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MRCPsych Part A > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

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1
Q

Define pharmacokinetics

A

Time course and disposition of drugs in the body (what the body does to the drug)

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2
Q

Processes of Pharmacokinetics?

A

Absorption
Distribution
Metabolism
Elimination

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3
Q

What influences a drugs absorption?

A

Form of drug
Rate of blood flow to site of administration
Solubility of drug (pH of drug, size of particles, pKA of drug - pH at which precisely half of drug is in its ionized form)
Route of administration

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4
Q

Negatives of oral administration of medication

A

Variable plasma concentration

Absorption may be erratic and subject to metabolism by liver and gut mocsa

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5
Q

What is first-pass effect?

A

Where a drug is metabolised by liver and gut mucosa

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6
Q

Mechanism of absorption of drugs from GI tract?

A

Active transport
Passive diffusion (most common)
Pore filtration

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7
Q

Factors influencing absorption of drugs from GI Tract?

A 
Intestinal motility
Gastric emptying
Gastric and intestinal pH
Intestinal microflora
Area available for absorportion
Integrity of blood flow
Presence/absence of food
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8
Q

What causes lower bioavailability or oral drugs?

A

Lack of absorption from GI tract

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9
Q

Affect of food on first–rate metabolism?

A

Delays gastric emptying

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10
Q

Which drugs can lead to delayed gastric emptying?

A

Those with anticholinergic effects - TCAs, opiates etc

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11
Q

Effect of grapefruit juice on drug absorptino

A

Grapefruit juice inhibits O-glycoprotein which increases absorption of certain medication, but downregulating intestinal CYP3A4 and CYP1A2.

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12
Q

Which drugs does grapefruit increases drug oral bioavailability?

A 
High first pass metabolism:
Calcium antagonists felodipine and Nimodipine
Terfenadine
Carbamazepine
Triazolam
Midazolam/diazepam
Simvastatin
Methyrlprednisolone
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13
Q

Where does most absorption of oral medication take place and why?

A

Small intestine - less acidic
Large surface area
long transit time

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14
Q

Where are slow or sustained release drugs mainly absorbed if taking orally?

A

Large bowel

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15
Q

Effect of enteric coating of capsules ?

A

Slow rate of disintegration so prolong effects of drug, reduce peak plasma concentration and thereby reduce SE.

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16
Q

Which type of oral preparation of drugs are absorbed quicker?

A

Liquid as disintegration is not required.

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17
Q

What is dissolution rate of oral medication dependent on?

A

Size of drug particle
Solubility of drug
Properties of intestinal fluid e.g. pH

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18
Q

When does absorption occur with IM medication?

A

10-30 minutes

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19
Q

Does first-pass metabolism occur with IM medication?

A

Rarely

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20
Q

What affects absorption of IM medications?

A

Blood flow
Aqueous solubility
Lipid soluble are absorbed quicker.
Low molecular weight are absorbed faster.

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21
Q

Which route results is the most rapid method of absorption?

A

IV

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22
Q

Which route is quickest for achieving therapeutic concentration?

A

IV

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23
Q

Bioavailability and first-pass metabolism of IV medications?

A

No first-pass metabolism

100% bioavailability

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24
Q

Which route has highest risk of life-threatening SE?

