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Pharmacology FPP > Drug Metabolism And Excretion > Flashcards

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.

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2
Q

Examples of drugs that are inactive until metabolic

A

Codeine : Morphine
Enalapril : Enalaprilat

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3
Q

Which drug has 3 metabolites but one of them active

A

Carbamazepine

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4
Q

Where does drug biotransformation occur

A

Mainly Liver (but other places as well)

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5
Q

Where does drug biotransformation occur

A

Mainly in the liver, but also other parts of the body

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6
Q

What transporter removes drugs that have undergone phase 1 and or 2 reactions in phase 3

A

P-glycoprotein

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7
Q

What are the 2 stages of drug metabolism

A

Phase 1 and Phase 2

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8
Q

What is the phase 1 reaction

A

functionalization /nonsynthetic reactions

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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

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10
Q

What reactions take place in phase 1 reaction

A

Oxidative, reductive and hydrolytic reactions. Others cyclization and decyclization

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11
Q

Can phase 1 reaction be enough metabolism

A

Yes
Drug can be polar enough after phase 1

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12
Q

What happens in phase 2 reaction

A

Conjugation with endogenous substrate to further increase aqueous solubility

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13
Q

What phases is the true detoxification stage

A

Phase 2

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14
Q

What are some endogenous substrates used in phase 2

A

glucoronide, sulfate, acetate, amino acid, glycine etc

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15
Q

Where can microsomal enzymes be found

A

Located on sER in the liver, kidney, lungs , intestinal mucosa

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16
Q

Examples of microsomal enzymes

A

Monooxygynases, cytochrome P450, UGT, epoxide hydroxylases

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17
Q

What phase makes use of microsomal enzymes

A

Phase 1 and Phase 2

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18
Q

Where are non microsomal enzymes found

A

•Cytoplasm, mitochondria, plasma

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19
Q

Examples of non microsomal enzymes

A

•Esterases, amidases,

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20
Q

Which enzymes family oxidase drugs

A

Microsomal cytochrome P450 monooxygenase family of enzymes, oxidize drugs

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21
Q

What kind of drugs do the cytochrome p450 monooxygenase metabolizes

A

•Act on structurally unrelated drugs

•Metabolize the widest range of drug

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22
Q

Describe the cytochrome p450 enzyme

A

membrane-bound, heme-containing protein.

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23
Q

How many families, subfamilies and gender are in the CYP family

A

57 genes, with 18 families and 44 subfamilies.

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24
Q

In CYP3A4, what’s the family, subfamily, and gene

A

family 3, subfamily A, and gene number 4.

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25
Q

What are the biological factors that can affect the metabolism of a drugs

A

Species/Strain differences - fast acetylators vs slow acetylators
Disease state
Sex differences(M F )
Circadian rhythm
Age
Diet –
Pregnancy

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26
Q

What are factors that can modify drug metabolism

A

• Induction of drug metabolizing enzymes
• Inhibition of drug metabolizing enzymes
• Biological Factors

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27
Q

What’s the inhibitors of CYP450 do

A

Cause Decreased degradation of co-medicated drugs, which leads to Increased drug plasma concentrations, hence Risk of severe adverse events.

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28
Q

Examples of CYP450 inhibitors

A

Inhibitors: cimetidine, Isoniazid, MAO Inhibitor (Phenelzine)

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29
Q

What’s of inductors of CYP450 do

A

Causes Increased degradation of co-medicated drugs , which leads to Decreased drug plasma concentrations ,hence Loss of pharmacological effect and Risk of therapeutic failure.

