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Cell physiology and pharmacology > Lecture 17- Pharmacokinetics II (drug elimination) > Flashcards

Lecture 17- Pharmacokinetics II (drug elimination) Flashcards

1
Q

drug out invovles

A

metabolism and elimiantion

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2
Q

elimiantion

A
  • Term used to cover both metabolic and excretory processes
  • Elimination removes both exogenous and endogenous molecular species
  • Evolutionary advantage in recognising xenobiotics- potential toxins
  • Protective and homeostatic function
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3
Q

metabolism largely takes place in ….. via which enzymes

A

the liver, phase I and II enzymes

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4
Q

Phase i and II enzymes

A

icnrease ionic charge enhancing renal elimination

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5
Q

main route of elimination

A

Main route of drug elimination is the kidney

  • Glomerular filtration
  • Active tubular secretion
  • Passive tubular reabsorption
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6
Q

hepatic emtabolism is split into

A

phase i and II

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7
Q

Phase I and II enzymes

A
  • expressed throughout body tissue, however large hepatic reserve (first port of call after GI absorption)
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8
Q

what do phase I and II drugs do

A

metabolise drugs by increasing ionic charge- enhanced renal elimination

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9
Q

lipophilic drugs (not ionic)

A

diffuwe out of tenal tubules and back into plasma and cant be excreted

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10
Q

Phase I enzymes are what sort of enzymes

A

Cytochrome P450

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11
Q

where is cytochrome P450 enzyme found

A

located on external face of the ER

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12
Q

what reactions do cytochrome P450 catalyse

A
  • Redox
  • Dealkylation
  • Hydroxylation reactions
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13
Q

CYP450s are known as

A

veralite generalists

  • metabolise a wide variery of molecules
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14
Q

drugs metabolised by CYP450 go onto be either…

A

eliminated

or metabolised by phase II enzymes

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15
Q

some pro drugs activated by phase I metabolism

A

to active species

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16
Q

example of activation of prodrug

A

e.g. Codeine to morphine

Around 0-15% of codeine metabolised by CYP2D6 exhibits genetic polymorphism) to morphine.

  • Morphine has x 200 affinity for Opioid u-receptors as codeine
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17
Q

codeine metabolised by which CYP450 enzyme

A

CYP2D6

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18
Q

Cytochrome P450 enzymes

A
  • 3 superfamilies: CYP 1,2 and 3
  • Isozyme membranes in each family coded by suffix e.g. CYP3AD
  • Six isozymes metabolise 90% of drugs
  • Other isozymes exhibit variable hepatic expression
  • Each isozyme has a drug which is metabolises optimally
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19
Q

which isozyme of CYP450 contributes the most to drug transformation in humans

A

CYP 3A4/5

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20
Q

Phase II enzymes (hepatic enzymes) are mostly

A

cytosolic enzymes

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21
Q

phase II enzymes show ….. kinetics than phase i

A

more rapid kinetics

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22
Q

Phase II do what to drugs

A
  • Enhance hydrophilicity by further increasing ionic charge
    • Enhancing renal elimination
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23
Q

Phase II enzyme catalyse which reactions

A
  • Sulphation
  • Glucorinadation
  • Glutathione conjugation
  • Methylation
  • N-acetylation
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24
Q

metabolism usually renders drugs

A

pharmacologically inactive

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25
Q
A
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26
Q

factors affecting drug metabolism

A

age

sex

general health/ diet/ disease

Genetics

CYP450s

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27
Q

health and drug metabolism

A

HRH

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28
Q

HRH

A

heart, renal hepatic

  • decreased functional resevre of pahse I and II enzymes
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29
Q

CYP450s can be

A

inducted

inhibited

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30
Q

Phase 1 metabolism: CYP450 induction

A

If a patient is taking more than one drug at the same time, certain drugs can induce specific CYP450 isozymes

  • Induction mechanism:
    • Increased Transcription
    • Increase translation
    • Slower degradation
  • If another drug in body metabolised by induced CYP450 isozyme then rate of elimination will be increased
  • Plasma levels of drug will then fall
    • Can have serious therapeutic consequences if level of plasma drug drops significantly
  • Induction takes between 1-2 weeks

Example of CYP450 induction- Carbamesepine (CBZ)

  • Anti-epiletic metbaolised bgy CYP3A4
  • CBZ induces CYP3A4
    • Lowering its own levels affecting control of epilepsy
  • CBZ needs careful monitoring
31
Q

Phase metabolism: CYP450 inhibition

A

Example of CYP450 inhibition : Grapefruit juice

  • Grapefruit juice inhibits CYP 3A4
  • CYP 3A4 metabolised verapamil used to treat hypertension
  • Consequence can be much reduced BP and fainting
32
Q

whcih CYP450 does grapefruit juice inhibit

A

CYP 3A4

33
Q

CYP2C9

A

is not expressed in 1% caucasians and 1% africans

34
Q

CYP2C9 metabolises

A
  • NSAIDS
  • Tolbutamide
  • Phenytoin
35
Q

CYP219

A

not expressed in 5% Caucasians and 30% Asians

36
Q

CYP219

A
  • Omeprazole
  • Valium
  • Phenytoin
37
Q

CYP2D6 metabolises

A

codein and is highly polymorphic

38
Q
  • CYP2D6 is highly polymorphic
    • Categorised into
A
  • Poor- may not experience pain relief (codeine has a lower affinity to u-opioids receptors than morphine)
  • Normal
  • High
  • Ultrarapid metabolisers (hyperactive in 30% east africans)
39
Q

