Pharmacology Flashcards
Levidopa/Carbidopa
Used in Parkison’s.
Levodopa = metabolic precursor of dopamine.
Carbidopa = peripheral decarboxylase inhibitor, which prevents peripheral breakdown to increase CNS levels.
Selegline
MAO-B inhibitor
Used in early Parkinson’s as breaks down dopamine selectively.
Caution with SSRIs.
Entacapone
Used in Parkinson’s to increase the half-life of L-dopa so there are less motor fluctuations and dyskinesia.
Donepezil
Selective reversible AChE inhibitor.
Binds at peripheral site.
Given once daily.
Dose 5-10mg.
ADRs: N+V, insomnia, diarrhoea, bradycardia.
Rivastigmine
Reversible AChE inhibitor. Also acts on butylcholinesterase.
Given BD.
Dose 1.5-6mg BD.
Also available as transdermal patch.
Galantamine
Selective competitive AChE inhibitor. Also acts as antagonist at nicotinic receptors.
Given BD.
Dose 12mg BD.
ADRs: N+V.
Not subsidised in NZ.
Memantine
NMDA-receptor antagonist.
Blocks excitotoxic glutamate activity.
Indicated in moderate/severe dementia.
Acetylcholinesterase inhibitors
Indications: Alzheimer’s, Lewy body, Parkinson’s, vascular dementia.
Better evidence in mild/mod than severe.
Contraindications: FTD, pure alcoholic dementia, large strokes, MCI.
Stabilise symptoms for 6-12 months, with subtle improvement in 50% (sx improved include apathy, spontaneity, delusions/hallucinations).
Bupropion
Dopamine + NA reuptake inhibitor.
Indicated in smoking cessation (reduces withdrawals, post-cessation weight gain) and depression.
ADRs: psychiatric sx, seizures
Varenicline
Nicotine α4β2 partial receptor agonist
Indicated in smoking cessation
ADRs: nausea, dry mouth, depression/SI
Disulfiram
Prevents ETOH breakdown by aldehyde dehydrogenase.
Indicated in alcohol abuse as negative reinforcement.
ADRs: can affect liver and thyroid
Naltrexone
Opiate receptor antagonist
Used in alcohol dependence as reduces pleasure, no withdrawal, no negative effects, minimal ADRs/interactions
But high relapse rate, withdrawal sx if using opiates
Acamprosate
GABA analogue, acts on GABA and glutamate systems, allosteric modulator of GABA-A
Used in alcohol dependence
Dose: <60kg = 333mg TDS, >60kg = 666mg TDS
Lofexidine
α2A adrenergic receptor agonist
Can be used in opiate withdrawal to reduce sx
Methadone
Full opioid agonist
Start low and give incremental doses as per withdrawal scale
Usual dose 60-120mg, can take 6 weeks to stabilise
Need to monitor LFTs and QTc
Advantages: well absorbed, long half-life (OD dosing, in urine for 3 days), used in pregnancy
Suboxone
Buprenorphine (long acting partial mu agonist, weak kappa agonist, delta agonist) + naloxone (opioid antagonist).
Diminishes cravings and helps with withdrawal.
Safe in overdose due to ceiling effect. Blocks other opioid agonists in dose-dependent fashion. Can precipitate withdrawal so first dose given when already in withdrawal.
Usual dose 2-8mg. Half-life 24-37 hours.
Advantages: milder withdrawal, alleviates cravings, long-acting, greater blockade effect
Caution with CYP3A4 inhibitors (inducer).
First generation antipsychotics
Predominantly dopamine blockers in mesolimbic pathway (to reduce psychotic sx), but not selective, so also act on mesocortical (secondary negative sx, depression, cognitive dysfunction), nigrostriatal (EPSE) and tuberoinfundibular (raised PL) pathways.
Second generation antipsychotics
Combination of D2 blockade plus 5HT-2 blockade, which causes reciprocal increase in dopamine, so effects more specific to mesolimbic pathway, with reduced side effects.
Variable in how tightly they bind D2 and how quickly they dissociate.
If used in high doses, dopamine blockade exceeds 60-80%, and they start to act as typical antipsychotics.
