Pharmacokinetics Concepts Flashcards
1
Q
What is pharmacokinetics?
A
The study of movement of a drug into and out of the body - the study of what the body does to the drug
2
Q
What is pharmacodynamics?
A
The study of drug effect and the mechanisms of action - what the drug does to the body
3
Q
What is pharmacogenetics?
A
The effect of genetic variability on the pharmacokinetics, or the dynamics of a drug on an individual
4
Q
What are the main processes involved in drug therapy?
A
- Pharmaceutical process
- Pharmacokinetic process
- Pharmacodynamic process
- Therapeutic process
5
Q
What question is asked when considering the pharmaceutical process?
A
Is the drug getting into the patient
6
Q
What question is asked when considering the pharmacokinetic process?
A
Is the drug getting to its site of action
7
Q
What aspects does the pharmacokinetic process consist of?
A
- Absorption
- Distribution
- Metabolism
- Elimination
8
Q
What question is being asked when considering the pharmacodynamic process?
A
Is the drug producing the required pharmacological effect?
9
Q
What question is being asked when considering the therapeutic process?
A
Is the pharmacological effect being translated into a therapeutic effect?
10
Q
Draw a diagram illustrating the relationship between pharmaceutical process, pharmacokinetic process, pharmacodynamic process, and therapeutic process
A
11
Q
Draw a diagram illustrating the stages of ADME in relation to a time-concentration graph
A
12
Q
What is meant by oral bioavailability?
A
The fraction of a dose which finds its way into a body compartment, usually the circulation
13
Q
What is the bioavailability for an intravenous bolus?
A
100%
14
Q
How is the bioavailability worked out for all other routes apart from IV?
A
You compare the amount reaching the body compartment by that route with intravenous bioavailability
15
Q
Give the equation for the calculation of oral bioavailability?
A
= area under the curve (oral) / area under the curve (IV)
16
Q
What is meant by area under the curve when calculating oral bioavailability?
A
The area under the curve of plasma concentration x time post dose - this is the total drug exposure
17
Q
What factors affect bioavailability?
A
- Drug formulation
- Age
- Food
- Vomiting/malabsorption
- Fire pass metabolism
18
Q
What is first pass metabolism?
A
Any metabolism occuring before the drug enters the systemic circulation
19
Q
In what locations can first pass metabolism occur?
A
- Gut lumen
- Gut wall
- Liver
20
Q
What produces the first pass metabolism effect in the gut lumen?
A
- Gastric acid
- Proteolytic enzymes
- Grapefruit juice
21
Q
What drugs are affected by the first pass metabolism in the gut lumen?
A
- Benzylpenicillin
- Insulin
- Ciclosporin
22
Q
What produces the first pass affect in the gut wall?
A
P-glycoprotein efflux, which pumps drugs out of the intestinal entrocytes and back into the lumen
23
Q
What drugs are affected by first pass metabolism in the gut wall?
A
Ciclosporin
24
Q
What produces the first pass effect in the liver?
A
Drugs get oxidised and conjugated
25
What drugs are affected by the first pass effect in the liver?
* Propanolol
* Morphine
26
What does the distribution of a drug refer to?
Its ability to 'dissolve' in the body
27
What are the two key factors associated with drug distribution?
* Protein binding
* Volume of distribution
28
When are many drugs bound to circulating proteins?
Once they are in the systemic circulation
29
Give 4 proteins that bind drugs in the systemic circulation?
* Albumin
* Globulins
* Lipoproteins
* Acid glycoproteins
30
What kind of drugs does albumin bind?
Acidic drugs
31
What kind of drugs do globulins bind?
Hormones
32
What kind of drugs to lipoproteins bind?
Basic drugs
33
What kind of drugs do acid glycoproteins bind?
Basic drugs
34
What binding state must drugs be in to have a pharmacological effect?
Most must be unbound (free)
35
Why must most drugs be unbound in order to have a pharmacological effect?
Because only the fraction of the drug that is not protein-bound can bind to the cellular receptors, pass across tissue membranes, gain acess to cellular enzymes etc
36
What does the level of free drug determine?
The action of the drug at its target receptor, and its elimination
37
What can displacement of drugs from binding sites produce?
Protein binding drug interactions
38
What affect may changes in protein binding have?
Can cause changes in drug distributino
39
When are changes in protein binding important?
If one of three criteria are met;
* High protein binding
* Low Vd
* Narrow therapeutic ratio
40
What factors affect protein binding?
* Hypoalbuminaemia
* Pregnancy
* Renal failure
* Displacement by other drugs
41
Regarding distribution, what is true of drug that is not bound to plasma proteins?
It is available for distribution to the tissues of the body
42
Are drugs found in body fluids, or in tissues?
Some are distributed only to body fluids, whereas others are found extensively in body tissues
43
What is volume of distribution?
