Drug Metabolism And Excretion Flashcards
1
Q
What is drug metabolism/Biotransformation
A
chemical modification of drugs in the body which transforms relatively lipophilic agents into produce more polar, hydrophilic products which can easily be excreted.
2
Q
Examples of drugs that are inactive until metabolic
A
Codeine : Morphine
Enalapril : Enalaprilat
3
Q
Which drug has 3 metabolites but one of them active
A
Carbamazepine
4
Q
Where does drug biotransformation occur
A
Mainly Liver (but other places as well)
5
Q
Where does drug biotransformation occur
A
Mainly in the liver, but also other parts of the body
6
Q
What transporter removes drugs that have undergone phase 1 and or 2 reactions in phase 3
A
P-glycoprotein
7
Q
What are the 2 stages of drug metabolism
A
Phase 1 and Phase 2
8
Q
What is the phase 1 reaction
A
functionalization /nonsynthetic reactions
9
Q
What’s happens in phase 1 reaction
A
Convert parent compound into a more polar (hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) eg. oxidation
10
Q
What reactions take place in phase 1 reaction
A
Oxidative, reductive and hydrolytic reactions. Others cyclization and decyclization
11
Q
Can phase 1 reaction be enough metabolism
A
Yes
Drug can be polar enough after phase 1
12
Q
What happens in phase 2 reaction
A
Conjugation with endogenous substrate to further increase aqueous solubility
13
Q
What phases is the true detoxification stage
A
Phase 2
14
Q
What are some endogenous substrates used in phase 2
A
glucoronide, sulfate, acetate, amino acid, glycine etc
15
Q
Where can microsomal enzymes be found
A
Located on sER in the liver, kidney, lungs , intestinal mucosa
16
Q
Examples of microsomal enzymes
A
Monooxygynases, cytochrome P450, UGT, epoxide hydroxylases
17
Q
What phase makes use of microsomal enzymes
A
Phase 1 and Phase 2
18
Q
Where are non microsomal enzymes found
A
•Cytoplasm, mitochondria, plasma
19
Q
Examples of non microsomal enzymes
A
•Esterases, amidases,
20
Q
Which enzymes family oxidase drugs
A
Microsomal cytochrome P450 monooxygenase family of enzymes, oxidize drugs
21
Q
What kind of drugs do the cytochrome p450 monooxygenase metabolizes
A
•Act on structurally unrelated drugs
•Metabolize the widest range of drug
22
Q
Describe the cytochrome p450 enzyme
A
membrane-bound, heme-containing protein.
23
Q
How many families, subfamilies and gender are in the CYP family
A
57 genes, with 18 families and 44 subfamilies.
24
Q
In CYP3A4, what’s the family, subfamily, and gene
A
family 3, subfamily A, and gene number 4.
25
What are the biological factors that can affect the metabolism of a drugs
Species/Strain differences - fast acetylators vs slow acetylators
Disease state
Sex differences(M F )
Circadian rhythm
Age
Diet –
Pregnancy
26
What are factors that can modify drug metabolism
• Induction of drug metabolizing enzymes
• Inhibition of drug metabolizing enzymes
• Biological Factors
27
What’s the inhibitors of CYP450 do
Cause Decreased degradation of co-medicated drugs, which leads to Increased drug plasma concentrations, hence Risk of severe adverse events.
28
Examples of CYP450 inhibitors
Inhibitors: cimetidine, Isoniazid, MAO Inhibitor (Phenelzine)
29
What’s of inductors of CYP450 do
Causes Increased degradation of co-medicated drugs , which leads to Decreased drug plasma concentrations ,hence Loss of pharmacological effect and Risk of therapeutic failure.
