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PMP-102 > Drug Metabolism and Kinetics (PK) > Flashcards

Drug Metabolism and Kinetics (PK) Flashcards

1
Q

What are the Three Phases of Drug Action

A

1) Pharmaceutical Phase: Disintegration of the pill / capsule in gastrointestinal tract (GI), release of the drug, dissolution of drug

2) Pharmacokinetic Phase: Absorption from GI tract into bloodstream and what the body does to the drug

3) Pharmacodynamic Phase: Mechanism by which the drug interacts with the molecular target. What the drug does to the body.

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2
Q

What makes a Good Drug?
(Pharmockinetcis + Pharmodynamics)

A

Pharmacokinetics =
Absorbed well by the body
Reaches target easily
Not modified, inactivated, or removed from the body too quickly

Pharmacodynamics =
Effective at targeting the disease process
Not toxic

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2
Q

What makes a Good Drug?
(Pharmockinetcis + Pharmodynamics)

A

Pharmacokinetics =
Absorbed well by the body
Reaches target easily
Not modified, inactivated, or removed from the body too quickly

Pharmacodynamics =
Effective at targeting the disease process
Not toxic

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3
Q

Potency vs Efficacy

A

Potency:
Dose required to achieve the effect.
Measured as the 50% effective concentration (EC50).
Units of concentration

Efficacy:
The maximal effect.
Measured as “response.”
Usually a percentage.

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4
Q

graph

A

increase

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5
Q

ADME

A

a) Absorption
b) Distribution
c) Metabolism
d) Elimination

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6
Q

a) Absorption

A

Process of drug entering the body and therapeutic agent entering the blood

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7
Q

b) Distribution

A

Drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids of various compartments in the body

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8
Q

c) Metabolism

A

Biotransformation / chemical conversion of drug molecules

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9
Q

d) Elimination

A

Clearance of drugs and metabolites from the body (urine, bile, faeces)

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10
Q

Absorption - Routes of drug administration

A

Intramuscular - Oily vehicles Irritating Neutral (muscle)

Inhaled - Volatile Neutral (lung)

Neural - Transderm/Topical/ Subcuteneous (skin)

Intravenous - Polar/ charged High MW (molecular weight) drugs (systemic circulation)

Oral, Buccal Sublingual, Rectal (systemic circulation)

Stomach (pH 1-3):
Acidic/ neutral drugs

Intestine (pH 6-8):
Basic/ neutral drugs

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11
Q

Absorption - Factors affecting drug absorption

A

Solubility: Drugs need to be water-soluble to pass into the blood for distribution

Ionisation: Drugs need to be close to neutral to pass through membranes

Stability: Drugs need to be chemically stable until they reach their site of action

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12
Q

Factors affecting drug absorption:

A

Solubility: Drugs need to be water-soluble to pass into the blood for distribution

Ionisation: Drugs need to be close to neutral to pass through membranes

Stability: Drugs need to be chemically stable until they reach their site of action

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13
Q

Factors affecting drug distrobution:

A

Plasma solubility: Including binding to plasma proteins (bind and release)

Lipophilicity: Balance between water and fat solubility. Influences drug levels in blood, muscles, adipose tissue, and organs

Perfusion: Level of blood flow to a tissue. Major organs (heart, liver . . .) well perfused, but brain is a special case – blood-brain barrier.

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14
Q

Elimination

A

After metabolism, organisms want to get metabolites and exogenous molecules out of their system.

If the drug is removed without metabolism, the process is called excretion

Major routes: Urine (renal), faeces (biliary)

Minor routes: Exhalation (lungs), sweat / other bodily fluids

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15
Q

Metabolism

A

Metabolic enzymes attack drug molecules forming metabolites

Metabolites may be inactive, less active or even more active than parent drug molecules

They can also have a different activity – side effects and toxicity

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16
Q

Metabolism of drugs is necessary for:

A

Designing new drugs which do not form unacceptable metabolites

Designing pro-drugs / understanding pre-drug strategy

Understanding half-lives and tailoring drug action

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17
Q

Metabolism of drugs is necessary for:

A

Designing new drugs which do not form unacceptable metabolites

Designing pro-drugs / understanding pre-drug strategy

Understanding half-lives and tailoring drug action

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18
Q

How many metabolites will there be? . . . . Zero to many

A

For most drugs there will be fewer than 10 major metabolites, but there can be several “minor” metabolites

Minor metabolites are also important – accumulation of minor metabolites can be extremely toxic
No metabolites – sodium cromoglicate
1 major metabolite – oxazepam glucuronide
> 10 major metabolites - chlorpromazine

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19
Q

What are the Phases of Metabolism?