A

IV

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25
Define permeation of a drug?
Lipid membrane permeability of drug molecule
26
Which type of drugs cannot cross lipid cell membrane?
Hydrophilic
27
Difficulty of lipophilic drugs?
Struggle to cross water layer in extracellular space
28
What factors affect permeation of a drug?
Lipid solubility | Concentration gradient
29
Which drug forms contribute to concentration gradient?
Free drug forms (i.e. not bound)
30
How can permeation take place?
Simple diffusion | Facilitated diffusion
31
What is simple diffusion?
Along concentration gradient w/o specific transport mechanism
32
What is active transport?
Transport against concentration gradient with ATP dependent energy expenditure
33
What form of a drug crosses the lipid membrane of a cell?
Non-ionized form
34
Which form of a drug is more water soluble; ionized or non?
Ionized
35
Consequence of ionized drug form being more water soluble?
Become trapped in glomerular filtrate and do not get reabsorbed. Therefore renal clearance is higher.
36
Which drug OD can be treated with alkalinization?
Aspirin | Barbituate
37
Acidification helps with elimination of which drug?
Amphetamines | Phencyclidine
38
What does distribution of a drug refer to?
Where in the body it can be found | Drug achieving equilibrium between different compartments
39
What factors influence drug distribution?
``` Haemodynamic factors Plasma protein binding Permeability factors Blood-brain barrier Blood-CSF barrier ```
40
How do haeodynamic factors affect drug distribution?
Organs with high blood perfusion receive highest distribution and redistribution seen in second distribution phase to tissues.
41
Which organs have high blood perfusion?
Brain Kidneys Liver
42
Which route of administration leads to fastest distribution of a drug?
IV
43
Are bound or unbound parts of a drug the active part?
Unbound (unbound fraction)
44
What type of binding is plasma protein binding to drugs?
Reversible i.e. not covalent
45
When does protein binding of drugs become clinically relevant?
In renal disease where proteinuria can occur, i.e. less protein for drugs to be bound, thereby higher concentration of active drug form.
46
Which plasma protein do acidic drugs mostly bind to?
Albumin
47
Which plasma protein do alkaline drugs mostly bind to?
Alpha1-acid glycoprotein
48
Which plasma protein do psychotropic drugs mainly bind to?
Most are basic, so alpha1acid glycoprotein and lipoproteins
49
What is the equation for volume distributino?
Vd =Q/Cp Vd = volume distribution Q = quantity of drug Cp = plasma concentration at time of administration (zero time)
50
What does volume distribution refer to?
Apparent volume in which ingested drug is distributed in body.
51
What does a high volume distribution of a drug suggest?
Drug has high affinity for tissues outside body water such as brain and fat.
52
What does low Volume distribution suggest?
Drug is concentrated in blood
53
Plasma concentration of drug if drug is highly protein bound?
High (plasma protein exists in plasma)
54
What factors affect distribution of drug to the brain?
Brains regional blood flow Blood-brain barrier Drug's affinity for receptors in brain
55
Composition of blood-brain barrier
Capillary endothelium of brain which contains tight junctions acting as a membrane/singe sheet.
56
What molecules does blood brain barrier prevent?
Proteins Immunoglobulins Bacteria Viruses
57
Factors that can affect permeability of blood brain barrier?
``` Fever HI Hypoxia Hypercapnia Retrovirusis inflammation HTN Vasculitis Cerebral irradiation Ageing ```
58
How can you measure the integrity of the blood-brain barrier?
Measuring leakiness to labelled IgG olecules or gadonium
59
What types of molecules can easily pass the blood-brain barrier?
Unionized Less protein bound High lipid-water partition coefficient
60
Reason behind circumventricular organs?
Survival benefit as certain toxic substances stimulate postrema area and induce vomiting
61
Where is the blood-CSF barrier?
Choroid plexus
62
Structure of blood-CSF barrier?
Tight junctions between adjacent epithelial cells (as opposed to adjacent in blood brain barrier)
63
What is bioavailability?
How much of an administered drug reaches its target The extent to which drug reaches systemic circulation compared with same quantity of drug taken IV i.e. fraction that circumvents first pass effect
64
How to measure PO bioavailability?
Plot plasma concentration against time for a given dose | Area under curve is proportional to amount of drug in plasma
65
How to measure bioavailability fraction between PO and IV medication
Plot plasma conc against time for a given dose for PO drug. | Divide area under curve for PO medication with area under curve for IV at same dose.
66
What determines bioavailability fraction?
Absorption Distribution Elimination
67
