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68 Cards in this Set

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Action of Benzos
Modulation of the γ-aminobutyric acid type A (GABA-A) receptor

opens the chloride channel, hyperpolarises the cell, leading to postsynaptic inhibition

readily crosses the BBB
Benzo ADRs
ataxia, confusion, memory loss, cog impairment, blurred vision
(especially of concern in the elderly)

behavioural changes (e.g. irritability, aggression, disinhibition)

(more common in children & elderly & patients with a history of aggression & alcohol abuse)
Benzo parenteral admin risks
Hypotension
Respiratory depression
(esp with repeated injections or continuous infusions of clonazepam, diazepam, midazolam)
Minimise parenteral Benzo risks
low dose
slow infusion/injection
large lumen vessel
4 commonly used benzos in neurological medicine
clobazam
clonazepam
diazepam
midazolam
Clobazam
class?
indications?
1,5-benzodiazepine
less sedating than other benzos
usually used as adjunctive Tx for refractory seizures
variable tolerance between individuals
Clonazepam
class?
indications?
specific ADRs?
benzodiazepine
mainly used in Tx of status epilepticus & refractory seizures
sedation is less common in children than adults
beh changes & excess salivary/bronchial secretions more common (in children)
Diazepam
class?
ideal admin?
pharmacokinetics?
Benzo
IV (undiluted) - rapid effects (minutes)
IM - variable & inefficient absorption
long elimination T1/2
redistributes outside CNS rapidly
seizure relapse may occur after 2 hours in 50% of cases
Midazolam
class?
ideal admin?
pharmacokinetics?
benzo
effective plasma concentrations with IM, buccal, intranasal admin
short elimination T1/2
useful for infusion Tx (e.g. refractory status epilepticus)
renally excreted active metabolites may accumulate in renal failure
Carbamazepine
class & mechanism of effect?
antiepileptic, blocks voltage-gated Na+ channels
(inhibit firing of action potentials)
Tx for Trigeminal neuralgia
carbamazepine
(antiepileptic Na+ channel blocker)
Carbamazepine metabolism & active metabolite?
metabolised by CYP3A4
(induces CYP3A4 to increase its own metabolism after 4-5 days of Tx - "autoinduction")
active metabolite = carbamazepine-10,11-epozide
Carbamazepine adverse interactions
bone marrow suppression with drugs causing agranulocytosis (e.g. clozapine)
inhibited metabolism with macrolide antibiotics ('mycins') = carbamazepine toxicity
Carbamazepine ADRs
dose related = sedation, ataxia, dizziness, diplopia, headache, nausea
(minimise with slow dose titration)

reversible mild leukopoenia is common (discontinue if infection or WCC < 2.0x10^9)

anti-diuretic action at high doses (usually mild asymptomatic hyponatraemia)

