CA Pharmacology Flashcards
What is the MoA of phenytoin and carbamazepine?
Block voltage-dependent Na+ channels → ↓excitability
Phenytoin has a ________ therapeutic range, ________ kinetics, and ____________ PK r/s.
This causes phenytoin to have ____________ clearance, where clearance ________ with ________ concentration
Phenytoin has a narrow therapeutic range, saturable kinetics, and non-linear PK r/s (zero order kinetics).
This causes phenytoin to have capacity-limited clearance, where clearance decreases with increasing concentration
Can phenytoin be used in pregnancy?
No! Contraindicated!
Phenytoin has ________ bioavailability, and absorption is ________ but _______
Phenytoin has high bioavailability (95%), and absorption is complete but slow
Can phenytoin be taken together with enteral feeds? Why or why not?
No
↓bioavailability when taken together with enteral feeds (space apart by 2hrs)
True or false?
Taking a lower dose of phenytoin is more effective as compared to taking a higher dose
True
Lower bioavailability is observed at high doses >400mg/dose
Does phenytoin require dose adjustment in renal impariment? Why or why not?
True
Phenytoin is highly protein bound (90%).
Renal impairment may lead to uremia/ hypoalbuminuria → displace phenytoin and ↓protein binding → ↑free phenytoin and more toxic ADRs
True or false?
Phenytoin dominantly undergoes linear hepatic metabolism
False
Though phenytoin does undergo hepatic metabolism (100%), it is non-linear (capacity limited clearance)
Does phenytoin induce or inhibit metabolising enzymes? What enzymes does phenytoin affect?
Induce CYP2C9, CYP2C19, CYP3A, UGT
True or false
Carbamazepine is highly protein bound and hepatically eliminated
True
75-85% protein binding, 100% hepatic elimination (autoinduction)
Does carbamazepine induce or inhibit metabolising enzymes? What enzymes does phenytoin affect?
Induce CYP450, CYP1A2, CYP2C9, CYP2C19, CYP3A, UGT
Carbamazepine undergoes ________. This causes ________ clearance and ________ half-life of carbamazepine with repeated doses → ________ metabolism of other drugs
Maximal effect of the above occurs ________ after initiation.
Hence do not start with desired maintenance dose (risk of dose-dependent SEs), but instead gradually ________ dose over initial few weeks
Carbamazepine undergoes autoinduction. This causes increased clearance and shorter half-life of carbamazepine with repeated doses → increases metabolism of other drugs
Maximal effect of the above occurs 2-3 weeks after initiation.
Hence do not start with desired maintenance dose (risk of dose-dependent SEs), but instead gradually increase dose over initial few weeks
What is the MoA of sodium valproate?
Block voltage-dependent Na+ and Ca+ channels → ↓excitability
Also inhibits GABA transaminase → ↑GABA → ↑inhibition
HLA alleles associated with carbamazepine are:____________.
These alleles can cause ____ and _____
HLA-B1502 and HLA-A3101
Causes SJS and TEN
True or false
Phenytoin, carbamazepine, and sodium valproate can be used in all types of seizures
False
Phenytoin and carbamazepine cannot be used in absence seizures.
Sodium valproate experiences ____________. This causes ________ protein binding at ________ concentration.
um valproate experiences saturable protein binding. This causes decreased protein binding at increasing concentration.
True or false?
Sodium valproate has ____high/low____ protein binding.
High (75-95%)
Does sodium valproate induce or inhibit metabolising enzymes? What enzymes does valproate affect?
Inhibit CYP2C9, UGT, epoxide hydrolase
What is the MoA of diazepam?
Binding of GABA is ↑by benzodiazepine → ↑binding of GABA on GABA receptors on Cl- channels → Cl- channels open → ↑influx of Cl- ions → hyperpolarization → ↑inhibition
What happens during acute toxicity/ overdose of diazepam? What is used to treat it?
SEs: severe respiratory depression, esp when w alcohol
Tx: flumazenil (benzodiazepine antagonist)
True or false?
Diazepam and barbituates are associated with withdrawal symptoms/ tolerance and dependence
True
True or false
Benzodiazepines have higher dose-dependent depression of CNS as compared to barbiturates
False
Opposite!
Benzodiazepines reaches a peak. Whereas barbiturates just keeps increasing linearly so more dangerous, hence not used often nowadays
Tolerance and dependence occurs due to ______________.
