ADRs, DDIs and pharmacogenetics Flashcards
Phase I drug metabolism
modification of functional groups in order to increase clearance of the drug
Drug metabolism function and location
F(x): detox for xenobiotics and metabolism of endogenous cmpds
Locations:
liver and GI tract, also: kidneys, lungs, skin, brain
Phase II drug metabolism
addition of molecules to a (pro-)drug –> increase polarity in order to increase excretion of the drug conjugate
fate for drugs that increase QTc interval
never go to market!
= dangerous, esp. with P450 inhibition, so not approved by FDA
Mechanisms for DDIs that alter absorption
- alter gastric pH
- Chelating agents
- alter gastric motility
- alter GI flora
consequences of altering gastric pH (DDI)
some drugs require low pH for activation,
so = inhibited by drugs that increase gastric pH
antacids, H2 blockers –l aspirin, azoles/antifungals (need low pH)
chelating agent DDIs
chelating agents IRReversibly bind antibiotics/resins to antacids,
inactivate both.
example of DDI that alters gastric motility
L-DOPA increases motility, so increases emptying rate & excretion rate
–> other drugs taken = less effective at normal dose
Mech. of DDI altering GI flora
steroid conjugates hydrolyzed by flora, so decrease activation if decrease flora activity.
ie:
antibiotics kill flora –> (may) decrease f(x) of some birth controls
mech. for DDIs that alter drug metabolism
some P450 polymorphisms increase OR decrease metabolism
–> increase risk of therapeutic failure (esp. –> slow metabolizers)
ie: CYP2D6 – CNS/CV drugs
CYP2C19 – PPIs
CYP2C9 – Warfarin
CYP3A4 – MANY drugs!
P450 inhibition “Perpetrator”
a drug which causes inhibition of a P450 subtype
does not necessarily affect it’s own metabolism
P450 inhibition “Victim”
a drug whose metabolism is blocked bc another drug inhibits it’s specific P450 subtype
- danger from inhibition depends on the victim drug’s toxic potential and therapeutic index
Cimetadine (aka tagamet)
blocks MANY CYPs –> slows metabolism
* can be helpful for decreasing size of therapeutic dose*
Cause of increased QTc
Efflux of K+ from myocytes bc pump = inhibited,
–> delays repolarization and causes arrhythmia (!)
P450 Induction (DDI)
Inducing cmpd binds to nuclear Rs and increases DNA transcription –> increase P450 synthesis and activity
=> increase clearance, so decrease drug effect,
OR Liver damage (if metabolite = toxic)
P450 inducing compounds
- Rifampin
- Dexamethasone
- phenobarbital
- St. John’s wort
Requirements for successful P450 induction
- inducer present for long enough duration
- inducer binds to correct spot on DNA
- P450 turnover rate is ideal (not too fast or too slow)
Drug Distribution (as DDI)
Blocking P-gp pump –> increase CNS penetration and GI absorption; (via mdri gene)
counteract by: decrease bioavailability of drug
Ex: less anti-histamine across BBB –> “Non-drowsy”
Renal F(x) DDIs
- block/reduce P-gp pump activity
- decreased Renal Tubular Secretion (ie: saturated transporters)
Ex:
amoxicillin –> methotrexate transport
P-gp Pump
protein efflux pump in epithelial tissues (ie: brain BBB, renal tubules, etc.)
= protective mechanism for body
drugs/compounds that Inhibit CYP3A4 activity
- cyclosporine —> increases [statins] in plasma
- Grapefruit juice
Also: HIV meds, Beta blockers, Ca2+ blockers, statins, etc.
Common differences in Women (special pop.)
pharmaokinetics
Absorption: low. - low gastric empty rate, high gastric pH - low alcohol dehydrogenase, low CYP3A4 Distribution: high. - high % body fat, low muscle mass
common diff. in Women (special pop.)
pharmacoDynamics
- higher risk for “torsades de pointes” (heart problem)
(bc avg QTc 20ms greater than men) - on average have MORE ADRs
DDIs specific to Women
(some) antibiotics –l oral contraceptives
also: higher use of dietary supplements –> unknown DDIs
Common diff. in Maternal-Fetal Unit (special pop.)
