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Yr 2 Pharm + Therapeutics > 4+5: Pharmacokinetics and Drug Metabolism > Flashcards

4+5: Pharmacokinetics and Drug Metabolism Flashcards

1
Q

Summarise the journey of a drug through the body (AADME)

A

Administration
Absorption
Distribution
Excretion

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2
Q

Types of routes of administration

A

Local - restricted to one area
Systemic - entire organism exposed to drug
Enteral - via GI tract (oral/liquid), easiest
Parenteral - avoiding GI tract (IV)

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3
Q

Pros of IV drug infusion

A

V quick onset of action - Rapid systemic exposure
High bioavailability
May be used for drugs w short half lives

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4
Q

Route of drug absorption

A

Drug enters GI tract, absorbed and taken to liver via hepatic portal sysstem and enters systemic circulation.

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5
Q

How would you administer drug if need slow absorption

A

Intramuscular/dermal routes

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6
Q

How do drug molecules move in the body

A
  1. Bulk flow transfer in blood stream

2. Diffusion transfer over short distances

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7
Q

Method of crossing barriers

A
  • Diffusing through lipid (if of a suitable nature)
  • Diffusing through aq pore in the lipid (if they are polar)
  • Carrier molecules
  • Pinocytosis- the cell engulfs the molecule and takes it in.
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8
Q

Drug is in dynamic equilibrium w ionised/unionised forms. Ratio of ionised:unionised depends on:

A

pH of env

pKa of molecules

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9
Q

How does ion-trapping work

A

When in circulation, drug is in dynamic equibilirium. The unionised form is taken up by proteins whihc traps it in protein-drug complex. This prolongs half life of the durg

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10
Q

Factors influencing distribution of drug

A

Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability
Localisation in tissues

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11
Q

Describe how regional blood flow effects distribution of the drug

A

o Tissues w high perfusion are likely to be exposed to a higher concentration of the drug.
o Some tissues may increase in perfusion when their activity increases e.g. skeletal muscle
o Highly metabolically active tissues tend to have a greater blood flow and denser network of capillaries so absorb quicker

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12
Q

Describe how extracellular binding (plasma protein binding) affects distribution of the drug

A

When drug is bound to a plasma protein, it cant be absorbed. It will persist for long time whilst bound.
50-80% of acidic drugs tend to bind plasma proteins

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13
Q

Desccribe how capillary permeability affects distribution of drugs

A

Diff tissues have diff permeabilities. Distribution depends on capillary structure:
 Fenestrated= more permeable to drugs
 Continuous= found in normal vessels, has water filled gap junctions.
 Discontinuous= large gaps between endothelial cells

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14
Q

Describe how localisation in tissues affects drug distribution

A

Fat isnt highly perfused so it’s v lipophilic env. Drugs that are lipophylic tend to localise and persist in fatty tissue.

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15
Q

How does liver excrete drugs

A

Tends to be large molecular weight drugs w tend to b lipophilic concentrated in bile
Abx also tend to be biliary drugs

Biliary excretion can cause problems because of the enterohepatic circulation. The drug or metabolite gets excreted into the gut but then it can get reabsorbed and returned to the liver via the enterohepatic circulation. This leads to drug persistence- increases the duration the drug is left in the body prolong the pharmacology.

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16
Q

How does kidney excrete drugs

A

Majority of excreted drug gets into urine via active secretion rather than ultrafiltration.
- Glomerulus: drug protein complexes not filtered
- PCT: active secretion of acids + bases
PCT + DCT: lipid soluble drugs are reabsorbed

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17
Q

Other less common routes of excretion of drugs:

A

lungs breathe air out, sweat, saliva, skin, GI secretions, milk, genital secretions

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18
Q

Define bioavailability

A

proportion of the administered drug that is available within the body to exert its pharmacological effect.

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19
Q

Define apparent volume of distribution

A

the volume in which a drug appears to be distributed- an indicator of the pattern of distribution.

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20
Q

Define biological half life

A

the time taken for the concentration of a drug (in blood/plasma) to fall to half its original value.

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21
Q

Define clearance

A

vol of plasma cleared of the drug per unit time

22
Q

Define first order kinetics

A

First Order Kinetics: amount of drug decreases at a rate which is proportional to the concentration of drug remaining in the body.

23
Q

Clearance of drug following first order kinetics can be mathematically shown as:

A

Cl = Vd x Kel (where Kel = Log2/t0.5)

24
Q

Define zero order kinetics

A

A constant amount of drug is removed per unit time, amount of drug decreases at a rate independent of the concentration of a drug remaining in the body.

25
Q

What does 0 order kinetics imply

A

It implies a saturable metabolic process, usually enzymic. Once the enzymes are saturated, the rate of removal of the drug peaks and remains constant.

