ADME Three Flashcards Preview

Toxicology and Pharmacology > ADME Three > Flashcards

Flashcards in ADME Three Deck (28)
Loading flashcards...
1
Q

What is the most important site of drug metabolism?

A

The Liver

2
Q

What places in the body can drug metabolism occur?

A

Liver
GI tract- bacteria and proteases
Intestinal walls- CYPs
Plasma- esterases (i.e breaks down acetylsalicylsate-aspirin)

3
Q

What does drug metabolism result in?

A

Drug is converted by metabolising enzymes into water soluble metabolite

4
Q

Why do metabolic enzymes convert drugs into water soluble metabolite?

A

Water soluble metabolite is:

  • less likely to diffuse into cells and reach receptors (relies on passive diffusion to do this)
  • Favours increased excretion in urine or bile(very large mw weight)
  • Usually abolishes activity and terminates drug action
5
Q

What are the exceptions to metabolite enzymes that breakdown drugs but dont deactivate them?

A
  • Can promote activity i.e prodrugs: acetylsalicylate
  • No change in activity: diazepam into nordiazepam
  • Produces toxic metabolites (paracetamol-only if too much)
6
Q

How many phases of drug metabolism are there?

A

Up to two

7
Q

What is phase 1 of drug metabolism?

A

Addition or uncovering of a reactive group

i.e
Oxidation
Reduction
Hydrolysis

Makes molecules more susceptible to phase two reactions

8
Q

What is phase two?

A

Conjugation of endogenous molecule with drug

i.e
Glucurnoide
Sulphate
Glutathione

Makes the molecule more polar, ideal for substrates in active transport and excretion (more water soluble)

9
Q

What is the most important reaction for phase one metabolism?

A

Oxidation is the most important reaction for phase one metabolism of all drugs

10
Q

What are the most important enzymes for the oxidation reactions?

A

CYPs = cytochrome P450 mixed function oxidase systems

11
Q

Of the CYPs which are the most involved?

A

CYP1, CYP2 and CYP3

12
Q

What does the oxidation reaction require?

A

O2, NADPH and cytochrome P450 reductase- huge range of substrates

This also oxidases a range of endogenous compounds.

Drug+ O2+H+ + NADPH forms Oxidised drug+H2O+NADP+

13
Q

Whats an example of phase one action?

A

Phenytoin: (lipophylic)

Phase one: Hydroxylation, (OH forms) becomes slightly water soluble but INACTIVE now

Phase two: Conujugation by UDP glucuronosyl transferase (addition of Uridine Diphosphate Glucuronide)

Now is inactive and very water soluble.

14
Q

So what metabolic processes can a drug directly undertake?

A

Phase one: can be excreted sometimes, otherwsie followed by phase two then excretion

Or

Straight to phase two and excretion (formation of a drug conjugate.)

15
Q

What are the two methods of excretion?

A
Bile excretion (faecal excretion)
Renal excretion (urine)
16
Q

What are the factors influencing drug metabolism?

A

Mainly: The patients genetic constitution

Also:
Organ function
Diseases +other drugs
Diet+cigarettes+alcohol 
age+sex+pregnancy
17
Q

How many people dont respond to a drug?

A

1 in 5

18
Q

How many people have a toxic response to a drug?

A

20-30%

19
Q

How many people actually respond to the drug in the intended way?

A

50-60%

20
Q

Whats an example of a drug that neonates have reduced metabolism for?

A

Theophylline, as they get older the half life decreases

21
Q

As people age how does their body clearance change?

A

Drug Clearance ability decreases with age, but not too clinically relevant

22
Q

Using theophylline what is the half life in several population categories?

A

Neonates = 30-60hrs
Children = 2-4hrs
Adults (non-smokers) = 6-10hrs
Adults (smokers) = 4-6hrs

Do get the same effect the drug maintenance dose must vary between populations

23
Q

What happens to enzymes once exposed to an inducing agent?

A

When exposed to an inducing agent, enzyme synthesis initiated within 24hr of exposure, increasing over 3-5days.

This inducing effect causes increased enzymes that results in the removal of dug from a system faster

24
Q

Once inducing agent is discontinued what happens to the induction effect?

A

Effect decreases over 1-3 weeks after inducing agent is discontinued.

25
Q

What environmental factors lead to the inducing effect?

A

Smoking
Eating BBQ meat
Ethanol

Barbiturates
Rifampicin

26
Q

What happens when drug metabolism is inhibited?

A

Rapid onset within 1 day

Exaggerated response with increased risk of toxicity

27
Q

What are some examples of reversible inhibitors of drug metabolism?

A

Grapefruit juice

Lead (complex with CYP)

28
Q

The induction of enzymes control what?

A

The induction of enzymes in the gut wall and liver determine the amount of drug that makes it into the blood stream from administration (bioavailibility)