* in general*
HUGE lack of controlled studies (unethical)
–> pregnant women usually go untreated or take standard adult dose
Common diff. in Maternal-Fetal Unit (special pop.)
pharmacoKinetics
Absorption: low.
- low gastric empty rate, slow GI transit time
Distribution: high.
- high plasma volume, high CO/HR/SV
Metabolism: change/low.
- low P450 activity (varies by person and CYP)
- low [albumin]p, high serum pH (minimal change [active]serum)
Clearance: altered.
- high renal and blood flow –> high GFR; BUT low hepatic BF
Rules for placental transfer
Best transfer if:
low molec. weight, high lipid solubility, non-ionized.
placental perfusion LEAST during contractions
teratogen
a chemical that induces fetal malformations
severity depends on:
- stage of dvpt @ time of exposure
- mom & baby genotypes
“critical tissue [ ]” (for teratogens)
insult to fetal development does not occur until reach specific [ ] in tissue.
==> sharp “dose-effect relationship” (small difference in amt of exposure btwn no effect and horrible effects)
FDA testing Grades for maternal-fetal drugs/dosing
(A, B, C, D, X)
A = safe, well-studied
C = safe in studies on non-pregnant ppl
X = proven UNsafe
common diff. in Pediatrics/Infants (special pop.)
pharmacoKinetics
Absorption: low.
- low pH, low GI motility
Distribution: high Vd.
* high free fraction ( [active] in plasma)
Metabolism and excretion: both Low.
* canNOT glucouronidate –> morphine = toxic!*
what measurement used to determine dosage in pediatrics?
use (total) Body Surface Area (aka: BSA).
–> Under-dose if use weight
Special conditions in infants that change rapidly with age
ie: days-weeks
- pH: start ~neutral, get more acidic
- GFR: increases. kids have HIGH clearance relative to size
(Bc increase drug clearance –> need to increase dose) - hepatic dvpt: increase CYP3A4 w/ maturity (and other CYPs)
- no CYP1A2 (for caffeine) until 2 months old!
Common diff. in Elderly (special pop.)
pharmacoKinetics
Distribution: High for lipophilic, Low for hydrophilic.
Metabolism: Low (esp. low CYP3A)
Clearance: Low (esp. renal)
- No change in absorption or phase II rxns*
Specific DDIs especially common in Eldery
none specifically,
but VERY high risk bc avg. # chronic meds = very high.
Elderly ADRs = 2.5 x # adult ADRs (!)
Mechanisms of toxicity (7)
- Reversible binding
- Covalent binding
- Free Radical Generation
- Heavy Metals
- Xenobiotic Metabolism (into toxins)
- Chemical mixtures
- Idiosyncrasy
Reversible binding toxicity
Dose-related exaggeration OR unrelated to therapeutic effect
(binds to same or different R as therapy target)
Antidote: R antagonist
Ex: CO binds to Hemoglobin (treat w/ pure O2)
Covalent Binding toxicity
= electrophilic attack –> inhibits normal f(x).
Antidote: depends on substance.