What is presystemic metabolism?
Reduction in amount of medication reaching systemic circulation due to absorption and first-pass metabolism
68
Where does first-pass metabolism occur?
Gut mucosa Liver Muscle tissue
69
What can reduce first pass metabolism?
Hepatic impairment
70
What is bioequivalence?
Measurement of comparability of plasma levels of two different formulations of same active compound when given at same dose and same route of administration.
71
When are two products said to be bioequivalent?
When graphical trace of heir plasma level plot against time are superimposible.
72
When is bioequivalence relevant?
When changing brands of same compound.
73
What is Xenobiotics?
Mechanism by which a foreign agent (such as drug molecule) is metabolized and eliminated from body.
74
What does metabolism/biotransformation do to the drug?
Renders it less lipid-soluble and more water-soluble. | Therefore more readily eliminated
75
Principle site of metabolism in body?
Liver
76
Where can metabolism of drugs occur?
``` Liver GI Plasma Lungs Kidneys Suprarenal cortex Placenta Skin Lymphocytes ```
77
Main metabolic routes?
Oxidation Reduction Hydrolysis Conjugation
78
What happens in phase 1 of drug metabolism?
Oxidation, reduction and hydrolysis, making molecule suitable for phase 2.
79
What happens in phase 2 of drug metabolism?
Conjugation reactions such as gluronidation resulting in polar compounds (mainly inactive) that are exrectable in bile or urine are formed.
80
What is needed for molecule to be renally excreted?
Relative molecular mass >300
81
How is a molecule excreted if its relative molecular mass is <300?
Excretion via bile
82
What enzymes are most psychotropic drugs oxidized by?
Hepatic cytochrome CYP-450 | CYP3A4
83
What are CYP enzymes responsible for?
Inactivation for most psychotherapeutic drugs
84
Where do CYP enzymes mainly act?
Endoplasmic reticulum of hepatocytes and cells of intestines.
85
How can drug interactions influence the CYP system?
Induction Non-competitive inhibition Competitive inhibitino
86
How many caucasians lack the CYP2D6 enzyme?
5-10%
87
% of East Asians who lack CYP2C19 enzyme?
15-20%
88
Which drugs inhibit CYP system?
SSRIs - particularly fluoxetine. | Carbamazepine
89
Which drug an increase clozapine levels by x0?
Fluvoxamine, which can induce seizures
90
Effect of Fluoxetine on other drugs
Fluoxetine increases TCAs via 2D6 and 219. | Fluoxetine increases clozapine plasma conc.
91
Effect of Carbamazepine on other drugs
Decreases plasma conc of COCp
92
Affect of antidepressants on warfarin?
Antidepressants can inhibit metabolism of warfarin leading to bleeding.
93
Which antipsychotic and antidepressant compete with each other for same metabolic enzymes?
TCAs and Haloperidol
94
Which two medications induce their own metabolism?
Carbamazepine and phenobarbitone
95
Non-medical CYP inducers?
Brussel sprouts EtOH Smoking
96
Non-medication CYP inhibitors?
Grapefruit juice | Caffeine
97
Psychotropics metabolized by CYP2D6?
``` All TCAs Fluoxetine Paroxetine Trazadone Nefazodone Valproate All neuroleptics Risperidone ```
98
What psychotropics inhibit CYP2D6
``` Paroxetine Fluoxetine Neuroleptics Amitriptyline Clomipramine ```
99
Which CYP enzyme is most prominent in gut wall mucosa?
CYP3A4
100
Which psychotropics are metabolized by CYP3A4?
``` Clomipramine Fluvoxamine Mirtazapine Nefazodone Carbamazepine Most benzos ```
101
What stimulates CYP3A4?
Carbamazepine | Barbituates
102
What inhibits CYP3A4?
Ca channel blockers Fluoxetine Nefazodone
103
Describe autoinduction in Carbamazepine
Carbamazepine is metabolized by hepatic CYP2D6, which in turn induces carbamazapines.
104
Impact of autoinduction on Carbamazapine
Rate of metabolism of carbazapine (and other P450 substrates) increases over first several weeks of treatment. This can delay final steady state until 3-4 weeks after initiation. Hence level must be monitored and dose often raised during early phase of treatment.
105
Which enzyme is affected by smoking and caffeine?
They affect glucoronidation reaction via UGT enzyme and CYP1A2.
106
Which drugs are metabolised by CYP1A2 and thereby affected by smoking and caffeine?
Clozapine | Olanzapine
107
Effect of caffeine on CYP1A2
Competitive inhibition
108
Effect of caffeine on clozapine and olanzapine
Increases levels
109
Effect of smoking on CYP1A2
Polyaromatic hydrocarbons in cigarrettes induce the enzyme.
110
Which effects are seen sooner of CYP1A2; inducers or inhibitors?
Inhibitors (caffeine)
111
Major routes of drug excretion
``` Urine Faeces Bile Sweat Tears Saliva Sebum Breast milk ```
112
Most suited compounds for renal excretion?
Ionized | Non-lipid soluble
113
Factors that influence drug excretion?
``` Increased age = decreased excretion Reduction in renal blood flow Renal impairment Alterations in re-absorption: urine pH Low Na ```
114
What is pH of normal urine?
