Pharmacokinetics & pharmacodynamics Flashcards
What is the MOA of barbituates
Act on GABA receptors and increase the DURATION of chloride channel opening
MOA of cyproheptadine
H1 antagonist (it also has 5HT-2 antagonist action)
What can cyproheptadine be used for?
Treatment of sexual dysfunction caused by increased serotonin transmission, particularly anorgasmia
Some evidence it could be used to treat akathisia (unlicensed)
MOA of Aripiprazole
Partial D2 agonist
Partial 5-HT1A agonist
High affinity antagonist at 5-HT2A
Low/moderate affinity antagonist of H1 and alpha-1
Is lamotrigine advised for acute mania?
NO
What changes to receptors would you see with chronic administration of antidepressants?
Down regulation of beta receptors
Which antidepressant is a weak inhibitor of P450?
Citalopram (and escitalopram)
MOA of valproate
Complex - inhibits catabolism of GABA, reduces turnover of arachidonic acid, reduces levels of protein kinase C, promotes brain derived neurotrophic factor expression
What is the active metabolite of trazodone?
mCPP
What does mCPP do?
Agonist at 5HT2C receptors
Bruxism is most associated with which class of drugs?
Stimulants
MOA of Varenicline
Partial nicotinic agonist
What is efficacy?
How well the drug produces the expected response
What does efficacy depend on?
Affinity
Potency
Duration of receptor action
Half life
Which medications are effective for premature ejaculation?
Fluoxetine & sertraline
What does mirtazapine preferentially block at lower doses?
H1
Which receptors does mirtazapine act on?
Alpha 2 blocker - increases serotonergic activity - antidepressant
Alpha 2 autoreceptor blocker - increases noradrenergic activity - antidepressant
H1 blocker - sedation, weight gain, dry mouth
5HT3 blocker - antiemetic
5HT2C blocker - antidepressant
5HT2A blocker - reduces akathisia
Which receptors does Risperidone act on?
Antagonist of 5-HT2A, D2, alpha-1, alpha-2 and H1
Which drug has high D2/high 5Ht2A activity?
Risperidone
Which drug has low D2 and high 5HT2A activity?
Clozapine
Which drug has high D2 and low 5HT2A activity?
Haloperidol
Which antipsychotic is a predominant D2 antagonist at therapeutic doses?
Sulpride (minimal D3 antagonist/partial agonist action)
MOA of Amisulpride
D2/D3 antagonist
Blocks autoreceptors, increasing synaptic dopamine levels
Which are the most sedative TCAs?
Dothiepin and amitriptyline
What can cause anorgasmia?
Alpha 1 antagonism
Raised prolactin
Which antipsychotic is best tolerated in Parkinson’s disease?
Quetiapine
What is the suggested pharmacological basis for clozapine-related hypersalivation?
M4 agonism
Half life of methadone
24 hours
Effect of non-competitive antagonists on receptor sites
Alter the receptor site so that the effects can reversed only partially by increasing dose of agonist drug
Effect of non-competitive antagonists on agonists
Reduces potency and efficacy of agonists
Which TCA has the largest evidence base in ADHD?
Desipramine
Which TCA has stimulant effect?
Desipramine
How does tyramine enter the presynaptic neuron?
Amine uptake pumps
4 main mechanisms of absorption
- Passive diffusion
- Facilitated diffusion
- Active transport
- Endocytosis
Where does most absorption from the gut take place and why?
Small intestine
Less acidic than stomach
Large surface area
Long transit time
Where does the absorption of most MR formulations take place?
Large bowel
Drugs which are 95-99% protein bound
Diazepam
Chlopromazine
Amitriptyline
Imipramine
Drugs which are 90-95% protein bound
Phenytoin
Valproate
Clomipramine
Principle plasma protein responsible for binding to acidic drugs
Albumin
Principle plasma protein for binding to basic drugs
Alpha-1 acid glycoprotein
Are most psychotropic drugs acid or base?
Basic
Equation for volume of distribution
Vd = Quantity of drug/plasma conc. at time of administration
What does high volume of distribution suggest?
Drug concentrated in cells or fatty tissues and not the blood
What is a high figure for Vd?
500-1000
What is the BBB made up of?
Capillary endothelium which have tight junctions
What type of molecules can cross BBB easily?
Unionized molecules that are less protein bound
Which parts of the brain lack BBB?