Benztropine
Anticholinergic and antihistamine
Used in movement disorders, such as parkinsonism and dystonia, and EPSE, such as akathisia.
Not useful in tardive dyskinesia.
ADRs: dry mouth, blurry vision, nausea, constipation
Benztropine overdose presents with confusion, trouble swallowing, hot and dry skin, dilated pupils, tachycardia, urinary retention, irregular pulse, fainting or seizures.
Antidote = physostigmine
Tetrabenazine
Inhibits vesicular monoamine transporter and depletes presynaptic dopamine.
Used for treatment of hyperkinetic movement disorders, such as tardive dyskinesia, hemiballismus, Huntington’s chorea, tics.
Depletes dopamine so can lead to depression/SI.
Bromocriptine
Partial D2 agonist
Used in NMS, as well as hyperprolactinaemia and acromegaly
Aripiprazole
Partial D2 agonist, 5HT-2A antagonist, partial 5HT-1A agonist.
High affinity for receptor but low intrinsic activity (Goldilock’s effect).
Can be used as augmentation to reduce side effects.
Highly protein bound (99%).
Long half-life (94 hours).
CYP3A4 substrate.
Amisulpride
Selective D2/D3 antagonist.
D3 are presynaptic autoreceptors in frontal lobe so antagonism increases dopamine.
At <400mg, amisulpride enhances dopamine transmission.
At higher doses, it blocks D2 and can cause raised PL.
Purely excreted renally. Can be used in hepatic disease. Avoid in renal impairment.
Given BD at doses >300mg to increase therapeutic effect and reduce adverse effects.
Chlorpromazine
D1/D2/D3/D4 antagonist
Also acts as antagonist of 5-HT, H1, alpha1-2, M1-M2
Highest risk of sunburn due to increased skin photosensivity
Clozapine - Mechanism + Metabolism
D2 and 5HT-2 antagonist with hit-and-run mechanism (highest dissociation rate)
Highest affinity for D4
Potent anticholinergic
CYP1A2 - so caffeine increases levels and smoking reduces levels
CYP3A4 responsible for 35% of clozapine metabolism - so drug interactions
Clozapine - Side effects
- Most epileptogenic antipsychotic
- Agranulocytosis (usually first 18 weeks, contraindicated with carbamazepine)
- Myocarditis (usually first 8 weeks)
- Cardiomyopathy
- VTE and PE
- Constipation
- Tachycardia
Flupenthixol
D2 antagonist, also acts on 5HT
Typical antipsychotic
Antidepressant effect at lower doses
Available as depot
Haloperidol
D2 antagonist
Typical antipsychotic
Can be used in renal and hepatic impairment, and in pregnancy (1st line for mania)
Indicated for tics in Tourette;s
Available as depot
Olanzapine
D2 and 5HT-2 antagonist, H1 blockade (sedating)
Can be used in renal impairment.
CYP1A2 involved (nicotine, caffeine).
Half-life 30 hours.
Highest passage across placenta of SGAs, associated with high birth weight, macrosomia, increased ICU admissions.
Need to monitor for post-injection syndrome.
Paliperidone
D2 and 5HT-2 antagonist
Major active metabolite of risperidone
Low potential for drug interactions as limited hepatic metabolism
Half-life 24-28 hours
Quetiapine
D2 (higher dissociation so lower risk of EPSE) and 5HT-2 antagonist, H1 blockade (sedating)
CYP3A4 involved
Half-life 6-12 hours so multiple daily dosing
Risperidone
D2 and 5HT-2 antagonist
At higher doses, binds selectively to D2 so more risk of EPSE and high PL.
Potent alpha-1 blocker so first dose hypotensive effect.
Extensive first pass metabolism by CYP2D6 to 9-OH risperidone.
Half-life of metabolite = 24 hours.
Second highest passage across placenta.
Sertindole
Strong D2 and 5HT-2 antagonist
Potent alpha-1 blocker
Highest potential for QTc prolongation
Sulpride
Dose-related antagonist at presynaptic D3 (<800mg/day) and postsynaptic D2 (>800mg/day).
Purely renally excreted. Avoid in renal impairment. Recommended in hepatic disease.
