Pharmacodynamics Flashcards
Barbiturates work by…
Increasing the duration of chloride channels opening - act on GABA receptors
How does chronic administration affect beta-adrenergic receptor function?
Down-regulates them –> this occurs with most anti-D after 2-4 weeks and has been postulated as a therapeutic mechanism
Trazadone has what receptor functions
5-HT2A antagonist
5-HT2C antagonist
Serotonin reuptake inhibitor
–> classified as a serotonin antagonist and reuptake inhibitor
–> metabolite mCPP (active) - 5HT2C agonist
Compare/contrast the functions of Sulpride and Amisulpride
Sulpride - D2 receptor antagonist (minimal D3 activity)
Amisulpride - D2/D3 receptor antagonist
- Note at low doses amisulpride blocks autoreceptors increasing synaptic DA –> this may have improve -ve symptoms in mesocortical region
- At higher doses blocks D2 receptors reducing +ve symptoms
How does Buspirone work?
5HT1a partial agonism - anxiolytic effects may be at presynaptic and postsynaptic receptors
[]How does Acamprosate work?
NMDA antagonism
It is a synethetic taurine and NMDA receptor antagonist that actually increases GABA-ergic functioning
What antipsychotic is best tolerated in Parkinson’s?
Quetiapine - has lowest capacity to worsen motor symptoms
Avoid Risperidone and typical antipsychotics
Aripiprazole, Olanzapine, Ziprasidone are likely to worsen motor symptoms
How do anti-D differ in terms of capacity to inhibit P450 enzymes?
How do anti-D differ in terms of capacity to inhibit P450 enzymes?
Sertraline very little P450 activity
Citalopram/Escitalopram weak inhibitor of CYP1A2 & CYP2D6
Fluvoaxmine, Fluoxetine and Paroxetine are classified as potent inhibitors
Compare TCA’s with regards to capacity for more and less sedation
Amitriptyline and Dotheipin - more sedating
Clomipramine, Imipramine, Lofepramine, Nortryptyline - less sedating
What is cyproheptadine, how does it function and what are its indications?
H1 receptor blockade
5-HT antagonist
Used to treat SSRI induced anorgasmia and akasthesia with antipsychotics although the later is unlicensed
Which SSRI have less harmful effects for sexual dysfunction?
Fluoxetine
Setraline
Would a rapid cycling bipolar likely respond well to Lithium
No - responds poorly to medication
What receptor mechanisms have been linked to weight gain in clozapine
Alpha-2 adrenergic antagonism, D2 antagonism, H1 antagonism, increased serum leptin (leptin hypersensitivity)
What is the ceiling effect for partial agonists?
The size of their effect depends on the availability of competing neurotransmitters - if the neurotransmitter is readily available the less efficient partial agonist will decrease the effect (Aripiprazole) if not available a partial agonist may increase its effect
How can the effect of a competitive antagonist be reversed?
By increasing the dose of the agonist
Competitive antagonists only reduce potency but not efficacy of agonists. Therefore increasing the amount of agonists available will reduce the antagonist effect
Competitive antagonists:
- Atropine at muscarinic receptor
- Proponalol at Beta-adrenergic receptors
Does increasing the dose of an agonist reverse the effects of a non-competitive antagonist?
No
Non-competitive antagonists affect the receptor site so increasing agonist concentration will only partially reverse the effect
E.g. Ketamine and PCP on NMDA receptors
What is law of mass action?
That increasing the percentage of occupied receptors increases the response until all receptors are occupied - increasing dose beyond this will not lead to improvements in response
Define potency and what factors does it depend on?
Potency is the required dose of a drug needed to reach a particular effect compared to another drug with a similar receptor profile
Depends on:
- Affinity –> how well a drug binds to a receptor
- Efficacy –> how well a drug produces an expected response - this is affected by affinity, potency, duration of action and sometimes half-life
- Proportion of drug that reaches the receptor
What is the D2 blocking ratio
Ratio of selectivity for D2 blockade : 5HT2 blockade
- Atypical antipsychotics show high selectivity for D2 blockade
State the mechanisms of the following drugs
a) Aripiprazole
b) Amisulpride
c) Sulpride
d) Asenapine
e) Chlorpromazine
f) Clozapine
g) Lurasidone
a) DA partial agonist - goldilocks effect where it antagonises DA in high activity areas (mesolimbic - reduces positive symptoms) and increases activity in low activity areas (mesocortical - reduces negative symptoms). Acts on post synaptic and autoreceptors.
b) D2 and D3 antagonism - equal pre and postsynaptic activity (low affinity for D1 like). Less activity for non-dopaminergic receptors
c) D2 antagonism only - low doses it works on presynaptic receptors (-ve symptom improvement) at high doses it acts on postsynaptic receptors (+ve symptoms improvement)
d) Asenapine - D2 and 5HT2A antagonist and alpha-2-blockade. Weight and prolactin neurtral. Licensed for mania
e) Moderate D2 blockade and muscarinic blockade - sedation
f) High 5HT2 to D2 ratio. High affinity for D4 but also antagonist of D1, D2, D3. Antagonises alpha-1, alpha-2, muscarinic receptors (M1, M3, M5) & H1. ? agonises M4 to account for hyper-salivation. Fast dissociation rate (like Quetiapine) hit and run profile.
g) High D2 and 5-HT2a antagonism. Also antagonism of 5-HT7. Less effect on H1 (? weight neutral) and alpha-1 (less orthostatic effect)
Outline the mechanism of action of
a) Olanzapine
b) Risperidone & paliperidone
c) Quetiapine
a) High 5HT2 / D2 blocking ratio (antagonism of both). Also blocks D4 and 5HT6. Significant anticholinergic effects and histamine
b) High 5HT2a antagonist also D2 blockade - in higher doses can D2 blockade like typical can cause high prolactin
c) Quetiapine has a hit and run D2 activity like Clozapine. High anticholinergic effects like Olanzapine. Lower 5HT2a activity compared to other antipsychotics
What is the most potent TCA?
