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Flashcards in Drugs affecting ion channels and transporters Deck (17):

Characteristics of ion channels and transporters

Major cations: H, Na, K, Ca, Mg
Major anions: Cl, HCO3, PO4
Ion channels and transporters are selective for particular ions
Channels allow diffusion through membranes in direction of electrochemical gradient
Transporters allow movement against electrochemical gradient


Common ion channels

Voltage gated ion channels: Na channel e.g. neuronal, L-type Ca channel e.g. heart and vessels, N-type Ca channel e.g. presynaptic nerve terminal, K channels e.g. delayed rectifier K channels
Other K channels: inward rectifying K channels, Ca activated K channels
Ligand gated ion channels: (ionotrpic receptors) nicotinc ACh receptor/Na channel e.g. skeletal muscle, GABA receptors e.g. CNS, Cl channels, cyclic nucleotide gated channels


Common ion transporters

Na-K-ATPase (sodium pump)
H-K-ATPase (proton pump)
Co-transporters (symport pumps):
Na-HCO3 co-transporter
Na-glucose co-transporter
Na-K-Cl co-transporter
Exchangers (antiport pumps)
Na-Ca exchanger (NCX)
Na-H exchanger (NHE)
Cl-HCO3 exchanger


Na-K-ATPase (sodium pump)

Primary determinant of resting membrane potential by maintaining EC gradients for Na and K (low intracellular Na, high intracellular K)
An ATPase has alternate phosphorylation and dephosphorylation of binding sites
Primary active transport
EC gradient provides potential energy for many non ATP-consuming transporters (secondary active transport)


Actions of cardiac glycosides

Major actions are slowing and strengthening
Positive inotropy, negative chronotropy
Positive inotropic action via inhibition of sodium pump, which increase the concentration of intracellular sodium, decreasing calcium extrusion by NCX
Negative chronotropic action via increased parasympathetic outflow (central action)


Uses of cardiac glycosides in heart failure

Positive inotropic action leads to better systolic function
Negative chronotropic action leads to better diastolic filling
Especially beneficial in patients with atrial fibrillation
Benefit to patients with sinus rhythm uncertain
Reduces frequency of acute decompensation (less hospitalisation ) but no beneficial effect on mortality


Uses of cardiac glycosides in supraventricular tachycardias

Especially to control ventricular rate in AF
Side effects and cautions: narrow therapeutic index- GI disturbances, CNS effects, palpitations may indicate toxicity
Potential for toxicity increased if hypokolaemia, hypomagnesia, renal impairment, elderly


L-type calcium channels

Voltage operated calcium channels allowing inward flux of Ca
Expressed in may cell types including cardiac myocytes and vascular smooth muscle cells
Long lasting, large capacitance current
Share general structure of other voltage operated calcium channels (N-type, T-type)
Topology of alpha1 subunit confers specific properties
Alpha2, beta, sigma and gamma are accessory subunits


L-type calcium channel blockers

Sometimes (inaccurately) called calcium antagonists
Inorganic channel blockers include Cd, Co, Ni, La
Organic channel blockers interact with different sites on alpha1 subunit
Phenylalkylamines e.g. verapimil and benzothiazepines e.g. diltiazem are non-dihydropyridines
Also used are 1,4-dihydropyridines


General cardiovascular actions of calcium channel blockers

Verapamil causes lots of negative inotropy in the mycoardium, lots of negative chronotropy in the SA/AV nodes and some peripheral and coronary vasodilatation
Nifedipine causes +/- negative inotropy in the myocardium, positive chronotropy in the SA/AV nodes and lots of peripheral and coronary vasodilatation
Diltiazem causes some negative inotropy in the myocardium, some negative chronotropy in the SA/AV nodes and some peripheral and coronary vasodilatation


Actions of verapamil

Relatively cardioselective properties but some effects on vascular smooth muscle tone
Slows SA and AV node conduction leading to slowing of HR
Reduces Ca entry during muscle depolarisation leading to reduced force of contraction


Actions of diltiazem

Dual action on heart and vessels
Slows heart rate
Negative inotropy
Peripheral and coronary vasodilatation


Actions of 1,4-dihydropyridines

Predominant effect on vascular smooth muscle tone leading to peripheral vasodilatation leading to reduced TPR
Coronary and cerebral vasodilatation
Less negative inotropy and negative chronotropy than with verapamil or diltiazem
Reduced TPR leads to reflex tachycardia
A large class of agents with some differences in vascular bed selectivity


Uses of calcium channel blockers in hypertension

All classes of CCBs are useful for hypertension
Diltiazem and verapamil especially if angina
First line in Afro-Caribbean and patients > 55 years (ACD rule)
1,4-DHPs especially for isolated systolic hypertension
1,4-DHPs sometimes combined with beta blockers to counteract reflex tachycardia


Uses of calcium channel blockers in angina

All classes of CCb are useful for prophylaxis in mild/moderate stable angina without LV contractile dysfunction
Reduce cardiac afterload, leading to reduced oxygen consumption
Coronary vasodilator leads to increased oxygen supply
Also useful in coronary artery spasm (variant angina)


Other uses of calcium channel blockers

Supraventricular tachycardias- verapamil
Raynaud's phenomenon (vasospasm of peripheral arteries)- nifedipine
Nimodipine as cerebral vasodilator to preventischaemic injury after sub-arachnoid haemorrhage


Funny current

A mixed Na-K inward current activated by hyperpolarization
Modulated by the autonomic nervous system
Important regulator of pacemaker activity in SAN
Ivabradine is a specific blocker of funny current
Used for treatment of angina with normal sinus rhythm or stable heart failure with normal rhythm