A
  1. Phase I Transformations
  2. Phase II Transformations
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20
Q
  1. Phase I Transformations
A

Mostly in liver
Chemical Modifications
Oxidation, Reduction, Hydrolysis

21
Q
  1. Phase II Transformations
A

Mostly in Liver
Conjugation with an exretion-promoting group
E.g. glucuronic acid, sulfate, glycine (hydrophilic)
E.g. bile acids (hydrophobic)

22
Q

What happens during metabolism - what is the goal?

A

Living organisms aim to eliminate all foreign materials as quickly as possible

Polar Drugs will be excreted quickly by the kidneys

Non-polar Drugs need to be chemically modified to make them more hydrophilic so they can be eliminated more easily

23
Q

Phase I Metabolism
= Chemically diverse small molecules
transformed to more polar compounds

A

CYP- P450 Reactions
Hydroxylation
Epoxidation
Dealkylation
Deamination
Oxidation
Dehalogenation

Non-CYP Reactions
Oxidation
Hydrolysis
Reduction
Deamination

24
Q

Phase I – CYP-P450 Enzymes

A

Haemoproteins (contain haem)
Located in the liver cells

Belong to the monooxygenases (class of enzymes)

33 different cytochrome P450 enzymes, split into four families (CYP1-CYP4)

Subfamilies within each family designated by a letter

Each enzyme within subfamily is designated by a number

25
Q

Phase I - Mechanism of action

A

Split molecular oxygen so one of the oxygen atoms is introduced into the drug, the other ends up in water

26
Q

Phase I – P450:
Explain step 1 of the Oxidation of Carbon:

A
  1. Oxidation of exposed alkyl groups / exposed regions of cycloalkyl rings

a) Oxidation of terminal methyl groups
b) Oxidation of penultimate
carbon on alkyl substituents
c) Oxidation at most exposed or most activated region of the cycloalkyl ring

27
Q

Explain step 2 of the Oxidation of Carbon:

A
  1. Oxidation of activated carbon centres (next to sp and sp2 carbons) – they are more likely to be oxidised than exposed carbon atoms
28
Q

Explain step 3 of the Oxidation of Carbon:

A
  1. Dealkylation of amines, ethers and thioethers via oxidation of activated carbon
29
Q

Explain step 4 of the Oxidation of Carbon:

A
  1. Dehalogenation of alkyl halides

Oxidation to carboxylic acids by aldehyde dehydrogenases

30
Q

Explain step 5 of the Oxidation of Carbon:

A
  1. Oxidation of alkenes and aromatic rings

Oxidation of unsaturated sp2 and sp carbon centres present in alkenes, alkynes and aromatic rings

Hydroxylation: introduction of hydroxyl group to a carbon

CHOOSE site that is opposite group because it is most activated

31
Q

Hydroxylation

A

introduction of hydroxyl group to a carbon

32
Q

Phase I – P450: Oxidation of Nitrogen

A
33
Q

Phase I – P450: Oxidation of Sulfur and Phosphorous

A

C=S goes to Desulfurisation

Thiols can be oxidised to disulfides

Phosphorous is oxidated

34
Q

Phase I – Catalysed by Flavin-containing Monooxygenases

A
35
Q

Phase I – Catalysed by Other Enzymes
1. Oxidative Reactions

A

Primary alcohols&raquo_space; (alcohol dehydrogenase / NAD+) secondary alcohols&raquo_space;(NAD+) ketone

Aldehydes&raquo_space; (dehydrogenase / NAD+)&raquo_space; Primary amines&raquo_space; (monoamine oxidases) aldehyde [oxidative deamination]

36
Q

Phase I – Catalysed by Other Enzymes
2. Reductive Reactions

A

aldehyde (alcohol dehydrogenase)&raquo_space; alcohol

Ketone (reductases / NADPH)&raquo_space; alcohol

Alkyl halide&raquo_space; R - H

Ar - NO2 (Nitro)&raquo_space; Ar - NH2

RS– SR&raquo_space; 2RSH

37
Q

Phase I – Catalysed by Other Enzymes
3. Hydrolysis of esters and amides

A

Catalysed by non-specific esterases and amidases (peptidases) in plasma, liver, kidneys, intestine

ester (esterases)&raquo_space; aldehyde + HO-R
Amino acid (peptidases)&raquo_space; aldehyde + HNR2

