sodium channel blockers (full coverage)

Sodium Channel Blockers

Jacinto, Adrien Kyle M.(Our Lady of Fatima University)

Adrien Kyle M. Jacinto, RPh (Confidential File)


Sodium(Na+)

• Major Extracellular Cation• Function: Excitatory/Activator


Channels/Transport

• Regulatory proteins that take part in trans- membrane signaling and regulates ionic composition.


Sodium Channel

Function:• Play a central role in the transmission of action potentials along a

nerve


Types Of Na+ Channels

• Voltage gatedThere’s a regulation of channels depending on charges (Ions) approaching to cell membranes (either open or close the channel).• Ligand gated (nicotinic acetylcholine receptor) Ligand binding alters

channel/receptor conformation and opens the pore


Physiology of the Nerve Impulse

Resting potential• Na (3 ions) outside the cell.• K (2 ions) inside the cell.• -70mvolts


Physiology of the Nerve Impulse

Action potential• All or none response


Action potential’s 5 distinct phases

Phase 0: • Depolarization phase• Opening of Na Channel (influx of Na into the cell)Phase 1:• (Partial) repolarization• Closure of Na ChannelPhase 2:• Plateau• Opening of K and Ca ChannelsPhase 3:• Repolarization• Closure of Ca Channel, efflux of K Phase 4:Stabilization phase (Membrane is stable)• Resting potential• Established when movement of K out of cell is equal to their movement into the cell• All channels are closed


Class I: Sodium Channel Blockers

MOA:• Blockade of the Sodium ChannelsSub classification of SCBs:• Antiarrhythmic/Antidysrhythmics • Local Anesthetics• Antiseizure/Anticonvulsants


Dysrythmia/Arrhythmia

•An abnormality in the rhythm of the heartbeat• Two basic types of dysrhythmias• Tachydysrhythmias: heart rate is increased• Bradydysrhythmias: heart rate is slowed


Types


Atrial fibrillation


Generation of Dysrhythmias

Two fundamental causes•Disturbances of automaticity•Disturbances of conduction•Atrioventricular block• Reentry (recirculating activation)


Cardiac Conduction Pathways


Electrical Properties of the Heart

• Impulse Conduction: pathways and timing• SA node—pacemaker of heart•AV node•His-Purkinje system


The Electrocardiogram

•Major components of an ECG• P wave

• Depolarization in the atria

• QRS complex• Depolarization of the ventricles

• T wave• Repolarization of the ventricles

• Three other components• PR interval• QT interval• ST segment


Common Dysrhythmiasand Their Treatment

• Supraventricular• Impulse arises above the ventricle•Atrial flutter •Atrial fibrillation• Sustained supraventricular tachycardia (SVT)

•Ventricular• Sustained ventricular tachycardia• Ventricular fibrillation• Ventricular premature beats•Digoxin-induced ventricular dysrhythmias• Torsades de pointes


Most antidysrhythmic drugs act by blocking ion channels in myocardial cells.


The flow of ions through ion channels in myocardial cells


Classification ofAntidysrhythmic Drugs• Vaughan Williams classification• Class I: sodium channels blockers• Class II: beta blockers• Class III: potassium channel blockers• Class IV: calcium channel blockers•Other: adenosine, digoxin, and ibutilide


Class I: Sodium Channel Blockers

Membrane stabilizing agents• Class IA agents Quinidine, procainamide (Procanbid), dysopyramide (Norpace)• Class IB agentsTocainide, Mexiletine (Mexitil), Lidocaine (Xylocaine), Phenytoin (Dilantin)• Class IC agentsEncainide, Flecainide (Tambocor), Propafenone (Rythmol)• Other class I: Moricizine


Class IA Agents

Quinidine, procainamide, Dysopyramide• Effects on the heart• Blocks sodium channels• Slows impulse conduction• Delays repolarization• Blocks vagal input to the heart

• Effects on the ECG•Widens the QRS complex• Prolongs the QT interval

• Therapeutic uses• Used against supraventricular and ventricular dysrhythmias


Class IA Agents

• Adverse effects• Diarrhea• Cinchonism• Cardiotoxicity• Arterial embolism• Alpha-adrenergic blockade, resulting in hypotension• Hypersensitivity reactions