Weakly acidic
115
Affect of Low Na Urine on Lithium?
Increases lithium reabsorption and decreases excretion, leading to toxicity
116
What is clearance?
Volume of blood cleared of a particular drug in unit time
117
What is clearance directly proportional to?
Volume of distribtuion
118
What is the equation for clearance?
Cl=kxVd Cl = clearance k = constant of proportionality (first order elimination constant)
119
Relationship between clearance and drugs with first order kinetics?
Clearance is constant irrespective of dose as rate of elimination is directly proportional to plasma level
120
Which drugs have renal elimination?
``` Lithium Amisulpride Sulpride Gabapentin Acamprosate Amantadine ```
121
What is the half-life of a drug?
Time taken for plasma concentration of a drug to have = t1/2
122
What is the distribution half-life?
Following IV injection, rapid fall in plasma drug conc caused by redistribution of drug into tissues. Distribution half life = time taken for this redistribution to halve the inital peak conc.
123
What is the elimination half life?
Time taken for elimination process to halve plasma drug conc
124
What type of elimination can drugs undergo?
First order kinetics | Zero order kinetics
125
What is first order kinetics?
When constant fraction of drug is cleared per unit time
126
Affect of first order kinetics on dose of drugs and its subsequent clearance?
When amount of drug in plasma/dose administered increases, clearance proportionally increases.
127
What would a graph of first-order kinetics look like?
Exponential decay versus time.
128
What is the elimination half life in first order kinetics?
Time to eliminate 50% of a given amount, or time to achieve a decrease in plasma level to 50% of original
129
In first order kinetics, what does rate of elimination depend on?
Drug concentration
130
What is zero-order kinetics?
Constant amount of drug is cleared per unit time, irrespective of amount of drug in plasma concernation/dose.
131
Danger of zero-order kinetics?
Increasing dose may result in toxicity.
132
What does rate of elimination depend on in zero-order kinetics?
Availability of enzymes, slow release formula etc | NOT dose of drug
133
What is a steady state?
When rate of drug going in = rate of drug going out. Fluctuations in plasma level do not get eliminated.
134
How long does it take for a drug to reach steady plasma level?
4-5 t1/2 | Dependent on elimination t1/2 of drug.
135
What does steady state depend on?
Dose administered
136
What can help reach steady state more rapidly?
Loading dose
137
What is a quantal curve?
Dose-response curve: Plots the percentage of a population showing a specified, pre-defined categorical drug effect against dose administered. Plots drug conc against continuous effects of the drug.
138
What can be determined from a quantal curve?
Median effective dose or median toxic dose. | Therapeutic index
139
What is the median toxic dose?
Dose at which 50% of patients experience a specific toxic effect
140
What is the median effective dose?
Dose at which 50% of patients have a specified therapeutic effect.
141
What does a steep drug-response curve suggest?
Little variability
142
Which type of curve in a quantal curve plot suggests great variability in patient sensitivity to the effects of a drug?
Flat curve
143
What is the therapeutic index?
Relative measure of toxicity or safety of a drug. Defined as the ratio of the median toxic dose to median effective dose. Or: ratio of minimum plasma conc causing toxic effects to that causing a therapeutic effect.
144
What is therapeutic index only useful for?
Dose-dependent side effects
145
What is the therapeutic window?
A specified plasma conc value, only within which certain drugs appear to have therapeutic efficacy.
146
What happens to the elderly in terms of body composition?
Increase in total body fat. Decrease in total muscle mass. Decrease in total body water.
147
Effect of changes in body composition in the elderly on drugs?
Larger volume of distribution and longer half-life of lipophilic chemicals because of their increased sequestration in fat. e.g. benzo excretion is slower in the elderly.
148
What happens to plasma proteins in the elderly?
Decreased plasma protein binding capacity
149
Effect of decreased plasma protein binding efficacy in the elderly on dugs?
Higher proteinuria Reduced plasma protein synthesis by liver - reduced albumin, protein affinity decreased, acid glycoprotein increased. Higher free drug plasma conc - increased metabolism and clearance of free drug. More frequent protein binding interactions. Phenytoin is affected.
150
Effect of ageing on the liver?
Decreased hepatic blood flow. | No change in metabolism.
151
Impact of liver changes in the elderly on drug kinetics?
>80 y/o, CYP system declines. Decreased hepatic first pass effect. Lorazepam>Diazepam in elderly.
152