38
Q

Phase II Metabolism

Conjugation reactions generally result in more polar compounds. These are rapidly eliminated via urine and / or bile

A

A less polar molecule is attached to a suitable, more-polar “handle”
Glucuronidation
Sulfation
Amino acids (glutathione, glycine, glutamine)
Acetylation
Methylation

39
Q

Phase II - Glucuronidation

Glucuronic acid conjugation is the most common reaction

A

Phenols, alcohols, hydroxylamines, carboxylic acids form O-glucuronides by reaction with UDP-glucuronate

The product is excreted in the urine (or bile if MW > 300 g/mol)

Sulphonamides, amides, amines and thiols form N- or S-glucuronides.

C-glucuronides are possible when there is an activated carbon next to carbonyl group

40
Q

Glucuronic acid derives from amino asides;

A

sulphonamine
hydroxylamine
thiol

41
Q

Phase II – Sulphate Conjugation
Less common and only involves phenols, alcohols, arylamines, N-hydroxy compounds

A

Catalysed by sulfotransferases, using the cofactor 3’-phosphoadenosine-5’-phosphosulfate

42
Q

Phase II – Amino Acid Formation
Consider corboxylic acid group and its conjugate to amino acids

A
  • Drugs bearing a carboxylic acid group can conjugate to amino acids by the formation of a peptide link
  • The carboxylic acid is activated by formation of a coenzyme A thioester which is then linked to the amino acid
43
Q

Explain the amino acid formation as an equation;

A

aldehyde (drug) [ATP / Acyl CoA synthetase]&raquo_space; drug=O-AMP (which is alcyl group) [CoASH)&raquo_space; Drug+O-SCoA (amino acid + N-acyltransferase)&raquo_space; Drug=O-amio acid

44
Q

Phase II – Glutathione Conjugate

Explain the main 2 steps that happen
(what reacts with what, what transforms to what)

A

The nucleophilic group of the tripeptide glutathione can react with electrophilic functional groups (epoxides, alkyl halides etc)

This forms glutathione conjugates which can be transformed to mercapturic acids (easily excreted in the bile)

45
Q

Phase II – Methylation & Acetylation

What is the effect of Methylation and acetylation of the polarity of the drug?

Methylation?
Acetylation?

A

Methylation and acetylation decrease the polarity of the drug

Methylation (-CH3): Phenols, amines, thiols
Acetylation (-CH3C=O): Primary amines

46
Q

Explain what the The First Pass Effect is;

A

Drugs that are taken orally pass directly to the liver once they enter the blood supply&raquo_space; exposed to metabolism before they are distributed around the rest of the body

% of the drug will be transformed before it reaches its target

Drugs administered via a different route (e.g. injection, inhalation) avoid the first pass effect –distributed around the body before they reach the liver

47
Q

Breakdown of phases of metabolism

A

PHASE I (Oxidation, Reduction, Hydrolysis)
PHASE II (conjugation)

DRUG > Primary metabolite > Secondary metabolite / Breakdown product > Conjugate > Breakdown of conjugates

48
Q

Kinetics of Metabolism – 1st Order

The metabolic transformation of drugs is catalysed by enzymes

What kinetics do the reaction follow (who)?

A

Most of the reactions follow Michaelis-Menten Kinetics;
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/(𝑲𝑴+[𝑺])

In most clinical situations, [S] «< KM, therefore:
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/𝑲𝑴

49
Q

Kinetics of Metabolism – Zero Order

(Consider size of [S] to Km)

A

With some drugs, the doses are very large, [S]&raquo_space;> KM, therefore:
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/([𝑺])= Vmax

50
Q

ZERO order

A

The enzyme is saturated by a high free-drug concentration and the rate of metabolism remains constant over time (drugs such as aspirin, ethanol)

A constant amount of drug is metabolised per unit time and the rate of elimination is constant and does not depend on the drug concentration

51
Q

1st order

A

The rate of drug metabolism and elimination is directly proportional to the concentration of free drug

A constant fraction of the drug is metabolised per unit time

PMP-102 (49 decks)

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