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Pharmacokinetics Flashcards

1
Q

What is pharmacokinetics?

A

the study of how an organism affects a drug
Provides a mathematical basis for the description and
prediction of the time course of drugs (and their metabolites) in the body.

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2
Q

What is pharmacodynamics?

A

the study of how the drug affects the organism

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3
Q

Pharmacokinetics refers to the quantitative study of ADME. What does this stand for?

A

ABSORPTION
DISTRIBUTION
METABOLISM
ELIMINATION

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4
Q

Define absorption.

A

All processes from the site of administration (anything non-intravenous) to the site of measurement (typically blood)

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5
Q

Define distribution.

A

The reversible transfer of drug between the site of measurement and other sites within the body.

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6
Q

Define metabolism.

A

The irreversible loss of drug from the body by biochemical conversion

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7
Q

Define elimination.

A

The irreversible loss of drug from the site of measurement within the body.

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8
Q

Define excretion.

A

The irreversible loss of drug from the body

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9
Q

Define disposition.

A

Elimination + distribution

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10
Q 
What do the following stand for...
AUC
Cmax
Tmax
MTC
MEC?
A 
area under the curve
max concentration
time to max concentration
minimal toxic concentration
minimal effective concentration
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11
Q

Drugs must move across hydrophobic diffusion barriers - how? (2)

A

Diffusion

Carrier-mediated transport

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12
Q

Where are the majority of drugs absorbed from?

What is key here? (2)

A

GI tract

solubility (dissolution) and ionisation

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13
Q

What is solubility dependent on?

What is solubility a major determinant of?

A

The properties of the tablet i.e. surface area, drug concentration, thickness
Drug plasma levels

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14
Q

How do large insoluble molecules (e.g. glucose and proteins) move through the plasma membrane?

A

Carrier-mediated transport - they require a carrier molecule

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15
Q

Give some examples of carrier molecules. (4)

A

Ion channels, ABC transporters, water channels, ATP pumps, etc…

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16
Q

What is facilitated diffusion?

How does it differ for water-soluble and lipid soluble agents?

A

A passive process where solute moves down a concentration or charge gradient
Water-soluble agents use aqueous pores in the membrane, while lipid soluble agents diffuse through the membrane

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17
Q

What is active transport?

A

the movement of solute against a concentration (or other) gradient
utilises energy directly

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18
Q

Cell membranes are generally only permeable to…?

Why?

A

uncharged solutes

hydrophobic fatty acids repel charged molecules

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19
Q

What equation determines the proportion of a substance that is ionised at a given pH?

A

Henderson-Hasselbach equation

pH = pKa + log (A-/Ha)

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20
Q

If pH < pKa, what does this mean?

A

The non-ionised form of an acid dominates.

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21
Q

In the acidic stomach (pH 1.5 - 3.5), weak acids are present in what form - ionised or non-ionised?

A

Non-ionised

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22
Q

What can impair absorption of weak acids? (4)

A

– Gastric pH is elevated by drugs (i.e. PPIs, H2 antagonists, antacids)
– Gastric pH is physiologically higher in neonates as their gastric secretions are relatively achlorhydric (pH 6-8)
– Gastric resections (primarily for cancer) remove acidic
environment
– Modified delivery systems reduce solubility in the stomach and thus increase delivery to intestines (pH >6)

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23
Q

Solubility and diffusion - which favours ionised/non-ionised?

A

Solubility favours ionised species, diffusion favours nonionised

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24
Q

What factors affect gastrointestinal absorption? (4)

