Drugs acting on sodium channels
- Integral membrane proteins
- Responsible for generating and regulating the electrical signals through the tissues.
- Controlling the flow of ions across secretory and epithelial cells, and regulating cell volume
- Exist in three states closed, open and inactivated.
Phase 4: resting potential. During this time there is a slow k leak.
Phase 0: change in membrane potential (to threshold of -70) causes fast sodium channels to open briefly then close.
Phase 1: outward flow of K
Phase 2: Inward Ca current opposing K flow. Ca flow is a lot more gradual and actually began to take over from Na in phase 0
Phase 3: Ca channels gradually inactivate and the K efflux exceeds Ca influx.
Types of Na+ Channels
- Epithelial sodium channels(ENaCs)
- Voltage gated(Nav)
- Ligand gated
Distal kidney tubule, Alveolar epithelium, Distal colon, Peripheral nervous system, Brain, Heart, Endocrine cells, Smooth and skeletal muscles, NM junction
Structure of Na+ channel
- Consist of a large α-subunit associated with other proteins, such as β-subunits.
- An α-subunit forms the core of the channel and is functional on its own.
- ß-subunit displays altered voltage dependence and cellular localization.
- α-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6.
- The highly conserved S4 region acts as channel’s voltage sensor.
- The voltage sensitivity of this channel due to positive amino acids located at every fourth position.
- When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions.
- Resting: This is the closed state, which prevails at the normal resting potential. During this state, the activation gate is closed and the inactivation gate is open.
- Activated: This is the open state favored by brief depolarization. There is an abrupt flipping open of the activation gate and slow closure of inactivation gate.
- Inactivated: Blocked state resulting from a trap door-like occlusion of the channel by a floppy part of the intracellular region of the channel protein i.e. by the inactivation gate
Impermeability to other ions
- The pore of sodium channels contains a selectivity filter made of negatively charged amino acid residues, which attract the positive Na+ ion and keep out negatively charged ions such as chloride.
- The cations flow into a more constricted part of the pore that is 0.3 by 0.5 nm wide, which is just large enough to allow a single Na+ ion with a water molecule associated to pass through.
- The larger K+ ion cannot fit through this area. Differently sized ions also cannot interact as well with the negatively charged glutamic acid residues that line the pore.
Sodium Channels – Function
- Transmission of action potentials along a nerve thereby enabling co-ordination of higher processes ranging from locomotion to cognition.
- ENaCs are responsible for sodium reabsorption in the distal kidney tubule, and have similar functions in the alveoli and the colon
Conditions in which they are used
- Epilepsy or convulsions, Neuropathic pain, Stroke and ischemia, Local anesthesia, Cardiac arrhythmias
SODIUM CHANNEL BLOCKERS
- find application in a large spectrum of membrane hyper excitability disorders
- Cardiac arrhythmias, Epilepsies, Myotonias, Chronic pain
Phenytoin is a first line antiepileptic drug for-
1. GTCS, SPS, CPSs.
Dose: 100 mg BD, maximum 4OO mg/day; Children 5-8 mg/kg/day
2. Status epilepticus: occasionally used by slow i.v. injection (fosphenytoin has replaced it)
3. Trigeminal neuralgia: second choice drug to carbamazepine
- Trigeminal neuralgia: DOC
- CPS, GTCs, SPS.
- Manic depressive illness and acute mania: as an alternative to lithium
- Dose: 200-400 mg TDS; Children 15-30 mg/ kg/day
- ADE: Acute intoxication- coma, convulsions, Hypersensitivity
- DOC-absence seizures, Myoclonic and atonic seizures
- Alternative/adjuvant drug for GTCS, SPS and CPS.
- Mania and bipolar illness: As alternative to lithium.
- Valproate has some prophylatic efficacy in migraine.
- Also Preventing release of excitatory neurotransrnitters, mainly glutamate and aspartate
- Broad-spectrum. refractory cases of partial seizures and GTCS, it has now been shown effective as monotherapy as well.
- ADE: Sleepiness, dizziness, diplopia, ataxia and vomiting..
- Dose: 50 mg/day – 300 mg/day
- Not to be used in children.(Rash may be a severe reaction, particularly in children, requiring withdrawal)
- Weak CA inhibitor
- GABA potentiation by a postsynaptic effect and antagonism of certain glutamate receptors
- Dose: Initially 25 mg OD, increase weekly upto 100-200 mg BD as required
- Supplementing primary antiepileptic drug in refractory SPS, CPS and CTCS.
- Recently approved for prophylaxis of migraine.
- Class I – blocker’s of fast Na+ channels
- Subclass IA
- Cause moderate Phase 0 depression
- Prolong repolarization
- Increased duration of action potential
- Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period
- Procainamide – increases refractory period but side effects
- Disopyramide – extended duration of action, used only for treating ventricular arrthymias
- Subclass IB
- Weak Phase 0 depression
- Shortened depolarization
- Decreased action potential duration
- Lidocane (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias
- Mexiletine – oral lidocaine derivative, similar activity
- Phenytoin – anticonvulsant that also works as antiarrhythmic similar to lidocane
- Subclass IA
- Subclass IC
- Strong Phase 0 depression
- No effect of depolarization
- No effect on action potential duration
- Flecainide (initially developed as a local anesthetic)
- Slows conduction in all parts of heart,
- Also inhibits abnormal automaticity
- Also slows conduction
- Weak β – blocker
- Also some Ca2+ channel blockade
- Flecainide (initially developed as a local anesthetic)
- Indirectly fascilates Ca++ entry through Na++/ Ca++ exchanger
- ADE: Constipation, postural hypotension, Headache
- Dose: 0.5-1gm BD as SR tab
ALS à Riluzole
Inactivation of voltage-dependent sodium channels on glutaminergic nerve terminals, blocks some of the postsynaptic effects of glutamic acid by non-competitive blockade of N-methyl-D-aspartate (NMDA) receptors.
Ambroxol – neuronal Na+ channel blocker
- Mucolytic agent with antioxidant, anti-viral and anti-inflammatory properties.
- Dose: 15-30 mg TDS
- ADE: Rhinorrhoea, lacrimation, gastric irritation
At higher doses it also inhibits Na+ reabsorption in PT, but this is clinically insignificant. It decreases Ca2+ excretion and increases urate excretion.
- It selectively binds to extracellular face of the membrane associated Na+K+ ATPase of myocardial fibres and inhibits this enzyme.
- Inhibition of this cation pump results in progressive accumulation of Na+ intracellularly. This indirectly results in intracellular Ca2+ accumulation.
Furosemide – Na+K+ 2 Cl- cotransporter inhibitor
- Uses – Edema, Acute pulmonary edema, Cerebral edema, Hypertension, Hypercalcaemia of malignancy
Thiazide à Na+Cl- symporter
- Saxitoxin à Neurotoxin, preventing normal cellular function and leading to paralysis
Tetrodotoxin à Human poisonings occur when the flesh and/or organs of the fish are improperly prepared and eaten. Tetrodotoxin interferes with the transmission of signals from nerves to muscles and causes an increasing paralysis of the muscles of the body.
SODIUM CHANNEL OPENERS
- A sodium channel opener inhibits stimulation of human peripheral blood mononuclear cells.
- found in a number of Chinese herbal remedies.
- Most cases of acute poisoning result from the ingestion of herbs containing aconitine.
- Early and delayed after-depolarizations in ventricular myocytes, which may be due to increased intracellular calcium and sodium, biventricular tachycardia and torsade de pointes.