Introduction to PK and PD Flashcards
(183 cards)
1
Q
What is PK
A
What the body does to the drug
2
Q
What is involved in PK?
A
Measuring ADME
3
Q
What is involved in Absorption?
A
Bioavailability, it influences extent of absorption.
4
Q
What is bioavailability?
A
Fraction of dose absorbed into the systemic circulation.
5
Q
What does bioavailability determine?
A
Determines dose adjustment depending on which route is given.
6
Q
What is Volume of distribution?
A
It is the extent of drug distribution in the body.
7
Q
What does Vd determine?
A
Determines the loading dose of a drug.
8
Q
Why does Vd determine loading dose?
A
The loading dose is the amount of drug needed to be given to reach target in the body.
9
Q
What is metabolism?
A
How the body chemically changes the drug to eliminate it.
10
Q
What is Elimination?
A
The body’s process of getting rid of the drug.
11
Q
What measures a drug’s efficiency in elimination?
A
Clearance
12
Q
What is clearance?
A
A measure of how efficiently the body removes the drug.
13
Q
What does clearance of a drug determine?
A
It determines maintenance dose rate.
14
Q
How does clearance determine maintenance dose rate?
A
CL tells you how fast a drug is getting rid from the body, and therefore how much you need to give to replace lost drug.
15
Q
What is half-life?
A
Determines how long until half of the drug is eliminated from the body.
16
Q
What does half-life determine?
A
How often you need to dose to replace lost drug.
17
Q
How does CL and t1/2 differ?
A
CL is how fast the drug is eliminated, t1/2 is how fast it takes for half of the drug to be eliminated.
18
Q
What is PD?
A
What the drug does to the body
19
Q
What does PD involve?
A
Understanding MoA of drugs, Concentration-time profiles, Potency, therapeutic windows, drug-drug interactions, and side effects.
20
Q
What is bound drug?
A
When a drug reaches systemic circulation, some of it may bind to plasma protein.
21
Q
Why is unbound drug important?
A
Only unbound drugs can elicit pharmacological effect, bind to tissues and be eliminated.
22
Q
What is the relationship between bound and unbound drug?
A
They are in equilibrium, meaning as unbound drug is eliminated, the bound drug becomes unbound and takes its place.
23
Q
What is mono-exponential PK?
A
A model which explains PK of a drug which is distributed instantaneously and uniformly.
24
Q
What is Ka?
A
Absorption rate constant
25
What is Kel?
Elimination Rate constant
26
What is AUC?
Represents the total amount of drug that has been absorbed into the systemic circulation.
27
What is multi-exponential PK?
A model which explains PK of a drug which diffuses into tissue then the central circulation.
28
What is a decline in plasma concentration in mono PK due to ?
Only due to elimination.
29
What is a decline in plasma concentration in multi PK due to?
First due to distribution and elimination then elimination only.
30
Is alpha or beta phase more important in multi PK?
Beta
31
Why is beta more important?
It represents the elimination phase.
32
What is intravenous infusion?
Long-term infusion with zero-order input and first-order output.
33
Describe the input and output of Intravenous infusion?
IV infusion has zero-order (constant) input and first-order output (exponential).
34
What is steady state?
When input rate is equal to elimination rate
35
How long until steady state is achieved?
After 4.3 half-lives.
36
What is bioequivalence?
Biochemical similarity between two drugs that share same active ingredient and desired outcomes.
37
Generic brands in Australia must...
Show same drug exposure and concentration range.
38
Generics may differ from the original up to...
5% of the original.
39
Which drugs do not need bioequivalent studies?
IV, topical, solutions, oral BCS Class 1 drugs.
40
Why do some drugs not need bioequivalence studies?
Their absorption and permeability is predictable.
41
What is the 0.80-1.25 rule in bioequivalence studies?
A drug is considered bioequivalent when the 90% confidence interval (CI) of the ratio of Cmax and AUC is between 0.80 to 1.25
42
What is the process of drug absorption?
