Drugs and Liver disease Flashcards
(28 cards)
In what zone of the hepatic lobule do heptocytes receive the most oxygen?
Zone 1 - Periportal zone, it’s the one closest to the short axis, so is closest to the portal canals and supply of arterial blood
Zone 3 - Centrilobular zone, hepatocytes receive least oxygen as they’re furthest from the short axis
Outline the role of the liver in drug metabolism
- Number of drugs metabolised by liver, including complex processes involving Cytochrome P450 enzymes
- Drug metabolism can be defined as enzyme-catalysed conversion of drug into a metabolite
- Liver main site for drug metabolism, although some processes do occur in gut wall, lungs, blood plasma
Why are drugs difficult to excrete? What does metabolism do to overcome this?
- Lipophilic nature of most drugs promote passage through a biological membrane to site of action, making them difficult to excrete
- Lipophilic - Able to dissolve, be dissolved in, or absorb lipids (fats).
- Metabolism converts lipophilic chemicals to hydrophilic products to facilitate elimination
- Liver hepatocytes contian all the necessary enzymes to metabolise drugs, with the main family of enzymes being cytochrome P450 enzymes.
- These are a large family of releated enzymes housed n the ER of the cell
Explain the 2 phases of drug metabolism
Phase 1 - Occurs in ER, catalysed primarily by family of cytochrome P450 enzymes; mainly to make substrate into polar compound
Phase 2 (conjugation) to make drug more water soluble e.g. glucoronidation is most prevalent; (enzyme systems mainly cytosolic). The attachment of an ionised group to the drug. These groups can include glutathione, methyl or acetyl groups. These metabolic processes usually occur in the hepatocyte cytoplasm. The attachment of an ionised group makes the metabolite more more water soluble.
Describe Cytochrome P450 enzymes
Cytochrome P450 - Superfamily of membrane-bound haemoprotein isozymes with distinct classifications
Over 50 isozymes discovered to date, 6 of these are responsible for approx 80% drug metabolic reactions:
- In humans 3 main CYP families (CYP1, CYP2 & CYP3) involved in drug metabolism.
- most common:CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
e.g. CYP3A4: **3= family; A= subfamily; 4= specific isoform
These enzymes may be induced or inhibited by other agents
Describe the term prodrug and describe this in terms of enalapril and codeine
Prodrug - drugs administered in inactive form
- Require metaboli conversion to their active metabolite or bioactivation; pharmacologically active metabolite
- E.g. enalapril converted to enalaprilat, which acts as an antihypertensive agent
- Codeine, also prodrug metaboliseed via CYP2D6 to its active by-product, morphine
- Some metabolites can be toxic such as those produced from paracetamol (usually detoxified by phase 2 conjugation)
In what 3 ways can drugs behave? What 2 cytochrome P450 enzymes make up the bulk of drug metabolism?
Can behave as substrates, inhibitors and inducers of human CYP
Certain drugs are known inhibitors and inducers of specific CYP enzymes.
CYP3A4 and CYP2D6 make up the bulk of drug metabolism, and drugs that interact with these enzymes should, therefore, merit closer evaluation and monitoring
Substrates - Reacting moelcules that binds to active sites of enzyme
How do inhibitors of P450 differ? What might enzyme inhibition result from?
- Inhibitors = Decrease drug metabolism
- Differ selectively towards isoforms, and are classified by their mode of action
- Some compete for the active site but not substrates
- Enzyme inhibition may result from:
- Non-competitive or competitive inhibition of CYP enzymes by a second drug e.g. of hepatic enzyme inhibitors include cimetidine, fluconazole and erythromycin
- Differ selectively towards isoforms, and are classified by their mode of action
What do inducers do? What might enzyme induction result in? Describe the action of St John’s Wart
Inducers increase activity of microsomal oxidases and conjugating systems (increase drug metabolism)
Enzyme induction may result in:
- Increased CYP enzyme synthesis
- Faster drug metabolism, leading to subtherapeutic drug concentrations
- Risk for ineffective drug therapy:
- Over 200 drugs cause enzyme induction, decreasing pharmacological effects e.g drugs that cause enzyme induction: barbiturates, rifampicin, ethanol etc.
- St John’s Wort known inducer of CYP3A4 and can lead to decreased plasma concentration of various prescription mechanisms
What are the effects of induction or inhibition?
- In cases of treatment failure due to CYP induction, treatment goals would not be adequately met: adjust dose of medication
- In cases of drug toxicity due to CYP inhibition, presenting symptoms would display signs of overdose
- Grapefruit juice known inhibitor of CYP3A4 and can have opposite effects
What drugs are inducers, use acronym CRAPGPS?
- Carbamazepine
- Rifampin
- Alcohol
- Phenytoin
- Griseofulvin
- Phenobarbital
- Suulfonylureas
What drugs are inhibitors?