26
Q

Clearance of drug following 0 order kinetics can be mathematically shown as:

A

Cl (clearance of drug) = time x Kel (where Kel = dC/dt)

27
Q

Give an example of something that follows zero order kinetics

A

alcohol

28
Q

Define hepatic first pass metabolism

A

metabolic conversion of the drug into something that’s diff before the drug enters general circulation/ effect that occurs the v first time that drug passes through liver

29
Q

What happens in Phase 1 metabolic change

A

Polarity remains largely unchanged.
3 types of Phase I chemical activtiy includes: oxidation, reduction + hydrolysis
Functional groups serve as point of attachment for phase 2 reactions
It often inactivates chemicals but can also activate them (prodrugs).

30
Q

What happens in Phase 2 metabolic change

GGAASM

A

Addition of large polar endogenous groups to drugs to allow excretion as more water soluble. 6 types of chemical acctivity:

Glucorodination
Glutathione conjugation
Acetylation
Amino acid conjugation
Sulphation
Methylation
31
Q

How many enzymes involved in cytochrome P450 system and where are they found

A

57

liver + SER

32
Q

Cytochrome P450 mediated oxidation reaction

A

RH (drug) + NADPH + O2 + H+ = ROH (oxidised drug) + NADP+ + H2O

33
Q

Cyclic manner of CYP450 enzyme and its oxidation reactions (8steps)

A
  1. Drug binds to P450 at catalytic active site and interacts w Fe3+ w is in oxidised state.
  2. Electron is donated by NADPH (it’s preferred over NADH); it’s picked up by P450 complex, reducing Fe3+ to Fe2+.
  3. Molecular O2 binds to catalytic active site.
  4. Electron rearrangement occurs. Fe2+ loses e (Fe3+) and O2 carries the extra e and becomes unstable.
  5. A second e from NADPH reduces Fe3+Fe2+.
  6. Fe2+ donates e to O2 (Fe3+). O2 is v unstable. Drug is still unchanged
  7. Drug is converted to hydroxylated derivative. Cleave the reactive oxygen as water by picking up two protons.
  8. Drug is released and P450 returns to the cycle with iron in oxidised state (Fe3+) ready to undergo the next cycle
34
Q

4 oxidative reactions

A
  • Hydroxylation
  • N-demethylation: oxidation of methyl group in N env (C on an N)
  • O-demethylation: oxidation of methyl group on an O
  • N-oxidation: oxidation of N group. This generates an amine oxide. Flaving containing monooxygenase catalyses this reaction.
  • Alcohol oxidation: alcohol dehydrogenase catalyses it. has 0 order kinetics. Alcohol is metabolised into acetaldehyde and then to acetic acid.
35
Q

Flavin Containing Monooxygenase Deficinecy

A

Humans generate trimethylamine in their GI trac w smells terrible + is lipophilic.
Liver: FCM converts trimethylamine into trimethylamine N-oxide w is odourless + polar so cna be excreted in urine.
Those w FCM deficiency produce trimethylamine but cant metabolise + excrete it so sweat/breathe it out aka fish odour syndrome.

36
Q

Which order reactions are P450 + flavin containg monooxygenase

A

first-order reactions

37
Q

Reductive reactions are less common. Where do they take place

A

GIT as low O2 env. Most reductases are bacterial enzymes colonising our gut.

38
Q

Hydrolysis enzymes

A

Esterase: hydrolysis of ester
Amidase: hydrolysis of amide

39
Q

Enzymes for each Phase 2 reaction

A 
Glucorodination: glucuronyl transferase
Gluthione: glutathione-S-transferase
Acetylation: acetyl transferase
Amino acid conjugation: acyl transferase
Sulphation: sulphotransferase
Methylation: methyl transferase
40
Q

Conjugating agent + target functional group for glucuronidation

A

UDP-glucuronic acid

-OG, - COOH, -NH2, -SH

41
Q

Conjugating agent + target functional group for glutathione conjugation

A

glutathione

electrophiles

42
Q

Conjugating agent + target functional group for acetylation

A

Acetyl Co A

-OH, NH2

43
Q

Conjugating agent + target functional group amino acid conjugation

A

glycine, glutamine, taurine

-COOH

44
Q

Conjugating agent + target functional group for sulphation

A

3’-phosphoadenosine-5’-phosphosylphate

-OH, -NH2

45
Q

Conjugating agent + target functional group for methylation

A

S-adenosyl-methionine

-OH, -NH2

46
Q

Most common phase 2 reaction

A

glucuronidation

47
Q

Glucoronidation

A

Catalysed by glucuronyl transferase to form the sugar derivative of the xenobiotic.
It makes quite a large molecular weighted molecule so has issues w glomerular filtration and is often excreted by bile

48
Q

Methylation’s effects on polarity

A

it decreases it

49
Q

Sulphation

A

xenobiotic is taken w PAPS w is a sulfate donor. It is sulfated to produce sulfuric acid derivative of molecule which is v polar + Water soluble

50
Q

Which phase 2 reaction is imp process toxilogicallyh

A

glutathione conjugation - glutathione is tripeptide (glycine, glutamine + cystein). It reacts w electrophiles w must be removed bc damage DNA + proteins

51
Q

Imp part of glutathione molecule is

A

cystein bc it has thiol which is the part which reacts w electrophiles

Yr 2 Pharm + Therapeutics (9 decks)

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