Drug Metabolism Flashcards
What is a prodrug? How is it converted?
Prodrug: pharmacologically inactive compound designed to maximize the amount of active species that reaches its site of action.
-converted with hydrolysis of an ester or amide linkage
What is biotransformation? What is the point of biotransforming a drug?
The process by which a drug is converted from its nonpolar state to a polar metabolite
-to create an inactive, and more polar compound that can be excreted
What occurs in Phase 1 reactions? where do they often occur? What are age group related changes to this reaction?
- converting a parent drug into a polar metabolite (often still active) by adding or unmasking a functional group (-OH, -NH2, -SH)
- often a reduction, oxidation, hydrolysis with cytochrome P450, located in ER of hepatocyte
- geriatric patients lose phase 1 first (newborns have slower rates of phase 1 vs. adults)
What occurs in Phase 2 reactions? Pneumonic from First Aid?
- Conjugation reactions (Glucuronidation-add a sugar, acetylation, sulfation) usually yields very polar, inactive metabolites (renally excreted).
- conjugation is the formation of a covalent linkage betwn functional group made in phase 1 and endogenous derived glucuronic acid, sulfate, or acetate
- Pneumonic: Geriatric patients have GAS (glucurondiation, acetation, sulfate) BUT NO PHASE 1
Where do most biotransformations occur? All organs? All parts of cell? Name 3 drugs that are metabolized more in the GI tract than in the liver?
- liver: main site
- also gi tract, kidneys, and lungs
- mainly in smooth ER but also in cytosol, mitochondria, nuclear envelope, and plasma membrane
- clonazepam, chlorpromazine, cylcosporine
What are some endogenous biotransformations that occur? (3) What is the function of the following: CYP5, CYP7A, and CYP51
- endogenous biotransformatons: biosynthesis of bile acids, hormones, and eicosanoids
- CYP5: thromboxane A2 synthase is a fatty acid in the arachidonic acid cascade. Inhibited by NSAIDS
- CYP7A: first and rate limiting step of bile acid synthesis. Only way for body to eliminate cholesterol in liver
- CYP51: key in converting lanosterole to cholesterol
T/F 1. Phase 2 reactions can occur before Phase 1
2. Biotransformations always lead to the formation of inactive product
- True. Occasionally, order is reversed
2. False. biotransformation can lead to formation of another compound w/ different effect in body
What 3 ways can a biotransformation occur?
- Drug–> inactive metabolite
- drug–> active metabolite
- Prodrug–> drug
What are the inducers of the P-450 system? Pnuemonic?
-inducers activate P450 and thus promote metabolism
-Chronic alcohol use, modafinil, St. John’s wort, phenytoin, phenobartibital, nevirapine, rifampin, griseofulvin, carbamazepine
-Chronic alcoholic Mona Steals Phen-Phen and Never Refuses Greasy Carbs
(also barbiturates, phenytoin, carbamzepine are all anticonvulsants)
P-450 CYP2D6: Identify how the nomenclature works and what each number/letter stands for
- 2 is for the family (greater than 40% AA sequence same)
- D is for the subfamily (greater than 55% AA sequence same)
- 6 is for the isoform (unique to a enzyme; most specific)
What is a polymorphism? Give an example. When is this really bad?
- A difference in DNA sequence found in 1% or higher in a population
- example: mephenytoin (anti-epipletic) poor metabolism: polymorphism in metabolism found in 3% in whites but 20% in Asians (20% of Asians can’t metabolize)
- very bad when you have a drug w/ narrow theuraptic range so that a poor metabolizer (w/ concentration for longer duration) can overdose
Describe the codeine intoxication associated with ultrarapid CYP2D6 metabolism
-codeine is metabolized to morphine once in the body by CYP2D6. When you metabolize this too fast, it is covered to morphine too quickly. One of the hallmark symptoms of morphine is respiratory arrest, so patient can die
What CYPs are responsible for metabolizing 90% of used drugs (5)
2C9, 1A2, 2C19, 2D6, 3A4
What are the substrates for the cytochrome 450 system? Pneumoic?
- anti-epileptics, antidepressants, antipsychotics, anesthetics, theophylline, warfarin, statins, OCP’s
- Always, always, always, always, think when starting others
____ has 70 different drug oxidations (CYP)
CYP2D6
What drugs are substrates for CYP3A4?
tylenol, codeine (narotic), cyclosporin A (immunosuppresant), diazepam, lidocaine, lovastatin (cholesterol med), taxol (cancer drug), warfarin (anticoagulant)
What are inhibitors to cytochrome p450 system for drug clearance? First aid pneumoic?
- inhibitors of p450 slow down metabolism and cause increased concentration of drugs in the system
- acute alcohol abuse, gemifibrozil, ciprofloxacin, isoniazid, grapefruit juice, quinidine, amiodarone, ketoconazole, macrolides, sulfonamides, cimetidine, ritonavir
- A cute Gentlemen “Cipped” Iced Grapefruit juice quickly and kept muching on soft cinammon rolls
Class notes: erythromycin (antibiotic) and itraconazole (antifungal) also added to list
What is the issue with giving Seroquel (quetipine that is a autism drug) with Clarithromycin (an antibiotic)?
- clarithromycin competes for CYP3A4, which metabolizes quetipine
- quetipine has arrhythmogenic properities so when it stayed in the body long, it causes torsades de pointes arrhymias
What are some classic diseases that lower drug metabolism (6).
hepatitis, alcoholic liver disease, fatty liver, biliary cirrhosis, decreased hepatic blood flow as a result of cardiac insufficiency OR use of beta blockers
T/F. Carbamezapine (via CYP 3A4) clears faster in adults than children?
False. faster in children
What is gray baby syndrome?
toxic accumulation of chloramphenicol metabolites leading to cardiovascular collapse
When does phase 2 sulfation develop?
in utero
How is someone a slow acetylator in phase 2 reactions? Who is most likely to be this way? What are the consequences?
- due to less NAT2 enzyme production
- occurs in blacks an whites at 50% (more freq in northern europeans)
- more likely for drug-induced autoimmune disorders and bicyclic aromatic amine-induced bladder cancer
What affect do genetic polymorphism have on succinylcholine?
Succinylcholine is metabolized only half as rapid in patient w/ genetic defect in pseudocholinesterase than ppl with normal psuedocholinesterase