Clomipramine - TCA with most SRI selectivity
Describe some of the suggested mechanisms of Lithium?
A drug which is poorly understood however works on 2nd messenger systems inositol and putatively increases serotoninergic transmission
- Increases tryptophan uptake
- Down regulates 5-HT1a, 1B and 2
- Enchances serotonin release
- Inhibits IMPase which breaks down inositol
How does Mirtazapine work?
Noradrenaline and specific Sertonin Antagonist
5HT2 anatagnosim
Alpha-1 and Alpha-2 adrenergic antagonism
H1 antagonism
Muscarinic antagonism
Which MAOI does moclobemide have selectivity for?
MAO-A - moclobemide is reversible and selective
Which is the most potent SSRI
Paroxetine - has significant anticholinergic SE effects though
Is Trancypromine selective?
No its a non-selective irreversible MAOi
How does Buproprion work?
Dopamine and Noradrenaline reuptake inhibitor - also a nicotinic receptor antagonist
How does Trazadone work?
5HT1a receptor antagonist (presynaptic) - SERT reuptake inhibition - weak effect
5HT2A/2C antagonist - SE - insomnia, sexual dysfunction
Alpha-1 and alpha-2 adrenergic blockade
H1 antagonism
How does St John’s Wart work?
Weak MAOI and weak SSRI
How do the following mood stabilisers work?
a) Valproate
b) Gabapentin
c) Topiramate
d) Carbamazepine
e) Phenytoin
f) Pregabalin
g) Lamotrigine
a) GABA agonist and NMDA antagonist (also inhibition of phosphokinase C and functional dopamine antagonism)
b) inhibits release of excitatory neurotransmitters at alpha-2-delta-1 sites of voltage gated calcium channels
c) GABA agonist, NMDA antagonist and NA channel stabiliser
d) Stabilises Na channels
e) Stabilises Na channels
f) Ligand of alpha-2-delta subunit of voltage gated calcium channels in CNS. More potent high therapeutic index and less dose related SEs
g) NMDA antagonist and stabilises Na channels
How do benzodiazepines work?
Full agonists of omega site of GABA-A channels (apart from clonazepam which is a partial agonist).
Here they bind to increase the frequency of channels opening and the duration of opening (note do not effect number of channels).
Binding facilitates chloride ions to enter and inhibitory neurotransmission. No effect in absence of GABA
How doe Z drugs differ from BDZ?
Still GABA-A agonists however do not work on all three receptor subtypes
Zopiclone and zolpidem only work on omega-1
Zalepron does work on all 3
How do the ADHD drugs work?
Stimulants:
- Dexamphetamine - NA and DA reuptake inhibitor
- Lisdexamphetamine - prodrug converted by an enzyme in RBC into dexamphetamine and L-Lysine. NA and DA reuptake inhibitor
- Methylphenidate - NA and DA reuptake innihibor
Non-stimulants:
- Atomoxetine - NERT - selectively
- Clonidine - alpha-2 adrenergic agonist - minics NA
- Guanafacine - selective alpha-2a adrenergic agonism mimicking NA
Which ADHD drugs are metabolised by the CYP450 enzyme system
- Dexamphetamine/Lisdexamphetamine - minimally
- Atomoxetine - YES - CYP2D6
- Guanafacine - YES - CYP3A4 - note guanfacine can increase levels of valproic acid
Outline the SE of ADHD drugs?
Stimulants all can cause headache, appetite reduction
Dexamphetamine/Lisdexamphetamine can cause weight loss or less weight gain
Atomoxetine can increase HR and BP
Clonidine can cause orthostatic hypotension and dizziness
What are the agonistic effects of different opiod receptors?
Mu:
- Analgesia
- Euphoria
- Constipation
- Resp depression
Kappa
- Euphoria
- Dysphoria
- Diuresis
- Analgesia
Delta
- Anxiolysis
- Analgesia
Outline the mechanisms of action of
a) Methadone
b) Buprenorphine
c) Naloxone
d) Naltrexone
a) Full mu receptor agonist
b) Partial agonist of mu receptors (also k to some extent and maybe weak delta antagonist). Metabolised by CYP3A4
c) Naloxone antagonises all receptors (mu, kappa, delta)
d) Naltrexone antagonises mu and kappa receptors (lesser extent delta) - patients need to be opiod free for 7-10 days. Metabolite is competitive and reversible antagonist (active)
What is an uncommon side effect of naloxone?
Non-cariogenic pulmonary oedema
Outline the half lives of methadone, buprenorphine, naloxone and natrexone
Methadone 15-22hr
Buprenorphine 22-24hr
Naloxone 30-120 mins
Naltrexon 4-6hrs
Which has more affinity for mu receptor methadone or buprenorphine?
Buprenorphine - 5 x affinity
What are opiod withdrawal symptoms mediated by?
Noradrenaline - mu receptors on noradrenaline cells in the locus coerlus (pons) inhibit activity - therefore when opiods not present increased NA activity
Sweating, shivering, runny nose and eyes - drugs that can be prescribed for these include Lofexidine and Clonidine - alpha-2-adrenergic agonists (Lofexidine is favoured due to less antihypertensive effect).
