Drugs and the liver Flashcards
Importance of the liver in drug metabolism
1) increase hydrophilicity of drugs
2) deactivate and eliminate drugs
3) Phase I rxns
4) Phase II rxns
how/why liver disease affects drug PK & PD
Complex combined effects on drug pharmacokinetics
- Hepatic blood flow ==> drugs with very high extraction ratio = decreased “first pass” metabolism effect and those drugs == morphine, propranolol, CCBs, Nitroglycerin
- Hepatocellular mass
- Hepatocyte function
Concomitant other drug Rx; inhibition/induction
Other organ dysfunction contributes e.g. hepatorenal syndrome, severe renal dysfunction
Nutritional status may affect Phase II reactions
how drug metabolism –> variability in PK –> PD
Factors
- Other drugs (inhibition & induction)
- Gender: CYP 3A4 F > M and M > F»_space; drug dependent
- Pharmacogenetic differences
- Age - premature baby vs neonate vs the elderly
- Hepatic disease
- Environment-EtOH, foods/diet, herbals, smoking, ?others
major patterns/culprits of drug related hepatotoxicity
- Acute hepatocellular injury
- -> (i) zonal necrosis [Direct toxin effect-dose related] == CCl4, halogenated benzenes; Acetaminophen, (& aspirin); High dose IV amiodarone; Methotrexate; cocaine
- -> (ii) viral-like acute hepatitis == NSAIDs; HMG Co-A red. inh. (statins); INH, rifamycins (rifampin etc), pyrazinamide; HIV drugs (NNRTIs & PI’s); Halogenated anesthetics; Oncology TKI’s & Mabs - Cholestasis with inflammation +/- allergic features == Amoxicillin/clavulanate, (beta lactams), captopril, clopidogrel, erythromycin, irbesartan, nevirapine, PTU, rifampin, sulfonamides, sulfonylureas, terbinafine
- cholestasis with no inflammation or necrosis == estrogens, androgens, OCPs
- Steatosis == Ethanol & TPN; Amiodarone; Corticosteroids, OCPs; HIV NRTI’s (e.g. Lamivudine/ZDV);
Tamoxifen; Tetracyclines; Valproic acid - (less common) hepatic tumors == angiomas, estrogens, high-dose OPCs, carcinomas, angiosarcomas, androgens
principles of optimal prescribing in severe liver dysfx
- what are the important clinical effects of liver disease
(i) avoid hepatotoxic agents
(ii) avoid pro-drugs activated by hepatic metabolism
(iii) use agents cleared by non-hepatic processes
(iv) (a) be aware of difficulties with reduced drug clearance- (b) measure plasma concentrations if available to avoid toxicity & optimize therapy
(v) avoid drugs that precipitate/worsen hepatic encephalopathy == opiates, sedatives /psychoactive drugs; sodium overload and electrolyte disturbance; GI irritants; hypoglycemic agents; anticoagulants
(vi) careful use of diuretics, hypokalemia, alkalosis promotes NH4+ entry into CNS
(vii) careful glucose monitoring
Important clinical effects
- Reduced biosynthesis of coagulation factors –> PT/INR
- Impaired gluconeogenesis –> hypoglycemia
- Increased fluid retention e.g. NSAIDs, corticosteroids, piperacillin (sodium)
- Increased CNS depressant effects of CNS active drugs
Describe the Cyp450 system
which are usually involved in drug metabolism
major drug metabolizing enzyme system
- found mainly in liver, GI tract, kidney (10%)
Phase 1 enzymes
CYP3A 4/5 (55%)
CYP2C9/CYP2C19 (20%)
CYP2D6 (25%)
A 43 yo male Caucasian diabetic is well controlled on long and short acting insulins. He has erectile dysfunction and takes tadalafil 5 mg once daily most days. He has heard from his friends that you can take 20 mg/ day for “special occasions”. Over the past several days he has noticed difficulty and pain on swallowing - white plaques on his oropharynx that you can scrape off
- Dx?
- Tx?