Area postrema of the medulla
Median eminence
Subfornical organ
Where is the blood-CSF barrier found?
Choroid plexus
What are tight junctions located between in blood-CSF barrier?
Adjacent epithelial cells
What is bioavailability?
How much of an administered drug reaches its target
How do you determine the bioavailability fraction?
Area under the curve obtained for orally administered drug divided by area under the curve for IV administered drug
Give an example of a TCA that undergoes high degree of first pass metabolism
Imipramine - only 30-80% of the oral dose enters the systemic circulation
What is bioequivalence?
Measure of comparability of plasma levels of 2 different formulations of the same active compound when given at the same dose and same route of administration
What does xenobiotics refer to?
The mechanism by which a foreign agent such as a drug molecule is metabolised and eliminated from the body
Where is the principal site of drug metabolism?
Liver
What are the 4 major metabolic routes?
Oxidation
Reduction
Hydrolysis
Conjugation
What happens in phase 1 metabolism?
Oxidation, reduction and hydrolysis
A molecule suitable for conjugation is produced
What happens in phase 2 metabolism?
Conjugation by reactions such as glucueonidation
Where is a molecule generally excreted if it has a relative molecular mass of less than 300?
Kidneys
Where is a molecule generally excreted if it has a relative molecular mass of more than 300?
Bile
What % and what race of people lack the CYP2D6 enzyme?
5-10% of Caucasian people
What class of drug and which drugs in this class particularly inhibit CYP system?
SSRIs
Particularly fluoxetine and fluvoxamine
Which drugs can induce their own metabolism?
Carbamazepine
Phenobarbitone
Which food/lifestyle factors are CYP inducers?
Alcohol
Smoking
Brussel sprouts
Which food/lifestyle factors are CYP inhibitors?
Grapefruit juice
Caffeine
Which major psychotropics are metabolised by CYP2D6?
All TCAs All neuroleptics Fluoxetine Paroxetine Valproate Risperidone
Which major psychotropics are metabolised by CYP3A4?
Most benzos
Mirtazapine
Fluvoxamine
Via which enzyme do smoking and caffeine affect glucuronidation?
UGT (and also by CYP1A2)
What is risperidone metabolised by?
CYP2D6
CYP3A
What is aripiprazole metabolised by?
CYP2D6 CYP3A
What is Quetiapine metabolised by?
CYP3A
What is clearance?
Term used to describe the rate of elimination of a drug
The volume of blood cleared of a particular drug in a unit of time
What is clearance directly proportional to?
Volume of distribution
Which drugs are excreted renally without significant liver breakdown?
Lithium Amisulpride Sulpride Gabapentin Acamprosate Amantadine
What is half life defined as?
Time taken for the plasma concentration of a drug to halve
Rate of elimination in zero order kinetics
Constant
Rate of elimination in first order kinetics
Directly proportional to drug concentration
Which drugs undergo zero order kinetics?
Modified release preparations and depots
Ethanol
Phenytoin
What happens to gastric pH in elderly?
Increases
Physiological changes in neonates
Higher body water
Lower adipose tissue
BBB more permable
Low conc of albumin
Physiological changes in pregnancy
Delayed gastric emptying
Increase Vd
Decreased albumin
Increased GFR and renal clearance
Which class of psychotropic drugs should be used with caution in renal disease?
Benzos
Why should you use diazepam with caution in end stage renal disease?
Diazepam half life unchanged but its metabolite desmethyldiazepam may accumulate
Effect of TCAs on l-dopa
Reduce absorption of l-dopa
Half life of fluoxetine and norfluoextine
Fluoxetine 4-6 days
Norfluoxetine 4-16 days
Which SSRIs do not have active metabolites?
Fluvoxamine and paroxetine
Which is the most selective SSRI?
Citalopram (and escitalopram)
What is the most potent SSRI?
Paroxetine
Which SSRI can reduce the clearance of diazepam and therefore should not be given together?
Fluvoxamine
What is citalopram metabolised by?
CYP2C19 and then by CYP2D6
How does fluvoxamine affect theophylline?
Reduces clearance of theopyhlline by around 3 fold via CYP1A2 inhibition
Half life of citalopram
33 hours
Fluvoxamine half life
17-22hrs
Paroxetine half life
22 hours
Sertraline half life
26 hours
What is the advice for starting drug that can fatally interact with MAO?
