Factors affecting real world drug use

What is Torsades des pointes?

Fast heart beat as there QT interval is prolonged

• Caused by drugs that block hERG-I_Kr - controls K channels

• Drugs that cause this don’t get past trial

What is CYP2D6*4 and what durgs are affected by it?

Not having functional CYP2D6

• Antipsychotics are cleared by it

What is a side effect of antipsychotics?

Movement disorders

How does TPMT enzymes control thiopurines?

• 6-TG metabolites are cleared by TPMT

• Thiopurines act through 6-TG metabolites

What is irinotecan and its active metabolite?

Toperisomerase I inhibitor used in bowel and rectal cancers

• SN-38 and is cleared by UGT1A1

What is Gilbert’s syndrome?

Increase of bilirubin in the blood as the liver processes it slower

• Caused by inherited mutation in UGT1A1

What other UGT polymorph clears SN-38?

UGT1A7 clears it better but

• Subject to variations at W208R and 57/TG

What CYP enzme activates opiates and what is the process?

CYP2D6

• Codeine→morphine, oxycodone→oxymorphone, hydrocodone→hydromorphone and tramadol→M1

• Demthlyated to their more active metabolites

Can opiates be used in patients with CYP2D6*4/*4s?

Yes not all opiates are dependent on CYP2D6 to be activated

• Oxycodone, morphine, hydromorphone, fentanyl and buprenorphine can be used

• Codeine, tramadol, hydrocodone are less effective

What polymorphism metabolises PPIs?

CYP2C19 - codes for a liver enzyme

• CYP2C19*2/*2s

Why are cure rates 100% in CYP2C19*2/*2 patients?

They are poor metabolisers of PPIs

• Breakdown is slower so treatment is more effective

Why would PPI dosage increase in CYP2C19*17/*17s?

This polymorph means the patient has 2 increased function alleles and is an ultrarapid metaboliser

• Increased enzyme activity

• Faster metabolisation of PPI

• Lower concs of active PPI

• Higher risk of treatment failure so increase dose

What tests can be done to get information on polymorphisms?

Genotype is a strong predictor for efficacy

• Phenotyping - measures conc of plasma

• Genotyping - analyses DNA

What factors affect metabolism in the elderly and what main drugs are affected?

• Liver blood flow is 40% lower

• Renal function is impaired

• Polypharmacy

• Depression

• High intrinisic clearance drugs - propranolol, metoprolol, pethidine

• Low intrinisic clearance drugs - phenytoin, diazepam, NSAIDs

Why do low intrinisc clearance drugs affect metabolism in the elderly?

As extraction is low, changes cause large changes in plasma levels

Why are concentrations really important for neonates?

• They have poor renal clearance for vancomycin and ampicillin as they have immature CYPs

• Drug clearance is 10x slower than adults

• Prematures have slower clearance

• Drugs like NSAIDs, lorazepam, AZT and morphine derivatives have longer half lives

Why do neonates have resistance to paracetamol toxicity?

• Cleared faster

• Metabolises to a sulphate

• Lack CYP2EI to metabolise it

What food can increase clearance?

BBQ meat has CYP1A1/2

• Increased clearance of clozepine, caffeine, theophylline and haloperidol

What is the relationship between gender and metabolism?

Women are smaller and lighter so can clear drugs quicker

• CYP3A4/2C9 - steroids, macrolides, statins

• The enzymes are susceptible to hormone (period) change

What are the effects of menopause on metabolism?

• Increased CYP1A2 activity - less oestrogen-related inhibition may allow enzyme to become more active, some medicines may be broken down faster.

• Reduced CYP3A4 activity - activity may decrease, slowing the metabolism of certain medicines.

• Changes in glucuronidation - reduced oestrogen may alter phase II metabolism, affecting how some medicines are eliminated

What are the effects of hormone replacement on metabolism?

• CYP1A2 inhibition - oestrogen-containing HRT may reduce CYP1A2 activity, slowing metabolism of some medicines.

• Changes in drug concs - slower metabolism may increase drug concentrations and the risk of adverse effects.

• Route - oral oestrogen passes through the liver before the systemic, transdermal oestrogen bypasses this first-pass. Their effects on liver proteins and drug interactions differ

Why are asian people more addicted to smoking?

Low expression of CYP2A6 which clears nicotine

What changes does drinking make on clearance?

• Warfarin clearnce increases

• TCA clearance is reduced

How is alochol metabolised?

Ethanol + Alcohol dehydrogenase (ADH) →

Acetaldehyde (toxic metabolite) + Aldehyde dehydrogenase (ALDH) →

Acetate (less toxic product)

How do ALDH2 affect alcohol metabolism?

Reduced enzyme activity

• Acetaldehyde not broken down efficiently into acetate.

• Acetaldehyde accumulates in the blood.

• Can cause facial flushing, nausea, headaches and a rapid heartbeat.

• Effects may reduce alcohol consumption, but continued drinking increases the risk of certain cancers

How do ADH1B affect alcohol metabolism?

Faster alcohol breakdown

• Certain variants make the ADH enzyme convert ethanol to acetaldehyde more rapidly.

• Contributes to acetaldehyde accumulation, especially when combined with reduced ALDH2 activity.

• Effects are associated with a lower risk of alcohol dependence