Effect of ageing on the kidneys?
Decreased in renal blood flow - 10% per decade after 4th decade. Reduced eGFR.
153
Impact of kidney changes in the elderly on drug kinetics?
Frequent toxicity of renally eliminated drugs.
154
Impact of age on the GI tract?
GI blood flow decreases. | Gastic pH increases as acidity drops.
155
Impact of age-related changes in GI tract on drug kinetics?
Decreased gastric first pass metabolism. | Reduction in gastric wall content of dopa decarboxylase = 3-fold increase in conc of levodopa in elderly.
156
Impact of age on the brain?
Decreased number of brain Ach postsynaptic receptors. Choline acetyltransferase is diminished. Level of brain Acetylcholinestrase decreased.
157
Impact of age-related changes in the brain on drug kinetics?
Anticholinergic SEs are more pronounced = increased delirium.
158
Changes in neonates body composition?
Higher proportion of total body water and extracellular body water Lower proportion of adipose tissue
159
Changes in neonates renal function?
eGFR is lower in those <3-5 months old
160
GI changes in neonates?
Lower gastric acidity | Increased gastric emptying time
161
Brain changes in neonates?
More permeable blood-brain barrier
162
Liver changes in neonates?
Microsomal enzyme activity in liver is lower in those <2 months old Lower plasma conc of albumin in neonates
163
Affect of pregnancy on GI tract?
Delayed gastric emptying | Decreased GIT motility
164
Affect of pregnancy on body composition?
5% increased volume of distribution | Decreased drug-binding capacity
165
Affect of pregnancy on the kidneys?
Increased renal clearance & eGFR
166
Affect of pregnancy on the liver?
Decreased albumin level | Induced liver metabolic pathway
167
Affect of reduced renal function on diazepam?
Half-life unchanged | Metabolite, desmethyldiazepam may accumulate, causing excessive sedation.
168
Affect of reduced renal function on lorazepam?
Half life increased from 8-25 hours to 32-72 hours | Dose should be reduced by 50% to avoid excessive sedation
169
Affect of reduced renal function for SSRIs?
Citalopram: half normal dose Paroxetine: reduce dose Sertraline: do not use in renal impairment Fluoxetine: continue normal dose
170
Affect of renal impairment in Amisulpride dose?
This is renally excreted, and is therefore contra-indicated.
171
Affect of renal impairment on Risperidone?
Risperidone and its active metabole are excreted in urine so renal impairment leads to prolonged elimination half-life
172
How long does it take for TCAs to reach peak plasma conc?
1-12hours
173
Why are 7-9% of caucasians slow metabolisers of TCAs?
CYP2D6 polymorphism
174
Affect of clearance of TCAs in kids and the elderly?
Children: clear more TCAs from body Elderly: less
175
Half-life of TCAs?
Close to 24h
176
Can TCAs cross blood-brain barrier?
Yes
177
Binding of TCAs on plasma proteins?
Significant - 80-95%
178
What is measured to assess therapeutic dosing of TCAs?
``` Plasma levels (not serum). Determined after 5-7days when steady state is reached, and 8-12 hours after last dose to avoid false peaks. ```
179
When is clear therapeutic window seen for nortriptyline?
Between 50-150 ng/ml
180
Active metabolite for Imipramine?
Desipramine
181
Active metabolite for Amitriptyline?
Notriptyline
182
Active metabolite for Trazadone and Nefazodone?
mCPP
183
Active metabolite for Fluoxetine?
Norfluoxetine
184
Active metabolite for Sertraline?
Desmethylsertraline
185
Which psych medications decrease metabolism of morphine and thereby contribute to opioid toxicity?
Amitriptyline Clomipramine Through UDP glucuronyl transferase interaction
186
What induces metabolism of TCA and thereby reduces its levels?
``` Smoking Phenytoin Carbamazepine OC pills Barbituates ```
187
Impact of smoking on TCAs?
Induces metabolism, thereby reducing TCA levels.
188
Impact of phenothiazines on TCA levels?
Mutual inhibition of metabolism, thereby increases both TCA and antipsychotic levels
189
What drugs inhibit TCA metabolism and thereby increase TCA plasma levels?
``` Quinidine Cimetidine Fluoxetine Paroxetine Phenothiazine Disulfiram Methylphenidate ```
190
Affect of TCA on warfarin?
TCAs increase warfarin levels = increased risk of bleeding
191
Affect of TCAs on Clonidine?
TCAs reduce clonidine levels, thereby can lead to hypertensive crises
192
Affect of TCAs on MAOIs?
Reduce tyramine entry via monoamine reuptake channels. Synergistic serotonergic enhanceent (esp clomipramine). Thereby higher risk of seretonin syndrome and lower risk of cheese reaction.
193
Affect of TCAs on L-Dopa?
Reduce absorption of L-dopa, thereby lower l-dopa efficacy in Parkinsons
194
Affect of TCAs on morphine?
Amitroptyline and clomipramine decrease metabolism of morphine through UDP glucuronyl transferase interaction, thereby increase opioid toxicity
195
Impact of food on sertraline?
Sertraline availability increased by presence of food
