Drug metabolism (1)

Question 1

A perfect world

Answer 1

• 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

Question 2

Therapeutic window

Answer 2

Question 3

Patient life changes relevant to successful drug therapy

Answer 3

• 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

Question 4

Deleterious drug interaction

Answer 4

• 2 main reasons for drug therapies not working
  
  • PK- ADME reasons
  • PD- drug not working at receptor level

Question 5

extremes of drug therapy

Answer 5

• Failure of drug therapy => Anti-convulsant. Oral contraceptive
• Drug (accumulation) toxicity => Cyclosporin renal toxicity, Terbinafine-cardiotoxicity

Question 6

Therapeutic index

Answer 6

• 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

Question 7

Clearance

Answer 7

• 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

Question 8

Clearance/Removal of drugs

Why does this happen

Answer 8

• 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

Question 9

Clearance / Removal of drug difficulties

Answer 9

• 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

Question 10

Threat from oil soluble agents

Answer 10

Question 11

Threat posed by endobiotics

Answer 11

• Hormones must be stable
• Their stability means they are out of control
• Some processes must be fine-tuned
• Hormones must be inactivated quickly

Question 12

The treat posed by xenobioitics

Answer 12

• Membrane disruption
• Resemble hormone
• Environmental toxins are turning us all into girls

Question 13

CLEARANCE/REMOVAL OF DRUGS/TOXINS

HOW DOES THIS HAPPEN

Answer 13

• 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

Answer 14

• Liver has 2 inputs
  
  • Hepatic artery- from systemic blood supply
  • Hepatic portal vein- from GI tract

Question 15

Process of drug clearance

Answer 15

*

Question 16

How do CYP450 work?

Answer 16

• 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

Question 17

Main biotransformation human Cytochrome P450 isoforms

Answer 17

• 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

Question 18

Biotransformation and first pass

How much drugs into the system

Answer 18

• Barriers: gut/liver metabolism
• Liver/gut first pass depends on extraction ratio

Question 19

High extraction drugs

Answer 19

• Changes in extraction has some impact on plasma levels
• Examples
  
  • Pethidine, metoprolol, propranolol, lignocaine and verapamil

Question 20

Low extraction drugs

Answer 20

• Changes in extraction has a large impact on plasma levels
• Examples
  
  • Phenytoin, paracetamol, diazepam, naproxen and metronidazole

Question 21

Bioavailability (F)

Answer 21

• How much drug reaches the plasma after an oral dose
• F= (blood conc after IV dose - Blood Conc after oral dose) / Blood conc after IV dose
• Depends on whether the drug is high or low extraction
• 100mg dose and only 20 mg reaches plasma F=20%
• If gut metabolism is prevented, F might increase to 50% so plasma levels more than double
• If liver extraction increases, F might approach zero

Question 22

Biotransformation effects on drug therapy

Answer 22

• Changes in biotransformation can massively influence patient welfare
• Drug failure or drug toxicity
• Next: How biotransformation adapts and fails to adapt to changing regimens