idiosyncratic ADRs = diarrhoea, hepatitis, rash

severe = Stevens-Johnson syndrome/toxic epidermal necrolysis
(10x higher risk in Asian population)
Carbamazepine pharmacokinetics
Controlled release preps = lower max plasma concentration than equivalent dose of immediate release preps (15% less bioavailability)
may induce seizures in patients switching from immediate release to equivalent dose controlled release
Benzo dependence, tolerance & withdrawal
Dependence develops rarely in patients taking normal therapeutic doses of these drugs for short periods (eg 1-2 weeks)
1/3 of patients on long-term treatment may have difficulty in reducing or stopping benzodiazepines
Tolerance occurs more with the sedative and hypnotic effects than with other benzodiazepine effects.
All benzodiazepines can produce withdrawal symptoms:
Abrupt discontinuation can result in symptoms of increasing anxiety, sleep disorder, aching limbs, nervousness and nausea (seizure in high dose withdrawal)
Ethosuxamide
class?
mechanism of action?
antiepileptic
T-type Ca2+ channel blocker
Ethosuxamide
interactions?
susceptible to inducers/inhibitors of CYP3A4
(e.g. carbamazepine induces CYP3A4 = less ethosuxamide concentration, sodium valproate inhibits CYP3A4 = higher ethosuxamide concentration)
increases phenytoin levels
reduces valproate levels
Ethosuxamide
ADRs?
N&V, abdo pain, lethargy, dizziness, ataxia (often not dose dependent)
severe: SJS, connective tissue syndromes resembling SLE, fatal blood dyscrasias
Gabapentin
class?
mechanism of effect?
Analogue of GABA.
(exact mechanism of action unknown)
theory: inhibit glutamate synthesis, elevate GABA levels, interact with subset of voltage gated Na+ channels & spinal Ca2+ channels
Gabapentin
pharmacokinetics
metabolism
interactions
excretion
absorbed by a saturable amino acid uptake system in the gut
bioavailability decreases as dosage increases
(e.g. 60% absorption fromm 300mg, 40% absorption from 900mg)
does not bind to plasma proteins
does not induce liver enzymes
minimal interaction profile
renally excreted unchanged (reduced dose requirement in renal impairment)
Gabapentin ADRs
somnolence, dizziness and ataxia (minimised by gradual dose titration)
Lacosamide
class?
mechanism of action?
pharmacokinetics?
interactions?
antoepileptic
selective enhancement of slow inactivation of voltage-gated Na+ channels
no significant interactions
IV & oral doses are bioequivalent
Lacosamide ADRs
transient = dizziness, headache, diplopia
cardiac = prolonged PR
renal = contraindicated in renal failure
Lamotrigine
class?
mechanism of action?
antiepileptic
blocks voltage-gated Na+ channels to prevent release of glutamate & aspartate and stabilise presynaptic neuronal membranes
Lamotrigine
ADRs
CNS = dizziness, diplopia, ataxia, blurred vision, somnolence, insomnia, tremor at high doses
derm = varying severity - mild rash to SJS
(higher risk = in children, concurrent valproate, rapid dose increase)
Lamotrigine interactions
higher risk of skin reactions with valproate
higher risk of carbamazepine ADRs
Levetiracetam
class?
mechanism of action?
broad spectrum anticonvulsant, useful as monotherapy & adjuct Tx