main routes of drug elimination is

A

the kidney

40
Q

other routes of drug excretion

A
  • Bile
  • Lungs (vapour breathed out)
  • Genital secretions
  • Saliva
  • Breast milk
41
Q

renal excretion involeds which 3 processes

A
  1. Glomerular filtration
  2. Active tubular secretion
  3. Passive tubular reabsorption
42
Q

renal capillaries

A
  • Fenestrated
  • Increased permeability to enable optimised exchange of ions/molecules
43
Q

outline glomerular filtration

A

Glomerular filtration is a physiological function of kidney nephrons. The ultrafiltrate, which appears in the lumen of the proximal convoluted tubule, is composed of water and solutes that can pass through the filtering membrane of the capillaries. Under physiological conditions, the large molecular weight proteins and blood cells do not pass through the capillary wall and hence do not appear in the luminal fluid. Therefore, glomerular filtration is relatively nonselective. The benefits of the filtration process are that it disposes of excess fluid, solutes, and metabolism byproducts and that it serves to detoxify the system by disposing of chemicals identified as foreign.

44
Q
  1. glomerular filtraton
A
  • Afferent arteriole form ball of glomerular capillaries in the bowman’s capsule (20% renal blood flow)
  • Small molecules such as ions, water, solutes and unbound drugs can pass through into the nephron to be excreted as urine
45
Q
  1. active tubular secrtion
A

Proximal tubule

  • Remaining 80% of blood filtered via peritubular capillaries (capillaries that run alongside the nephron)
  • High expression of OATs and OCTs to allow unbound drugs to be secreted/ pass from the circulation and into the nephron to be excreted as urine
46
Q

OATs and OCTs Facilitated diffusion/ secondary AT

A

Carry ionised molecule’s out of the blood (reverse of process in s.intestine)

47
Q

OAT

A

urate, penicillin’s, NSAIDs and antiviral

48
Q

OCT

A

morphine, histamine, chloropromazines

49
Q
  1. Passive tubular reabsorption
A

Distal tubular reabsorption

  • Along total tubule length water is resorbed
  • Along tubular length [solute] increases
    • Passive reabsorption of lipid-soluble, unionised drug, which has been concentrated so that the intra-luminal conc is greater than that in the perivascular space
50
Q

What about drug with weak acid/ base?

A

Same as s. intestine but reversed.

Remember drugs must be neutrally charge to be passively reabsorbed

51
Q

normal urine pH

A

6-7.5

52
Q

drug that are weak acids

A
  • Low pH (acidic urine in DCT): increases absorption of weak acids
    • Protonate them, meaning they become neutral and can be reabsorbed
  • High pH (alkaline urine in DCT): decreases absorption of weak acid
53
Q

drugs that are weak bases

A
  • Low pH (acidic): decreases absorption
    • Protonated, becomes ionised so wont be reabsorbed
  • High pH (basic): increase absorption
    • Lose proton, becomes naturally chargedà reabsorption
54
Q

what is clearance

A

the volume of plasma cleared of drug per unit time

measured in ml/min

55
Q

total body clearance =

A

hepatic clearance + renal clearance

56
Q

volume of distribution

A

The volume into which a drug appears to distribute with a concentration equal to that of plasma.

57
Q

Vd and clearance predicts

A

how long the drug will stay in the body:

58
Q

T1/2

A

drug half life

59
Q

drug half life

A

‘The amount of time over which the concentration of a drug in plasma decreases to one half of that concentration value it had when it was first measured’

60
Q

how to calculate drug half life

A
61
Q

T1/2 is dependnet on

A

Vd and clearance

  • If clearance stays same and Vd increases then t12 also increases

If CL increases and Vd stays the same then T12 decreases

62
Q

Thus, after two half-lifes

A

25% of the drug is left; after three, 12.5%; and after 4 half-lives, 6.25%.

The half-life determines the length of the drug’s effect.

63
Q

first order kinetics also known as

A

lienar elimination kinetics

64
Q

first ordrr kinetics

A
  • For most drugs, the elimination occurs at a rate directly proportional to the concentration of the drug—i.e., the higher the drug concentration, the higher its elimination rate (e.g., 50% per unit time, as shown in the figure).

o Rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time

65
Q

first order kinetics is

A

predictable

66
Q

What happens when Elimination Processes become Saturated?

A

When processes are saturated they become rate limited- they cannot go any faster - ALL enzymes or carriers working flat out à zero order kinetics

67
Q

zero order kinetics also known as

A

non linear kinetics

68
Q

zero order kinetics

A
  • Elimination of a constant quantity of the drug per unit time independent of the concentration of the drugs
  • With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large.
  • Therefore, the plasma drug concentration is much greater than the Michaelis constant Km, and drug metabolism is constant and independent of the dose
69
Q

zero order kinetics and therapeutic response

A

response can suddenly escalate when elimination mechnaimsm are satruated

e.g. alcohol

70
Q

clinical importance of zero order kinetics

A

v

71
Q

which type of drug is more dangerous

A

zero order- cannot predict half life

72
Q

Few zero order kinetics drugs used in elderly/ infants

A
  • Decreased/ immature capacity
  • Polypharmacy
73
Q

Few zero order kinetics drugs used in seriously ill (cancer, liver disease and alcoholicss)

A
  • Signif reduced hepatic/renal capacity easier to saturate
74
Q

example of zero order kinetics drugs

A
  • Alcohol
  • MDMA
  • Paracetamol at a high dose

Cell physiology and pharmacology (20 decks)

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