• Drug interactions• Digoxin


Class IB Agents

Tocainide, Mexiletine, Lidocaine, Phenytoin

• Effects on the heart and ECG• Blocks cardiac sodium channels

• Slows conduction in the atria, ventricles, and His-Purkinje system

• Reduces automaticity in the ventricles and His-Purkinje system• Accelerates repolarization

• Adverse Effects• CNS effects• Drowsiness• Confusion• Paresthesias


Class IC Agents

• Block cardiac sodium channels•Delay ventricular repolarization•All class IC agents can exacerbate existing dysrhythmias

and create new ones• 3 class IC agents• Encainide• Flecainide• Propafenone


Moricizine

• General Class I agent• Has characteristics of all three subclasses• Used for symptomatic ventricular and life-threatening dysrhythmias


Local Anesthetics (-Caine)

• Reversibly block impulse conduction along nerve axons and other excitable membranes that utilize sodium channels • Affect permeability of nerve membranes to Na ions- prevent Na ions

from entering the nerve- Cannot depolarize- particular section of the nerve cannot be stimulated


Basic Pharmacology of Local AnestheticsChemistry• Lipophilic group (aromatic ring)• Intermediate chain (ester or amide)• Ionizable group (tertiary amine)


Basic Pharmacology of Local Anesthetics

Chemistry• Increase lipophilic character= Increase potency= Decrease metabolism= Increase toxicity


2 classes

• Ester • More prone to hydrolysis• Short duration of action• Cocaine (prototype)

• Amide• More stable• Lidocaine (prototype)


Specific agents

• The choice of local anesthetic for a specific procedure usually based on duration of action


• Addition of a vasoconstrictor epinephrine or phenylephrine3 purpose

• Retards the removal of drug from the injection site• Prolongs the duration of action of short and intermediate action local

anesthetics• Prevent systemic toxicity


Onset of action

• Can be accelerated by the use of solutions saturated with CO2 (carbonated)


Repeated injection

• Can result in loss of effectiveness (e.g. tachyphylaxis) due to extracellular acidosis. • Local anesthetics are commonly marketed as hydrochloride salts (PH

4.0-6.0)


Use/s

• Since local anesthetics are membrane-stabilizing drugs they are used to treat patients with neuropathic pain syndromes.• Parenteral (e.g. IV Lidocaine) and Oral (e.g. Mexiletine, Tocainide)


Use/s

• Topical local anesthesia is often used for eye, ear, nose, and throat procedures and for cosmetic surgery.


2 major forms of toxicity

• Direct neurotoxicity• When administered around the cord or other major nerve trunks

• Systemic effects• When absorbed from the site of administration


Effects on other organs

• CNS effectsLow doses: Sleepiness, light-headedness, visual and auditory disturbances and restlessnessEarly symptoms: tongue numbness and metallic tasteHigher conc.: Nystagmus and muscular twitching, Overt tonic-clonic convulsions followed by CNS depression and death.(to avoid: premedication with benzodiazepine, e.g. oral diazepam or midazolam parenterally


Seizure

• Can also be treated with small doses of thiopental, propofol, midazolam, or diazepam• The muscular manifestations of seizures can be suppressed by short

acting neuromuscular blocking agents e.g succinylcholine


Neurotoxicity

• At high conc., all local anesthetics can be toxic to nerve tissue.Chlorprocaine and lidocaine• Neurotoxic when used for spinal anesthesia, producing so called

transient radicular irritation


Transient radicular irritation

• This toxicity results from pooling of high conc. Of local anesthetics in the cauda equina


Cardiovascular system

• Block cardiac Na channels = depress abnormal cardiac pacemaker activity, excitability and conduction• At very high concentration = blockade of Ca channels

• Severe hypotension

• Cardiovascular collapse and death• Usually occur only after large doses of 0.75% bupivacaine (most cardiotoxic)


Levobupivacaine

• (S)-isomer• Appears to have lower propensity for cardiovascular toxicity than the

racemic mixture or (R)- isomer and has recently approved for clinical use


Ropivacaine

• Another newer local anesthetic• Similar to bupivacaine• Available only as (s)-stereoisomer, which has inherently less affinity

for cardiac Na channel


Hematologic effects

• Prilocaine (> 10mg/kg)• Metabolite = o-toluidine (oxidizing agent)