Wait at least 2 weeks after stopping MAOI
Half life of venlafaxine
3.5hrs
Which drug should never be started when on MAOIs?
Pethidine - can cause excitatory reaction which can result in death
Half life of duloxetine
12 hours
Trazodone half life
5-9 hours
Buspirone half life and subsequent effect on dosing
2-11 hours
3x daily dosing
St John’s Wort MOA
Acts via multiple monoamine reuptake inhibition
How long does it take for mirtazapine to reach peak plasma concentration?
2 hours
Bioavailability of mirtazapine
50%
Metabolism of mirtazapine
CYP2D6 CYP3A4
What type of metabolism does Agomelatine undergo extensively?
First pass
Metabolism of Agomelatine
CYP1A2 (90%)
CYP2C9 (10%)
Time taken for lithium to achieve steady state
4-5 days
Initial half life of lithium and what does it increase to/
Initially 18 hours then increases to 36 hours after 1 year of chronic use
Where is lithium excreted?
Proximal tubules
Which drugs increase lithium levels?
ACE inhibitors Loop diuretics Fluoxetine NSAIDs Thiazides
Which drugs decrease lithium?
Osmotic diuretics Caffeine Aminophylline Theophylline Carbonic anhydrase inhibitors
Half life of valproate
9 to 16 hours
Bioavailability of valproate
100%
Which drugs can increase carbamazepine levels?
Verapamil
Diltiazem
Valproate - displaces carbamazepine from plasma protein therefore increased carbamazepine levels
Which depot drugs are esterified in sesame oil?
Fluphenazine, haloperidol and perphenazine
Which depots are esterified in coconut oil?
Flupenthixol, piptiazine, zuclopenthixol
When is the peak level generally following depot injection?
Around 1 week
Half life of aripiprazole
90 hours
Half life of olanzapine
30 hours
Half life of quetiapine
6 hours
half life of clozapine
16hours
Half life of risperidone
15 hours
What does risperidone undergo extensive first pass metabolism to form?
9-hydroxyrisperidone
What catalyzes the hydroxylating of risperidone to 9-hydroxyrisperidone
CYP2D6
What length of oral tapering is required for aripiprazole depot?
2 weeks
Oral bioavailability of donepezil
100%
Half life of donepezil
70 hours
Half life of rivastigmine
1.5 hours
Half life of methylpenidate
2-3 hours
How can SSRIs affect atomoxetine levels?
SSRIs can raise levels
At supratherapeutic doses, what happens to fluoxetine metabolism?
Goes from first order to zero order kinetics
What happens in zero order kinetics?
Constant amount of drug cleared per unit of time
3 main compartments that drugs are distributed in
- Vascular
- Extra-cellular
- Intracellular
Which part of CYP system does fluoxetine inhibit?
2D6 and 3A4
Which drugs does fluoxetine increase the concentration of?
Haloperidol
Carbamazepine
Phenytoin
Which enzyme is responsible for oxidative metabolism of most psychotropic drugs?
Cytochrome P450
Does venlafaxine have high or low binding to plasma proteins?
Low
How long between stopping ssri and starting mao should you wait?
5-6 weeks
How are 95% of drugs eliminated (kinetics)?
First order
Examples of zero order kinetics
Ethanol Phenytoin High dose salicylates High dose fluoxetine High dose omeprazole
How can you treat amphetamine overdose?
Urinary acidification
After how many half lives should you assume that a drug is eliminated?
4-5
Zaleplon half life
1 hour
Which drug can be given as loading dose in acute mania?
Valproate
Effect of NSAIDs on lithium
Decreases excretion
How do NSAIDs cause decreased lithium excretion?
Inhibit the synthesis of renal prostaglandins, reducing renal blood flow and increasing renal re-absorption of sodium and therefore lithium
Which are the least sedative TCAs?
Lofepramine
Nortriptyline
Which TCA is safest in overdose?
Lofepramine
Which psychiatric drugs are CYP3A4 inducers?
Carbamazepine
St John’s Wart
Phenytoin
Topiramate
Is bioavailability affected by gender?
No
Zolpidem half life
2.6 hours
What is sensitisation?
Enhancement of drug effects following repeated administration of the same dose of drug
Which drugs skip phase 1 metabolism and go straight to phase 2?
Lorazepam
Oxazepam
Temazepam
What is fluvoxamine a potent inhibitor of?