Withdrawal effects involve:____________ (4)
Is important to withdraw ___________
Frequency of use
Disturbed sleep, rebound anxiety, tremor, and convulsions
Gradually
Diazepam is a ________ benzodiazepine.
Long-acting
Lasts around 1-2 days
What is the MoA of Phenobarbital?
Same MoA as benzodiazepines, but at a site distinct from them
Binding of GABA is ↑by benzodiazepine → ↑binding of GABA on GABA receptors on Cl- channels → Cl- channels open → ↑influx of Cl- ions → hyperpolarization → ↑inhibition
True or false?
Indication of diazepam is all seizures?
True
What are the indications of phenobarbital?
- Sedative-hypnotic
- AED for paediatric/ neonatal pts (IV loading dose f/b IV/PO maintenance dose)
True or false?
Flumazenil is effective for treating barbiturate overdose
False
Flumazenil only blocks benzodiazepine sites, not effective for treating barbiturate overdose
What are the indications of levetiracetam? State which are monotherapy and which are adjunct.
Monotherapy: partial onset seizures in newly diagnosed epilepsy
Adjunct: partial onset, myoclonic, and primary generalised tonic-clonic seizures
What is the MoA of lamotrigine?
Block voltage-gated Na+ channels → inhibit release of glutamate → prevents sustained repetitive neuronal depolarization
What are the indications of lamotrigine? State which are monotherapy, adjunct, and initial.
Adjunct/ monotherapy: partial and generalised seizures
Adjunct/ initial: Lennox-Gastaut syndrome
Monotherapy: typical absence seizures
What are the DDIs of lamotrigine? Which anti-epileptic drug increases or decreases t1/2?
↓t1/2: carbamazepine and phenytoin
↑t1/2: valproate
What are the indications of topiramate? State which are monotherapy, adjunct, and prophylaxis.
Monotherapy: partial and generalised seizures
Adjunct: Lennox-Gastaut syndrome
Prophylaxis: migraine headaches in adults (not for acute tx!)
True or false?
Topiramate is predominantly cleared renally
True
True or false?
Topiramate is a potent inducer of drug-metabolising enzymes
False
True or false
All ASM may result in an increase in suicidal ideation and behvaiour. Should discontinue drug when patient experiences/ exhibits such symptoms
False!
Risk of stopping ASM is greater than the benefit of discontinuing it to reduce SEs
Close monitoring done instead
List 3 antiepileptic drugs
- Phenytoin
- Carbamazepine
- Sodium valproate
- Diazepam
- Phenobarbital
- Levetiracetam
- Lamotrigine
- Topiramate
What is the MoA of cafergot?
Ergotamine:
Alpha-adrenergic and 5-HT receptors (5-HT1B/1D) agonists on intracranial vessels → vasoconstriction
Inhibit norepinephrine uptake and adrenoreceptors → prolonged vasoconstriction
Caffeine:
Adenosine A1, A2A and A2B receptor antagonists → vasoconstrict cerebral vasculature
May ↑GI absorption of ergotamine by ↑solubility of ergotamine and ↓ gastric pH
Cafergot is a combination of ________ and ________
Caffeine and ergotamine
What is the indication of cafergot?
Acute tx of migraine (given at 1st symptom of attack)
What are the ADRs of cafergot?
Common: N/V, cramps, insomnia, transient lower limb muscle pain
Rare: hypersensitivity, MI, ergotism (vascular ischaemia)
Where is cafergot contraindicated in?
Pre-existing conditions:
* Stroke/ TIA
* Ischemic coronary artery disease
* Coronary artery vasospasm
* Uncontrolled HTN
* Peripheral vascular disease
* Gastrointestinal ischemia
* Hx of hemiplegic/ basilar migraine
Concomitant use of triptans within 24hrs
Potent CYP3A4 inhibitors (proteases inhibitors, macrolides)
(similar to triptans, vasoconstriction)
Fill in the blanks, regarding the PK of cafergot:
Routes: ________
F = _______
_______ absorbed, max plasma concentrations reached in _______
_______ protein bound
CYP_____ __________
Routes: Oral, rectal
F = 2-5% (low)
Rapidly absorbed, max plasma concentrations reached in 1.5-2hrs
Highly protein bound
CYP3A4 inhibitor
What are the DDIs of cafergot?
CYP3A4 inhibitors (causes increased ergot toxicity → vasospasm and tissue ischaemia)
Vasoconstrictor agents: ergot alkaloids, sumatriptan, other 5HT1 agonists
True or false?