• Patients appears cyanotic and the blood chocolate colored.• Treatment:• IV administration of methylene blue or ascorbic acid


Allergic reactions

• Butyrylcholinesterase/Pseudocholinesterase• Enzyme responsible for the metabolism of the ester type local anesthetics in

plasma (also in liver and glia)


Local anesthetics: Ester

• Procaine HCl (Novocaine)• Used for dental procedures

• Tetracaine HCl (Pontocaine)• For spinal anesthesia

• Benzocaine• Topical for wounds and ulcers

• Dibucaine• 15-20X more potent and 15X more toxic than procaine


Cocaine

• From coca leaves. “The divine plant of incas”• Sympathomimetic• Blockade of norepinephrine reuptake results in vasoconstriction and

Hypertension• May precipitate cardiac arrhythmias• Lead to ischemia


Local anesthetics: Amide

• Lidocaine (Xylocaine)• Rapid and long duration of action• Causes fever and hypersensitivity reactions more than procaine• With anti-arrhythmic activity• Most neurotoxic when given as spinal anesthesia causing transient radicular

irritation


Bupivacaine

• For peripheral nerve block, caudal and epidural anesthesia


Seizures

• Characterized by excessive, hypersynchronous discharge of cortical neuron activity, which can be measured by electroencephalogram (EEG).


Convulsions

• Violent, involuntary contractions of voluntary muscles.*A patient may have epilepsy or a seizure disorder without convulsions


3 major phases of seizure:

• Prodrome- precede the seizure by hours or days. Changes in mood/behavior typically occur. Include aura subjective sensation (unusual smell, flashing light..)• Ictal phase- seizure itself. Its onset is heralded by scream or cry.• Postictal phase- after seizure. The patient typically exhibits lethargy,

confusion and behavioral changes.


Epilepsy

• A chronic seizure disorder, usually recur unpredictably in the absence of consistent provoking factor.• Intermitent derangement of nervous system due to sudden,

excessive, disorderly discharge of cerebral neurons.


International classification of epileptic seizures


Classification based on etiology

• Primary seizure• Idiopathic. Have no identifiable cause

• Secondary seizure• Symptomatic/Acquired seizure• Occurs secondary to an identifiable cause• Intracranial neoplasms, Infectious diseases(Meningitis, measles, mumps,

syphillis, influenza, toxoplasmosis), high fever (children), congenital diseases, Metabolic disorder(hypoglycemia, hypocalcemia), Alcohol or drug withdrawal, lipid storage disorders, and developmental abnormalities.


Treatment

• Therapy is aimed at control (drugs do not cure)Notable Adverse effects:• Nausea and vomiting• Drowsiness-Sedation• Ataxia• Rash• Hyponatremia• Weight gain or weight loss• Teratogenicity• osteoporosis


Mechanism of Action

• Inhibition of voltage gated Na channels to slow neuron firing• Enhancement of the inhibitory effects of the neurotransmitter GABA• Inhibition of Ca channel (T-type)• Block NMDA glutamate receptors• Enhance/facilitate K channel


Na Channel blockers

• Blocks voltage gated Na channel by selectively binding to the channel in the inactive state and slowing its rate of recovery• Phenytoin (Dilantin)• Fosphenytoin (Cerebyx)• Carbamazepine (Tegretol)• Oxcarbamazine (Trileptal)• Valproic acid (Valproate, Depakene, Depakote)• Lamotrigine (Lamictal)• Topiramate (Topamax)• Zonisamide (Zonegran)


Phenytoin (Dilantin)

• Oldest non-sedative antiepileptic drug• DOC for partial and generalize tonic-clonic seizure• Elimination converts from 1st order elimination (proportional to its

concentration) to zero order elimination (fixed amount per unit time), usually at high therapeutic levels



Drug interaction• Enzyme inducer

• Decrease blood levels of many medications, but increases blood levels of phenobarbital and warfarin