Disintegration, dissolution then absorption.
43
How may oral drugs be absorbed?
Through passive diffusion along the concentration gradient or active transport against the concentration gradient.
44
What type of kinetics does passive diffusion go through?
First-order kinetics.
45
Why does passive diffusion go through first-order kinetics?
The rate of absorption is depended on the concentration. The higher the concentration, the faster it is absorbed.
46
What type of kinetics does active transport go through?
Zero-order kinetics.
47
Why does active transport go through zero-order kinetics
Active transport is subject to competition, such as inhibition or drug-drug interactions and therefore it may reach saturation. This means a fixed rate can be absorbed at a time.
48
What are factors that may affect drug absorption? (5)
Formulation, Solubility, Lipophilicity, Molecular size, and Ionisation.
49
How does formulation affect absorption?
Solution/suspension do not need to disintegrate before absorption.
SR is made to be slowly absorbed.
Oral drugs may be subjected to first-pass metabolism.
50
How does solubility affect absorption?
The more soluble a drug is, the faster it will dissolute and therefore be absorbed.
51
How does lipophilicity affect absorption?
The more lipophilic a drug is, the easier it is to pass through membranes to enter central circulation.
52
How does ionisation affect absorption?
The more ionised a drug is, the less permeable it is.
53
What is the relationship between hydrophilicity and lipophilicity of a drug?
A drug must be lipophilic enough to pass through plasma membranes and hydrophilic enough to be absorbed in the GI tract.
54
Where are drugs mainly absorbed?
In the small intestine.
55
Why is the small intestine the ideal place for absorption?
It has a large surface area, rich blood supply and favourable pH (6.5-7)
56
What is gastric emptying?
Time taken for a drug to move from the stomach to the small intestine for absorption.
57
What does gastric emptying influence?
Onset and rate of absorption.
58
How long does gastric emptying take in fasted and fed state?
1 h for fasted state, 7-12 h for fed.
59
When must gastric emptying be considered?
In polar drugs which are absorbed slower, in drugs which rely on active transport and in acid labile drugs which may disintegrate due to stomach acid.
60
What is first-pass metabolism?
The body's break down of drugs that pass through the liver before reaching systemic circulation.
61
Why may some drugs never enter systemic circulation?
Degraded in lumen, metabolised by CYP450s, subjected to PGP
62
What are the MoA of drugs?
Agonists, Antagonists, Modifiers and Modulators (enhance, attentuate)
63
What are the drug targets?
Receptors. Enzymes, Ion channels, Transporters
64
What is Enterohepatic Recirculation?
Phenomena where drugs are recycled in the liver.
65
How does enterohepatic recirculation happen?
When drugs enter the liver and is conjugated (metabolised), the gut microflora can cleave onto the conjugated groups and remove them, returning the drug to its original form.
66
What can impede enterohepatic recirculation?
Use of antibiotics which kill the gut's microflora
67
How can disease affect absorption?
Diseases that affect intestinal blood flow, GI motility, gastric emptying will affect drug absorption.
68
What are some diseases that affect drug absorption?
Crohn's Disease reduces gastrointestinal transit time
Celiac alters absorption due to damaged villi
Liver disease reduces first pass metabolism
Cystic Fibrosis reduces gastrointestinal transit time and pH
69
How does food affect drug absorption?
Eating fatty foods can delay gastric emptying and delay absorption.
Food-drug interactions can delay absorption.
70
What determines the rate of absorption?
Absorption rate constant.
71
What determines the extent of absorption?
Bioavailability.
72
In normal kinetics, the terminal phase of the oral drug is... to the IV drug
Parallel
73
What does the terminal phase represent in normal kinetics?
Elimination rate constant (Kel)
74
In flip-flop kinetics, the terminal phase of the oral drug is...than the IV drug
Shallower
75
What does the terminal phase represent in flip-flop kinetics?
