Drug metabolism (2) Flashcards
Adaptations of biotransformation
- What if toxin levels rise in diet
- Endogenous system must be controlled e.g. mentral cycle
- What if we keep giving someone an oily aromatic-like chemical which resembles an endogenous chemical
- The drug metabolising system will resist
Biotransformation (CYP) adaptation 1
A 22-year-old male epileptic: carbamazepine started 200mg daily, over 4 weeks rises to 1400mg to maintain plasma levels within the therapeutic window
- Plasma levels not maintained within the therapeutic window at each dose level for more than a few day
- So carbamazepine clearance must have been increasing, until a plateau is reached
- Levels then remain within the therapeutic window
Biotransformation (CYP) adaptations 2
A 33-year-old male epileptic (phenytoin (300 mg/day) and carbamazepine (600 mg/day). Phenytoin was in the therapeutic range, carbamazepine undetectable.
A 50% reduction of the phenytoin dosage allowed the carbamazepine plasma concentrations to rise to therapeutically effective levels
- No carbamazepine because drug clearance has increased to the point where F=0
- The reduction in phenytoin dosage, attenuated the high clearance of carbamazepine, allowing plasma levels to ascend to the therapeutic window
Biotransformation (CYP) adaptations 3
A 49-year-old male epileptic phenytoin at 600 mg/day and carbamazepine at 2300 mg/day) The phenytoin withdrawn abruptly. Within four days, the patient became gradually more lethargic and confused, The carbamazepine dosage was reduced to 1200 mg/day and the confusion and sedation disappeared
- Initially co-administration of 2 drugs was successful
- Withdrawal of phenytoin, cause carbamazepine overdose effect without change in dose
- Carbamazepine blood levels climbed above the therapeutic window into toxicity
- Caused by a fall in carbamazepine clearance when the phenytoin was withdrawn
Biotransformation (CYP) adaptations 4
A 64-year-old obese male (simvastatin 10 mg daily). Lack of clinical response led to a fivefold increase in dosage.
Patient admitted to hospital with rhabdomyolysis.
Patient admits he took St. John’s Wort, which he stopped when his mood was sufficiently elevated, around a few days prior to the toxicity
- The statin ineffective with St.Johns Wort- indicating that the drug was being cleared at a higher rate than normal
- GP unaware of St.Johns Wort extract (Enzyme inducer)
- The patient abruptly stopped taking the herbal extract and the clearance of the statin gradually fell while the dose did not, so the drug accumulated and exerted toxicity
Biotransformation (CYP) adaptations 5
Patient under treatment for tuberculosis:
(rifampicin, INH, ethambutol, pyrazinamide) and epilepsy (phenytoin)
Stops medication for several days during annual Christmas
binge drinking. Resumes drugs, within hours, becomes confused and ataxia. Develops fever/chills
- Inductive effect lost: high dose of phenytoin no longer cleared rapidly-leads to accumulation
- TB gradually recurs
Inducers: clinical effects
- INDUCERS- rifampicin, steroids, St.Johns Wort, AED (anti-epileptic drugs)
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Common Features
- Some of the drug’s clearance were not stable until a relatively high dose was employed
- One drug (or herbal preparation) was able to grossly accelerate the clearance of another agent(s)
- The changes in plasma levels were sufficiently great to either lead to toxicity or total loss of efficacy
- The toxic effects occurred gradually over days, rather than hours
- The increase in drug clearance caused by other drugs was fully reversible
Biotransformation Adaptation: Induction
- Enzyme induction- An adaptive increase in enzyme capability in response to increased drug load
- Takes 1-3 weeks to achieve full effect
- Fully reversible
- Drugs bind to nuclear receptors (most common PXR/CAR)- st Johns wort, Rifampicin
- Or Cytoplasmic receptors (AHH)
- This activates DNA response elements
- DNA transcription of appropriate mRNAs increase
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Problems with inhibition of biotransformation
NB- inhibition of drug metabolism is a rapid process
- May occur after practionier- inspired inclusion in regimen of potent inhibitor of CYP’s
- The toxic responses occurred within hours rather than fays, after the regimen change
- Toxic effects will usually be rapidly reversible once the inhibiting drug is withdrawn (not always)
- A result of self-medication or change in diet/routine, without practitioner knowledge
CYP P450 inhibitors
- MOST potent- Half lifes are really important to potency
- SSRI’s, grapefruit juice, MDMA
- LESS potent
- Azoles (Ketoconazole, fluconazole, voriconazole), gemfibrozil
Inhibition and high pre-synaptic metabolism
- High impact on plasma levels
- Serious problem in low TI drugs
CYP P450 Inhibition
Sudden death due to torsades des pointes
- Extended QT interval (recharge for the heart) (>0.45 sec) means the heart cannot repolarise fast enough
- If QT is too long then the heart is repolarising as it is starting the next cycle (firing again)- the heart can then lose control
- Drugs cause this because ion channels depend on a heRG receptor- anything blocks this receptor the heart will not repolarise
- heRG receptors can be blocked by a lot of drugs (85) of them, these have to be in toxic concentrations
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CYP inhibition
Torsades des pointes
- Normal heart rhythm
- Torsades des Pointes
- Causes: Amiodarone, Pimozide, Terfenadine
Clinical consequences of inhibition
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Torsades des Pointes- prolonged QT
- Amiodarone, terfenadine, pimozide)
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Sedation- Anti-convulsants
- excessive sedation (midazolam in ITU)
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Rhabdomyolysis- Statins
- Use fluvastatin/Pravastatin (NOT CYP3A4)
- Excessive hypotension- Nifedipine/Felodipine
- SSRI accumulate- Bruxism, Fatigue, Insomnia
CYP INHIBITION
- speed of events is important
- Rhabdomyolysis is more gradual