• Adverse effects• Dermatological: Maculopapular rash sometimes with fever, SJS, and

lupus erythematosus• Hirsutism• Acne• Gingival hyperplasia


Gingival hyperplasia



• CNS side effect: Ataxia, Dysarthria, Insomnia, Transient hyperkinesia• Decreased folic acid, thyroxine and vitamin K with long term use• Fetal Hydantoin syndrome

• Growth retardation, microencephaly, and craniofacial abnormalities (e.g. cleft palate) possibly due to epoxide metabolite of phenytoin


Fosphenytoin (Cerebyx)

• Prodrug• Converted to phenytoin in blood• Administered IM/IV

Phenytoin Na never given IM= can cause tissue damage and necrosis


Congeners of Phenytoin

• Mephenytoin (Mesantoin)• Norvanol – Metabolite that contributes most of antiseizure activity of

mephenytoin

• Ethotoin (Peganone)• Phenacemide


Carbamazepine (Tegretol)

• TCA (Bipolar)• First choice for complex partial and generalized tonic clonic seizuresContraindicatiobs:• May exacerbate absence or myoclonic seizureAdverse effects:• Common: Diplopia and ataxia, GI disturbances, sedation


Carbamazepine (Tegretol)

• Drug interactions:• Enzyme inducer• Exhibits autoinduction (It Metabolize itself)


Oxcarbazepine (Trileptal)

• For primary and secondarily generalize tonic clonic seizure• Prodrug.• Half life: 1-2 hour• Fewer adverse effects than CBZ, Phenytoin


Eslicarbazine (Stedesa)

• Prodrug• Advantage: Once daily dosing regimen


Valproic acid (Depakote)• Other MOA:

• Inhibition of T-type Ca channel• Increases GABA production and Decreases GABA metabolism (Inhibition of GABA

transaminase)

• Indication:• Simple or complex partial, and primary generalize tonic clonic.• Highly effective for photosensitive epilepsy and juvenile myoclonic epilepsy

• Contraindication:• Liver disease


Valproic acid (Depakote)

• Drug interaction:• Enzyme inhibitor

• Adverse effects:• Weight gain• Hair loss• Ankle swelling


Lamotrigine (Lamictal)

Other MOA:• Inhibits voltage gated Ca channel (N and P/Q type)• May inhibit release glutamateIndications:• Adjunct therapy

• for simple and complex partial seizure• Generalized seizures of Lennox- Gestaut syndrome

• Contraindications:• Make myoclonic seizure worse


Lennox Gestaut syndrome

• Most distressing childhood epilepsy (Movement disorder)• Frequent fits and gradual mental retardationAdverse effects:• Rash (10%)• Increased alertness


Topiramate (Topamax)

• Other MOA:• Ebhances post-synaptic GABAA Receptor currents• Kainate receptor antagonists (blocks certain type of glutamate channel)

• Indications:• Adjunct therapy for partial and primary generalized.• Decreases tonic and atonic seizures in children with Lennox Gestaut

syndrome


Topiramate (Topamax)

• Adverse effects:Weight lossMetabolic acidosisKidney stone formation• Contraindication:History of kidney stone• Drug interaction

• Enzyme inducer interact with it.


Zonisamide (Sonegran)

• Sulfonamide derivative. Broad spectrum• Other MOA:

• Inhibits T-type Ca channels• Binds to GABA receptor• Facilitates dopaminergic and serotonergic neurotransmission

• Indications:• Adjunct treatment of partial seizure in adults• Broad spectrum:

• Myoclonic seizure• Infantile spasm• Generalized and atypycal absense seizure• Lennox Gestaut seizure


Zonisamide (Sonegran)

Drug interactions:• Phenytoin and Carbamazepine decrease its half life by halfAdverse effects:• Weight loss (Inc. serotonin levels)


Lacosamide (Vimpat)

• Amino acid related compound• Also binds to collapsin-response mediator protein (CRMP) thereby

blocking the effect of neurotropic factors such as BDNF and NT3 on axonal and dendritic growth


Rufinamide (Banzel)

• Triazole derivative• Prolong the inactive state of Na channel• Adjunct for Lennox Gestaut syndrome


Others

Tetrodotoxin• From Puffer fishBetrachotoxin • From Colombian frog

MOA: Block the Na channelResponse: Hyperpolarization (Inactivation of neurons)

sodium channel blockers (full coverage)

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