Triptans have a more potent vasoconstriction effect than ergotamine.
False!
Ergotamine and dihydroergotamine have more potent vasoconstriction effect (hit more receptors than triptans), hence its place in practice have been mostly replaced by triptans
What is the MoA of sumatriptan?
Selective serotonin (5-HT1B and 5-HT1D) receptor agonist →:
* Vasoconstriction of intracranial extracerebral blood vessels
* Inhibition of vasoactive peptide release by trigeminal neurons
* Inhibition of nociception neurotransmission within trigeminocervical complex
↓ neurogenic inflammation/ inhibits trigeminal nerve activity, but does not alter cerebral blood flow)
What is the indication of sumatriptan?
Acute tx of migraine, should be taken early when pain intensity is mild
What are the ADRs of sumatriptan?
Common: dysgeusia, chills, pressure, tightness, serotonin syndrome (transient ↑BP, flushing)
Rare: minor disturbances in LFTs
Where is sumatriptan contraindicated in?
Pre-existing conditions:
* Stroke/ TIA
* Ischemic coronary artery disease
* Coronary artery vasospasm
* Uncontrolled HTN
* Peripheral vascular disease
* Gastrointestinal ischemia
* Hx of hemiplegic/ basilar migraine
Concomitant use of MAOi or within 2w of discontinuation of MAOi therapy
Concomitant use of ergotamine-containing/ ergot-type medication within 24hrs
(similar to ergotamines, vasoconstriction)
What are the routes of administration for sumatriptan?
Oral, nasal, IV
Sumatriptan is eliminated by ________ mediated by ______
Oxidative metabolism, MAO
True or false?
If sumatriptan is not effective in treating patient’s medication, should change drug class.
False
Lack of response to one triptan does not predict response to other triptans -> trial of another triptan
True or false?
Triptans can cause recurrence of migraine, and so an additional dose should be taken to alleviate this.
True
20-50% of pts experience recurrence of migraine 48hrs after 1st dose → take additional dose of triptan
What is the MoA of CGRP mABs?
Monoclonal Ab CGRP (receptor) inhibitor → prevent signalling
CGPR: calcitonin gene-related peptide, is a nociceptive neuropeptide at trigeminal ganglion and causes vasodilation → trigger migraine-like headaches
List 2 CGRP mABs. State where do they exert their effect on.
Block CGRP receptor on trigeminal nerve: erenumab
Block CGRP: eptinezumab, fremanezumab, galcanezumab
CGRP stands for:
Calcitonin gene-related peptide
What is the indication of CGRP mABs?
Prophylaxis of migraine in adults
What are the ADRs of CGRP mABs?
Hypersensitivity, injection site reactions, constipation, nausea, pruritus, raynaud, HTN, joint pain, nasopharyngitis ?
Raynaud: a disorder that causes decreased blood flow to the fingers. In some cases, it also causes less blood flow to the ears, toes, nipples, knees, or nose.
Clinical benefits of CGRP mABs can be seen within ________
3 months, but note that long-term partial blockade effect is unknown
What is the route of administration of CGRP mABs? How often is the dosing frequency?
SC, monthly
Erenumab has ________ kinetrics at therapeutic doses, as CGRP receptor binding is ______
Linear, saturated
What is the MoA of NSAIDs?
Inhibit prostaglandin synthesis → prevent neurologically mediated inflammation in the trigeminovascular system
What is the indication of NSAIDs?
Mild to moderate migraine attacks
What are the ADRs of NSAIDs? When should NSAIDs be used with caution/ avoided?
GI discomfort (dyspepsia, N/V, diarrhoea), CNS (somnolence, dizziness)
Caution/ avoid: prev PUD, renal disease, severe cardiovascular disease, hypersensitivity to aspirin
What are some CNS dose-dependent common adverse effects of ASMs?
Headache, drowsiness, fatigue, dizziness, confusion, nystagmus, ataxia, visual disturbances, mental changes
can anyhow whack and be correct ~ ML
What are some GI dose-dependent common adverse effects of ASMs?
N/V
can anyhow whack and be correct ~ ML
What are some psychiatric & cognitive dose-dependent common adverse effects of ASMs?
unusual behaviour (behavioural changes), slurred speech
can anyhow whack and be correct ~ ML
What are some strategies to mitigate ASM dose-dependent A/E?