Ex: Acetominophen into toxic intermediate… (highly reactive)
if overdose/deficient GSH enzyme –> build up and damage
Treat: N-acetylcysteine (GSH substitute)
Free Radical toxicity
metabolic activation (or natural cause) --> high amt reactive species ==> damage tissue. Treat: free radical scavengers
Causes of Free radical toxicity
Drugs: paraquat, Fe (Fenton rxn)
natural: aging, caner, neurodegeneration, coronary artery disease
Heavy metals that cause toxicity
- Arsenic
- Lead
- Mercury
- Digoxin
Lead poisoning
from: air/pollutants, paints
Dx: accumulates in bones (“lead line” on x-ray), blood test
Sx: anemia, colic, renal injury, HTNN, cognitive impairment (in children)
Treat: chelation, remove source of exposure
Arsenic Poisoning
From: groundwater
Mech: inhibits synth of Acetyl CoA/glutathione, replaces PO4-
Sx: keratosis (benign), malignant skin lesions/lung carcinomas, peripheral neuropathy, GI effects, anemia
(multiple targets across body)
Treat: chelation
Mercury poisoning
(“mad hatters”)
Sx: behavioral/cognitive deficits, renal toxicity (if exposed to salt form)
Treat: chelation
Digoxin poisoning
Sx: heart arrhythmias
Treat: digoxin antibody
whole Ab is too big to be excreted, so gets cleaved…
Fab w/ bound digoxin = excreted
Chelation
process of surrounding heavy metal (reactive) with cmpd in order to minimize damage to tissues
Use: EDTA, BAL, or Succimer
Xenobiotic metabolism
Metabolic activation of a cmpd into toxin/carcinogen
Treat: enzymes to inhibit metabolic transformation into toxin
ex:
1. Aflatoxin (from grain/peanut molds) –> liver cancer
Also: Methanol and EtOH
Metabolism of methanol into toxin
Methanol –(alcohol dehydrog.)–>formaldehyde–> formic acid
* formic acid = toxic! (acidosis, blindness, coma)
Treat: give EtOh or fomepizole (both inhibit Alcohol Dehydrog.)
Treating alcoholism
EtOH –(alc.deh.)–> Acetaldehyde –(ALD) –> acetate
* ALD = aldehyde Dehydrogenage*
Acetaldehyde = toxic, so use Disulfram to inhibit ALD…
build up acetaldehyde –> induce sickness when drink alcohol
Idiosyncratic toxicities
= uncommon effects when given standard dose (usually tolerated)
can be: allergies, tissue sensitivities, metabolism polymorphisms.
** always involve adduct formation (bind to something extra)**
ex:
slow/fast metabolizers of Warfarin, not therapeutically effective
(should inhibit Vit K activation -X-> coagulation)
Warfarin:
Polymorphisms affecting metabolism
= anticoagulant, blocks Vit K activation.
- Cyp2C9: slow elimination
- VKORC: multiple polymorphisms @1 locus –> low/med/high dose variants
Dapsone:
polymorphisms affecting treatment
= topical acne med.
G6PD: if deficient –> FATAL hemolytic anemia
* also w/ fava beans
Maraviroc:
genetic variation affecting treatment
aka “Selzentry”
= anti-retroviral for a SPECIFIC HIV trope.
ONLY effective for CCR5-tropic HIV,
– must test virus type 1st, but very effective if IS that variant –
Irinotecan:
genetic variants affecting treatment
aka “camptostar”
= anti-neoplastic injection for metastatic colon/rectal carcinomas –> topoisomerase inhibitor.
UGT1A1: if deficient –> neutropenia
(decreased clearance -> increased [ ]plasma)
6-Mercaptopurine:
genetic variants affecting treatment
aka “purinethiol”
= purine analog for Acute Lymphatic Leukemia.
TPMT enzyme (ThioPurine S-Methyl Transferase): if low, drug = toxic! -- Test blood for polymorphism before use --
Trastuzamab:
genetic variation affecting treatment
aka “Herceptin”
= HER2 antagonist for Her2 over-expressing breast cancer.
No benefit if NOT Her2 over-expressing.
– test biopsy cells to check –
Imatinib:
genetic variation affecting treatment
aka “gleevac,”
treats Philadelphia-chrom. + (cancer-causing) CML.
ONLY works if have Philadelphia chromosome translocation.
Tamoxifen:
genetic variants affecting treatment
aka “Nolvadex
= Estrogen R antagonist (anti-cancer med)
- ONLY works if cancer is Estrogen R +.
- Cyp2D6 polymorphism: if deficient, higher recurrence rate