196
Protein binding ability of SSRIs?
Most are highly protein bound except for escitalopram (56% bound)
197
What metabolizes fluoxetine?
Norfluoxetine - similar activity on 5-HT reuptake as fluoxetine.
198
Half-life of fluoxetine?
4-6 days
199
Half-life of norfluoxetine?
4-16 days
200
Active metabolites of fluvoxamine and paroxetine?
None
201
Pharmacokinetics of Fluoxetine and paroxetine?
Nonlinear; changes in dose can produce proportionally large plasma levels. This is because they can both inhibit their own clearance at clinically relevant doses.
202
Which SSRI is most selective?
Citalopram
203
Which SSRI is most potent?
Paroxetine
204
How does Fluoxetine work?
Weakly inhibits noradrenaline reuptake and binds to 5-HT2C receptors.
205
How does sertraline work?
Weakly inhibits noradrenaline and dopamine reuptake.
206
Impact of high dosage of Paroxetine?
Significant anticholinergic activity - binds to nitric oxide synthase.
207
Impact of fluoxetine and olanzapine taken together?
Increase brain concentrations of noradrenaline.
208
Which disorders respond to SSRIs?
``` Depression GAD Panic disorder OCD Bulimia PMD - if sertraline/paroxetine produces positive effect. ```
209
What can fluvoxamine reduce clearance of?
Diazepam and its active metabolite, N-desmethyl diazepam, thus can cause accumulation.
210
What metabolises citalopram?
CYP2C19, and then CYP2D6.
211
What metabolizes sertraline?
Demethylation by CYP3A3 and CYP3A4
212
Enzyme profile of Fluoxetine
Inhibits 2C19, 3D6. | Partially metabolized by 2D6
213
What does Fluoxetine interact with?
``` Increases: All TCAs - particularly Clomipramine and Imipramine (both 2C19 and 2D6). Citalopram Sertraline Moclobemide Duloxetine Mirtazapine Velafaxine ```
214
Enzyme profile of Paroxetine?
Metabolized by 2D6 | Inhibits 2D6
215
Which drugs does Paroxetine increase?
``` All TCAs Citalopram Fluoxetine Fluvoxamine Duloxetine Mirtazapine Venlafaxine ```
216
Enzyme profile of Fluvoxamine
Inhibits 1A2, 2C19, 3A4
217
Which drugs does Fluvoxamine increase?
``` Clomipramine Doxepine Trimipramine Duloxetine Mirtazapine Citaloprame Escitaloprame Sertraline Trazadone ```
218
Enzyme profile of Duloxetine?
Inhibits 2D6
219
Which drugs does Duloxetine increase?
``` All TCAs Citalopram Fluoxetine Paroxetine Fluvoxamine Mirtazapine Venlafaxine ```
220
Enzyme profile of Desipramine and Clomipramine?
Inhibits 2D6
221
Which drugs do Desipramine and Clomipramine increase?
``` All TCAs Citalopram Fluoxetine Fluvoxamine Duloxetine Mirtazapine Venlafaxine ```
222
Which drugs lead to potential serotonin toxicity?
Desipramine | Clomipramine
223
What causes nonlinear pharmacokinetics of paroxetine and fluoxetine?
Autoinhibition of CYP2D6
224
Effect of Fluvoxamine on Theophylline?
Reduces clearance 3-fold via CYP1A2 inhibition.
225
What do you need do if prescribing theophylline with fluvoxamine?
Theophylline dose reduced by 1/3. | Monitor plasma conc of theophylline.
226
Plasma elimination half-life of Paroxetine for single dose?
10h
227
Plasma elimination half-lifeof Paroxetine for multiple doses?
21h
228
Pharmacokinetics of Paroxetine?
Nonlinear
229
Plasma elimination half-life of single dose of Fluvoxamine?
11h
230
Plasma elimination half-life of multiple dose of Fluvoxamine?
14h
231
Pharmacokinetics of Fluvoxamine?
Nonlinear
232
Plasma elimination half-life of Sertraline (single dose)?
26h
233
Pharmacokinetics of Sertraline?
Linear
234
Plasma elimination half-life of single dose of Citalopram?
33h
235
Pharmacokinetics of Citalopram?
Linear
236
Pharmaco-kinetics of single dose of Fluoxetine?
Nonlinear
237
Plasma elimination of half-life of single dose of FLuxoetine?
1.9 days
238
Plasma elimination half-life of multiple doses of Fluoxetine?
5.6 days (7-15 days)
239
Impact of Fluvoxamine on Warfarin?
Warfarin plasma conc increases by 98% and prothrombin time is prolonged.
240
What is the advice regarding starting medications that interact irreversibly with MAOIs?
Wait 2 weeks before starting
241
Affect of prescribing MAOIs and Pethidine?
Depressive (pronounced sedation due to opioid toxicity) | Excitatory (serotonin excess)
242
Symptoms of serotonin excess?
``` Agitation Hyperpyrexia Cardiovascular collapse Coma Death ```
243
Important characteristics of Pethidine?
Serotonin releasing property | Reuptake inhibitino property
244
Which drug must never be used with MAOIs?
Pethidine
245
Impact of Amphetamine and Methylphenidate?
Amphetamine induces serotonin release | Methylphenidate does not
246
Protein binding of Venlafaaxine?
Low protein binding
247
Half life of Vanlafaxine?
3.5 ours
248
What is the metabolite of Venlafaxine?
O-desmethyl venlafaxine
249
Half-life of metabolite of venlafaxine?
9 hours
250
What metabolises the metabolite of venlafaxine?
P450 CYP 2D6
251
Half-life of Duloxetine?
12 hours
252
What metabolizes Duloxetine?
CYP450 (hepatic)
253
Protein binding of Duloxetine?