A
  • pH
  • Blood flow to stomach/intestine
  • Gastrointestinal tract transit time
  • Gastric contents
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25
Most drugs are either ____ acids or _____bases (weak/strong).
WEAK
26
Clopidogrel and omeprazole - what is the interaction? | What is therefore recommended?
omeprazole added to clopidogrel therapy reduces the inhibition of platelet aggregation Concomitant use of clopidogrel and omeprazole or esomeprazole is to be discouraged unless considered essential. Consider PPIs other than omeprazole or esomeprazole, or other gastrointestinal therapy such as H2 blockers (except cimetidine) or antacids
27
Why do antacids have multiple interactions? | How many this be avoided?
Can interfere with absorption of other drugs, e.g. by forming insoluble chelate complexes Typically suggests taking 1-2 hours apart from other medications
28
What is p-glycoprotein? | Where is it extensively expressed?
ATP-dependent efflux pump with broad substrate specificity. Intestinal epithelium, liver, proximal tubule and blood brain barrier.
29
Which p-gp varient is associated with multi-drug resistance?
ABCB1/MDR1 gene
30
Define bioavailability.
the fraction of unchanged drug that is absorbed intact and reaches the site of measurement Bioavailability (F) is defined as a unity (100%) for an intravenous preparation, and all other routes are compared to this.
31
What is doxazosin?
α1-adrenoceptor antagonist licenced for treatment of hypertension
32
Standard immediate release formulation of doxazosin | describe the pharmacokinetics.
linear PK across dosing range (1-16 mg/day). Bioavailability 65% tmax = 2h t1/2 = 14h
33
Why does doxazosin require slow dose titration?
Post-dose hypotension and risk of orthostasis
34
Distribution - what is it dependent on? (4)
– plasma protein binding – ratio of compartment blood flow to compartment size – barriers to distribution (i.e. blood brain barrier) – affinity of drug for tissue (Kp)
35
Define volume of distribution (Vd).
Hypothetical value that relates the amount of drug in the body to the amount at the measured site Vd equals the volume of fluid required to contain the total amount of a drug in the body at the same concentration as measured in the plasma
36
Equation for Vd.
Vd = amount in body/conc. in plasma
37
If drug is highly lipid soluble, what will the Vd be?
high
38
High Vd can also reflect...?
high tissue binding
39
What are compartment models?
Mathematically describes the movement of drug around the body
40
How is metabolism categorised?
phase I and phase II
41
Describe phase I metabolism - type of reactions, enzymes...
Catabolic reactions e.g. oxidation, reduction and hydrolysis P450 enzymes important Reactive handle introduced to facilitate phase II
42
Describe phase II metabolism - type of reactions
Anabolic reactions; e.g. conjugation Usually results in inactive compounds Usually results in polar molecules; this increases renal elimination
43
Cytochrome P450 - what are they?
proteins of a superfamily containing heme as a co-factor.
44
Cytochrome P450 - where are they located?
Located in mitochondria and endoplasmic reticulum.
45
P450 enzymes are prone to induction and inhibition. Give two examples.
Drugs can act as their own P450 inducers/inhibitors | Non-drugs can modify (e.g. grapefruit juice)
46
Give examples of P450 inducers.
``` – Carbamazepine – Rifampicin / ritonavir – Alcohol (acute) – Phenytoin / phenobarbitone – Griseofulvin / Fluconazole – St John’s Wart – Isoniazid (CYP2A1) ```
47
Give examples of P450 inhibitors.
``` – Clarithromycin / azithromycin /erythromycin – Amiodarone – Dexamethasone – Valproate – Metronidazole – Cimetidine – Ciprofloxacin – Isoniazid (CYP1A2) – Grapefruit juice – Ketoconazole – Ritonavir – Verapamil / Diltiazem – Alcohol (chronic) ```
48
How does codeine exert its analgesic effect?
conversion of codeine to morphine by CYP2D6.
49
Phenotype - poor metaboliser Prevalence - ? Genotype - two non-functional alleles
Phenotype Prevalence Genotype | 5-10%
50
Phenotype - intermediate metaboliser Prevalence - 2-11% Genotype - ?
One reduced and one non-functional allele
51
Phenotype - extensive metaboliser Prevalence - 77-92% Genotype - ?
Two functional or reduced function alleles, or one | functional with a non-functional or reduced function allele
52
Phenotype - ultra-rapid metaboliser Prevalence - ? Genotype - more than two functional alleles
1-2% (30% ethiopian)
53
CYP2C9 inhibitors - examples. (5)
``` – Amiodarone – Efavirenz – Fluconazole – Fluvastatin – Ketonazole ```
54
CYP2C9 inducers - examples. (4)
– Carbemazepine – Phenobarbitol – Phenytoin – Rifampicin
55
Why enzyme metabolises S-warfarin?
CYP2C9
56
What is first pass metabolism? | Where does it usually occur?
Metabolism of a drug before it reaches the site of measurement Gut wall or liver
57
Why is levodopa given with DOPA decarboxylase inhibitor?
To avoid first pass metabolism
58
Why are transdermal patches applied above nipples?
To avoid hepatic drainage
59
Explain how rectal medications avoid hepatic first pass metabolism.
blood supply is systemic rather than portal
60
Renal excretion - what molecules are filtered through the glomerulus?
Unbound molecules <20k Da
61
Renal excretion - where does active tubular secretion predominantly take place?
proximal tubule
62
Explain zero order kinetics and give some examples.
– Constant rate of drug is eliminated/metabolised – Independent of drug concentration – Mechanism saturable – e.g. ethanol, phenytoin, high dose salicylates, theophylline
63
Explain first order kinetics.
Rate of drug elimination/metabolism is proportion to [drug] concentration Therefore has a drug half-life Mechanism non-saturable e.g. 95% of all drugs
64
What does half life (t1/2) represent?
The time for the (plasma) drug concentration to decline by half.
65
How many half-lives to 90% steady state?
3.3
66
How many half-lives to <5% of initial concentration?
5
67
What does clearance measure?
Measures of the ability of the body to eliminate a drug
68
CLTotal = ?
(CLRenal + CLHepatic + CLother)
69
What is the unit of clearance?
volume per unit time
70
CL organ = Q organ X E organ | What does this mean?
Clearance is the product of the organ’s blood flow (Q) and the extraction ratio (ER) of the drug
71
Total clearance can be derived from known values. | CL total = ?
(F x Dose) / AUC

CSP 2 (12 decks)

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