Absorption rate constant (ka)
76
Which rate is faster in normal kinetics?
Ka > Kel
77
Which rate is faster in flip flop kinetics?
Kel > Ka
78
What does increasing the Ka result in?
Shorter Tmax, Higher Cmax, Unchanged AUC
79
What does increasing the Kel result in?
Reduced Tmax, Cmax and AUC
80
What does increasing the bioavailability affect?
Unchanged Tmax, Increased Cmax, Increased AUC
81
What is drug distribution?
Movement of the unmetabolised drug in the body.
82
What does drug distribution depend on?
Depends on body and blood composition.
83
What are the trends of body composition?
Fat mass is increasing with age, Muscle and water mass is decreasing with age.
84
Does body composition change even without overall weight change?
Yes
85
How does body composition affect distribution?
People with higher fat are more likely to benefit from lipophilic drugs instead of hydrophilic.
People with lean body mass are more likely to benefit from hydrophilic drugs instead of lipophilic.
86
Which part of ADME is most affected by body composition?
Distribution.
87
What is the blood composition in the body?
55% plasma 45% blood cells.
88
How much of the blood is protein?
7% of the plasma is protein.
89
How much albumin is present in the blood?
60% of the proteins in the blood are albumin
90
What is albumin?
Protein produced by the liver important for drug transport.
91
What does albumin do?
it binds to drugs and controls how much is unbound. When unbound drug levels are low, albumin releases more.
92
What happens if albumin levels are too low?
Drugs cannot bind to albumin, and there is a higher concentration of unbound drug. This can lead to stronger effects or toxicity.
93
What is an example of blood-borne drug transport?
Hormones are lipophilic drugs which enter the circulation, and are carried around the body by binding to albumin.
94
What does albumin protect drugs from?
When drugs are bound to albumin, they are protected from degradation and therefore have a longer half-life.
95
Can more than one drug bind to albumin at the same time?
Yes, albumin has more than one binding site.
96
Case example of relationship between fat mass and fatty drugs?
Hexachlorobenzene poisoining case in Turkey.
97
Why did patients with hexachlorobenzene poisoning suffer for decades?
Fatty drugs stay in the fatty tissue for a long time. The more fat one has in their body, the longer a drug may stay.
98
What are drug effluxers?
Drug effluxers pump out drugs out of the body.
99
What are some types of effluxers?
ABCB1, ABCG2 and P-gp
100
What is ABCG2?
It is a efflux protein which is mainly expressed in the duodenum epithelial cells, with decreasing expression to the rectum.
101
Why is ABCG2 important?
It is a crucial barrier to drugs trying to reach the brain. It protects foetus against toxins ingested by the mother.
102
What is P-gp?
Efflux protein which is minimally expressed in the duodenum epithelial cells, with increasing expression in the rectum.
103
Why is drug distribution in the body Important?
Influences both the rate and extent of drug distribution in the body.
104
What is the rate of distribution dependent on?
Affinity for tissue, tissue capacity and blood flow rate.
105
How is a drug's affinity for tissue calculated?
Using the equilibrium distribution ratio (kp)
106
What does equilibrium distribution ratio (kp) show?
Ratio of concentration in tissue to concentration in venous blood.
107
What influences drug macromolecule binding to proteins?
Influenced by affinity of drug for the macromolecules, concentration of macromolecules and competition from other drugs or endogenous molecules.
108
Which proteins in plasma bind to which drugs?
Albumin binds to acidic drugs, alpha-1 glycoprotein binds to basic drugs and lipoproteins binds to neutral lipophilic drugs.
109
Protein binding is...
Stereoselective. This means that one enantiomer of a drug is more likely to bind to a protein than the other. (e.g. S-Warfarin)
110
How does pregnant women's body composition change?
Increased total body water, increased cardiac output, increased body fat, reduction in albumin.
111
How does Vd of hydrophilic and lipophilic drugs differ in pregnant women?
Vd for hydrophilic drugs will increase by 50%. Vd for lipophilic drugs may also increase by 25% due to increased body fat.
112
What is the clinical significance of protein binding?
Changes in plasma protein binding may affect how the drug behaves in the body (its pharmacokinetics), but they usually do not significantly change the amount of drug that reaches the site of action or the overall drug effect in the patient.
113
What determines infant exposure to drugs in breast milk? (4)
Maternal plasma concentrations, milk-to-plasma ratio, interval between drug intake and next feed, volume of milk and infant weight.
114
What type of drug is unlikely to pass into breast milk?
Highly protein bound drugs do not really pass into breast milk.
115
What does the liver do? (5)
Maintains blood glucose, cholesterol levels, pH, neutralises neurotransmitters and hormones, removes waste and pathogens
116
What does the liver produce? (4)
Amino acids, albumin, bile and coagulation factors.
117
How much bile does the liver produce per day?
600 mL - 1 L
118
What is the purpose of bile?
Assists breakdown of fats, neutralises stomach acid, removes toxins from body.
119
Is the hepatic vein or artery oxygenated?
Artery
120
What happens when the liver fails?
Low blood sugar, easily bleeding, excess oestrogen, jaundice, infection, acidosis
121
Where does most metabolism occur?
The liver.
122
What is involved in Phase 1 Metabolism?
CYP450 Oxidation, reduction and hydrolysis
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What is involved in Phase 2 Metabolism?
Conjugation reactions (acetylation, sulphation, methylation, glucoronidation)
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What is involved in Phase 3 Metabolism?
Transport of metabolites out of cells for excretion.
125
What can cause CYP450 variability?
Inducer drugs which can up-regulate mRNA production, inhibition drugs such as antivirals and antifungals.
126
What is necessary for CYP450 synthesis?
Iron
127
Which enzymes are involved in Phase 2 metabolism?
UGTs, SULTs, NAT1 and NAT2, GSTs, TPMTs, COMTs
128
What are UGT enzymes for?
Increases hydrophilicity of drugs by adding glucuronic acid to drugs.
129
What are SULT enzymes for?
Increases hydrophilicity of drugs by adding sulfuric acid.
130
What are NAT 1 and 2 enzymes for?
Inactivates and detoxifies drugs by adding acetyl group
131
What are GST enzymes for?
Detoxifies the drug by adding glutathione group.
132
What are TMPT enzymes for?
Inactivates thiopurine drugs by adding methyl group.
133
What are COMT enzymes for
Methylates drugs and inactivates them.
134
Which drugs do UGTs enzymes metabolise?
Wide variety drugs as they are the main Phase 2 pathway.
135
Which drugs do SULTs enzymes metabolise?
Metabolises essential endogenous compounds such as dopamine, opioids
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Which drugs do GSTs enzymes metabolise?
Most compounds are substrates of GST
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Which drugs do TPMTs enzymes metabolise?
Class of immunosuppressant drugs known as thiopurine drugs
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What drugs do COMTs enzymes metabolise?
Catechol structured drugs such as dopamine and epinephrine
139
Which enzymes are part of phase 3 metabolism?
ABC transporters like P-gp or SLC transporters
140
What is the difference between ABC and SLC transporters?
ABC like P-gp and MDR are efflux whereas SLC like OATs and OCTs are influx
141
What factors affect metabolism?
Dose, frequency, route of administration, drug-drug interactions, food interactions, age, disease, pharmacogenomics.
142
What is the Extraction Ratio (ER)?
A measure of how efficiently the liver removes the drug from the blood as it passes through.
143
What does ER =1 indicate?
All of the drug is removed in one pass.
144
What does ER =0 indicate?
None of the drug is removed in one pass.
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What is a high extraction ratio?
ER > 0.7
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What is a low extraction ratio?
ER < 0.3
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What are some drugs with a high extraction ratio?
Cocaine, nicotine
148
What are some drugs with a low extraction ratio?
Diazepam, Warfarin
149
Liver disease is more likely to reduce clearance in drugs with...
A high extraction ratio
150
What is biliary excretion?
Process where the body excretes drugs and its metabolites through the bile into the faeces.
151
What are the three steps of urine formation?
Glomerular filtration, tubular reabsorption and tubular secretion
152
What happens in Glomerular Filtration?
Blood enters the kidney and filters water, salta and glucose out of the blood.
153
How much of the blood entering the kidney returns back to the systemic circulation?
99%
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What is Glomerular Filtration Rate? (GFR)
120 mL/min Measure of kidney function.
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How does the kidney maintain a stable GFR?
By regulating afferent arteriole diameter.
156
What is the afferent arteriole diameter?
The afferent arteriole is the vessel that brings blood into the kidneys.
157
What happens in tubular reabsorption?
The body reabsorbs glucose, waters and amino acids from the filtrate made by the glomerular, back into the blood.
158
What is tubular secretion?
Extra wastes, drugs and ions are removed from the blood into the filtrate.
159
What are the three major families of renal drug transporters?
SLC, ABC and MATE
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What is SLC renal drug transporter?
Influx enzymes that move drugs from the blood into the kidney cells. Includes OATs and OCTs
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What is ABC renal drug transporter?
Efflux enzymes which use ATP to move drugs from the kidney cells to the urine. Includes P-gp and MRP2
162
What is MATE renal drug transporter?
Efflux enzymes that move Na+ and H+ coupled anti-port mechanisms from the kidney cells into the urine. They do not use ATP.
163
How is GFR measured?
Using the amount of creatinine cleared
164
How is the amount of creatinine cleared measured?
Using Cockcroft and Gault Equation
165
How does urine pH affect reabsorption?
Only unionised can be absorbed in the tubules, some drugs can be ionised due to the urine's pH
166
Which drugs become ionised in acidic urine?
Weak base drugs
167
Which drugs become ionised in alkaline urine?
Weak acid drugs
168
What is normal urine pH range?
5-8
169
How to know which renal process is predominating?
Net secretion: CLR > fu x GFR
Net reabsorption: CLR < fu x GFR
Net filtration: CLR = fu x GFR
170
What is linear kinetics?
The amount of drug, its conc. in the body is proportional to its dose, and as a result, it follows first-order kinetics
171
Why do some drugs follow non-linear kinetics?
In some cases, drugs rely on enzymes or carriers, which are subject to saturation and thus follow zero-order kinetics.
172
Non-linear Pk is...
Dose dependent.
173
In linear kinetics, Vd, F, Kel, Ka, t1/2, and clearance...
Stay the same despite drug dose alterations.
174
In non-linear kinetics, Vd, F, Kel, Ka, t1/2, and clearance...
May change over time with drug dose alterations.
175
Where does the saturation that causes non-linear PK occur?
Saturation of the absorption, distribution, metabolism and elimination enzymes.
176
Describe saturation in absorption?
Saturation of active transporters of drugs can cause a plateau in concentrations.
177
Describe saturation in distribution?
Saturation in plasma binding sites, and in tissue binding sites means more drug stays unbound and cannot read the target tissue.
178
Describe saturation in metabolism?
Saturation of the CYP450 enzymes means drugs cannot metabolise the drug any faster, and metabolises the same amount of drug per unit time.
179
Which drug is susceptible to saturation of metabolism?
Phenytoin, even at standard doses.
180
What is the michaelis-menten equation used for?
Predicts how fast an enzyme will work at different substrate concentrations, such as modelling metabolism processes for phenytoin.
181
What are some clinical implications on non-linear pharmacokinetics? (4)
Unpredictable drug-drug interactions, making dosing harder to predict, steady state never truly achieved, therapeutic drug monitoring needed.
182
How can poisons affect the GI transit time?
It can either slow down or speed up GI tract transit times.
183
How can poisons slow down GI transit time?
