ic4 - neuropharmacology for antimigraine and antiepileptic drugs Flashcards
what are examples of some other brain cells and its functions
astrocytes, oligodendrocytes, schwann cells
astrocytes have protective, tropic support, electrolyte balance and its own membrane potential, it is important for maintaining homeostasis and formation of BBB and supports neurons by ensuring they have sufficient O2, metabolites and are not exposed to external environment and removes waste
oligodendrocytes forms the myelin sheath for brain neurons
schwann cells forms the myelin sheath for PNS neurons
what is the process of synaptic transmission
[initiation] when action potential reaches the terminal, it causes opening of voltage gated Ca channels in presynaptic membrane which gives rise to influx of Ca2+ -> Ca2+ acts on Ca2+ sensitive vesicle membrane proteins (VAMPs) to release vesicles from its cytoskeleton and facilitated vesicle docking to presynapse, fusion with presynaptic membrane and exocytosis -> result in release of neurotransmitters
to regulate, presynaptic autoreceptors are activated together with postsynaptic receptors to inhibit further release of neurotransmitter via feedback inhibition
[propagation and termination] neurotransmitters in the synpatic cleft activates postsynaptic receptors, signal terminates by action of catalytic enzymes and/or reuptake transporters
what are the different neurotransmitters and its respective features (type, location, function etc)
- glutamate (excitatory, found in pyramidal neurons in neocortex, implicated in learning and memory)
- GABA - gamma-aminobutyric acid (inhibitory, receptors are impt for action of sedatives)
- ACh (from nucleus basalis of meynert, implicated in learning, arousal and reward)
- dopamine (from substantia niagra, involved in motor system and reward)
what are the potential drug targets of synaptic transmission that can produce agonistic or antagonistic effects
a drug that is agonistic in nature will increase neurotransmission while a drug that is antagonistic in nature will decrease neurotransmission
[agonist] increase synthesis of neurotransmitter molecules, increase number of neurotransmitter molecules by destroying degrading enzymes, bind to autoreceptors to block inhibitory effects on neurotransmitter release, increase release of neurotransmitter from terminal buttons, binds to postsynaptic receptors and either activate them or increase effect on them as per a neurotransmitter would, block deactivation of neurotransmitters by blocking degradation or reuptake
[antagonistic] block synthesis of neurotransmitter molecules, cause neurotransmitter molecules to leak from vesicles and get destroyed by degrading enzymes, block release of neurotransmitters from terminal buttons, binds to autoreceptors and activate their inhibitory effects on release of neurotransmitters, binds to postsynaptic receptors to block neurotransmitter binding thus blocking its effect
what are the functions of the BBB
- modulation of entry of metabolic substrates
- control ion movements
- prevent access of toxins into CNS and peripheral neurotransmitters from escaping into bloodstream from autonomic nerve endings
what are the types of drugs and its movement across the BBB
non saturable and saturable
[non saturable] movement by transmembrane diffusion (incr amount of drug incr rate across BBB), suitable for drugs of low MW (<5kDa) and high lipid solubility (but note not too high lipid solubility as it can cause high affinity -> drug either gets sequestered in BBB capillary bed or gets uptaken by peripheral tissues), movement is affected by charge, tertiary structure and degree of protein binding and degree of P-gp expression
[saturable] movement by transporter system and once saturated an incr in amount of drug will not affect rate, has 10x higher uptake rate than transmembrane diffusion, uptake rate is regulated by cerebral bloodflow, co factors, hormones/ peptide modulators
what is transmembrane diffusion movement of drugs affected by
charge, tertiary structure, degree of protein binding, expression of P-gp (an efflux transporter thus overexpressors of P-gp leads to lower rate)
what is transport system movement of drugs affected by
cerebral bloodflow, co factors, hormones/ peptide modulators
what is “epilepsy”
epilepsy is a condition of repeated seizures
what is the pathophysiology of epilepsy
neuronal depolarisation is dependent on membrane potential
a seizure occurs due to excessive synchronous depolarisation usually starting from defined regions (foci) and spreading to other regions