CYP1A2
MOA of clonidine
Presynaptic alpha-2 receptor agonist
Decrease the amount of noradrenaline released
In which condition would drugs that alter protein binding become important?
Renal disease where proteinuria can occur
Which antidepressant exhibits autoinhibition?
Paroxetine
What needs to be balanced to allow high permeability across a membrane?
Hydrophillic and lipophillic properties
Active metabolite of imipramine
Desipramine
What metabolises imipramine to desipramine?
CYP2C19
Example of a partial agonist at the benzodiazepine receptor
Clonazepam
What is an ionotropic receptor?
Ligand-gated ionic channels
Examples of ionotropic receptors
5HT3
NMDA
GABA-A
Glutamate
What is a metabtropic receptor?
Slower response involving G-proteins which bind to the intracellular portion of the receptor and activate a second messenger
Examples of metabotropic receptors
D1-5 NA Serotonin 5HT1-7 (except 3) Muscarinic Opioid - mu
Which type of receptor binding produces maximal response?
Full agonist
What type of binding has a ceiling effect?
Partial agonist
What is an inverse agonist?
Agent that binds to the same receptor but produces the opposite pharmacological effect - no drugs work this way
How can a competitive antagonist be reversed?
By increasing the agonist dose
What is potency?
Minimum dose needed to produce an effect
What is efficacy?
Maximal response produced
How do non-competitive antagonists work?
Alter the receptor site
Effects of non-competitive antagonist on potency and efficacy?
Reduces both potency and efficacy
What is affinity?
Ability of drug to bind to its appropriate receptor
Difference in Sulpride MOA at low and high doses
Pure D2 antagonist
Low dose - presynaptic receptors blocked
High dose - post synaptic receptors blocked
MOA Lurasidone
D2 Antagonist
5HT2A blocker
High affinity for 5HT7
MOA Ziprasidone
5-HT2A and D2 antagonist
Also antagonises 5-HT1D, 5-HT2C, D3 and D4
MOA Zotepine
5HT2A, 5hT2C, D1, D2, D3, D4 antagonist
Potent NA reuptake inhibitor
MOA Agomelatine
5HT2C antagonist - enhances NA and dopamine neurotransmission
Direct agonist at melatonin MT1 and MT2
MOA Amoxapine
Dopamine antagonist and serotonin-noradrenaline reuptake inhibition
MOA Buproprion
Dopamine and noradrenaline reuptake inhibitor
Which TCA is most potent?
Clomipramine
TCA with least anticholinergic action
Desipramine
MOA of carbamazepine
Prolongs sodium channel inactivation
MOA of Gabapentin
Binds to alpha 2 delta subunit of the voltage-dependent calcium channel in the CNS
MOA of lamotrigine
Blocks voltage-gated sodium channels leading to modulation of glutamate
MOA of levetiracetam
Indirectly enhances GABA system
MOA of pregabalin
GABA analogue structurally but binds to alpha2delta subunit of voltage-dependent calcium channel
MOA of topiramate
Selective inhibitor of glutamate ampa receptors, blocks Na+ receptors and has indirect GABAergic activity
MOA of Vigabatrin
GABA transaminase inhibitor
Which is the least selective Z drug?
Zopiclone
MOA of amphetamine
Releases stored monoamines especially NA and dopamine
MOA of LSD
5HT2A partial agonist producing hallucinogenic effect
MOA of MDMA
2 isomers:
R- isomer - LSD-like effect
S+ isomer - amphetamine-like property
What inactivates acetylcholine?
Acetylcholinesterase
Butylcholinesterase
Non-competitive inhibitor of both AChE and BChE
Tacrine
MOA of modafinil
Activates hypocretin producing neurons possibly though alpha 2 or alpha 1 adrenergic agonist properties
4 groups of CYP2D6 variations
- Poor metabolisers
- Intermediate metabolisers
- Extensive metabolisers
- Ultrarapid metabolisers
Which group of CYP2D6 variations do most Caucasians fit into?
Poor metabolisers
Which group of CYP2D6 variations do most Asians fit into?
Intermediate metabolisers
Which group of CYP2D6 variations do most North Africans fit into?
Ultrarapid metabolisers
In which gender group is antipsychotic response shown to be superior?
Women
Which enzyme appears to be less active in women than men?
CYP1A2