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Biochemical Pharmacology > Metabolism & Elimination > Flashcards

Metabolism & Elimination Flashcards

1
Q

First-order kinetics

A

The amount of drug metabolised per unit time is proportional to the plasma concentration of the drug (Cp)

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2
Q

Zero-order kinetics

A
  • A constant amount of drug is metabolized per unit time
  • Metabolic capacity can become saturated at higher concentrations
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3
Q

Inducible biotransforming enzymes

A

Drug-metabolizing systems are inducible, broad-spectrum enzymes with some predictable genetic variations

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4
Q

Three essential aspects of drug metabolism

A
  1. First-order kinetics
  2. Zero-order kinetics
  3. Inducible biotransforming enzymes
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5
Q

Name 4 ways metabolism can occur

A
  1. Convert an active drug into an inactive drug.
  2. Convert an active drug to an active or toxic metabolite.
  3. Convert an inactive prodrug to an active drug .
  4. Convert a non-excretable drug to an excretable metabolite (lipophillic to hydrophillic)
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6
Q

Main site of metabolism

A

Liver

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7
Q

Primary goal of metabolism

A

Drug inactivation

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8
Q

How does the liver carry out metabolism?

A

Uses enzymes to convert drug from one form to another (usually less active) form.

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9
Q

Cytochrome P450 system

A
  • Large group of related enzymes in the liver
  • Main job is detoxifying foreign chemicals including drugs
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10
Q

Liver enzymes

A
  • Embedded in smooth endoplasmic reticulum
  • Drug must cross plasma membrane to get there
  • More important for lipophilic drugs
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11
Q

Smooth Endoplasmic reticulum:

A
  • Responsible for proteins to function within a system
  • For folding and transporting proteins and enzymes
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12
Q

Phase I reactions

A

“Functionalisation”
Giving the drug some activity controlled by 3 processes
* Oxidation
* Reduction
* Hydrolysis

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13
Q

Phase II reactions

A

Conjugation
- adding molecules to metabolites to change function

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14
Q

Phenytoin

A
  • Highly lipophillic molecule
  • React with membranes and enzymes in metabolic system
  • More soluble in water, can pass better through blood
  • Drug activated in phase 1
  • 4HP changed by UGT which is glucuronide and makes it soluble in water
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15
Q

Cytochrome P450 enzymes

A
  • Haem Proteins
  • Large superfamily of related enzymes
  • CYP + number
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16
Q

How do cytochrome P450 enzymes differ from each other?

A
  • Amino acid sequence
  • sensitivity to inhibitors and inducers
  • specificity of reactions they catalyse
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17
Q

Oxidation

A

Drug oxidation requires:
* Drug (‘DH’)
* Cytochrome P450 enzyme
* Molecular oxygen
* NADPH (reduced coenzyme)
* NADPH-P450 reductase

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18
Q

Ferrus enzyme state 3+

A
  1. Drug come in, moves across membrane .
  2. Input of electron from NADPH changes iron state from 3+ to 2+ state.
  3. Ferrus state binding to drug oxygen bonds aswell as enzyme drug oxygen complex.
  4. Ferrus is converted back to ferric state and OH is removed from complex with electron left water generated out (electron removed).
  5. Transfer of oxygen to drug creating hydroxyl ending up with DOH, Drug hydroxyl state generated.
  6. Cleavage of DOH from iron portion drug (center of enzyme).
  7. Hydroxyl metabolite kicked out of system and cycle can restart again.
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19
Q

Phase I Reactions not involving CYP450

A

Alcohol dehydrogenase
* Methanol to formaldehyde (toxic)

Monamine oxidase
* Oxidation of catecholamines and tyramine

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20
Q

Reduction

A

Reduction = electron gain
Addition of H to N, O, or C=

21
Q

Examples of reduction

A

Nitro groups changed to an amine
R-NO2 > R-NH2
e.g choloramphenicol (antibiotic)

Carbonyl groups changed to a hydroxyl
R-C=O > R-C-OH
e.g. haloperidol (influence brain pathways)

22
Q

Hydrolysis -
Drugs containing esters

A

RCOOR’ > RCOOH + HOR’
- e.g. aspirin
Hydrolysed by non-specific esterases
- In liver, plasma, GIT

23
Q

Hydrolysis - Aspirin

A

Acetylsalicilic acid -needs to change process by hydrolysis catabolic chop of acetyl group and leave active O2 within its place
Salicyclic acid - drug can be active once hydrolysis occurred, used for fever
Reversible or irreversible reaction
Aspirin breakdown- cleavage of hydrolysis