dysregulated discharges due to unbalanced excitatory and inhibitory receptor or ion channel function which favours depolarisation
what is the classification of seizures
- generalised seizures (tonic clonic, absence, myoclonic, atonic)
- partial seizures (simple, complex)
- status epilepticus
differentiate between the types of generalised seizures
generalised seizures includes tonic clonic, absence, myoclonic and atonic
[tonic clonic] aka grand mal, involves tonic and clonic movements at the same time, tonic movement = muscle stiffening and loss of consciousness, clonic movement = muscle spasm and jerk
[absence] aka petite mal, start from staring spells and can be mistaken for simple daydreaming
[myoclonic] think of it as body jolts (like theres electricity), involves sudden incr in muscle tone
[atonic] think of it as drop attacks, involves sudden decr in muscle tone
differentiate between the types of partial seizures
partial seizures are categorised into simple and complex
[simple] consciousness not impaired
[complex] consciousness impaired
differentiate between generalised grand mal seizure, generalised petite mal seizure and partial seizure ECG and which part of the brain is affected
generalised seizures affect frontal, temporal and occipital lobes
grand mal ECG is alot more crazy looking than petite mal ECG (still can see waves)
partial seizures affect frontal and temporal lobes
what is the possible moa of antiepileptics
- decrease membrane excitability by altering Na and Ca conductance during action potential
- enhance effects of inhibitory GABA neurotransmitters
list examples of antiepileptics
PHT, CBZ, VPA, PB, diazepam, levetiracetam, lamotrigine, topiramate
what are the first line antiepileptics for newly diagnosed generalised tonic clonic seizures
PHT, CBZ, VPA
what is the moa for PHT
blockade of voltage dependent Na channels which prevents further influx of Na thus preventing action potential
what is PHT indicated for
PHT is indicated for all types of seizures except absence seizures
what is the PK characteristics of PHT
PHT has narrow therapeutic range, will require titration and monitoring due to saturation kinetics
PHT is also teratogenic
what are the s/e for PHT
dose related s/e of PHT includes drowsiness, confusion, nystagmus (misalignment of eyes), ataxia, unusual behavior, mental changes, coma, N
non related s/e of PHT includes hirsutism, hypersensitivity, gingival hyperplasia, acne, folate deficiency, osteomalacia
what is the moa of CBZ
blockade of voltage dependent Na channels
what is the indication for CBZ
for all types of seizures except absence
what are some PK characteristics of CBZ
CBZ is a cyp450 inducer which induces its own metabolism (thus half life decr with repeated dosing) and incr elimination of other drugs
CBZ is also affected by PGx, HLAB*1501 allele in Asians can incr risk of SJS/ TEN -> gives rationale for screening prior to initiating CBZ
what is the s/e of CBZ
dose related s/e of CBZ includes drowsiness, confusion, ataxia, slurred speech, N, mental changes, unusual behavior, coma, nystagmus (eyes becoming unaligned)
non dose related s/e of CBZ includes hypersensitivity, hirsutism, folate deficiency, gingival hyperplasia, osteomalacia, acne
what is the moa of VPA
blockade of voltage gated Na and Ca channels and also inhibits GABA transaminase enzyme which results in decr GABA breakdown and thus incr GABA
what is the indication for VPA
for all types of seizures including absence seizures
what are some PK characteristics of VPA
VPA is strongly bound to plasma protein which makes its F lesser than expected and bc of this VPA displaces other antiepileptics
what is the s/e of VPA
dose related s/e of VPA includes drowsiness, confusion, nystagmus (eyes becoming unaligned), slurred speech, N, ataxia, mental changes, unusual behavior, coma
non dose related s/e of VPA includes hirsutism, acne, gingival hyperplasia, hypersensitivity, folate deficiency, osteomalacia
what is the moa of diazepam
diazepam is a benzodiazepine that enhances effects of inhibitory GABA neurotransmitters by acting via GABA-A receptor Cl channels (aka a ligand gated binding site for GABA neurotransmitters) to potentiate influx of Cl- ions which leads to hyperpolarisation and causes neurons not to fire
what are the sites on GABA-A receptor Cl channels
it has various ligand binding site where one recognises GABA and another allosteric regulatory site recognises benzodiazepines
what are the indications for diazepam
alcohol withdrawal sx, anxiety, seizure, sedation, refractory seizure, status epilepticus, adjunct skeletal muscle spasm
what are the PK characteristics of diazepam