- Initiate at ____ dose and slowly ____ dose
- Avoid ____ ____ ____
- Restrict therapy to ____ drug only
- Administer largest dose at ____ (for bothersome symptoms)
- Give in ____ ____
- ____ ____ formulations
- Reduce ____ ____ dose
- Initiate at low dose and slowly uptitrate dose
- Avoid large dosage changes
- Restrict therapy to one drug only
- Administer largest dose at bedtime (for bothersome symptoms)
- Give in divided doses
- Sustained release formulations
- Reduce total daily dose
What are some idiocyncratic adverse effects of ASM?
- Blood dyscrasia (aplastic anaemia, agranulocytosis),
- Hepatotoxicity (1st Gen ASMs)
- Pancreatitis (SV)
- Lupus-like rxn
- Exfoliative dermatitis
- Hypersensitivity (SJS, TEN), rash
What PGx testing can be conducted for CBZ-induced SJS/TEN?
HLA-B*1502
if positive: avoid carbamazepine and phenytoin
Do you know the lamotrigine dosing guidelines?
If a patient taking valproate is initiated on lamotrigine, how do you uptitrate his dose?
Week 1-2: Take 25mg EOD
Week 3-4: Take 25mg OD
Week 5 until maintenance: Increase by 25-50mg per day every 1-2 weeks
Usual Maintenance dose (in 1-2 divided doses):
With Valproate only: 100-200mg OD
With Valproate and other meds (induce glucuronidation): 100-400mg OD
im so sorry
Do you know the lamotrigine dosing guidelines?
If a patient is initiated on lamotrigine, how do you uptitrate his dose?
Week 1-2: Take 25mg OD
Week 3-4: Take 50mg OD
Week 5 until maintenance: Increase by 50mg per day every 1-2 weeks
Usual Maintenance dose (in 1-2 divided doses):
225-375mg per day
im so sorry
Do you know the lamotrigine dosing guidelines?
If a patient taking phenytoin is initiated on lamotrigine, how do you uptitrate his dose?
or carbamazepine/phenobarbital/primidone
Week 1-2: Take 50mg OD
Week 3-4: Take 100mg OD (2 divided doses)
Week 5 until maintenance: Increase by 100mg per day every 1-2 weeks
Usual Maintenance dose (in 2 divided doses):
300-500mg per day
im so sorry
List at least 3 common ASMs with aromatic rings
Carbamazepine, Lamotrigine, Oxcarbazepine, Phenytoin, Phenobarbital
What component of aromatic ASMs causes immunogenecity through interactions with proteins or cellular macromolecules?
Arene-oxide intermediate
Which ASM can cause Gingival Hyperplasia?
Phenytoin
Which ASM can cause Hirsutism?
Chronic Phenytoin Therapy
Which ASM can cause Alopecia?
Valproate
Which ASM can cause Peripheral Neuropathy?
(long term) Phenytoin, Carbamazepine, Phenobarbitone
can try folate supplementation
Which ASM can cause Osteomalacia?** How?**
Phenytoin, Carbamazepine, Phenobarbitone
increased Vit D clearance, leading to secondary hypoparathyroidism, increased bone turnover and decreased bone density
Which ASM can cause Increased Weight Gain?
Valproate
gradually reversible with discontinuation
Which ASM can cause Anorexia / Weight Loss?
Topiramate / Felbamate
Reversible with discontinuation
Which ASM can cause Suicidal Ideation?
ALL ASMs.
Just start ASMs though.
Which ASM can cause Tolerance/ Dependence?
Benzodiazapems / Barbiturates
What are the associated withdrawal effects of Benzodiazepams / Barbiturates?
Disturbed sleep, rebound anxiety, tremor, convulsions
Choose the most appropriate answer regarding gabapentin and pregabalin:
* hepatic/renal elimination
* low/high protein binding
* no/have DDIs
- Renal elimination
- Low (0%) protein binding
- No DDIs
Choose the most appropriate answer regarding clozabam:
* hepatic/renal elimination
* low/high protein binding
* no/have DDIs
- Renal elimination
- High (80-90%) protein binding
- Have DDIs
What are the 4 pharmacological classes to look out for DDIs w ASM?
- Antidepressants and antipsychotics
- Immunosuppressive therapy
- Antiretroviral therapy
- Chemotherapeutic agents
What is the active component of Carbamazepine?
its active metabolite: Carbamazepine-10,11-epoxide (CYP3A4)
