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Pharmacology PED1003 > Drug elimination > Flashcards

Drug elimination Flashcards

1
Q

PK parameters of the distribution

A

The apparent volume of distribution (Vd) = Volume of fluid that would be required to contain the total amount of drug in the body (Q) at the same concentration as that present in the plasma (Cp)

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2
Q

The volume of distribution (Vd) =

A

The total amount of drug administered (Q) / Plasma concentration (Cp)

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3
Q

Factors affecting distribution

A

Blood perfusion of the tissue or organ.
Ability to cross a cell membrane.
Plasma protein binding ability

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4
Q

Blood brain barrier

A

Continuous layer of epithelial cells
Brain unaccessible to many drugs
Can become leaky with inflammation

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5
Q

The amount of drug depends on…

A

Concentration of free drug
Affinity for the binding site (2 per albumin molecule)
Concentration of protein

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6
Q

Albumin

A

Binds mostly acidic drugs (EG Warfarin, NSAIDS) and a small number of basic drugs (EG TCAs)

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7
Q

α1acid glycoprotein (AAG)

A

Binds mostly basic and neutral drugs. Increases inflammatory disease

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8
Q

Catabolism =

A

Break down substances by enzymes

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9
Q

Anabolism =

A

Build up of substances by enzymes

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10
Q

Oxidation =

A

Addition of oxygen and/or removal of hydrogen (loss of electrons)

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11
Q

Hydroxylation =

A

Conversion of a hydrogen to a hydroxyl group

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12
Q

Deamination =

A

Conversion of an amino group to a carbonyl group

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13
Q

Dehydrogenation =

A

Conversion of a hydroxyl group to a carbonyl group

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14
Q

Where does most oxidation occur?

A

Liver

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15
Q

Monooxygenases

A

Cytochrome P450
Alcohol dehydrogenase
Monoamine oxidases
Xanthine oxidase

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16
Q

Reduction =

A

Addition of hydrogen and/or removal of oxygen (gain of electrons)

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17
Q

Hydrogenation =

A

Conversion of carbonyl group to hydroxyl group

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18
Q

Hydrolysis =

A

Reaction with water, hydrogen binds to one compound, hydroxyl to the other.

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19
Q

Enzymes of hydrolysis reactions

A

Esterases

EG Cholinesterase, Peptidases and Amidases

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20
Q

Cytochrome P450 (CYP450) - Phase 1 reaction

A

Embedded on smooth ER
Require Oxygen, NADPH and NADPH-reductase
Large family of related but distant enzymes
Reduced P450s combined with CO = pink compound

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21
Q

CYP1A2

A

Paracetamol or caffine

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22
Q

CYP2C9

A

Ibruprofen or warfarin

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23
Q

CYP2E1

A

Paracetamol or alcohol

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24
Q

Variations in CYP450s

A

Species differences.
Genetic polymorphisms
Environmental factors

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25
Q

Other phase 1 enzymes

A

Aspirin esterase
Alcohol dehydrogenase
Butrylcholinesterase
CYP450s

26
Q

Butrylcholinesterase

A 
Aka Plasma Cholinesterase
Hydrolyses Suxamethonium 
Structurally similar to Ach
Overactivates cholinergic receptors on muscles to cause paralysis
Neuromuscular blockers
27
Q

Aspirin esterases

A

Aka Acetylsalicylate deacetylase

In plasma, hydrolyses aspirin to salicylate

28
Q

Alcohol dehydrogenase

A

In liver cell (hepatocyte) cytoplasm
Oxidases ethanol to acetaldehyde
Requires NAD+

29
Q

Phase 2 reactions

A

Anabolic - make up
If drug has reactive group either in the parent molecule or product of phase 1
Usually occurs in liver but also lung/kidney
Product usually inactive
PRODRUGS

30
Q

Conjugation =

A

Attachment of a substituent group

31
Q

Phase 1 reactions

A

Catabolic - break down
Functionalisation
Introduction of reactive group.
Products more reactive and sometimes more toxic

32
Q

Examples of prodrugs

A

Inactive drug -> Active drug
Diacetyl-morphine -> Morphine
Valacidovir -> Aciclovir
L-Dopa -> Dopamine

33
Q

Physiochemical properties of a drug

A

Mass transport in gut = faeces
Water soluble, filtered out by kidney = urine
Volatile gases = exhaled air
Secreted into glands = sweat and breast milk

34
Q

Elimination depends on…

A

Physiochemical properties of drugs and metabolites

35
Q

Total body CL (clearance) =

A

Sum of all organ CL processes.

Volume of plasma or blood cleared of the drug per unit of time to achieve overall elimination of drug from the body.

36
Q

Cp

A

Plasma drug concentration

37
Q

Co

A

Initial drug concentration

38
Q

Elimination rate constant (Kel) =

A

Total clearance (CLtot) / Volume of distribution (Vd)

39
Q

Vd

A

Volume of blood required to contain drug at plasma concentration

40
Q

Elimination half life (t1/2)

A

t1/2 = Ln2 / Kel (On Log Scale)
Time taken for plasma drug concentration to reduce by half
In regards to steady state, 4-5 half-lives are needed to reach the point at which drug accumulation and elimination are balanced.

