Pharmacokinetics & pharmacodynamics Flashcards
1
Q
What is the MOA of barbituates
A
Act on GABA receptors and increase the DURATION of chloride channel opening
2
Q
MOA of cyproheptadine
A
H1 antagonist (it also has 5HT-2 antagonist action)
3
Q
What can cyproheptadine be used for?
A
Treatment of sexual dysfunction caused by increased serotonin transmission, particularly anorgasmia
Some evidence it could be used to treat akathisia (unlicensed)
4
Q
MOA of Aripiprazole
A
Partial D2 agonist
Partial 5-HT1A agonist
High affinity antagonist at 5-HT2A
Low/moderate affinity antagonist of H1 and alpha-1
5
Q
Is lamotrigine advised for acute mania?
A
NO
6
Q
What changes to receptors would you see with chronic administration of antidepressants?
A
Down regulation of beta receptors
7
Q
Which antidepressant is a weak inhibitor of P450?
A
Citalopram (and escitalopram)
8
Q
MOA of valproate
A
Complex - inhibits catabolism of GABA, reduces turnover of arachidonic acid, reduces levels of protein kinase C, promotes brain derived neurotrophic factor expression
9
Q
What is the active metabolite of trazodone?
A
mCPP
10
Q
What does mCPP do?
A
Agonist at 5HT2C receptors
11
Q
Bruxism is most associated with which class of drugs?
A
Stimulants
12
Q
MOA of Varenicline
A
Partial nicotinic agonist
13
Q
What is efficacy?
A
How well the drug produces the expected response
14
Q
What does efficacy depend on?
A
Affinity
Potency
Duration of receptor action
Half life
15
Q
Which medications are effective for premature ejaculation?
A
Fluoxetine & sertraline
16
Q
What does mirtazapine preferentially block at lower doses?
A
H1
17
Q
Which receptors does mirtazapine act on?
A
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
18
Q
Which receptors does Risperidone act on?
A
Antagonist of 5-HT2A, D2, alpha-1, alpha-2 and H1
19
Q
Which drug has high D2/high 5Ht2A activity?
A
Risperidone
20
Q
Which drug has low D2 and high 5HT2A activity?
A
Clozapine
21
Q
Which drug has high D2 and low 5HT2A activity?
A
Haloperidol
22
Q
Which antipsychotic is a predominant D2 antagonist at therapeutic doses?
A
Sulpride (minimal D3 antagonist/partial agonist action)
23
Q
MOA of Amisulpride
A
D2/D3 antagonist
Blocks autoreceptors, increasing synaptic dopamine levels
24
Q
Which are the most sedative TCAs?
A
Dothiepin and amitriptyline
25
What can cause anorgasmia?
Alpha 1 antagonism
| Raised prolactin
26
Which antipsychotic is best tolerated in Parkinson's disease?
Quetiapine
27
What is the suggested pharmacological basis for clozapine-related hypersalivation?
M4 agonism
28
Half life of methadone
24 hours
29
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
30
Effect of non-competitive antagonists on agonists
Reduces potency and efficacy of agonists
31
Which TCA has the largest evidence base in ADHD?
Desipramine
32
Which TCA has stimulant effect?
Desipramine
33
How does tyramine enter the presynaptic neuron?
Amine uptake pumps
34
4 main mechanisms of absorption
1. Passive diffusion
2. Facilitated diffusion
3. Active transport
4. Endocytosis
35
Where does most absorption from the gut take place and why?
Small intestine
Less acidic than stomach
Large surface area
Long transit time
36
Where does the absorption of most MR formulations take place?
Large bowel
37
Drugs which are 95-99% protein bound
Diazepam
Chlopromazine
Amitriptyline
Imipramine
38
Drugs which are 90-95% protein bound
Phenytoin
Valproate
Clomipramine
39
Principle plasma protein responsible for binding to acidic drugs
Albumin
40
Principle plasma protein for binding to basic drugs
Alpha-1 acid glycoprotein
41
Are most psychotropic drugs acid or base?
Basic
42
Equation for volume of distribution
Vd = Quantity of drug/plasma conc. at time of administration
43
What does high volume of distribution suggest?
Drug concentrated in cells or fatty tissues and not the blood
44
What is a high figure for Vd?
500-1000
45
What is the BBB made up of?
Capillary endothelium which have tight junctions
46
What type of molecules can cross BBB easily?
Unionized molecules that are less protein bound
47
Which parts of the brain lack BBB?