fast acting (onset 0.5h)
long acting (half life 43h)
what are the s/e of diazepam
- toxicity and overdose (results in severe respiratory depression esp if used concom alcohol, treat with flumazenil)
- s/e during use (includes drowsiness, confusion, amnesia, impaired muscle coordination thus do not operate machinery)
- tolerance and dependence (tolerance is dependent on freq of dosing and refers to the same dose no longer producing the same efficacy and dependence suggests that there would be withdrawal effects such as disturbed sleep, rebound anxiety, tremor and convulsions thus impt to withdraw gradually)
what is the key characteristic to note for diazepam
it has abuse potential
what is flumazenil
flumazenil is a benzodiazepine antagonist with specificity for benzodiazepine binding site on GABA(A) receptor Cl channel
what is the moa of PB
potentiates effects of GABA-A receptor Cl channel but at a site distinct from benzodiazepines
what is the key characteristic to note for PB
it is replaced by benzodiazepines due to its even greater risk of developing tolerance and dependence
what are the PK characteristics of PB
long acting (1-2days)
what are the indications for PB
for pediatrics or neonatal patients, mostly in emergency settings (IV LD f/b IV/PO MD)
what are the s/e of PB
tolerance and dependence and withdrawal sx
what is the indication of levetiracetam
as adjunctive tx for partial onset seizures, myoclonic and primary generalised tonic clonic seizures
can be monotx for partial onset seizures in newly diagnosed epilepsy
what is the chemical structure of levetiracetam
a pyrrolidone derivative (chemically unrelated to existing ASM)
what are the PK characteristics of levetiracetam
highly soluble and permeable
low intra and intersubject variability thus no need for routine monitoring
PO or IV route
what are the s/e of levetiracetam
common s/e of levetiracetam: headache, vertigo, depression, cough, insomnia
rare s/e of levetiracetam: agranulocytosis, dyskinesia, suicidal, delirium
what is “dyskinesia”
uncontrolled involuntary movement
what is the moa of levotiracetam
unclear
what is the moa of lamotrigine
blocks voltage gated Na channels, inhibit release of glutamate, impedes sustained repetitive neuronal depolarisation
what is “lennox-gastaut syndrome”
severe childhood epilepsy
what are the indications for lamotrigine
mono or adjunctive tx for partial, generalised, tonic clonic seizures
monotx for absence
initial or adjunctive for lennox-gastaut syndrome
what are the PK characteristics of lamotrigine
linear r/s
PO and chewable thus suitable for children
half life generally shorter in children and half life significantly reduced by co administration with CBZ and PHT (bc both CBZ and PHT are inhibitors) vs increased by co administration with VPA (bc VPA is inducer)
what are the ASM suitable for absence
VPA and lamotrigine
what are the s/e of lamotrigine
common s/e of lamotrigine includes headache, irritability or aggression, tiredness
rare s/e of lamotrigine includes agranulocytosis, hallucination, movement disorders, SJS/TEN, hepatic failure
what is the moa of topiramate
unclear but likely incr GABA activation of GABA(A) receptor to enhance GABA induction of Cl- flux but does not incr channel opening time (or may act on benzodiazepine insensitive subtype of GABA-A receptors)
what are the indications for topiramate
mono for partial, generalised and tonic clonic
adjunctive for lennox-gastaut syndrome
prophylaxis of migraine in adults (BUT NOT ACUTE TX)
what are the PK characteristics of topiramate
linear r/s
PO
long plasma half life
predominantly renal CL
not a potent inducer of drug metabolising enzymes
what are the s/e of topiramate
common s/e of lamotrigine includes depression, fatigue, somnolence, N, weight changes
rare s/e of lamotrigine includes neutropenia, SJS/TEN, hepatic failure, mania, tremor, transient blindness
what is the chemical structure of topiramate
sulfamate substituted monosaccharide
what are the main considerations for ASM drug tx (regarding drug choice and regimen and monitoring)
individualisation according to seizure type, epilepsy syndrome, co medication, comorbidity, lifestyle and preferences
avoid polytherapy as much as possible
routine checking of drug levels without clear clinical indication not required and not cost effective
when should ASM be monitored
drug levels are not routinely monitored without clear clinical indication
only check drug levels routinely if (i) assessing compliance to drug tx for refractory epilepsy (ii) assessing sx due to potential drug toxicity (iii) titration of PHT dose
