10 - ADRs and interactions Flashcards
(26 cards)
How can drug toxicity be classified? (chemistry)
- Pharmacophore based
- Chemotype based
- Metabolism based
Pharmacophore based toxicity
Effects are based on primary pharmacology of agent
Give an example of a drug that has pharmacophore based tox and DOESNT act at target organ:
Loop agents (e.g. Bumetanide)
* Inhbit Na/K/2Cl symporter on thick ascending limb
* Specificty lost at high dose ➔ ototoxicity (deafness)
Chemotype dependent toxicity
Structure or physicochemical properties lead to interactions with critical endogenous macromolecules (proteins, nucleic acids etc.)
* Noncovalent bonding
What critical macromolecules are inhibited by non-convalent bonding by chemotype dependent agents?
Inhibition of CYPs, Phase II, transporters and ion channels
Whatr are toxicophores?
Chemical constituents known to impart toxic effects
* Group or masked group
* e.g. phenyl rings metabolised > epoxides
* not sufficient alone to suggest toxicity
Elimination of toxicity with structural analogues
Alpidem (anxiolytic) > hepatoxicity
Zolpidem has activity without toxicity
* Replacement of 2 chloride atoms with methyl groups > changed the metabolism
* Methyl groups are now oxidised > hydroxyls > carboxylic acids -> eliminated
Metabolism induced toxicity
Drugs harbouring latent reactive groups produced via metabolism
* Phase 1 (epoxides, aldehydes, quinones, quinoneimines)
* Phase 2 (electrophiles generated by placing leaving groups (e.g. SO4) on latent functional groups)
How can you classify nature of electrophiles and what does it tell us?
Can be classified as hard or soft
* provides clues to toxicological target
* Soft ➔ Proteins
* Hard ➔ DNA
Prazosin example
Phase I metabolism produces epoxide
* Amount of epoxide produced is not sufficient for being withdrawn
Drugs with rare ADR and trials
Rare events are very difficult to detect in small samples of patients/animals
* E.g. no clinical trial could be divised to detect Vioxx toxo events
What are the types of ADRs outlined by Edwards and Aaronson Classification
- Dose-related (A)
- Non-dose related (B)
- Dose and Time related (C)
- Time-related (D)
- Withdrawal (E)
- Unexpected failure (F)
Dose-related ADR (A)
AUGMENTING intended effect
* e.g. ADR with opioid (respiratory failure and death)
* Focus on cMax
Non-dose related ADR (B)
BIZARRE, unexpected, not based on MOA of the molecules
* e.g. penicillin allergy
* Hapton: Immunogenic substance created upon binding
Dose and Time related ADR (C)
Occurs through CHRONIC use
* e.g. HPA axis suppression of corticosteroids, suppress natural control
Time related ADRs (D)
DELAYED
* e.g. Carcinogenesis: smoking for 40y then getting cancer
Withdrawal ADR (E)
END OF USE: stop taking drugs and feel terrible
* e.g. opioid withdrawal syndrome
Unexpected failure of therapy ADR (F)
FAILURE: Unexpected failure of therapy
* Not taking enough
* ADR by drug interaction
What is Warfarin?
Inhibits clotting and has a low therapeutic index
Warfarin MOA
Impacts different points in clotting cascade
* blocks VKOR inhibiting conversion of oxidized vitamin K epoxide to reduced form
* Inhibit vitamin K–dependent γ-carboxylation of zymogens
* ↓ Vit K as cofactor for γ-glutamyl carboxylase which makes zymogens functional
Risk with Warfarin
Clot risk ↓ as warfarin conc. ↑
* But bleeding risk ↑ exponentially
* Combined risk > there is a narrow sweet spot (therapeutic range)
Warfarin enantiomer
S-Warfarin (more potent form)
* Metabolized by CYP2C9
* Genetic polymorphisms increase warfarin metabolism ➔ need to adjust dose
Which genotype has highest clearance of S-warfarin?
CYP2C9*1 / *1
Warfarin Drug Interactions
- CYP2C9 Inhibitors: Increased INR and risk of bleeding complications (e.g. bruising, nosebleeds (epistaxis), GI bleed, excessive bleeding following injury)
- CYP2C9 Inducers: Higher clotting risk, decreased INR (e.g. DVT risk, PE risk, Stroke risk, organ failure due to blocked arteries)