Trifluoperazine
D1/D2 antagonist
Typical antipsychotic
Thioridazine
Not available due to highest risk of prolonged QTc
Ziprasidone
D2 and 5HT-2 antagonist, 5HT-1A agonist, monoamine reuptake inhibitor
Acts as antidepressant at low doses (due to MAOI effect).
Reduces weight through 5HT agonism.
High risk for prolonged QTc.
CYP3A4 involved.
Half-life = 7-12 hours.
Zuclopenthixol
D1/D2 antagonist, 5HT-2 antagonist, alpha-1 adrenergic
Typical antipsychotic
Available as decanoate (depot), acetate (accuphase, effect peaks at 48-72 hours) and oral.
Interacts with paroxetine due to shared hepatic metabolism.
Lurasidone
D2/D3 antagonist, 5HT-2A/5HT-7 antagonist, 5HT-1A partial agonist, alpha-2c antagonist
Atypical antipsychotic
Used in bipolar depression, alone or as an adjunct.
Low risk of weight gain.
SSRIs - Mechanism
Block SERT (serotonin reuptake transporter) so serotonin remains in synaptic cleft and can bind to various serotonin receptors.
Initially, there is an increase in signaling across synapses that use 5HT as main neurotransmitter.
With time, increased occupancy of post-synaptic 5HT receptor downregulates release of 5HT from presynaptic neurons, which ultimately leads to downregulation of postsynaptic 5HT receptors.
Serotonin receptors involved in SSRIs
5HT1A = presynaptic autoreceptor, acts as brake.
5HT-2A = postsynaptic receptor, effects include anxiety, akathisia, emotional blunting, insomnia.
5HT-2C = postsynaptic, can lead to sexual dysfunction and anorexia.
5HT-3 = postsynaptic, can lead to nausea and diarrhoea, ligand gated.
5HT-7 = circadian rhythms.
SSRIs - side effects
Initial anxiety
Sleep disturbance
GI upset
Headaches
Hyponatraemia
GI bleeding
Sexual dysfunction
Side effects dominate when SSRI first started, but they should reduce as receptors down regulate.
Paroxetine has most weight gain and sexual side effects.
SSRIs - Interactions
Enzyme inhibitors so can increase levels of clozapine, olanzapine, benzos, TCAs, methadone.
Do not prescribe with MAOIs due to risk of serotonin syndrome.
Mirtazapine - Mechanism
NASSA (NA serotonin specific antagonist)
At doses of 15-30mg, it is primarily a serotonin antagonist, so effects are:
- 5HT-2A = antianxiety, treats akathisia, improves slow wave sleep
- 5HT-2C = increased appetite, no sexual effects
- anti-H1 = increased appetite, sedation
At doses of 45-60mg, it primarily has a noradrenergic dopaminergic effect, by antagonising alpha-2 presynaptic receptor, increasing NA and dopamine => broad spectrum antidepressant.
Mirtazapine - Side effects
Sedation at low doses (H1).
Weight gain, increased appetite.
Agranulocytosis.
Caution in epilepsy.
No sexual dysfunction.
Minimal risk of serotonin syndrome.
SNRIs - Mechanism
SNRIs = venlafaxine, duloxetine.
Serotonin noradrenergic reuptake inhibitors.
- Block SERT to increase serotonin.
- Block NET to increase NA and dopamine.
Broad spectrum effect.
Half-life 4-5 hours.
Venlafaxine predominantly acts as SSRI up to 225mg, then has SNRI effects above that.
SNRIs - Side effects
Side effects of both SSRIs and dopamine-related effects (activation, agitation).
Sexual dysfunction.
Hypertension at doses >225mg.
Greater risk of discontinuation syndrome.
Caution in epilepsy (seizure risk).
Agomelatine - Mechanism
Melatonin agonist (M1/M2) = improves slow wave sleep.
5HT-2C antagonist
Also increases frontal lobe dopamine and NA.
Agomelatine - Side effects
LFT derangement
No risk of serotonin syndrome
No sexual dysfunction
Tricyclics - Mechanism
Broad spectrum antidepressants
Act primarily as SNRIs by blocking SERT and NET.
Weak affinity for DAT.
Many also have high affinity as 5HT antagonists, alpha-1 adrenergic and NMDA receptors, and as sigma agonists.