30
Examples of CYP450 inducers
Inducers: barbiturates, carbamazepine, rifampicin, cyclophosphamide
31
What are inter specie differences
– rats/mice versus humans
You need 6.2 times more of the dosage given to man for rats
32
Examples of genetic differences that cause’s modification in drug metabolism
Fast metabolism – depolarizing muscle blockers, fast acetylators vs slow acetylators
33
How does disease state affect drug metabolism
Diseases affecting the liver will reduce rate of drug metabolism. For instance a bad liver would decrease the metabolism /first pass effect leading to increased bioavailability
34
How does sex difference affect drug metabolism
sex differences in expression of metabolic enzymes, Testosterone an enzyme inducer hence men would have reduce therapeutic effect of a drug
35
How can age affect drug metabolism with examples
Example of a baby with undeveloped UDP glucoronyl transferase needed to metabolize chloramphenicol , hence there Will chloramphenicol toxicity
36
How can diet affect drug metabolism and example
Filedipine and grape juice
Filedipine is a calcium channel blocker (for treating high BP) and grape juice increases the volume of blood ( an enzyme inhibitor)
Increases the effect of Filedipine and other calcium channels blocker
37
How does pregnancy affect drug metabolism
Progesterone is an enzyme inducer and placenta contains metabolizing enzymes
Hence drugs might be metabolized faster
38
How does circadian rhythm affect drug metabolism
Some drugs metabolize faster in the morning than at night
39
What’s another name for first pass effect
Presystemic Metabolism
40
How do you define first pass effect
Metabolism of drug during its passage from the site of absorption into the systemic circulation occurs with oral, skin, lungs
41
What drugs bypass first pass effects
Drugs given IV
42
What is bioavailability and how does first pass effects affect it
the extent and rate at which drugs are available for pharmacological actions, the higher the first pass effect, the lower the bioavailability
43
Examples of drugs with extensive first pass effect
Lidocaine,
propranolol,
nitroglycerin ,
morphine,
insulin
44
What can be done to drugs with high first pass effect to increase their bioavailability
high oral dose or via other routes of administration
45
What are factors that affect first pass effect
•- increased bioavailability in liver disease
•- effects of other drugs
•- individual variation in oral drug absorption
46
What is drug excretion
The irreversible elimination of unchanged parent drugs or their metabolites from the body via various organs of which the kidney is major and most important
47
What are the organs of drug excretion
kidney (urine),
tongue (saliva),
skin (sweat),
breast (breast milk),
lungs (breath),
Rectum/intestine (bile/faeces),
eye (tears) and
lastly through the hair.
48
Example of drugs excreted through the rectum
vancomycin & vincristine.
49
What drugs are excreted The the rectum
Drugs excreted into the bile
50
Example of 2 drug excreted through Feaces
vancomycin & vincristine.
51
What type of drugs are excreted in the saliva
Basic drugs are excreted in saliva (pH 5.8-8.4)
52
Example of drugs excreted in the tongue
Phenytoin,
diazepam,
theophylline,
caffeine &
lithium
53
How does drug excretion in the tear occur
occurs by passive diffusion of lipophilic, non-protein bound and unionized molecules from plasma across the eccrine and lacrimal glands.
54
Example of drugs excepted in the tears
cytarabine
55
Explain lung drug excretion
occurs mainly with anaesthetics.
56
Examples of drugs excreted by the skin
Alcohol,
antipyrine,
benzoic acid,
cocaine,
salicylic acid,
lead and
mercury.
57
Example of drugs excreted through breast milk
most drugs e.g. aspirin
58
Example of drugs excreted through the hair
phenobarbital,
methamphetamine & methoxyphenamine
59
What is the most important organ involved in the elimination of drugs
Kidney
60
How do kidneys excrete drugs
via its functional unit (nephron: glomerulus + tubules)
61
What is renal excretion
Glomerular filtration (GF) – tubular reabsorption (TR) + tubular secretion (TS).
62
What is glomerullar filtration
filter small molecules (<20000) such as water, sugar, salt and unbound drugs via pores at the base of the glomerulus.
63
What is renal reabsorbtion
Occurs by passive diffusion from the tubules into the peritubular capillaries, requires lipid solubility.
64
What is tubular secretion
Carrier mediated, independent of size nor protein binding. Excretes most drugs (~ 80%) and occurs at both proximal and distal convoluted tubules.
65
Example of drug with high molecular weight
Heparin
66
Example of drug high molecular weight plasma protein
Albumin (68000)
67
Example of highly protein-bound drugs
Warfarin (98%)
68
What drugs are not excreted in goomerular filteration
Most of the drugs with high molecular weight like heparin, high molecular weight plasma protein such as albumin (68000) and highly protein-bound drugs such as warfarin (98%)
69
Where are Water, lipid soluble drugs and other lipid soluble substances reabsorbed
at the distal tubule by diffusion across the renal tubule into the bloodstream
70
What is renal clearance
It is the volume of plasma containing the amount of substance that is excreted by the kidney per unit time.