A measure of how widely a drug is distributed in body tissues
44
Give the equation for calculating volume of distribution?
= dose / [drug]10
45
Where is volume of distribution a useful measure?
Useful in understanding dosing regimes
46
What is half life proportional to?
Vd and clearance
47
What is the body fluid distribution in a 70kg man?
* Intracellular space 55% (23L)
* Intravascular space 12% (5L)
* Interstitial space 33% (14L)
48
What can tissue distribution be affected by?
* Specific receptor sites in tissues
* Regional blood flow
* Lipid solubility
* Active transport
* Disease states
* Drug interactions
49
What is a drug initially metabolised by?
Phase 1 enzymes
50
What happens once a drug has been metabolised by phase 1 enzymes?
CYPs perform a variety of functions
51
What functions are performed by CYPs?
* Oxidation
* Dealkylation
* Reduction
* Hydrolysis
52
What happens after CYPs have performed their functions on drugs?
It either;
* Gets metabolised by phase II enzymes
* Go to the kidney
* Go to the gallbladder
53
What happens to drugs metabolised by phase II enzymes?
They then get conjugated with;
* Glucoronide
* Sulphate
* Glutathione
* N-acetyl
54
What happens to the products of conjugation of drugs that have gone down the phase II metabolism path?
They go to the gallbladder or the kidney
55
What does whether the products of phase II metabolism go to the kidney or the gallbladder depend on?
The molecular weight
56
What is true of the end product of conjugation of phase II metabolised drugs?
They are water soluble
57
What is the advantage of the products of conjugation of phase II metabolised drugs being water soluble?
* It enables rapid elimination from the body
* They are usually pharmacologically inactive
58
When do drugs go the kidney after phase I metabolism?
If the molecular weight is \<300
59
What happens to the drugs that go to the kidney?
They are excreted in urine
60
When do drugs go the gallbladder after phase I metabolism?
If the molecular weight is \>300
61
What happens to the drugs that go to the gallbladder?
They are excreted in bile
62
When can an active metabolite be produced?
* When a pharmacologically inactive compound is metabolised to one with pharmacological activity
* When a pharmacologically active compound is metabolised to other active compounds
63
What is it called when a drug is metabolised to a pharmacologically active compound in the body?
A 'pro-drug'
64
Give two examples of pro-drugs
* Inactive enalaprilat to active enalapril
* L-dopa metabolised to more active metabolite
65
What is the advantage of L-dopa being metabolised to a more active metabolite?
Improves distribution, and allows it to cross the blood brain barrier
66
Give two examples of where pharmacologically active compounds are metabolised to other active compounds
* Codeine to morphine
* Lorsartan to EXP3174
67
What are oxidation and reduction in phase 1 of drug metabolism in part dependant on?
Cytochrome P450 family of enzymse
68
What can the activity of cytochrome P450 enzymes be influenced by?
Enzyme-inducing and enzyme-inhibiting drugs
69
Other than enzyme-inducing and -inhibiting drugs, what else affects cytochrome P450 enzymes?
* Age
* Liver disease
* Hepatic blood flow
* Cigarette and alcohol consumption
70
Other than acting on cytochrome P450 drugs, what else do enzyme inhibiting and inducing drugs do?
Alter the rate of metabolism of other drugs
71
Where are the cytochrome P450 enzymes present?
Mainly in the liver, but also in the gut and lungs
72
What are the most important cytochrome P450 types?
* 2D6
* 2C9
* 2C19
* 3A
73
How does CYP2D6 vary depending on race?
* Absent in 7% of Caucasians
* Hyperactive in 30% in East Africans
74
What does CYP2D6 metabolise?
* Codeine
* Beta-blockers
* Tricyclics
75
What is CYP2D6 inhibited by?
* Fluxoetine
* Paroxetine
* Haloperidol
* Quinidine
76
How does CYP2C9 vary depending on race?
Absent in 1% of Caucasian and Blacks
77
What does CYP2C9 metabolise?
* Most NSAIDs
* S-warfarin
* Phenytoin
* Tolbutamide
78
What is CYP2C0 inhibited by?
Fluconazole
79
What is CYP2CP induced by?
* Carbamazepine
* Ethanol
80
How does CYP2C19 vary depending on race?
* Absent in 30% of Asians
* Absent in 5% of Caucasians
81
What does CYP2C19 metabolise?
* Diazepine
* Phenytoin
* Omeprazole
82
What is CYP2C19 inhibited by?
* Ketoconazole
* Omeprazole
* Isoniazid
* Fluoxetine
* Ritonavir
83
What is CYP2C19 induced by?
Rifampicin
84
What is CYP3A involved in the metabolism of?
* Calcium channel blockers
* Benzodiazepines
* HIV protease inhibitors
* Most statins
* Cyclosporin
* Non-sedating anti-histamines
85
What drugs act as CYP3A inhibitors?