Also have potent anticholinergic and antihistaminergic effects.
Tricyclics - Examples
Amitriptyline, nortriptyline
Clomipramine, desipramine, imipramine
Dosulepine, doxepine
MAOIs - Examples
Non-selective = phenelzine, tranylcypromine
Selective MAO-A = moclobemide
Selective MAO-B = selegline
MAOIs - Mechanism
Broad spectrum antidepressants
- Inhibit MAO to prevent breakdown of monoamine neurotransmitters
- MAO-A preferentially acts on serotonin, melatonin, adrenaline and NA
- MAO-B preferentially acts on phenethylamine and other trace amines
- Dopamine equally affected by both
MAOIs - Side effects
Hypertensive crisis - which can be fatal. Need to avoid eating food contained tyramine (cheese, fermented food, liver).
NARIs
Atomoxetine (used in ADHD) and reboxetine.
Noradrenergic reuptake inhibitors
Can cause liver failure and SI
Vortioxetine
SSRI + serotonin modulator, so blocks SERT to increase serotonin, but with minimal sexual dysfunction or weight gain.
5HT-7 antagonist = pro-cognitive effects.
SARIs
Nefazodone and trazodone.
Serotonin antagonist and reuptake inhibitor (of 5HT, NA and dopamine).
Also antagonist alpha-1 adrenergic receptors.
Buspirone
5HT-1A partial agonist with high affinity
Acts as a full agonist at presynaptic receptor, to decrease serotonin levels for anti-anxiety effect.
Acts as a partial agonist at postsynaptic receptors, for anti-depressant effects.
Also a D2 antagonist.
Half-life 2-12hours.
Can be used in depression, GAD.
Main side effect is dizziness (titrate dose slowly).
Cyproheptadine
Antihistamine with anti-serotonergic effects (5HT-1 and 2 blockade).
Used in treatment of serotonin syndrome
Lithium - Mechanism
Acts via “second messenger system”.
Effects include decreased NA release, increased 5HT synthesis, inhibition of excitatory neurotransmitters (dopamine, glutamate) and promotion of glutamate (inhibitory).
Likely has neuroprotective/neuroproliferative effects.
Lithium - Pharmacology
Half-life 18-36 hours.
Peak plasma concentration at 1-2 hours (standard release) or 4-5 hours (ER).
Starting dose 250mg BD or 400mg nocte. Loading dose 20-30mg/kg.
Bioavailability 80-100%
Follows zero order kinetics
Almost exclusively excreted by kidney as free ion
Lithium - Indications
Prophylaxis and treatment of mania, hypomania and depression in BPAD
Prophylaxis and treatment of unipolar depression
Augmentation agent to antidepressants
Note full prophylactic effect may take 6-12months
Lithium - Plasma levels
Narrow therapeutic/toxic ratio
Levels taken on day 7, 12 hours post-dose.
Targets:
- 0.4-0.6 for tx of depression
- 0.6-08 for prophylaxis
- 0.8-1.2 for tx of mania
Lithium - Toxicity
Level >1.5
Tremor, ataxia, dysarthria, nystagmus, renal impairment, convulsions, death.
Lithium - Side effects
Common - polyuria, thirst, tremor, impaired memory/cognition, hair loss, acne
Serious - hypothyroidism, hyperparathyroidism, renal damage
Lithium - Interactions
Avoid diuretics, ACEIs, ARBs, NSAIDs
All increase lithium level
Lithium - Pregnancy
Potential risk of fetal heart malformations, especially in 1st trimester.
If taken during pregnancy, levels may drop in later stages due to increased GFR.
Lithium passes freely into breast milk.
Valproate - Mechanism
Unknown, but proposed ideas include affecting GABA levels, blockage of voltage-gated Na+ channels, inhibiting histone deacetylases.
Valproate - Pharmacology
Half-life 16 hours
Bioavailability close to 100%
90% protein bound (levels may be inaccurate in hypoalbuminaemia, can displace other drugs such as warfarin, phenytoin, carbamazepine)
Metabolised by liver
Loading dose 20-30mg/kg
Valproate - Indications
Treatment of mania, mixed mood episodes, rapid cycling BPAD
Prophylaxis in BPAD
Valproate - Levels
Not routinely monitored as poor correlation with therapeutic efficacy.