71
How do you calculate renal clearance
CLr = Cu/Cp x Vu
72
What are the 2 types of half life
biological and plasma half life
73
What is biological half life
the time taken for a substance to lose half of its physiological, pharmacological or radioactive activity
74
What is plasma half life
Time required for the plasma conc of a drug to be reduced to half
75
What does plasma half life depend on
Rate of excretion and rate of metabolism
76
What is are 3 drug that has a short plasma half life and how often is the readministration
Noreadrnaline
Readministration is 2 minutes
Methadone
Readministration is 15 hours (one daily)
Fluoxetine
Readministration is 6 days (once weekly)
77
Factors affecting drug drug excretion
Lipid solubility
pH
Enterohepatic cycling
Particle size
Protein binding
Drug interactions
Renal disease
78
How does lipid solubility affect drugs excretion
decreases excretion except for drugs excreted vial the lungs.
79
Explain how pH affects the drug excretion
acidic drug becomes polar in alkaline urine and vice versa resulting in increase in their excretion. Hence alkalization and acidification can be used to increase or decrease urinary excretion
80
What’s used for urine alkalization
sodium bicarbonate, acetazolamide or potassium citrate
81
What’s used for urine acidification
ammonium chloride, sodium phosphate or potassium phosphate
82
How does enterohepatic cycle affect drug excretion and half life
Reduces excretion and increases half life
83
What is enterohepatic cycling
It’s the return of drugs from the intestine to the liver through the portal vein where they are originally metabolized, secreted and transported in the bile to the intestine that contain enzymes that hydrolize the metabolite to form parent drugs that are then carried to the liver for metabolism and the cycle goes on
84
Examples of drugs that undergo enterohepatic cycling
Chloramphenicol
Tetracycline
Flurbiprofen
Oestradiol
Phenytoin
Digitoxin
Colchicine
Leflunomide
85
How does particle size affect the drug excretion
Except for heparin which is a macromolecule, most drugs, their metabolites and other substances with molecular weight below 20000 pass freely through the glomerular capillary.
86
How does protein binding affect the drug excretion
plasma albumin has a molecular weight of 68000 and cannot pass freely through the glomerular capillary. Hence warfarin which is highly protein bound (98%) has very small concentration (2%) in the filtrate compare to plasma.
87
How does drug interactions affect excretion
Probenecid competes with penicillin for tubular secretion at the proximal tubule (inhibiting it’s excretion) thereby prolonging it’s time of action
88
How does renal disease affect drug excretion
It reduces excretion
89
Risk factor for renal disease
diabetes,
high blood pressure,
ethnic group,
old age,
family history
Smoking
90
What determines normal kidney function
GFR
91
What is GFR
The volume of fluid filtered through the glomerular capillaries into the bowman’s caplsule per unit time
92
What is the GFR of a normal kidney
100-130
93
GFR in kidney disease
<60
94
What’s your the GFR for kidney failure
<15
95
What is bioavailability
a measurement of the rate and extent to which the active ingredient in a drug product becomes available at the site of action (or in the systemic circulation)
96
What is absolute bioavailability
the fraction of an active ingredient of an orally administered drug that reaches the systemic circulation as intact drug (unchanged).
97
What is the Absolute bioavailability of drugs administered intravenously
100%
98
How do you determine absolute availability
determined by measuring the plasma concentrations of a drug at different time when the drug is administered orally and intravenously on different occasions.
Calculated as the ratio of area under the plasma concentration vs the time curve of drugs administered orally to that given via IV
99
What’s the formula for absolute bioavailability
AUCorally /AUCiv X 100%
100
How is the AUC calculated
Using the trapezoidal rule
AUC= 1/2 (length + breath) X height
101
What’s the shape of the plasma conc vs time curve
Trapezium
102
Factors that affect bioavailability
Factors that affect drug absorption
Variation in enzyme activity of the gut wall
Gastric pH
Intestinal motility
103
What is relative bioavailability
is a measure of the systemic availability of a generic or test drug product in comparaism to that of a Reference standard drug product containing the same active ingredient when they are administered through the same route in the same dosage form.
104
How do you calculate relative bioavailability
AUC test drug / AUC reference drug X 100%
105
What is bioequivalence
A generic DP is bioequivalent to a reference standard DP if their RB do not show Significant standard deviation when both drug products containing the same active ingredient in the same chemical and dosage forms are administered at the same dose through the same route and under the same experimental conditions.
106
How do you know that a test drug is bioequivalent to a standard drug
●To be bioequivalent the difference in relative bioavailabilities of two related drugs must not exceed + 20%.
107
Fate of ionized drugs in the renal tubules
They cannot be reabsorbed at renal tubular
They pass through glomerular filteration
They are excreted better than non ionized (it’s like they’re polar)
108
I’m what medium does acidic drugs get ionized
In basic medium
109
What’s the effect of acidic medium on the half like of an acidic drug
Increase the half life