Area postrema of the medulla
Median eminence
Subfornical organ
48
Where is the blood-CSF barrier found?
Choroid plexus
49
What are tight junctions located between in blood-CSF barrier?
Adjacent epithelial cells
50
What is bioavailability?
How much of an administered drug reaches its target
51
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
52
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
53
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
54
What does xenobiotics refer to?
The mechanism by which a foreign agent such as a drug molecule is metabolised and eliminated from the body
55
Where is the principal site of drug metabolism?
Liver
56
What are the 4 major metabolic routes?
Oxidation
Reduction
Hydrolysis
Conjugation
57
What happens in phase 1 metabolism?
Oxidation, reduction and hydrolysis
| A molecule suitable for conjugation is produced
58
What happens in phase 2 metabolism?
Conjugation by reactions such as glucueonidation
59
Where is a molecule generally excreted if it has a relative molecular mass of less than 300?
Kidneys
60
Where is a molecule generally excreted if it has a relative molecular mass of more than 300?
Bile
61
What % and what race of people lack the CYP2D6 enzyme?
5-10% of Caucasian people
62
What class of drug and which drugs in this class particularly inhibit CYP system?
SSRIs
| Particularly fluoxetine and fluvoxamine
63
Which drugs can induce their own metabolism?
Carbamazepine
| Phenobarbitone
64
Which food/lifestyle factors are CYP inducers?
Alcohol
Smoking
Brussel sprouts
65
Which food/lifestyle factors are CYP inhibitors?
Grapefruit juice
| Caffeine
66
Which major psychotropics are metabolised by CYP2D6?
```
All TCAs
All neuroleptics
Fluoxetine
Paroxetine
Valproate
Risperidone
```
67
Which major psychotropics are metabolised by CYP3A4?
Most benzos
Mirtazapine
Fluvoxamine
68
Via which enzyme do smoking and caffeine affect glucuronidation?
UGT (and also by CYP1A2)
69
What is risperidone metabolised by?
CYP2D6
| CYP3A
70
What is aripiprazole metabolised by?
CYP2D6 CYP3A
71
What is Quetiapine metabolised by?
CYP3A
72
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
73
What is clearance directly proportional to?
Volume of distribution
74
Which drugs are excreted renally without significant liver breakdown?
```
Lithium
Amisulpride
Sulpride
Gabapentin
Acamprosate
Amantadine
```
75
What is half life defined as?
Time taken for the plasma concentration of a drug to halve
76
Rate of elimination in zero order kinetics
Constant
77
Rate of elimination in first order kinetics
Directly proportional to drug concentration
78
Which drugs undergo zero order kinetics?
Modified release preparations and depots
Ethanol
Phenytoin
79
What happens to gastric pH in elderly?
Increases
80
Physiological changes in neonates
Higher body water
Lower adipose tissue
BBB more permable
Low conc of albumin
81
Physiological changes in pregnancy
Delayed gastric emptying
Increase Vd
Decreased albumin
Increased GFR and renal clearance
82
Which class of psychotropic drugs should be used with caution in renal disease?
Benzos
83
Why should you use diazepam with caution in end stage renal disease?
Diazepam half life unchanged but its metabolite desmethyldiazepam may accumulate
84
Effect of TCAs on l-dopa
Reduce absorption of l-dopa
85
Half life of fluoxetine and norfluoextine
Fluoxetine 4-6 days
| Norfluoxetine 4-16 days
86
Which SSRIs do not have active metabolites?
Fluvoxamine and paroxetine
87
Which is the most selective SSRI?
Citalopram (and escitalopram)
88
What is the most potent SSRI?
Paroxetine
89
Which SSRI can reduce the clearance of diazepam and therefore should not be given together?
Fluvoxamine
90
What is citalopram metabolised by?
CYP2C19 and then by CYP2D6
91
How does fluvoxamine affect theophylline?
Reduces clearance of theopyhlline by around 3 fold via CYP1A2 inhibition
92
Half life of citalopram
33 hours
93
Fluvoxamine half life
17-22hrs
94
Paroxetine half life
22 hours
95
Sertraline half life
26 hours
96
What is the advice for starting drug that can fatally interact with MAO?
Wait at least 2 weeks after stopping MAOI
97
Half life of venlafaxine
3.5hrs
98
Which drug should never be started when on MAOIs?