Candidiasis
Fluconazole
A 43 yo male Caucasian diabetic is well controlled on long and short acting insulins. He has erectile dysfunction and takes tadalafil 5 mg once daily most days. He has heard from his friends that you can take 20 mg/ day for “special occasions”. Over the past several days he has noticed difficulty and pain on swallowing - white plaques on his oropharynx that you can scrape off
- He was started on fluconazole 200 mg PO day one and then 100 mg PO daily. Three days later, about 2h after taking 20 mg of tadalafil, he complained of dizziness and collapsed at home and was brought to a local ER. He has a regular pulse of 116/min; supine BP 70/40 mm Hg; resp rate 20/min-Sp02 99% on room air. He was treated fluids and pressors and successfully resuscitated.
- How do you explain this patients clinical presentation?
Fluconazole –> attacks one of the fungal enzymes to decrease ergosterol synthesis
- the ergosterol shares a similar group to one of the Cyp enzymes (which metabolizes sildenafil)
when took fluconazole and sildenafil together –> decrease sildenafil clearance –> became hypotensive.
A 43 yo male Caucasian diabetic is well controlled on long and short acting insulins. He has erectile dysfunction and takes tadalafil 5 mg once daily most days. He has heard from his friends that you can take 20 mg/ day for “special occasions”. Over the past several days he has noticed difficulty and pain on swallowing - white plaques on his oropharynx that you can scrape off
- He was started on fluconazole 200 mg PO day one and then 100 mg PO daily. Three days later, about 2h after taking 20 mg of tadalafil, he complained of dizziness and collapsed at home and was brought to a local ER. He has a regular pulse of 116/min; supine BP 70/40 mm Hg; resp rate 20/min-Sp02 99% on room air. He was treated fluids and pressors and successfully resuscitated.
- How do you explain this patients clinical presentation?
Fluconazole –> attacks one of the fungal enzymes to decrease ergosterol synthesis
- the ergosterol shares a similar group to one of the Cyp enzymes (which metabolizes sildenafil)
when took fluconazole and sildenafil together –> decrease sildenafil clearance –> became hypotensive.
drugs that inhibit Cyp450 (what phase?)
Phase-I reactions
- CCB – verapamil, diltiazem, - Macrolides-erythromycin, clarithromycin; NOT azithromycin - Azoles-itraconazole, fluconazole, voriconazole, posaconazole - HIV protease inhibitors
- Cimetidine – ALL Cyp450 enzymes (metabolism of warfarin, diazepam, midazolam, cyclosporine, CCBs)
A 22 year old Caucasian male is in a methadone maintenance program for opiate abuse. Over a period of weeks he has become generally unwell with weight loss and fatigue and is found have > 500,000 HIV RNA copies/mL. He is started on ART which includes a PI/NNRTInh. and emtracitabine. After being on the ART therapy for 10 days, he complains for 36h he has had muscle aches, intermittent nausea/vomiting, abdominal cramps with diarrhea and episodes of profuse sweating.
Diagnosis & why did this patient exhibit these symptoms? How would you manage this patient?
Dx - Withdrawal from opiates
Why - Cyp inducer (NNRTInh) –> increased metabolism & clearance of methadone = inactivated
how long does Cyp inhibitor symptoms manifest?
within 24h
how long does Cyp induction symptoms manifest?
7-10d
drugs that inhibit Cyp450
Rifamycins: Rifampin, Rifapentine > Rifabutin
Anti-seizure: Carbamazepine (& ox..), phenytoin, & Pbarb etc
Anti-HIV Rx: Amprenavir, efavirenz, nevirapine
Miscellaneous: Aprepitant, artemesinin, bosentan, enzalutamide, modafinil, montelukast,
pioglitazone, St John’s wort
Lesser extent: prednisone, oral contraceptives
drugs that inhibit Cyp450
Rifamycins: Rifampin, Rifapentine > Rifabutin
Anti-seizure: Carbamazepine (& ox..), phenytoin, & Pbarb etc
Anti-HIV Rx: Amprenavir, efavirenz, nevirapine
Miscellaneous: Aprepitant, artemesinin, bosentan, enzalutamide, modafinil, montelukast,
pioglitazone, St John’s wort
Lesser extent: prednisone, oral contraceptives