24
Q

Hydrolysis - Amides

A

RCO|NHR’ > RCO-OH +H2NR’
e.g. lidocaine
hydrolysed by amidases
in liver

25
Q

Hydrolysis - Polypeptide drugs

A

E.g insulin, growth hormone
Transformed by peptidases
in plasma, RBC, and many tissues

26
Q

Conjugation

A

Attachment of a substituent group
Coupling to endogenous metabolite:
- Glucuronic acid (most common)
- Sulphuric acid
- Acetic acid (to drugs containing amino group)
- Amino acids (to carboxyl group)
- The tripeptide glutathione (cys-glu-gly)

27
Q

Glucuronidation

A

Glucuronyl (UDP-glucuronosyltransferase) most important
Acetaminophen = paracetamol

28
Q

Sulphonation

A

Sulfate (sulfotransferases)

29
Q

Methylation

A

Methyl (methyltransferases add on a methyl (CH3) group)
SAM has methyl group, when converted to SAH, methyl group removed from sulphur.

30
Q

Acetylation

A

Acetyl (acetyltransferases)

31
Q

Glycine Conjugation

A

Glycyl (transacylases)

32
Q

Glutathione Conjugation

A
  • Glutathione is a tripeptide derived from the following three amino acids;
    1. Cysteine
    2. Glutamate
    3. Glycine (cys-glu-gly)
  • Glutathione is added on to the drug by glutathione-S-transferase
    Important in paracetamol metabolism
33
Q

Paracetamol

A

Paracetamol limitation max 4 doses a day
Because above that more toxic by product produced.
95% produced by glutathione route
NAPQI toxic metabolite produced by the body
System can contain it in the body
System reroutes it away from haepatotoxicity,
Becomes non toxic and hydrophilic once conjugated If too much NAPQI produced, NAC administered

34
Q

CYP inhibitors

A

Important source of drug interactions
Differ in selectivity for different CYPs

35
Q

CYP inhibitors mechanism of action

A
  • Competition for same isozyme (most common)
  • Non-competitive inhibitors
  • Mechanism-based (Suicidal) inactivators
36
Q

Competiton

A

for same isozyme (most common)

37
Q

Non-competitive inhibitors

A
  • Ketoconazole forms a tight complex with the Fe3+ form of CYP3A4
  • Is not itself a substrate for the enzyme
38
Q

Mechanism-based (Suicidal) inactivators

A

Are transformed by the enzyme to reactive intermediate that irreversibly inactivates the enzyme
E.g. nerve agent - parathion

39
Q

Diet and Environment
Inducers:

A

Brussel sprouts and cigarette smoke induce CYPs

40
Q

Diet and Environment
Ihibitors:

A
  • Grapefruit juice inhibits drug metabolism
  • Flavonoids inhibit CYP3A4
  • Inhibits metabolism of co-administered drugs metabolised by same enzyme
    - Including anti-HIV agents, benzodiazepines, Ca2+ channel blockers, statins
41
Q

Drug Excretion Pathways

A
  • Leave the body in the urine;
    • UNCHANGED or as Polar metabolites
  • Some secreted into bile via liver
    • most reabsorbed via GIT
  • Some faecal elimination
  • Some excretion via lungs (volatile/gaseous agents)
  • Some excretion occurs in sweat or milk
    e.g., nursing mothers
42
Q

Drug Half-life (Elimination)

A

Elimination of drug
Concentration in plasma drops exponentially with time
Used to determine half-life (t½) of drug; time it takes for drug conc. to decrease by half

43
Q

Short half life

A

due to rapid metabolism or rapid excretion

44
Q

Long half life

A

due to extensive plasma protein binding, slow metabolism, or poor excretion

45
Q

Excretion of drugs

A

Bile acids and drugs are actively transported from liver into bile
- To gut and reabsorbed as active drug (e.g. morphine)
Or excreted (e.g. acidic and basic drugs)

Renal excretion
* Rate varies greatly among drugs
Penicillin
- Almost completely excreted in single pass through the kidney
Diazepam
- Cleared very slowly

46
Q

Renal excretion

A

3 Processes:
1. Glomerular Filtration
2. Active tubular secretion
3. Passive reabsoption

47
Q

Renal clearance

A
  • most important parameter for time course of action of drug at its molecular, cellular and organ targets
  • Rate of elimination of drug from body relative to the conc. of drug in plasma
    The volume of plasma from which a drug is eliminated by the kidney per unit time
48
Q

GFR and age

A

GFR declined slowly from 20yo
falling 25% at 50 years and 50% at 75 years

49
Q

Hydrolysis - Polypeptide drugs

A

E.g insulin, growth hormone
Transformed by peptidases
in plasma, RBC, and many tissues

Biochemical Pharmacology (9 decks)

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