interaction with synaptic vescicle-associated protein
Levetiracetam
pharmacokinetics?
interactions?
95% renal excretion of drug & inactive metabolites
no dose modification required between IV or oral
no known induction/inhibition of liver enzymes
no known drug interactions
Levetiracetam
ADRs?
CNS = dizziness, somnolence, asthenia, emotional lability, nervousness, aggression, irritability, agitation
Oxcarbazepine
class?
mechanism?
antiepileptic
(chemically related to carbamazepine)
blockade of voltage-gated Na+ channels
Oxcarbazepine
pharmacokinetics?
interactions?
~100% oral bioavailability
rapid metabolism to active metabolite (10-monohydroxy-oxcarbazepine)
renally excreted active metabolite (reduced dose in renal failure)
no ‘autoinduction’ (unlike carbamazepine)
dose related toxicity if administered with carbamazepine
Oxcarbazepine
ADRs?
common CNS = somnolence, headache, dizziness, diplopia, N&V, fatigue
dose related = moderate (usually asymptomatic) hyponatraemia
(usually more pronounced than seen in carbamazepine)
(more common in elderly)
severe = SJS/toxic epidermal necrolysis, erythema multiforme, hepatitis
Phenobarbitone
class?
mechanism of action?
antiepileptic
enhances activity of GABA by facilitating Cl- entry into neurones at GABAA receptors
Phenobarbitone
pharmacodynamics?
interactions?
ARCHETYPAL ENZYME INDUCER
acelerates the metabolism of many drugs
induces CYP3A4, CYO1A2, CYP2C
greatly reduces the plasma concentration of warfarin (up to 10x anticoag requirement)
inhibited by enzyme inhibitors (e.g. antidepressants)
increasedplasma concentrations with concurrent valproate
Phenobarbitone
ADRs?
severe = local tissue necrosis at injection site if undiluted
altered cognition, mood, behaviour
fatigue & listlessness (adults)
insomnia, hyperactivity, aggression (children & elderly)
Phenytoin
class?
mechanism of action?
pharmacokinetics?
antiepileptic
blocks voltage-gated Na+ channels
nonlinear pharmacokinetics
highly bound to albumin
Phenytoin
ADRs?
dose related = drowsiness, dysarthria, tremor, ataxia, diplopia, cognitive impairment
severe = SJS (10x increase risk in Asian patients)
long-term use = sensory peripheral neuropathy, cerebellar degeneration
reversible = gum hypertrophy, acne, hirsutism (esp in children)
Phenytoin
interactions?
numerous & complex (induces hepatic enzymes)
increased concentration with acute alcohol intake
decreased concentration with chronic alcohol intake
valproate increases unbound phenytoin concentration & inhibits metabolism
impaired efficacy of warfarin, lamotrigine, cyclosporin
increased metabolism of methadone (opioid withdrawal!)
Phenytoin
admin precautions?
IM - irritation, erratic absorption, risk of sterile abscess (not recommended)
IV - hypotension, cardiac arrythmias, long QT, purple glove syndrome
(consider slower infusion)
oral - feeding reduced bioavailability
Pregabalin
class?
mechanism of effect?
anticonvulsant & analgesic
analogue of GABA (structurally similar to gabapentin)
(does not appear to interact with GABA receptors or interfere with GABA synthesis)
theory of effect: bind to CNS voltage-gated Na+ channels, reduce release of glutamate, noradrenaline, substance P
Pregabalin
excretion?
ADRs?
Renal excretion (reduce dose in renal failure)
somnolence, dizziness, blurred vision, weight gain, peripheral oedema
raised CK (creatinine kinase)
Primidone?
class?
mechanism?
indications?
ADRs?
antiepileptic
a pre-metabolite of phenobarbitone
similar efficacy of phenobarbitone
often less well tolerated
also used to Tx essential tremor
similar ADRs to phenobarbitone
Sodium Valproate
mechanism of action?
blocks voltage-gated Na+ channels
blocks T-type Ca2+ channels in the thalamus (anti-absence seizure effect)
Sodium Valproate
indications?
epilespy & seizures
migraine
persistent post-traumatic headache
Sodium Valproate
pharmacokinetics?
~100% oral bioavailability
immediate release formulation - peak plasma concentration 1-4 hours
enteric coated formulation - 3-7 hours
90% protein binding
extensive hepatic metabolism
Sodium Valproate
ADRs?
commonest = tremor, hair loss, sedation weight gain
GIT = anorexia, N&V (reduced with enteric coated preps)
prolonged use = ?PCOS
altered platelet function & thrombocytopoenia
severe = hepatotoxicity, pancreatitis (increased risk in young children & congenital metabolic or mitochondrial disorders, e.g. carnitine or ornithine carbamoyltransferanse deficiency)
highly teratogenic
Sodium Valproate
interactions?
enzyme inhibitor
variable & unpredictable interactions with other antiepileptics
increased risk of SJS with concurrent Lamotrigine
Sulthiame
class?
mechanism of effect?
antiepileptic
reduces voltage-gated Na+ channel currents
weak carbonic anhydrase inhibitor (decreased intracellular pH of neurons which reduces excitability)
Sulthiame
ADRs?
interactions?
commonest = hyperventilation (often dose related)
sulfonamide drug = rash, SJS
nausea, anorexia, headache, dizziness, ataxia, psychosis
dose related distal & peri-oral paraesthesia
increased concentrations of phenytoin, primidone, phenobarbitone
Tetracosactrin
class?
mechanism of action?
indication?
antiepileptic
analogue of corticotrophin (ACTH)
unknown mechanism of action
Tx of infantile spasms
Tiagabine
class?
mechanism?
ADRs?
pharmacokinetics?
inhibits GABA re-uptake from the synapse
(enhanced GABA mediated inhibition)
fatigue, dizziness, confusion, tremor, N&V (most transient & dose related)
does not induce/inhibit enzymes
increased clearance with enzyme inducing drugs
no issues with renal function
Topirimate
class?
mechanism?
indications?
antiepileptic
blocks voltage-gated Na+ channels
enhances GABA mediated inhibition
weak carbonic anhydrase inhibitor
useful for prophylaxis of migraine (low dose) as well as an antiepileptic
Topirimate
ADRs?
pharmacokinetics?
common = cog impairment, psychosis, child beh problems, dysarthria, tremor, dizziness, ataxia, headache, fatigue, N&V, weight loss
rare = paraesthesia, renal calculi, myopia, glaucoma, anhydrosis