May be useful in non-adherence, suspected toxicity.
Trough level - 350-700 μmol/L
Valproate - Side effects
Common = N+V, dry mouth, somnolence, hair loss, peripheral oedema.
Serious = liver failure (monitor LFTs), pancreatitis, increased suicide risk, thrombocytopenia.
Can lead to hyperammonaemic encephalopathy in people with disorders of carnitine metabolism.
Valproate - Pregnancy
Highly teratogenic
Contraindicated in women of childbearing age
Valproate - Interactions
Can increase lamotrigine levels by inhibiting gluconuridation
Carbamazepine - Mechanism
Blocks voltage-gated Na+ channels, reduces glutamate release, decreases adrenaline/NA turnover
Carbamazepine - Pharmacology
Bioavailability 80%
Variable absorption
75% bound to plasma protein
Induces its own metabolism (CYP3A4)
Carbamazepine - Indications
Prophylaxis in BPAD, rapid cycling
Carbamazepine - Levels
Trough level 16-40 μmol/L
Check 4-6 monthly or if dose adjusted
Carbamazepine - Side effects
Common = drowsiness, headaches, N+V, constipation, dizziness
Serious = severe skin reactions (SJS, toxic epidermal necrolysis), agranulocytosis, aplastic anaemia, porphyria
Carbamazepine - Interactions
- Potent CYP3A4 inducer - interacts with OCP, antipsychotics (can decrease levels), methadone, thyroxine
- Levels may be increased by fluoxetine/paroxetine
- Contraindicated with clozapine
Lamotrigine - Mechanism
Blocks voltage-gated Na+ channels, with secondary effect on Ca2+ transport, leading to membrane stabilisation and decreased glutamate release.
Weak 5HT-3 antagonist.
Lamotrigine - Pharmacology
Half-life 28 hours
55% protein bound
Lamotrigine - Indications
Prevention of depression in BPAD
Not effective for mania
Lamotrigine -rash
About 8% get a rash in first 4/12 of tx.
In 0.1%, this is SJS or TEN, so lamotrigine must be stopped at first sign of a rash.
Risk of rash increased with rapid titration, higher doses, co-administration with valproate.
Lamotrigine - Interactions
Carbamazepine decreases levels by 50%
Valproate increases levels by 50%
COCP induces glucuronidation, increasing excretion x3
Gabapentin/Pregabalin
Structural analogues of GABA
Bind to voltage-gated Na+ channel
Act on 1-amino acid transporter and increases GABA availability in brain
Anxiolytic, analgesia and anticonvulsant effects
Tiagabine
Potent inhibitor of GABA uptake into neuros and glial cells, by selective inhibition of GAT1 (GABA transporter)
Used an anticonvulsant, as well as in anxiety and panic disorders
Vigabatrin
Selective irreversible GABA-transaminase inhibitor
Indicated as anticonvulsant
Topiramate
Modifies Na+ and Ca2+ dependent channels
Selective inhibitor of kainate-mediated AMPA glutamate receptors
Enhances GABA-mediated Cl- flux into neurons
Potentiates action of GABA-A receptor
Indicated in epilepsy, migraine prophylaxis
Benzodiazepines - Mechanism
Enhance effect of GABA on GABA-A receptor to decrease excitability of neurons, resulting in sedative, hypnotic, anxiolytic, anticonvulsant and muscle-relaxant properties
Benzodiazepines - half-lives
Short acting = midazolam (half-life 2hrs), triazolam
Intermediate acting = clonazepam (half-life 19-60hrs), lorazepam (half-life 10-20hrs) and temazepam
Long acting = diazepam (half-life 20-80hrs)
Benzodiazepines - Side effects
Withdrawal (due to decreased brain GABA function), tolerance and dependence
Drowsiness, dizziness, cognitive impairment (anterograde amnesia)
Paradoxical reactions
Can precipitate coma in hepatic impairment
Z-drugs
Very similar to benzodiazepines
Used for anxiolytic and hypnotic effects
Mechanism: agonists of GABA-A alpha-1 subunit on omega-1 receptor (also called benzodiazepine-associated receptor), which potentiates GABA
Similar benefits, risks and side effects to benzos
Prazosin
Alpha-2 presynaptic agonist
Reduces NA in brain to help with hyperarousal and nightmares