Highly protein bound
254
Metabolism of Trazadone and Nefazodone?
Extensive hepatic metabolism
255
Metabolite of Trazadone and Nefazadone?
M-chlorophenylpiparazine; stimulates 5-HT receptors
256
Half-life of Trazadone?
5-9 hours
257
Affect of Trazadone on receptors?
Weak inhibitor of serotonin reuptake | Antagonist of serotonin 5-HT2A and 5HT2C
258
Active metabolite of Trazadone?
M-chlorophenylpiperazine - 5-HT2C agonist
259
Half-life of active metabolite of Trazadone?
14 hours
260
Clinical impact of Trazadone metabolite?
Migraine Anxiety Weight loss
261
Sedation affects of Trazadone?
Acute sedative effects
262
Impact of Trazadone on other drugs?
Increase levels of digoxin, phenytoin and warfarin
263
What results in increased SE of trazadone?
CYP3A4 inhibitors can increase the metabolite but reducing its breakdown
264
Half life of buspirone?
2-11 hours
265
Metabolite of Buspirone?
1-pyrimidinylpiperazine
266
DIfference between Buspirone and its metabolite?
Metabolite achieves higher brain conc in brain
267
Receptor action of Buspirone?
Partial agonist on 5-HT1A receptors - presynaptic agonism leads to inhibition of release of serotonin with consequent anti-anxiety effects. Postsynaptic agonism leads to antidepressant acitivity.
268
How does Buspirone lead to antidepressant acitivity?
Postsynaptic agonism of 5HT-1A receptors.
269
Action of St johns wort?
CYP inducer
270
Which receptors does st johns worst act on?
Multiple monoamine ruptake inhibition
271
Which drugs does St Johns Worst decrease efficacy of?
Warfarin OCPs Anti-epileptics
272
What does non-response mean for antidepressants?
Minimal or <25% decrease in baseline severity of sx
273
What does partial response mean for antidepressants?
25-50% reduction in baseline severity
274
What does partial remission mean for antidepressant use?
>50% reduction but still some sx evident
275
What does remission mean in antidepressant use?
No sx; returning to normal function (<6 months from last episode)
276
What does relapse mean in antidepressant function?
Return to fully sx state when in remission
277
What does recovery mean in antidepressant use?
Extended remission sustained for longer than 6-12 months
278
What does recurrence mean in antidepressant use?
Onset of new episode of depression when in recovery
279
When does Mirtazapine reach peak plasma conc?
Within 2 hours
280
Protein binding of Mirtazapine?
85% binds to plasma proteins
281
Bioavailability of Mirtazapine?
50% due to first-pass metabolism
282
Pharmacokinetics of Mirtazapine?
First-order linear elimination over dose of 15-80mg
283
Elimination rate of Mirtazapine?
20-40 hours
284
What mediates metabolism of Mirtazapine?
CYP2D6 | CYP3A4
285
What drugs can increase plasma conc of Mirtazapine?
Paroxetine and Fluoxetine - inhibit CYP system.
286
What drug decreases Mirtazapine plasma conc>?
Carbamazepine - 60% decrease
287
Meabolism of Agomelatine?
First-pass metabolism CYP1A2 (90%) CYP2C( (10%
288
Bioavailability of Agomelatine?
Low
289
Protein binding of aAgomelatine?
95%
290
Haf-life of Agomelatine?
2.3 hours
291
Are lithium carbonate and citrate the same?
No
292
How long does it take for Lithium to reach a steady sate?
4-5 days
293
Protein binding of Lithium?
Not protein bound
294
Half-life of plasma Lithium?
18 years inititally, 1 year of chronic use increases this to 26 hours
295
Where is lithium excreted?
Proximal tubules in kidney - where sodium is filtered
296
Impact of loss of body sodium on lithium?
Increase lithium reabsorption as compensation in error - leads to toxicity
297
What drugs can increase lithium?
``` ACE inhibitors Loop diuretics Fluoxetine NSAIDs Thiazides ```
298
What drugs can decrease lithium levels?
``` Osmotic diuresis Caffeine Aminophylline Theobromine, Theophylline Carbonic anyhdrase inhibitors ```
299
Which medications can cause lithium toxicity within normal levels?
``` Carbamazepine Atracurium Haloperidol, clozapine Calcium channel blockers Metronidazole ```
300
How does carabimazepine cause lithium toxicity?
Increased antithyroid effect and neurotoxicity
301
How does Atracurium cause lithium toxicity?
Increased neuromuscular blockade
302
How do haloperidol and clozapine cause lithium toxicity?
Increased neurotixic effects
303
How do calcium channel blockers cause lithium toxicity?
Increased neurotoxicity
304
How does metronidazole cause lithium toxicity?
Increased neurotoxicity
305
What is Divalproex?
Semisodium compound of Valproate
306
What is Divalproex made of?
Half valproic acid | Half sodium valproate
307
Bioavailability of valproate?
Close to 100%
308
Characteristics of valproate?
Hydrophilic | Low volume of distribution
309
Half life of valproate?
9-16 hours
310
Protein binding of valproate?
90%
311
Characteristics of valproate at higher doses?