mainly excreted unchanged in urine
increased clearance with phenytoin & carbamazepine
Vigabatrin
class?
mechanism?
ADRs?
antiepileptic
irreversibly inhibits GABA transaminase (an enzyme involved in the degradation of GABA)
common = IRREVERSIBLE peripheral visual field constriction (often asymptomatic)
formal testing recommended
sedation, fatigue, headache, dizziness, confusion, ataxia, diplopia, memory impairment, insomnia, psychosis
Zonisamide
class?
mechanism?
antiepileptic
blocks voltage-gated Na+ channels
blocks T-type Ca2+ channels
weak carbonic anhydrase inhibitor
Zonisamide
ADRs?
dose related = drowsiness, dizziness, ataxia, memory/cog impairment, anorexia, agitation, irritability
sulfonamide drug = rash, SJS
renal calculi & metabolic acidosis (carbonic anhydrase inhibition effects - higher risk with concurrent Topirimate or other carbonic anhydrase inhibitors)
Zonisamide
interactions?
increased effects with other concurrent carbonbic anhydrase inhibitors (renal calculi & metabolic acidosis)
reduced T1/2 with enzyme inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone)
Anticonvulsant hypersensitivity syndrome
associated drugs?
carbamazepine
oxcarbazepine
phenytoin
barbituates
(NOT sodium valproate)
Anticonvulsant hypersensitivity syndrome
characteristics?
1-4 weeks into Tx = fever, rash, systemic organ involvement (lymphanenopathy, hepatitis, myositis, myocarditis, pneumonitis), SJS, toxic epidermal necrolysis
antiepileptics & BMD
cause?
management?
inducers of the cytochrome P450 system (ie carbamazepine, oxcarbazepine, phenobarbitone, phenytoin, and primidone) increase the metabolism of vitamin D
the cause with Sodium Valproate is not known
assess vitamin D status
supplement vitamin D
Amantadine
mechanism of effect?
clearance?
enhances dopaminergic transmission
mild antimuscarinic properties
NMDA (N-methyl-D-aspartate) antagonist
Renal clearance
Amantadine
indications?
Used in tremor-dominant Parkinson’s disease and to reduce levodopa induced dyskinesias.
Used to treat fatigue in MS
Used occasionally for influenzae A prophylaxis (resistance is common)
(interferes with the uncoating of the virus inside the cell
M2 inhibitor - blocks the ion channel formed by the M2 protein that spans the viral membrane)
Amantadine
ADRs?
most are transient, mild and dose related:
antimuscarinic effects = dry mouth, constipation, blurred vision, urinary retention
rarely = hallucination, confusion, delirium
50% of patients develop livedo reticularis
5-10% of patients develop ankle oedema
3 anticholinergics commonly used in movement disorders

name, admin, action?
benztropine (oral, IM or IV for acute dystonic reactions)

(also has an antihistamine sedative effect)
benzhexol (oral)
biperiden (oral)
benefits of anticholinergics in Parkinsonism?
limitations?
decreases cholinergic influence in the basal ganglia
seldom used in idiopathic Parkinson’s disease due to poor efficacy & ADRs
Mostly used to reduce extrapyrimidal effects caused by antipsychotic drugs
Drug-induced parkinsonism, dystonias & akinesias respond reasonably well
Less effective for Tx of tremor or akathisia
May aggravate tardive dyskinesia
anticholinergic ADRs?
dose related and due to anticholinergic actions:
peripheral effects = dry mouth, urinary hesitancy & obstruction, constipation, paralytic ileus, nausea, pupillary dilation, blurred vision, worsening of glaucoma
central effects = dizziness, hallucnations, euphoria, hyperpyrexia, central excitation, delirium
taper dosage rather than withdraw suddenly to avoid cholinergic dyscontinuation syndrome
anticholinergic interactions?
peripheral anticholinergic effects are exacerbated by other concurrent medications with anticholinergic properties:
e.g. TCAs & antihistamines