41
Q

Major systems concerned with elimination

A

Kidneys
Hepato-biliary system
Lungs

42
Q

Glucuronidation

A

Most common conjugation reaction
Important for both endogenous compounds (EG Bilirubin) and exogenous compounds
Mediated by UDP-glucuronyl transferases
Due to their polar nature, glucuronides are usually inactive and rapidly excreted

43
Q

Paracetamol metabolism - Therapeutic doses

A

Mainly by conjugation with sulphate and glucuronic acid.
Only a minor proportion metabolised by CYP450 to a toxic metabolite (NAPQI).
Toxic metabolite normally detoxified by glutathione

44
Q

Paracetamol metabolism - Overdose

A

Pathways of conjugation are saturated and co-factors are depleted and as such more paracetamol is metabolised via CYP450.
Toxic metabolites reacts with liver proteins instead of glutathione (depleted).
Tissue damage occurs leading to hepatic necrosis.

45
Q

Endogenous factors affecting drug metabolistation: Genetic Constitution

A

Each member of a population will be described as either a fast or a slow metaboliser.
Can have implications for therapeutic efficacy and/or toxicity of certain drugs

46
Q

Fast metabolisers

A

Normal enzyme activity
Lower plasma conc of the parent drug
Higher conc of the metabolite
Generally normal therapeutic response

47
Q

Slow metabolisers

A

Low enxyme activity
Higher plasma conc of the parent drug
Lower conc of the metabolite
May lead to exaggerated therapeutic response at normal doses

48
Q

Endogenous factors affecting drug metabolistation: Age

A

Individuals at extreme ages are affected.

Neonates (premature) - 
Low CYP and conjugating activity
Glucuronyl transferase
N-acetyltransferase
Lack of use of morphine in labour

Elderly -
CYP activity declines slowly with age
More variability in half-life of many drugs
Issues for drug development
Increased half-life of diazepam (memory impairment)

49
Q

Endogenous factors affecting drug metabolistation

A

Genetic constitution
Age
Disease

50
Q

Exogenous factors affecting drug metabolistation: Drugs, smoking, alcohol/chemicals

A

Exposure to chemicals represents an important factor in the perturbation of drug metabolising enzymes.
These compounds either induce or inhibit drug metabolising agents.
Induction and inhibition represents two important mechanisms by which drug interactions occur.

51
Q

Exogenous factors affecting drug metabolistation

A

Drugs
Smoking/alcohol
Environment exposure (including diet)

52
Q

Induction of drug metabolising enzymes

A

An increased synthesis of enzymes (Phase 1 and 2).
Results in increased metabolism of inducing agent (autoinduction).
Different inducers induce different enzymes/isozymes.
Smoking and ethanol (chronic exposure) both act as inducer.
Drugs which act as inducers of drug metabolising enzymes often induce their own metabolism.

53
Q

Inhibition of drug metabolising enzyme

A

Inhibition of the CYP system is caused by many drugs.
Reduced rate of metabolism and increased pharmacological effect.
For a drug to produce its pharmacological effect, it should achieve adequate concentrations at the site of action.
Basis of several drug-drug interactions.
Ethanol acts acutely to inhibit drug metabolism.

54
Q

Glomular filtration

A

20% of renal blood flow filtered through glomerulus.
Drugs if MW <20,000 diffuse into glomerular filtrate.
Plasma albumin (MW 68,000) almost completely held back.
Lipid solubility and pH don’t affect GH.
Highly ppb drugs found at lower concentration in filtrate than in plasma.
ppb is a barrier to glomular filtration

55
Q

Active tubular secretion

A

80% of renal blood flow passes the peritubular capillaries of the proximal tubule.
Drug molecules transferred to tubular lumen by two carrier systems which can transport against an electrochemical gradient.
Most effective method for drug elimination.
ppb is not a barrier to carrier mediated transport.
Many drugs share the same transporter which can lead to competition.
Low specificty

56
Q

Passive diffusion / tubular reabsorption

A

Volume of urine = ~1% of the filtrate.
Drug concentration increases as water is reabsorbed.
Highly lipid soluble drugs have high tubular permeability and are slowly excreted.
Highly water soluble drugs have low tubular permeability and concentrate in urine.

57
Q

Implications of induction

A

Decreased drug effectiveness on chronic exposure.
Need to increase drug dose.
In multiple drug therapy there may be problems when inducer is withdrawn from regimen.
Basis of many drug-drug interactions.
EG Rifampicilin and oral contraceptives

58
Q

pH partitioning

A

Acidic drugs accumulate in basic fluid compartments and visa versa.
EG Aspirin is a weak acid (pKa = ~3.5) so can move through lipid membrane.

59
Q

Mechanisms of elimination - Physiochemical properties of the compound.

A

Volatile gases are eliminated by exhalation.
Water soluble compounds are often eliminated to some degree unchanged in the urine.
Also may be excreted in the bile.
Lipid-soluble compounds typically undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile.

60
Q

Mechanisms of elimination - Saturable elimination

A 
Elimination mechanisms (such as enzymes) are typically not saturated at therapeutic doses of drugs, although there are a few exceptions (ie phenytoin).
Increasing dose will disproportionately increase concentration (linear to non-linear kinetics).
Often described with michaelis-menten kinetics.
61
Q

Absorption - pH and pKa

A

Many drugs are weak acids (proton donator) or bases (proton acceptor).
Degree of ionisation changes with respect to pH of solution - dependent on pKa of drug.
An orally administered basic compound with pKa 8.0 will be predominantly in ionised form in the stomach.

Pharmacology PED1003 (18 decks)

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