2 are
replenished by Ca+2 from the ECF
• The transport of Ca+2 takes place via the
Ca+2 channels
• Interfere with Ca+2 transport over excitable
membranes in different tissues
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Membrane effects of Ca+2
antagonists…
•
•
•
The channels have to be open for
Ca+2 to enter the cells
opened by changes in membrane
potential (Voltage-operated Ca+2 –
channels)
AND
Through hormone/neurotransmitter
mediated changes (receptor-operated
channels)
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Membrane effects of Ca+2
antagonists…
Calcium antagonists act on voltage operated
channels which are differentiated into:
• T-channels (transient):
- have small conductance and transient opening
times
-activated by small depolarisations from very
negative potentials
• Involved in the initiation of action potentials
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Membrane effects of Ca+2
antagonists…
• Occur in neuronal, smooth muscle,
cardiac, skeletal muscle cells
• Do not take part in intracellular Ca+2
homeostasis
• Inhibited by neurotransmitters e.g. NA &
dopamine
• Not affected by calcium antagonists
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Membrane effects of Ca+2
antagonists…
• N-type: neuronal channels
• L-type: have a high conductance and a
prolonged opening time
• Play a central role in the regulation of
intracellular calcium concentration
• Activated by changes in membrane
potential
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Membrane effects of Ca+2
antagonists…
• Also modulated by hormones and
neurotransmitters
• Very sensitive to calcium antagonists
• Considered to be their primary receptor
• Have a wide distribution
• High concentrations in atria, blood vessels
& skeletal muscle T-tubules
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Vascular effects of Ca+2
antagonists
• All of them dilate blood vessels
• Vasodilator effect is most pronounced with
dihydropyridines
• Within the dihydropyridines there are
marked differences of the vasodilator
effect
• Vasodilator effect occurs on arteries and
resistance vessels
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Vascular effects of Ca+2
antagonists…
• Have negligible effect on veins
• Strongly reduce coronary and skeletal
vascular resistance
• Insignificant effect on skin
• Small effect on renal vascular resistance
• Vasodilator effect is maintained during
chronic therapy in hypertensive patients
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Other effects on blood vessels
• Inhibit arterial smooth muscle proliferation
due to a decrease in vascular DNA
synthesis
• Inhibit platelet activation (platelets are a
rich source of vascular growth factors)
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Effect on renal function
• Calcium antagonists are vasodilators
that reduce BP without triggering renal
compensatory mechanisms that lead to
fluid and electrolyte retention with
classical vasodilators
• Renal blood flow & GFR are maintained
during acute and long-term treatment
with Ca+2 antagonists
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Effect on renal function…
• Have a diuretic & natriuretic effect inspite
of their relative lack of effect on GFR or
RBF which may suggest a tubular site of
action
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Effects on the heart
• Block slow Ca+2 channels
• Block myocardial cellular Ca+2 uptake
• Reduce the amount of Ca+2 available for
interaction with troponin
• Negative inotropic effect
• Phenylalkyalamines & benzothiazepines >
dihydropyridines
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Effect on the heart…
• The relatively strong vasodilator effects of
dihydropyridines trigger a baroreflexmediated rise in sympathetic nerve activity
• Leads to a +ve rather than –ve inotropic
effect
• Verapamil & diltiazem: direct –ve and
indirect reflexogenic inotropic effects
usually cancel each other
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Effect on AV conduction
• Limited to phenylalkylamines &
benzothiazepines
• Slow AV node conduction & sinus
pacemaker activity
• Dihydropyridines & piperazines are less
effective and may increase the heart rate
due to baroreflex-mediated alteration of
sympathetic nerve activity
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• Verapamil & diltiazem: good for treatment of
supraventricular tachyarrhythmias
• The coronary vasodilator effect of
dihydropyridines is useful for preventing
coronary spasms that are responsible for
causing angina
• Whereas as nitroglycerine acts predominantly
on large coronary arteries calcium antagonists
dilate large and small coronary arteries
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Effects on cardiac metabolism
• Cardiac ischaemia is followed by:
- a decrease in tissue ATP levels
-increase in free-radical production via
xanthine oxidase pathway
-alteration in ionic homeostatis
Leading to cardiac arrhythmias and
structural disorganization of the heart
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• Upon reperfusion, cells injured by the
above mechanisms accumulate large
amounts of Ca+2 (Ca+2-overload)
• This leads to further damage of the heart
• Ca+2 enters the myocardial cells via routes
that can be blocked by calcium
antagonists
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They also protect the heart from post
ischaemic injury by:
• Coronary vasodilatation
• Cardiac unloading
• Effect on adenosine metabolism
• Reduce cardiac hypertrophy due to
chronic hypertension
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Hemodynamic effects
• Verapamil & diltiazem cause a modest
lowering of BP (Blood Pressure) and TPR
(Total Peripheral Resistance) with little or
no depressive effect on cardiac function
• Dihydropyridines (nifedipine) reduce BP
via a strong fall in TPR with an early rise in
CO and HR
• Piperazines have insignificant short-term
BP-lowering activity
• (NB: BP=CO X TPR)
• (CO=Stroke X volume X HR)
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Clinical uses
•
•
•
•
Angina pectoris
Supraventricular tachyarrhthmias
Hypertension
migraine
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Unwanted effects
• Most of the unwanted effects of calcium
antagonists are extensions of their main
pharmacological actions
• Short acting dihydropyridines cause flushing
and headache due to their vasodilator action
• Chronic use of dihydropyridines e.g. nifedipine
often cause ankle swelling, related to arteriolar
dilatation and increased permeability of
postcapillary venules.
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Unwanted effects…
• Verapamil can cause constipation,
probably because of effects on calcium
channels in gastrointestinal nerves or
smooth muscle.
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Summary-Unwanted effects
• Headache, constipation (verapamil),
ankle oedema (dihydropyridines)
• There is a risk of causing cardiac failure or
heart block, especially with verapamil and
diltiazem
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H/W
• Read on the following:
1. Mechanism of action of calcium
antagonists
2. Pharmacokinetics of calcium antagonists
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Revision-H/W
• Giving examples, classify the calcium
channel blockers, their clinical uses and
unwanted effects
• Write short notes on the following:Pharmacological effects of calcium
channel blockers
Pharmacokinetics of calcium channel
blockers
NB: Further reading
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