- Valproate
- Ketoconazole
- Isoniazid
- Sulfonamides
- Chloramphenicol
- Amiodrane
- Erythromycin
- Quinidine
- Grapefruit juice
What drug does CYP1A2 metabolise?
Paracetamol (acetaminophen)
What drug does CYP2E1 metabolise?
Alcohol (Ethanol)
What drug does CYP2C9 metabolise?
Warfarin/ Coumadin
What drug does CYP2D6 metabolise?
CVS drugs
What drug does CYP3A4 metabolise?
Most common whatever that means 🤷♀️
Describe co-prescription and drug interactions
- Co-administration of medications can affect metabolism of each other
- Inhibitors mainly work on the enzyme lvls to block or compete at the site of metabolism
- Inducers act by increasing the gene transcription result in higher enzyme content
- Some drugs can increase and stabilise the enzyme to be more active, increasing overall metabolic rate
- Drug interaction - Pharmacological activity of one drug being altered by concomitant use of another drug/presence of other substance
- Drug interactions often classified as either pharmacodynamic or pharmacokinetic interactions
- Pharmacodynamic - Interactions include those that result in additive or antagonistic pharmacological effects
- Pharmacokinetic interactions involve:
- Absorption/GI interactions
- Distribution interactions
- Metabolism interactions
- Excretion interactions
Describe pharmacokinetics in terms of the mechanism of drug interactions
Absorption:
- Drugs forming complexes in GI tract (e.g. tetracycline’s form insoluble complexes with iron supplements/food/antacids)
- Change in GI pH (Ketoconazole needs acidic conditions for absorption. Antacid, H2 antagonists, PPI reduce acidity in gut
Distribution:
- Drug distributed around body by systemic circulation
- Some drugs will bind to plasma protein (only unbound drug available at tissue sites for activity
Metabolism:
- Enzyme inhibition by drug/food can result in inhibition of metabolism of another drug
- Grapefruit juice inhibits CYP3A4 therefore reduces the first-pass metabolism of Ca- channel blockers e.g., verapamil resulting in increased exposure
Excretion:
- Most drugs excreted either in bile or in urine, drug interaction after excretion could occur via:
- Changes to urine pH
- Competition for active transport
- Reduction in renal blood flow
Describe pharmacodynamic drug interactions
- Effects of one drug changed by presence of another drug at its site of action
- Pharmacodynamic drug interaction could either be:
- Synergisms - The therapeutic or toxic effects of 2 drugs are greater than the sum of effects of individual drugs e.g. sulfamethoxazole and trimethoprim, used as antimicrobial agents
- Additive - Net effect equal sum of individual drug effects; aspirin and warfarin increased anticoagulation, alcohol and CNS depressants
- Antagonistic - Drugs compete for same receptor e.g. beta-blockers propranolol and beta agonist salbutamol (antagonistic); warfarin and Vit K
Describe drug-food interactions
- Garlic and diabetic medication could cause dangerous decrease in plasma glucose lvl. Garlic also has anti-clotting properties (interact with anticoagulants)
- Milk contains elements of Mg and Ca which can chelate antibiotics like tetracycline, to decrease its absorption, and effect
- Grapefruit juice - Inhibits CYP3A4, increasing levels of antidepressants (sertraline), benzodiazepine, verapamil
- Vit K rich food reduce effectiveness of anticoagulants
- Alchohol beverages tend to increase depressive effect BDZ, antihistamines
Describe drug-disease interactions
- Drug-disease interactions occur when the drug worsens/exarcebates an existing condition
- Nasal decongestants + Hypertension - Increase BP
- NSAIDs+ Asthmatic patients - Airway obstruction (NSAIDs prevent PGs being synthesised, these are potent vasodilators)
- Nicotine + Hypertension - Increase HR
- Metformin + Heart failure - Increase lactate lvls
What factors affect drug metabolising enzymes?
- Age
- Gender
- Pregnancy
- Liver diseases
- Kidney diseases
- DM
- Solid Organ transplant
- Medication (drug-drug interaction)
- Polymorphism (e.g. SNP in CYP2D6)
How does liver disease affect drug metabolism?
- Drugs and the liver can affect each other in several ways:
- Liver disorders can change the way a drug is metabolised
- Some drugs can damage the liver
- Many factors (food eaten, genetics, use of other drugs) can effect the way liver metabolises drugs
- Liver disease may have complex effect on drug’s pharmacokinetics and biotransformation
- Some isoforms of CYP are more susceptible than other to liver disease
- Cytochrome enzymes 1A2 and 3A4 have at least 50% reduction in activity in cirrhosis
- Various liver diseases known to affect metabolism of drugs as well as endogenous compounds
- Reasons for observed changes in drug metabolism in patients with liver disease are:
- Altered hepatic blood flow
- Altered expression of drug-metabolising enzymes
- Altered availability of co-substrates
- Altered binding of drugs to plasma proteins
- Reasons for observed changes in drug metabolism in patients with liver disease are:
