Basic Principles of ADME Flashcards
(135 cards)
1
Q
What does ADME stand for?
A
Absorption
Distribution
Metabolism
Elimination
2
Q
What does a drug PK give us?
A
Which dose to give
Which administration route
How often to give a dose
Which administration formulation
3
Q
How do we get drug PK data?
A
Through experiments done as part of development research
4
Q
What are the stages in drug making?
A
Drug discovery
Preclinical experiments
Clinical trials
Phase IV
5
Q
What happens in drug discovery?
A
Identify target
New drug synthesis
6
Q
What happens in preclinical experiments?
A
In vitro + vivo
Testing drug activity
1st PK + PD data
7
Q
What happens in clinical trials?
A
Phase I = safety + dose range
Phase II = safety, efficacy, dose range + target disease population
Phase III = efficacy + comparison
8
Q
What happens in phase IV?
A
Observation = 10-15 years
9
Q
What is drug absorption?
A
Mass transfer process that involves the movement of unchanged drug molecules from site of administration into blood stream
10
Q
What is active transport?
A
Uniport, antiport + symport
11
Q
What is passive diffusion?
A
No involvement of membrane, slowest step, larger molecules diffuse more slowly
12
Q
What is facilitated diffusion?
A
Channel protein + carrier protein, sugar, amino acid + drugs with similar structures pass
13
Q
What is the cell membrane NOT permeable to?
A
High polarity
High molecular weight
Conformational freedom
14
Q
Describe uniport
A
Mediate transport of single drug
Facilitate mode of diffusion
Transport of non-diffusible substances
Never in contact with hydrophobic core
15
Q
Describe antiport
A
Coupled movement against conc gradient
16
Q
Describe symport
A
Transport 2 different substances simultaneously
17
Q
What is an example of uniport?
A
GLUT1 glucose carrier
18
Q
What is an example of antiport?
A
3 Na+/ Ca2+ antiporter in cardiac muscles
19
Q
What is an example of symport?
A
2 Na+/ glucose symporter
20
Q
What are the parameters that influence absorption?
A
Physiochemical properties of drug
Pharmaceutical dosage form
Anatomical + physiological characteristics
Administration route
21
Q
What are examples of physiochemical properties of drug?
A
Size
Hydrophilic
Lipophilic
22
Q
What are examples of pharmaceutical dosage form?
A
Sustained dosage form
23
Q
What are examples of administration route?
A
Systemic or topical
24
Q
What is dose?
A
Specific measured amount of drug needed to achieve a specific plasma conc
25
What is plasma conc?
Amount of drug which reaches the blood stream , gets distributed in body + so achieves specific conc
26
What happens if specific conc reaches target site?
= pharmacological effect
27
What is exposure?
Plasma conc vs time
28
What is area of curve equal to?
Actual body exposure to drug after administration of dose
29
How do you calculate area under the curve?
Initial dose X bioavailability
----------------------------------------
Clearance
30
How do you calculate AUC for IV?
Extrapolated plasma conc/ elimination rate constant
31
What is bioavailability?
Amount of drug reaching circulatory system from delivery system used
32
What does oral bioavailability depend on?
Absorption rate
33
Why is intravenous 100% bioavailability?
Administrated straight into circulation
34
What is the bioavailability factor?
Ratio of AUC of orally or intravenous administrated drug
35
What is the equation for bioavailability factor (F)?
AUC oral
------------- X 100
AUC iv
36
What factors influence bioavailability?
Lipid solubility + chemical form of drug = salt factor
Formulation = bioequivalence
Co-administration of other drugs
Presence of comorbidity affecting absorbance site
Susceptibility to gastric acid + enzymes
First-Pass effect
37
What are examples of comorbidity affecting absorbance site?
Diarrhoea
| Vomiting
38
What happens when a drug is not-H2O soluble?
Low bioavailability
39
How do you increase solubility of non-H2O soluble drugs?
Formulated as salts
40
What is bioequivalence?
Ensures all drug formulation on market has same bioavailability
41
What is drug distribution?
Reversible mass transfer of drug from one location to another within the body
42
What happens once the drug is absorbed?
Conc gradient exists
43
What does drug distribution depend on?
Blood flow
44
What happens if a drug is more lipid soluble?
More chance of reaching target
45
What must drugs do to interact with target?
Pass through capillary walls into intestinal fluid
46
Are drugs distributed equally across all organs?
NO
47
How does blood flow influence drug distribution?
Intensity of it
48
How does exercise increase drug distribution?
Cardiac output increases 5-6x
| = perfusion increases = distribution increases
49
How does concomitant diseases decrease drug distribution?
Heart failure = not enough perfusion
= distribution takes longer
= peak response to dose delayed
50
How does decreased renal clearance decrease drug distribution?
Delay drug excretion
51
What else can decrease/increase drug distribution?
Shock
52
What may drugs be held by plasma compartments by?
Albumin
Lipoproteins
α1- acid glycoproteins
53
Describe albumin protein binding
Weak acids bind
| Have 2 binding sites
54
Describe α1- acid glycoproteins binding
Cationic drugs at physiological pH
55
When is binding reversible?
Therapeutic conc
56
What must the drug be to enter target?
Unbound = free to leave plasma + diffuse + enter target
57
How do you calculate fraction of unbound drug (%)?
Unbound conc
----------------------
Total drug conc
58
What does it mean if FU is <5-10%?
Highly plasma protein bound drugs
59
What happens when you increase free unbound drug?
Decrease in plasma protein synthesis
60
How do you calculate vol of distribution?
Dose of drug (mg)
--------------------------
Drug serum conc (mg/L)
61
What is vol of distribution?
Vol of fluid required to contain total dose of drug in the body in same conc as that present in plasma
62
What does vol of distribution vary with?
Body weight
63
How many PK compartment models are there?
2
64
What is the first PK compartment model?
Organs + tissues with high blood flow
| = heart, kidney, liver, lungs + brain
65
What is the second PK compartment model?
Organs + tissues with low blood flow
| = bone, bladder + peritoneal cavity
66
What happens in first PK compartment model?
Drug absorbed then immediately distributed
67
What is the second PK compartment model divided into?
Central + peripheral
68
What is the central compartment?
Blood
69
What is the peripheral compartment?
Tissues where distribution of drug is slower
70
What is the prime site of drug metabolism?
Liver
71
What is the ultimate elimination organ?
Liver
72
Which organ is responsible for 1st-pass effect?
Liver
73
Where are most drugs metabolised?
Liver
74
What enzymes is involved in liver metabolism?
Cytochromes P450
75
Where are cytochrome P450s enzymes located?
Hepatocytes of liver
76
What is hepatic clearance of drugs?
Complex multistep process looking to removal of drugs from circulation
77
What is hepatic clearance (CLH)
Vol of blood from which drug is completely removed by liver per unit time
78
How do you calculate CLH?
Hepatic blood flow (QH) X hepatic extraction ratio (EH)
79
What is hepatic elimination ration (EH)
Fraction of drug extracted from blood during single pass through liver
80
What factors is hepatic clearance dependent on?
Fraction of unbound drug to albumin
Liver blood flow
Liver intrinsic clearance
81
What happens if parent compound is lipophilic?
Metabolite hydrophilic
82
What happens to H2O-soluble drugs?
Easily excreted in urine
83
What happens to drugs administrated IV, ID or SD?
Enter systemic circulation directly = reach target organs before hepatic modification
84
What happens to oral drugs?
Absorbed in GI tract + delivered by portal vein to liver
85
What is 1st-pass effect?
Allow liver to metabolise drugs before systemic circulation
86
What do oral drugs with extensive 1st-pass metabolism need?
Administration at a larger dose than IV formulation
87
What do drugs with low 1st-pass effect need?
Similar or slightly higher dose than IV
88
What does it mean if drugs have NO 1st-pass effect?
Low bioavailability
89
Do sublingual + rectal avoid 1st-pass effect?
YES
90
What are consequences of drug metabolism?
Metabolite products are less pharmacologically active
91
What the exceptions to consequences of drug metabolism?
Metabolite more active = pro-drugs
Metabolite is toxic
Metabolite is carcinogenic
92
What is small intestine metabolism important for?
Orally ingested chemicals
93
What type of reactions occur in drug metabolism?
Phase I
Phase II
Phase III
94
Describe Phase I reaction in drug metabolism
Convert parent compound into chemically active more polar metabolite
By adding/ unmasking functional groups
95
Describe Phase II reaction in drug metabolism
Occur at chemically reactive sites
Conjugation wit endogenous substrate to further increase aq solubility
Metabolites inactive
96
Describe Phase III reaction in drug metabolism
Transmembrane transport
Efflux of metabolites + parent compound to bile + urine
Antiporter activity
97
Describe oxidation reactions by Cytochrome P450s
Cytochrome P450s
O2 incorporated into drug
Oxidation = loss of part of drug
98
Describe Cytochrome P450s
Haem-containing proteins with smooth ER
12 gene families expressed in humans
GYP P450 nomenclature is genetically based
99
What factors affect metabolism?
Physio-chemical factors
Biological factors
Environmental factors
100
What are examples of biological factors?
Age, gender, genetics + state of health
101
What are examples of environmental factors?
Diet, stress, season (time of day) + pharmacokinetic drug-drug interactions
102
What is an example of Phase I reaction?
Oxidation
103
What is elimination?
Any process involved in excretion of drugs from the body
104
What are the major routes of elimination?
```
Kidney = urine
Liver = bile (faeces)
```
105
What are the minor routes of elimination?
Exhalation, sweat, saliva + breast mile
106
What happens in renal drug elimination?
Filtration in glomerulus
Reabsorption
Tubule excretion
107
What happens in filtration in renal drug elimination?
Free or unbound drugs filtered
| No albumin can pass through
108
What happens in reabsorption in renal drug elimination?
Glucose + amino acids reabsorbed
| No hydrophilic drugs reabsorbed BUT lipophilic do
109
What happens if metabolism increases H2O-solubilty?
Prevent reabsorption
110
What happens if change in pH/charge?
Prevent reabsorption
111
What is renal clearance?
Vol of plasma per unit time that get filtered of a drug
112
What does renal clearance give no information about?
How much drug cleared
113
What gives info about the drug being cleared?
Rate of elimination
114
How do you calculate rate of elimination?
Renal clearance X drug plasma conc
115
What are most drugs cleared by?
1st order kinetics
116
What is the half-life for each drug?
Individual + constant
117
What are closely related to renal clearance?
Glomerular filtration rate
| Creatinine clearance
118
What is glomerular filtration rate (GFR)?
Flow rate of a drug that is being filtered in Bowman's capsule
119
What is ROE?
Amount of drug eliminated
120
What is ROE dependent on?
Renal clearance + drug plasma conc
121
Why is rate of metabolism proportional to drug plasma conc?
Because metabolic enzymes are mot saturated
122
What happens if there is a higher drug plasma conc?
Higher the elimination rate
123
Is the same amount of drug metabolised the same amount getting eliminated?
YES
124
What is half-life?
Time it takes to eliminate 50% of drug
125
What does half-life determine?
Dose + dosing interval
126
What is the equ for t1/2?
0.693/ Ke
127
What % of drug is always excreted after 5 half-life times?
95%
128
Which part of the graph is zero order kinetics?
Plateau
129
What is the amount of drug metabolised per unit time in zero order kinetics?
Constant
130
When does zero order kinetics mostly happen + why?
Through overdoses = drug accumulates in body = increased side effects
131
What is biliary excretion?
Active secretion of endogenous + exogenous drugs/substances from hepatocytes in bile + duodenum
132
What is multiple dosing?
Some drugs given more than once via multiple doses = to achieve constant drug plasma levels
133
What is steady state?
Situation in which in take of drug is in eqm with elimination
134
When is steady state reached?
After 5 half life
135
What does multiple dosing depend on?
Half life