what is the pathophysiology of headache and migraines
vasodilation of intracranial extracerebral blood vessels result in activation of perivascular trigeminal nerves that releases vasoactive neuropeptides to promote neurogenic inflamm
central pain transmission may activate other brainstem nuclei thus resulting in assoc sx like N/V, photophobia and phonophobia
what might hyperresponsiveness of brain be a result of (what affects migraine threshold)
hyperresponsiveness of the brain may be a result of inherited abnormality in Ca and/or Na channels and Na/K pumps that regulate cortical excitability through release of serotonin and other neurotransmitters
migraine threshold may also be affected by increased levels of excitatory AA like glutamate and alterations in extracellular K
list examples of drugs that can be used for tx of headache and migraine
cafergot, sumatriptan, erenumab, paracetamol, NSAIDs
what is the role of serotonin
serotonin is an important mediator of migraine headaches as it is an agonist of vascular and neuronal 5HT1 receptor subtypes that are known to have vasoconstrictive effects on meningeal blood vessels and inhibition of release of vasoactive neuropeptides and pain signal transmission
what is the moa of cafergot
tonic action on vascular smooth muscles in the external carotid network which leads to vasoconstriction and thus prevents neuropeptides and inflamm mediators from leaking out, through stimulation of alpha adrenergic 5HT receptors (specifically 5HT1B and 5HT1D which are the two main receptor subtypes found on vascular structures that mediate vasoconstriction)
what are the indications for cafergot
cafergot is indicated for acute tx of migraine
what is the ingredient in “cafergot”
it contains caffeine and ergotamine
what are the PK characteristics of cafergot
PO or rectal
rapidly absorbed
high plasma protein binding thus low absolute F
inhibits cyp3A (do not use with 3A inhibitors like macrolides as incr exposure to ergot toxicity presents as vasospasm and tissue ischemia (as can have vasoconstrictive effects on not just 5HT1D receptor but also on other peripheral small vessels)
what are the ddi for cafergot
cyp3A inhibitors (eg. macrolides) as it can incr serum conc of cafergot which incr exposure to ergot toxicity
other vasoconstrictive agents (eg. ergot alkaloids, sumatriptan and other 5HT1 agonists)
what does ergot toxicity present as (recall what drug can cause this) and why
cafergot
presents as vasospasms and tissue ischemia as cafergot may bind to 5HT1D receptors on peripheral small vessels as well
what are the s/e for cafergot
common s/e of cafergot are N/V
rare s/e of cafergot is hypersensitivity, myocardial infarct and ergotism (vascular ischemia)
what is the moa of sumatriptan
selective agonist of vascular serotonin (5HT1D) receptor that selectively constricts carotid arterial circulation but does not alter cerebral blood flow, and also inhibits trigeminal nerve activity
what are the indications for sumatriptan
migraine with or without aura
what are the c/i for sumatriptan
hypersensitivity to triptans, concurrent MAOi, MI
why is sumatriptan c/i with concom MAOi
due to inability to clear drug thus toxicity issues arises
what are the PK characteristics of sumatriptan
PO, nasal, IV
rapidly absorbed
low plasma protein binding
eliminated primarily by oxidative metabolism mediated by monoamine oxidase A (MAO)
what are the s/e of sumatriptan
common s/e of sumatriptan includes dysgeusia (unpleasant taste), transient BP incr due to vasconstriction, flushing, sensation of cold, pressure, tightness
rare s/e of sumatriptan includes minor disturbances in LFTs but NOT hepatic failure
what is one key consideration for sumatriptan (regarding length of tx regimen)
do not use sumatriptan for more than 10 days a month
what is the moa of erenumab
erenumab is a MAb that is a calcitonin gene related peptide (GCRP) inhibitor
GCRP are found to relate to migraines as nociceptive neuropeptides transmits pain sensation and activates trigeminal ganglion that causes vasodilation which makes it leaky and results in vasoactive peptides like GCRP to leak out which potentiates vasogenic inflamm
blocking of GCRP can cause lost of nociceptive perception thus decr pain sensation and no vasodilation occurs
what are the indications for erenumab
prophylaxis of migraines in adults who have at least 4 migraine days per month
what are the PK characteristics of erenumab
SQ inj given monthly
what are the s/e of erenumab
hypersensitivity, inj site reactions, constipation, pruritis
what are the s/e of erenumab
hypersensitivity, inj site reactions, constipation, pruritis