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30
Q

Examples of CYP450 inducers

A

Inducers: barbiturates, carbamazepine, rifampicin, cyclophosphamide

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31
Q

What are inter specie differences

A

– rats/mice versus humans
You need 6.2 times more of the dosage given to man for rats

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32
Q

Examples of genetic differences that cause’s modification in drug metabolism

A

Fast metabolism – depolarizing muscle blockers, fast acetylators vs slow acetylators

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33
Q

How does disease state affect drug metabolism

A

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

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34
Q

How does sex difference affect drug metabolism

A

sex differences in expression of metabolic enzymes, Testosterone an enzyme inducer hence men would have reduce therapeutic effect of a drug

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35
Q

How can age affect drug metabolism with examples

A

Example of a baby with undeveloped UDP glucoronyl transferase needed to metabolize chloramphenicol , hence there Will chloramphenicol toxicity

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36
Q

How can diet affect drug metabolism and example

A

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

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37
Q

How does pregnancy affect drug metabolism

A

Progesterone is an enzyme inducer and placenta contains metabolizing enzymes
Hence drugs might be metabolized faster

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38
Q

How does circadian rhythm affect drug metabolism

A

Some drugs metabolize faster in the morning than at night

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39
Q

What’s another name for first pass effect

A

Presystemic Metabolism

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40
Q

How do you define first pass effect

A

Metabolism of drug during its passage from the site of absorption into the systemic circulation occurs with oral, skin, lungs

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41
Q

What drugs bypass first pass effects

A

Drugs given IV

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42
Q

What is bioavailability and how does first pass effects affect it

A

the extent and rate at which drugs are available for pharmacological actions, the higher the first pass effect, the lower the bioavailability

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43
Q

Examples of drugs with extensive first pass effect

A

Lidocaine,
propranolol,
nitroglycerin ,
morphine,
insulin

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44
Q

What can be done to drugs with high first pass effect to increase their bioavailability

A

high oral dose or via other routes of administration

45
Q

What are factors that affect first pass effect

A

•- increased bioavailability in liver disease
•- effects of other drugs
•- individual variation in oral drug absorption

46
Q

What is drug excretion

A

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
Q

What are the organs of drug excretion

A

kidney (urine),
tongue (saliva),
skin (sweat),
breast (breast milk),
lungs (breath),
Rectum/intestine (bile/faeces),
eye (tears) and
lastly through the hair.

48
Q

Example of drugs excreted through the rectum

A

vancomycin & vincristine.

49
Q

What drugs are excreted The the rectum

A

Drugs excreted into the bile

50
Q

Example of 2 drug excreted through Feaces

A

vancomycin & vincristine.

51
Q

What type of drugs are excreted in the saliva

A

Basic drugs are excreted in saliva (pH 5.8-8.4)

52
Q

Example of drugs excreted in the tongue

A

Phenytoin,
diazepam,
theophylline,
caffeine &
lithium

53
Q

How does drug excretion in the tear occur

A

occurs by passive diffusion of lipophilic, non-protein bound and unionized molecules from plasma across the eccrine and lacrimal glands.

54
Q

Example of drugs excepted in the tears

A

cytarabine

55
Q

Explain lung drug excretion

A

occurs mainly with anaesthetics.

56
Q

Examples of drugs excreted by the skin

A

Alcohol,
antipyrine,
benzoic acid,
cocaine,
salicylic acid,
lead and
mercury.

57
Q

Example of drugs excreted through breast milk

A

most drugs e.g. aspirin

58
Q

Example of drugs excreted through the hair

A

phenobarbital,
methamphetamine & methoxyphenamine

59
Q

What is the most important organ involved in the elimination of drugs

A

Kidney

60
Q

How do kidneys excrete drugs

A

via its functional unit (nephron: glomerulus + tubules)

61
Q

What is renal excretion

A

Glomerular filtration (GF) – tubular reabsorption (TR) + tubular secretion (TS).

62
Q

What is glomerullar filtration

A

filter small molecules (<20000) such as water, sugar, salt and unbound drugs via pores at the base of the glomerulus.

63
Q

What is renal reabsorbtion

A

Occurs by passive diffusion from the tubules into the peritubular capillaries, requires lipid solubility.

64
Q

What is tubular secretion

A

Carrier mediated, independent of size nor protein binding. Excretes most drugs (~ 80%) and occurs at both proximal and distal convoluted tubules.

65
Q

Example of drug with high molecular weight

A

Heparin

66
Q

Example of drug high molecular weight plasma protein

A

Albumin (68000)

67
Q

Example of highly protein-bound drugs

A

Warfarin (98%)

68
Q

What drugs are not excreted in goomerular filteration

A

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
Q

Where are Water, lipid soluble drugs and other lipid soluble substances reabsorbed

A

at the distal tubule by diffusion across the renal tubule into the bloodstream

70
Q

What is renal clearance

A

It is the volume of plasma containing the amount of substance that is excreted by the kidney per unit time.