Pethidine - can cause excitatory reaction which can result in death
99
Half life of duloxetine
12 hours
100
Trazodone half life
5-9 hours
101
Buspirone half life and subsequent effect on dosing
2-11 hours
| 3x daily dosing
102
St John's Wort MOA
Acts via multiple monoamine reuptake inhibition
103
How long does it take for mirtazapine to reach peak plasma concentration?
2 hours
104
Bioavailability of mirtazapine
50%
105
Metabolism of mirtazapine
CYP2D6 CYP3A4
106
What type of metabolism does Agomelatine undergo extensively?
First pass
107
Metabolism of Agomelatine
CYP1A2 (90%)
| CYP2C9 (10%)
108
Time taken for lithium to achieve steady state
4-5 days
109
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
110
Where is lithium excreted?
Proximal tubules
111
Which drugs increase lithium levels?
```
ACE inhibitors
Loop diuretics
Fluoxetine
NSAIDs
Thiazides
```
112
Which drugs decrease lithium?
```
Osmotic diuretics
Caffeine
Aminophylline
Theophylline
Carbonic anhydrase inhibitors
```
113
Half life of valproate
9 to 16 hours
114
Bioavailability of valproate
100%
115
Which drugs can increase carbamazepine levels?
Verapamil
Diltiazem
Valproate - displaces carbamazepine from plasma protein therefore increased carbamazepine levels
116
Which depot drugs are esterified in sesame oil?
Fluphenazine, haloperidol and perphenazine
117
Which depots are esterified in coconut oil?
Flupenthixol, piptiazine, zuclopenthixol
118
When is the peak level generally following depot injection?
Around 1 week
119
Half life of aripiprazole
90 hours
120
Half life of olanzapine
30 hours
121
Half life of quetiapine
6 hours
122
half life of clozapine
16hours
123
Half life of risperidone
15 hours
124
What does risperidone undergo extensive first pass metabolism to form?
9-hydroxyrisperidone
125
What catalyzes the hydroxylating of risperidone to 9-hydroxyrisperidone
CYP2D6
126
What length of oral tapering is required for aripiprazole depot?
2 weeks
127
Oral bioavailability of donepezil
100%
128
Half life of donepezil
70 hours
129
Half life of rivastigmine
1.5 hours
130
Half life of methylpenidate
2-3 hours
131
How can SSRIs affect atomoxetine levels?
SSRIs can raise levels
132
At supratherapeutic doses, what happens to fluoxetine metabolism?
Goes from first order to zero order kinetics
133
What happens in zero order kinetics?
Constant amount of drug cleared per unit of time
134
3 main compartments that drugs are distributed in
1. Vascular
2. Extra-cellular
3. Intracellular
135
Which part of CYP system does fluoxetine inhibit?
2D6 and 3A4
136
Which drugs does fluoxetine increase the concentration of?
Haloperidol
Carbamazepine
Phenytoin
137
Which enzyme is responsible for oxidative metabolism of most psychotropic drugs?
Cytochrome P450
138
Does venlafaxine have high or low binding to plasma proteins?
Low
139
How long between stopping ssri and starting mao should you wait?
5-6 weeks
140
How are 95% of drugs eliminated (kinetics)?
First order
141
Examples of zero order kinetics
```
Ethanol
Phenytoin
High dose salicylates
High dose fluoxetine
High dose omeprazole
```
142
How can you treat amphetamine overdose?
Urinary acidification
143
After how many half lives should you assume that a drug is eliminated?
4-5
144
Zaleplon half life
1 hour
145
Which drug can be given as loading dose in acute mania?
Valproate
146
Effect of NSAIDs on lithium
Decreases excretion
147
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
148
Which are the least sedative TCAs?
Lofepramine
| Nortriptyline
149
Which TCA is safest in overdose?
Lofepramine
150
Which psychiatric drugs are CYP3A4 inducers?
Carbamazepine
St John's Wart
Phenytoin
Topiramate
151
Is bioavailability affected by gender?
No
152
Zolpidem half life
2.6 hours
153
What is sensitisation?
Enhancement of drug effects following repeated administration of the same dose of drug
154
Which drugs skip phase 1 metabolism and go straight to phase 2?
Lorazepam
Oxazepam
Temazepam
155
What is fluvoxamine a potent inhibitor of?
CYP1A2
156
MOA of clonidine
Presynaptic alpha-2 receptor agonist
| Decrease the amount of noradrenaline released
157
In which condition would drugs that alter protein binding become important?
