Pharmacology Flashcards
What drugs alter Digoxin clearance, and what is the mechanism?
Clearance decreased due to increased MDR1 transporter activity
Drugs that cause this: amiodarone, dronedarone, quinidine, ritonavir, ranolazine
St John’s Wort acts on which CYP, and in which way?
Induce 3A4
Ciclosporin is key drug that is metabolised more
Celecoxib and Warfarin
Celecoxib inhibits CYP2C9, leading to raised s-Warfarin and thus increased warfarin effect. Can double INR
What transporter variant is associated with Imatinib resistance?
ABCG2
Furosemide and Lithium
Furosemide will increase serum lithium levels
As will HCT
Valproate and Lamotrigone
If used together, Lamotrigine needs dose adjustment
Ciclosporin metabolism
CYP3A4 in liver
Metabolism also occurs in small intestine via same CYP3A4
Pharmacokinetics
What the body does to a given drug (absorption, distribution, metabolism, elimination)
Pharmacodynamics
What the drug does to the body
Best measure of overall exposure to a drug
Area under the curve
For what drugs is Cmax most important?
Those with low therapeutic index - i.e. toxicity develops easily above therapeutic range
Bioavailability and hepatic extraction ratio
Hepatic extraction ratio = 1 - bioavailability
Volume of Distribution
Conceptual not actual volume. Would be the volume of fluid required to contain all of the drug in the body at the concentration it exists in plasma. More in the cells = bigger volume of distribution
Volume of distribution = total amount of drug in body/plasma drug concentration
How to determine a loading dose
Volume of distribution multiplied by target plasma concentration
What binds with highest affinity to albumin?
Acidic drugs
Salicyclic acid, warfarin, phenylbutazone, penicillins, sulphonamides
Has lower affinity for basic and neutral drugs, but high capacity for these which can cause displacement. Digitoxin, bilirubin and fatty acids can all bind.
Bioavailability versus clearance for drug metabolism
Drug with low bioavailability will be more affected by changes in metabolism or transporters in bowel than changes in clearance.
Calculation for half life
half life = 0.693 x Volume of distribution/clearance
First order versus zero order kinetics
First order: constant proportion of drug eliminated per unit time
Zero order: constant amount of drug eliminated per unit time
What is the therapeutic index?
Difference between dose at which adverse effect and therapeutic effects occur
Therapeutic index = adverse effect EC50/Therapeutic effect EC50
(EC50 = concentration of drug required to give half maximal response)
Tachyphylaxis
Rapid tolerance to drug - response to same plasma concentration decreases rapidly
Results in hysteresis loop.
Reverse Hysteresis Loop
Delay in onset and duration of effect due to:
- Prodrug/active metabolite
- Secondary messengers
- Redistribution phase
Potency
Measure of dose required to produce a response
NOT a measure of maximum response
So the lower the dose required, trhe higher the potency. Usually based on dose required to produce 50% of maximal effect/dose required to produce response in 50% of population
Dosing aims for Vancomycin
Measure with 24h AUC/MIC
Essentially give as much antibiotic as possible without causing toxicity
Aminoglycoside dosing aims
Target peak level >10x MIC
Measure Cmax/MIC
Concentration dependent and some post antibiotic effect
Fluoroquinolone dosing aims
Aim AUC >125
Measure with AUC/MIC
Concentration dependent and post antibiotic effect
Dosing aims for beta lactams
Time ? MIC
Aiming to be above MIC 40-70% of the time
Type 1 Error
False outcome by chance
Type 2 Error
Rejecting a true outcome by chance (sample size key)
Phase 1 drug trial:
Assessing safety, bioavailability, maximum tolerated dose, side effects
Phase 2 drug trial
Dose selection
Effect
Phase 3 drug trial
Efficacy in target population
Survival benefit
Common CYP Inducers
Rifampicin (1A2, 2B6, 2C8, 2C9, 2C19, 3A4/5) - so all but 2D6
Phenytoin ( 1A2, 2B6, 3A4/5)
Do -azoles typically inhibit or induce CYP enzymes?
Typically inhibit
Clopidogrel and CYP Enzymes
Inhibits: 2B6, 2C8
Substrate for 2B6, 2C19
Antibiotics and CYP enzymes
Mostly inhibitors other than Rifampicin
Cipro: 1A2 inhibitor
Clarithromycin: 2C19 inhibitor, 3A4/5 inhibitor
Erythromycin: 3A4/5 inhibitor
Inhibition or Induction of which CYP enzymes will influence Warfarin levels?
1A2, 2C9, 2C19, 3A4/5
Bioavailability Calculation
Two key calculations:
AUC of oral / AUC of IV
Also Bioavailability = 1 - hepatic extraction ratio
When using AUC, need to ensure have considered the doses in the question
Key clinical features of Serotonin Syndrome
Rapid onset within 24hr of commencing causative drug (i.e. whichever drug tips patient over into SS)
Autonomic dysfunction: diaphoresis, tachycardia
Neuromuscular excitability: hyperreflexia, clonus, increased tone
Altered mental state
Nausea, vomiting, diarrhoea
MAOI can cause hypotension (whereas hypertension overall more typical)
Acute management of Serotonin Syndrome
Discontinue all serotonergic drugs
Benzodiazepines for agitation/excessive muscle activity
Active cooling for hyperthermia
Antihypertensives
Cardiac monitoring
Consider need for intubation/sedation
Temperature indication for sedation/intubation in Serotonin Syndrome
> 41.1 degrees
Use non depolarising agent for paralysis, e.g. rocuronium. So don’t use Sux
Mechanism and key causes of Neuroleptic Malignant Syndrome
Dopamine blockade is key. Central C2 receptor blockade in nigrostriatal pathway and hypothalamus -> movement disorders, impaired thermoregulation, increases sympathetic tone, disrupted autonomic regulation, calcium release from muscle
First generation antipsychotics, second generation antipsychotics, metoclopramide, promethazine
Presentation of NMS
Insidious onset, can take 2-4 weeks
Cognitive changes early
Catatonia
Parkinsonism
Hyperthermia
Autonomic instability
Raised CK
No clonus or hyperreflexia
Management of NMS
Discontinue cause
Supportive
Dantrolene if severe
Dopamine agonists
ECT for refractory disease