Clonidine
Alpha-2 adrenergic agonist
Melatonin
Hormone released from pineal gland
Melatonin 1 and 2 receptor agonist
Mixed evidence of efficacy for sleep
Half-life 3-4 hours
Promethazine
H1 receptor antagonist, anticholinergic
Side effects = headache, antimuscarinic effects, psychomotor impairment, excitation in young/old
Methylphenidate
Ritalin = immediate release
Concerta = sustained release
Side effects: tachycardia, hypertension, anorexia, dry mouth, GI effects
First line for ADHD
N-acetylcysteine
Used for paracetamol overdose
Reduces oxidative and neuroinflammatory stress
Can also be used as augmentation agent in mood disorders, especially BPAD
Dantrolene
Direct or indirect ryanodine receptor antagonist, to decrease intracellular Ca2+ and relax muscles
Used in treatment of rigidity in NMS
Flumenazil
Selective GABA-A receptor antagonist
Used as antagonist and antidote to benzodiazepines, through competitive inhibition
Desfuroxamine
Used as antidote in iron overdose
BAL
Dimercaprol or British anti-Lewisite
Used as antidote in arsenic and lead poisoning
Sodium bicarbonate
Used to prevent metabolic acidosis in overdose of TCAs
Thyroxine
Usual maintenance dose 100mcg
Half-life of 7-10 days, but much longer biological effect
Children require larger doses by bodyweight
SSRIs - Half-life
Fluoxetine has longest half-life = 5-7 days (washout period is about 35 days). Least likely to cause discontinuation sx.
Paroxetine has shortest half-life (21hrs) so has highest risk of discontinuation sx.
Other SSRIs have half-life of 20-72 hours (so washout period about 2 weeks)
Ketamine
NMDA receptor antagonist
In sub-anaesthetic doses, it non-competitively binds to NMDA receptors as an antagonist
Baclofen
GABA-B agonist
Used as a muscle relaxant and to reduce alcohol cravings
Sildenafil
Phosphodiesterase inhibitor
Binds to PDE5 competitively, and inhibit cGMP hydrolysis, leading to an erection.
Zero order kinetics
When the clearance system is saturated, a constant amount is eliminated. This means the levels in the body will increase with increase in doses, so toxicity can occur.
For example; phenytoin, lithium, depots, alcohol.
First order kinetics
A constant fraction of the drug is eliminated regardless of dose. The rate of clearance only depends on concentration. Most psychotropics are excreted via first order kinetics.
Bioavailability
The fraction of the dose that reaches systemic circulation
Bioequivalence
Measure of the comparability of plasma levels of two different formulations of the same active drug
Non-competitive antagonist
Binds to receptor at site distinct from active site, and induces a confirmational change in receptor which alters the affinity of the receptor for the endogenous ligand, so that effects cannot be reversed completely by increasing the dose of agonist.
Irreversible antagonist
Binds to the receptor but cannot be displaced
Tigabine
A potent inhibitor of GABA uptake into neurons and glial cells, by inhibiting GAT-1, a GABA transporter.
Anticonvulsant.
Caffeine
Acts as antagonist of adenosine A1 receptors
Half-life 4-6 hours
Beta-blockers
Overdose leads to hypoglycaemia
Hence treat with glucagon
Antidepressant recommended post-MI
Sertraline
CYP1A2
Involved in metabolism of clozapine, olanzapine.
Inducers = smoking
Inhibitors = caffeine, grapefruit, fluvoxamine, ciprofloxacin
CYP2D6
Involved in metabolism of risperidone, codeine.
Inhibitors = SSRIs (especially paroxetine, fluoxetine)
Significant ethnic differences in rate of metabolism/enzyme levels
CYP3A4
Involved in metabolism of clozapine, quetiapine, ziprasidone, carbamazepine
Inducers = carbamazepine, phenytoin, barbituates, rifampicin
Inhibitors = erythromycin, ketoconazole, protease inhibitors
CYP2C19
Inhibitors = fluoxetine, fluvoxamine
Ethnic differences (20% of Japanese/Chinese are deficient)