* Anti-fungals
* Cimetidine
* Macrolides
* *Grapefruit juice*
86
Give 3 anti-fungals that act as CYP3A inhibitors
* Ketoconazole
* Flucoanzole
* Itraconazole
87
What drugs act as CYP3A inducers?
* Carbamazepine
* Phenytoin
* Rifampicin
* Ritonavir
* St Johns Wort
88
What are cytochrome P450 enzymes?
A superfamily of isoforms
89
What % of human drug metabolism are cytochrome P450 enzymes responsible for?
Around 90%
90
Give two examples of toxins metabolised by cytochrome P450 enzymes
* Carcinogens
* Pesticides
91
What is the result of the genetic differences in cytochrome P450 enzymes?
There are genetic differences in metabolism
92
Clinically, where is metabolism important?
In drug prescribing
93
What should be considered while prescribing to prevent interactions?
Over the counter medications and food
94
What factors are important in the metabolism of drugs?
* Race
* Age
* Sex
* Species
* Clinical or physiological condition
95
Where is the consideration of the effect of race on drug metabolism important?
In the development of pharmacogenetics
96
How does age affect the metabolism of drugs?
It is reduced in children and the elderly
97
Give an example of where metabolism is affected by gender?
Women are slower ethanol metabolisers
98
When is the consideration of the effect of species on drug metabolism important?
When considering drug development
99
What is the main route of drug elimination?
The kidney
100
Other than the kidneys, what are the other routes of drug metabolism?
* Lungs
* Breast milk
* Sweat
* Tears
* Genital secretions
* Bile
* Saliva
101
What processes determine the renal excretion of drugs?
* Glomerular filtration
* Passive tubular reabsorption
* Active tubular secretion
102
What drugs have their excretion affected by glomerular filtration?
Unbound drugs, *e.g. gentamicin*
103
Give an example of a drug where the excretion is affected by passive tubular reabsorption?
Aspirin
104
What is passive tubular reabsorption affected by?
* Urine flow rate
* pH
105
Give an example of a drug where the excretion is affected by active tubular secretion
Penicillin
106
What is clearance?
The ability of the body to excrete the drug
107
What is clearance mostly affected by?
GFR - *if the GFR is reduced, the clearance is reduced*
108
How is half life related to clearance?
They are inversely proportional
109
What are the categories of elimination kinetics?
* First order kinetics
* Zero order kinetics
110
Describe the elimination in first order kinetics
Linear
111
What is meant by elimination being linear?
The rate of elimination is proportional to the drug level - *a constant fraction of drug is eliminated in unit time*
112
Can half life be defined with first order kinetics?
Yes
113
Describe the elimination of drug in zero-order kinetics
Non-linear
114
What is meant by non-linear elimination?
The rate of elimination is constant
115
What kind of kinetics do most drugs exhibit at high doses?
Zero order
116
Why do most drugs exhibit zero order kinetics at high doses?
Because the receptors/enzymes become saturated
117
What is the problem with zero order drugs?
They are more likely to result in toxicity
118
Why are zero order drugs more likely to result in toxicity?
* No half life is calculable
* Small dose changes may produce large increments in dose, or lead to toxicity
119
What are the potential reasons for drugs requiring monitoring?
* Phamacokinetic reasons
* Known toxic effects
120
What are the pharmacokinetic reasons for drug monitoring?
* Zero order kinetics
* Long half-life
* Narrow therapeutic window
* At greater risk of drug-drug interactions
121
Give two examples of known toxic effects of drugs that would necessitate drug monitoring
* Bone marrow suppression
* Alteration in U&Es
122
How long does it take to reach a steady state during repeated drug administration?
3-5 half lives, *generally irrespective of dose or frequency of administration*
123
How long does it take to eliminate most of the drug once a steady state is reached?
4-5 half lives
124
What is the equation for calculating loading doses?
Vd x [Drug]target
125
What is the equation for calculating half life?
loge0.5 / k
= 0.693 / k
126
What is k?
The elimination rate constant, which is determined from the slope of the curve
127
What determines k?
The ratio of clearance to volume of distribution
128
How do you calculate half life from volume of distribution?
Vd / Cl
129
What is the result of half life being equal to Vd / Cl?
Half life is proportional to volume of distribution, or inversely proportional to clearance
130
What might you have to take account of when calculating half life?
Chronic kidney disease
131
Why may you have to account for chronic kidney disease in the half life calculation?
Clearance from the kidney is proportional to renal function (GFR), and so half life is inversely proportional to clearance
132
What is the result of most drugs not remaining in the plasma?
Distribution occurs in 2 or more compartments
133
Is the equilibrium of drugs between different body compartments equal?
No
134
What is the result of the equilibrium of drugs between different compartments being different?
The rate of elimination can be different