Renal disease where proteinuria can occur
158
Which antidepressant exhibits autoinhibition?
Paroxetine
159
What needs to be balanced to allow high permeability across a membrane?
Hydrophillic and lipophillic properties
160
Active metabolite of imipramine
Desipramine
161
What metabolises imipramine to desipramine?
CYP2C19
162
Example of a partial agonist at the benzodiazepine receptor
Clonazepam
163
What is an ionotropic receptor?
Ligand-gated ionic channels
164
Examples of ionotropic receptors
5HT3
NMDA
GABA-A
Glutamate
165
What is a metabtropic receptor?
Slower response involving G-proteins which bind to the intracellular portion of the receptor and activate a second messenger
166
Examples of metabotropic receptors
```
D1-5
NA
Serotonin 5HT1-7 (except 3)
Muscarinic
Opioid - mu
```
167
Which type of receptor binding produces maximal response?
Full agonist
168
What type of binding has a ceiling effect?
Partial agonist
169
What is an inverse agonist?
Agent that binds to the same receptor but produces the opposite pharmacological effect - no drugs work this way
170
How can a competitive antagonist be reversed?
By increasing the agonist dose
171
What is potency?
Minimum dose needed to produce an effect
172
What is efficacy?
Maximal response produced
173
How do non-competitive antagonists work?
Alter the receptor site
174
Effects of non-competitive antagonist on potency and efficacy?
Reduces both potency and efficacy
175
What is affinity?
Ability of drug to bind to its appropriate receptor
176
Difference in Sulpride MOA at low and high doses
Pure D2 antagonist
Low dose - presynaptic receptors blocked
High dose - post synaptic receptors blocked
177
MOA Lurasidone
D2 Antagonist
5HT2A blocker
High affinity for 5HT7
178
MOA Ziprasidone
5-HT2A and D2 antagonist
| Also antagonises 5-HT1D, 5-HT2C, D3 and D4
179
MOA Zotepine
5HT2A, 5hT2C, D1, D2, D3, D4 antagonist
| Potent NA reuptake inhibitor
180
MOA Agomelatine
5HT2C antagonist - enhances NA and dopamine neurotransmission
Direct agonist at melatonin MT1 and MT2
181
MOA Amoxapine
Dopamine antagonist and serotonin-noradrenaline reuptake inhibition
182
MOA Buproprion
Dopamine and noradrenaline reuptake inhibitor
183
Which TCA is most potent?
Clomipramine
184
TCA with least anticholinergic action
Desipramine
185
MOA of carbamazepine
Prolongs sodium channel inactivation
186
MOA of Gabapentin
Binds to alpha 2 delta subunit of the voltage-dependent calcium channel in the CNS
187
MOA of lamotrigine
Blocks voltage-gated sodium channels leading to modulation of glutamate
188
MOA of levetiracetam
Indirectly enhances GABA system
189
MOA of pregabalin
GABA analogue structurally but binds to alpha2delta subunit of voltage-dependent calcium channel
190
MOA of topiramate
Selective inhibitor of glutamate ampa receptors, blocks Na+ receptors and has indirect GABAergic activity
191
MOA of Vigabatrin
GABA transaminase inhibitor
192
Which is the least selective Z drug?
Zopiclone
193
MOA of amphetamine
Releases stored monoamines especially NA and dopamine
194
MOA of LSD
5HT2A partial agonist producing hallucinogenic effect
195
MOA of MDMA
2 isomers:
R- isomer - LSD-like effect
S+ isomer - amphetamine-like property
196
What inactivates acetylcholine?
Acetylcholinesterase
| Butylcholinesterase
197
Non-competitive inhibitor of both AChE and BChE
Tacrine
198
MOA of modafinil
Activates hypocretin producing neurons possibly though alpha 2 or alpha 1 adrenergic agonist properties
199
4 groups of CYP2D6 variations
1. Poor metabolisers
2. Intermediate metabolisers
4. Extensive metabolisers
5. Ultrarapid metabolisers
200
Which group of CYP2D6 variations do most Caucasians fit into?
Poor metabolisers
201
Which group of CYP2D6 variations do most Asians fit into?
Intermediate metabolisers
202
Which group of CYP2D6 variations do most North Africans fit into?
Ultrarapid metabolisers
203
In which gender group is antipsychotic response shown to be superior?
Women
204
Which enzyme appears to be less active in women than men?
CYP1A2