Increased free fraction may remain in plasma (rather than escaping to tissues) and thus be cleared by liver, leading to sublinear kinetics so that with highe rplasma conc, greater in creases in dose may be needed to yield desired increase in plasma levels.
312
Impact of valproate on diazepam?
Binding interaction so that valproate can increase free diazepam
313
Structure of carbamazepine?
Tricyclic structre
314
Metabolism of Carbamazepine?
Hepatic | Induces its own breakdown
315
Bioavailability of Carbamazapine?
80%
316
Plasma protein binding of Carbamazapine?
75%
317
Breakdown of Carbamazapine
Autoinduction of epoxide pathway via induction of CYP3A3/4
318
Half life of carbamazapine before autoinduction?
24 hours | Clearance: 25ml/min
319
Half life of Carbamazapine after autoinduction?
2-4 weeks into therapy: half life is 8 hours Clearance is 75ml/min
320
Active metabolite of carbamazpine?
CBZ-10,11-epoxide
321
Half-life of Carbamazpine metabolite?
6 hours
322
What steady state plasma conc of Carbamazpine is therapeutic?
4-12 ng/ml
323
What drugs can increase carbamazapine levels?
Verapamil Diltiazem Erythromycin can cause toxicity
324
What drug levels does Carbamazapine decrease?
Nimodipine | Felodipine
325
Affect of Valproate on Carbamazapine?
Valproate inhibits epoxide hydrolase, increasing plasma carbamazepine-epoxide levels without altering total plasma carbamazepine levels. Displaces carbamazepine from plasma proteins, increasing free carbamazepine.
326
Affect of carbamazepine on warfarin?
Reduces warfarin efficacy
327
Mood stabilizing effects of Gabapentin?
None
328
Which psych disorders is Gabapantin used in?
Anxiety | Bipolar
329
Plasma protein binding of Gabapentin?
Not bound to plasma protein
330
Where is gabapentin excreted?
100% in urine
331
Half life of Gabapentin?
4-9 hours
332
What can increase gabapentin clearance?
Increased physical activity
333
Bioavailability of Gabapentin?
Decreases as dose increases
334
Bioavailability of Gabapentin given at 900mg per day?
60%
335
Bioavailability of Gabapentin when given at 2400mg per day?
34%
336
Bioavailability of Gabapentin when given at 4800mg per day?
27%
337
Affect of hepatic metabolism on Gabapentin?
None
338
When is Gabapentin steady state reached?
1-2 days
339
When does Lamotrigine reach peak conc?
Within 3 hours postdose
340
Oral availability of Lamotrigine?
98%
341
Plasma protein binding of Lamotrigine?
56%
342
Half life of Lamotrigine?
24-36 hours
343
Which drugs reduce half life of lamotrigine?
Enzyme-inducing drugs: | Phenytoin, phenobarbital, carbamazepine
344
Which drugs increase half-life of Lamotrigine?
Valproate
345
Impact of Lamotrigine on Carbamazepine?
Lamotrigine increases carbamazepine-10,11-epoxide
346
When are peak plasma levels of typical antipsychotics reached, given as IM?
30 mins
347
When are peak plasma levels of typical antipsychotics reached when given orally?
1-4 hours
348
When is the steady state of antipsychotic reached?
3-5 days
349
Half life for elimination of antipsychotics?
10-30 hours
350
How long can depot forms of Haloperidol and Fluphenazine persist?
1-3 months if lipid storage and brain retention
351
Active matabolite of Thioridazine?
Mesoridazone
352
Active metabolite of Loxapine?
7-hydroxyloxapine
353
What are typical antipsychotics mainly substrates of?
CYP1A | CYP2D6
354
Which enzyme do typical antipsychotics inhibit?
2D6
355
Bioavailability of Chlorpromazine?
37%
356
What can decrease absorption of phenothiazines?
Antacids
357
What drugs reduce antipsychotic levels (typical)?
``` Enzyme inducers: Carbamazepine Phenytoin Ethambutol Barbituates ```
358
What drugs increase typical antipsychotic levels?
``` Clearance inhibitors: SSRIs TCAs Cimetidine Erythromycin Ciprofloxacin Ketoconazole ```
359
Kinetics of Fluophenthixol decanoate depot?
Peak levels 3-7 days post IM | Half-life 17 days
360
Kinetics of fluphenazine decanoate depot?
Peak levels 24 hours post-IM | Apparant half-life of 7-14 days
361
Affect of smoking on Fluphenazine decanoate and Haloperidol depot?
Reduces levels
362
Kinetics of Haloperidol decanoate depot?
Peak levels 7 days post IM | Half-life 3 weeks
363
Kinetics of Perphenazine decanoate depot?
Peak levels 1-7 days post IM | Half-life of 2 weeks
364
Kinetics of Pipotiazine palmitate depot?
Peak levels 1-2 weeks post IM | Half-life 2 weeks
365
Kinetics of Zuclopenthixol decanoate depot?
Peak levels 1 week post IM | Half-life 7-20 days
366
Half life of Risperidone?
15 hours
367
Chlorpomazine equivalent of Risperidone?
2mg/day
368
Half life of Clozapaine?
16 hours
369
Chlorpromazine equivalent of clozapine?
50mg/day
370
Half life of Quetiapine
6 hours
371
Chlorpromazine equivalent of Quetiapine?
75mg/day
372
Half life of Olanzapine?
30 hours
373
Chlorpromazine equivalent of Olanzapine?
5mg/day
374
Half life of Aripiprazole?
90 hours
375
Chlorpromazine equivalent of Aripiprazole?
7.5mg/day

MRCPsych Part A (22 decks)

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