71
Q

How do you calculate renal clearance

A

CLr = Cu/Cp x Vu

72
Q

What are the 2 types of half life

A

biological and plasma half life

73
Q

What is biological half life

A

the time taken for a substance to lose half of its physiological, pharmacological or radioactive activity

74
Q

What is plasma half life

A

Time required for the plasma conc of a drug to be reduced to half

75
Q

What does plasma half life depend on

A

Rate of excretion and rate of metabolism

76
Q

What is are 3 drug that has a short plasma half life and how often is the readministration

A

Noreadrnaline
Readministration is 2 minutes

Methadone
Readministration is 15 hours (one daily)

Fluoxetine
Readministration is 6 days (once weekly)

77
Q

Factors affecting drug drug excretion

A

Lipid solubility
pH
Enterohepatic cycling
Particle size
Protein binding
Drug interactions
Renal disease

78
Q

How does lipid solubility affect drugs excretion

A

decreases excretion except for drugs excreted vial the lungs.

79
Q

Explain how pH affects the drug excretion

A

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
Q

What’s used for urine alkalization

A

sodium bicarbonate, acetazolamide or potassium citrate

81
Q

What’s used for urine acidification

A

ammonium chloride, sodium phosphate or potassium phosphate

82
Q

How does enterohepatic cycle affect drug excretion and half life

A

Reduces excretion and increases half life

83
Q

What is enterohepatic cycling

A

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
Q

Examples of drugs that undergo enterohepatic cycling

A

Chloramphenicol
Tetracycline
Flurbiprofen
Oestradiol
Phenytoin
Digitoxin
Colchicine
Leflunomide

85
Q

How does particle size affect the drug excretion

A

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
Q

How does protein binding affect the drug excretion

A

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
Q

How does drug interactions affect excretion

A

Probenecid competes with penicillin for tubular secretion at the proximal tubule (inhibiting it’s excretion) thereby prolonging it’s time of action

88
Q

How does renal disease affect drug excretion

A

It reduces excretion

89
Q

Risk factor for renal disease

A

diabetes,
high blood pressure,
ethnic group,
old age,
family history
Smoking

90
Q

What determines normal kidney function

A

GFR

91
Q

What is GFR

A

The volume of fluid filtered through the glomerular capillaries into the bowman’s caplsule per unit time

92
Q

What is the GFR of a normal kidney

A

100-130

93
Q

GFR in kidney disease

A

<60

94
Q

What’s your the GFR for kidney failure

A

<15

95
Q

What is bioavailability

A

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
Q

What is absolute bioavailability

A

the fraction of an active ingredient of an orally administered drug that reaches the systemic circulation as intact drug (unchanged).

97
Q

What is the Absolute bioavailability of drugs administered intravenously

A

100%

98
Q

How do you determine absolute availability

A

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
Q

What’s the formula for absolute bioavailability

A

AUCorally /AUCiv X 100%

100
Q

How is the AUC calculated

A

Using the trapezoidal rule
AUC= 1/2 (length + breath) X height

101
Q

What’s the shape of the plasma conc vs time curve

A

Trapezium

102
Q

Factors that affect bioavailability

A

Factors that affect drug absorption
Variation in enzyme activity of the gut wall
Gastric pH
Intestinal motility

103
Q

What is relative bioavailability

A

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
Q

How do you calculate relative bioavailability

A

AUC test drug / AUC reference drug X 100%

105
Q

What is bioequivalence

A

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
Q

How do you know that a test drug is bioequivalent to a standard drug

A

●To be bioequivalent the difference in relative bioavailabilities of two related drugs must not exceed + 20%.

107
Q

Fate of ionized drugs in the renal tubules

A

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
Q

I’m what medium does acidic drugs get ionized

A

In basic medium

109
Q

What’s the effect of acidic medium on the half like of an acidic drug

A

Increase the half life

Pharmacology FPP (4 decks)

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