Top 100 Drugs: Carbamazepine, Gabapentinoids, Valproate, Lamotrigine, Levetiracetam

MOA of carbamazepine?

-MOA incompletely understood

-it inhibits neuronal sodium channels, stabilising resting membrane potentials and inhibiting repetitive neuronal firing

-this may inhibit spread of seizure activity in epilepsy and control neuralgic pain by blocking synaptic transmission in the trigeminal nucleus

important adverse effects with carbamazepine?

-the most common dose related adverse effect is GI upset and neurological effects

-other adverse effects include oedema and hyponatremia due to an antidiuretic hormone-like effect

-skin rashes

-hypersensitivity reactions

warnings with carbamazepine?

-carbamazepine exposed in utero is associated with neural tube defects, cardiac and urinary tract abnormalities and cleft palate

-women with epilepsy planning pregnancy should discuss treatment with a specialist and start taking high dose folic acid supplements before conception

-the risk of Stevens Johnsons syndrome is strongly associated with carriage of HLA-B*1502 allele. (most prevalent in han Chinese and Thai origin)

-caution required in hepatic, renal or cardiac disease due to increased risk of toxicity.

important interactions with carbamazepine?

-carbamazepine induces CYP P450 enzymes, reducing plasma concentration and efficacy of drugs that are metabolised by CYP enzymes (eg warfarin, oestrogens, and progestogens)

-carbamazepine is itself metabolised by these enzymes so ‘auto-induces’ its own metabolism over the first 2-3 weeks

-its concentration and adverse effects are increased by CYP inhibitors

-complex interactions occur with other antiepileptic drugs due to altered drug metabolism

-the efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold eg antipsychotics, tramadol.

gabapentinoids common indications?

-first line in neuropathic pain, including diabetic neuropathy

-gabapentin and pregabalin and licensed for the prevention of focal seizures in epilepsy

gabapentinoids MOA?

-gapapentin and pregabalin are related to y-aminobutyric acid, the major inhibitory neurotransmitter in the brain

-however they do not bind with GABA receptors and their MOA although not completely understood, seems to be mediated through inhibition of pre-synaptic VGCCs in the neocortex and hippocampus

-this reduces Ca2+ entry into the nuerons and inhibits release of excitatory neurotransmitters eg glutamate

-the resulting reduction of neuronal excitability in the brain explains the drugs anticonvulsant effects

Gabapentinoids important adverse effects?

-generally better tolerated than older antiepileptic drugs but side effects can still be problematic

-drowsiness

-impaired concentration

-dizziness

-ataxia

-weight gain

-recognised as drugs of misuse and dependency

warnings with gapapentinoids?

-doses should be reduced in renal impairment

-caution when used in those who have risk factors for substance misuse

important interactions with gabapentinoids?

-sedative effects may be enhanced when combined with other sedating drugs

otherwise not many other interactions

MOA of valproate?

-multiple actions

-increases activity of glutamic acid decarboxylase which increases production of GABA

-it also acts as a weak inhibitor of voltage dependent sodium channels

-together these effects reduce neuronal excitability, suppressing both initial seizure discharges and their propagation

important adverse effects with valproate?

-GI upset, neurological and psychiatric effects

-thrombocytopenia and transient increase in liver enzymes

-hypersensitivity reactions include hair loss

-rare, life threatening, idiosyncratic adverse effects include severe liver injury, pancreatitis, bone marrow failure

warnings with carbamazepine?

-avoid in women who could become pregnant unless there is no alternative, especially around the time of conception and in the first trimester of pregnancy

-it is the antiepileptic drug associated with the greatest risk of fetal abnormalities

-avoid in hepatic impairment

-reduce dose in severe renal impairment

important interactions with valproate?

-valporate inhibits hepatic enzymes, increasing plasma concentration and risk of toxicity with lamotrigine and drugs metabolised by CYP450 enzymes

-valporate itself is metabolised by CYP enzymes so its concentration is reduced by CYP inducers

-adverse effects are increased by CYP inhibitors

-the efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold eg tramadol and antipsychotics

Lamotrigine MOA?

-MOA incompletely understood

-like carbamazepine and phenytoin, it binds to voltage sensitive neuronal Na+ channels, producing use dependent inhibitor of Na+ influx into the neuron

-this impedes repetitive neuronal firing which is a characteristic of seizure activity

-lamotrigine also reduces release of the excitatory neurotransmitter glutamate

important adverse effects with lamotrigine ?

-headache, drowsiness

-irritability, blurred vision, dizziness, GI upset

-minority develop skin rash

warnings with lamotrigine ?

-avoid in ppl with a history of hypersensitivity to other antiepileptic drugs due to risk of cross-reactivity

-metabolised by hepatic glucuronidation so dose reduction may be necessary in in mod to severe hepatic impairment

can lamotrigine be used in pregnancy?

-yes as there is no evidence that it causes congenital malformations

important interactions with lamotrigine?

-drugs that induce glucoronidation and protease inhibitors may cause lamotrigine concentrations to fall, potentially leading to treatment failure

-glucoronidation is inhibited by valporate causing lamotrigine concentrations to rise, increasing the risk of toxicity

-severe hypersensitivity reactions are more common when lamotrigine is co-administered with valproate

MOA of levetiracetam?

-the molecular target of levetericetam is synaptic vesicle protein 2A (SV2A)

-SV2A is expressed throughout the brain, in both excitatory and inhibitory synapses as a glycoprotein located within the membranes of synaptic vesicles.

-synaptic vesicles are where neurotransmitters are stored

-during depolarisation, synaptic vesicles fuse with the pre-synaptic membrane to release neurotransmitters into the synaptic cleft

-through its effect on synaptic vesicle function, levetiracetam modulates the release of neurotransmitters

-this inhibits synchronised burst firing and reduces propagation of seizure activity

important adverse effects with levetiracetam?

-generally well tolerated

-drowsiness, weakness, dizziness, headache

-mood disturbances and psychiatric adverse effects are less common but more likely to cause discontinuation

warnings with levetiracetam ?

-levetiracetam is eliminated by the kidneys, so dosage reduction may be required in renal impairment

important interactions with levetiracetam ?

-has few clinically significant interactions