Drug metabolism (1) Flashcards
1
Q
A perfect world
A
- Patient takes their single drug regularl, takes no other drug, leads blameless healthy life
- Theoretically patient/HCP can look forward to successful drug therapy for as long as is necessary
2
Q
Therapeutic window
A
3
Q
Patient life changes relevant to successful drug therapy
A
- Greatest impact on drug therapy
- Other drugs (practioniers idea’s)
- Some supplements (patient’s mother’s idea)
- Patient’s activities (patient’s idea)
- Timeframe
- How long do you have before a serious problem occurs
4
Q
Deleterious drug interaction
A
- 2 main reasons for drug therapies not working
- PK- ADME reasons
- PD- drug not working at receptor level
5
Q
extremes of drug therapy
A
- Failure of drug therapy => Anti-convulsant. Oral contraceptive
- Drug (accumulation) toxicity => Cyclosporin renal toxicity, Terbinafine-cardiotoxicity
6
Q
Therapeutic index
A
- Therapeutic index = Toxic concentrations / Normal therapeutic range
- Wide TI drugs: SSRI’s
- Narrow TI: TCA, barbiturates, phenytoin
- Changes in narrow TI drug concentrations are more serious
7
Q
Clearance
A
- Clearance is the removal of drug by all process from the biological systems (more about clearance of pharmacologically active marterial)
- If clearance increase = Drug disappears
- If clearance decrease = Drug accumulates
8
Q
Clearance/Removal of drugs
Why does this happen
A
- Drugs, toxin, food-borne chemicals, environmental chemicals threaten homeostasis
- Even our own chemicals, that we made for ourselves, such as hormones, can threaten homeostasis
- NB- aromatic A ring= estrogen
- Control of cellular environment is not just everything, it is ONLY THING
9
Q
Clearance / Removal of drug difficulties
A
- Living systems struggle to clear Highly oil-soluble chemicals
- In the kidney, the filtered oily agent will simply be reabsorbed
- At the collecting tubule stage
- The patient can only really clear water-soluble chemicals through urine and faeces
10
Q
Threat from oil soluble agents
A
11
Q
Threat posed by endobiotics
A
- Hormones must be stable
- Their stability means they are out of control
- Some processes must be fine-tuned
- Hormones must be inactivated quickly
12
Q
The treat posed by xenobioitics
A
- Membrane disruption
- Resemble hormone
- Environmental toxins are turning us all into girls
13
Q
CLEARANCE/REMOVAL OF DRUGS/TOXINS
HOW DOES THIS HAPPEN
A
- They must be made more water soluble (so the kidneys can remove them)
- They must be made heavier (more routes of excretion)
- Tasks carried out by the biotransformation organs: Liver, Gut, Kidneys
- Pre-systemic metabolism/clearance
14
Q
A
- Liver has 2 inputs
- Hepatic artery- from systemic blood supply
- Hepatic portal vein- from GI tract
15
Q
Process of drug clearance
A
*
16
Q
How do CYP450 work?
A
- Most biotransformation enzymes are found in the endoplasmic reticulum- P450’s
- 60-70% of drugs are metabolised by CYP3A4
- Fe is the key to this
- It’s about gaining and losing electrons
- P450 sits in the endoplasmic reticulum- which is very lipophilic- most drugs are lipophilic as well so when they’re taken up there more likely to go into the endoplasmic reticulum, so are chemically drawn to P450 sites
- P450’s have a flexible active site can bind many shapes/functional groups (much like a hand), once bound the enzymes to draw the molecule to the Fe group in which it is then oxidised and its physicochemical properties change
17
Q
Main biotransformation human Cytochrome P450 isoforms
A
- CYP2D6: SSRI’s, anti-psychotics, TCA, opiates
- INDUCERS= rifampicin, Anti-convulsant
- CYP3A4(5): Sterioids, Macrolides, Cyclosporine, Terfenadine, Statins, Methadone, Oestradiol
- INDUCERS= Steroids, rifampicin, Anti-convulsant, St.Johns Wort
- CYP2C: Warfarin, TCA’s, Fluoxetine, Anti-convulsant
- INDUCERS= Rifampicin, Anti-convulsant
