Clinical pharmacology + ADME Flashcards
Pharmacokinetics
Time course of a drug from absorption to elimination
Determines drug regimen
- Dose
- How often
Therapeutic drug monitoring
Measuring plasma concentration after patient takes drug
Absorption mechanism
Active Transport
Bulk flow of water
Passive diffusion
Active transport
Drugs structurally-related to endogenous chemical
Bulk flow of water
Small water-soluble drugs
Passive diffusion
Movement of drugs
Small Intestines
Large surface area = 200m^3
Good blood flow
Long residence time
- High levels of unionised drugs
First-pass metabolism
Drug absorbed from small intestines to liver via hepatic portal vein
Calculate Bioavailability (F)
F = AUC oral / AUC iv
Clearance (Cl)
Volume of plasma cleared of drug per unit of time
- ml/min
- l/hr
Calculate Clearance
Clearance = Renal clearance + Hepatic clearance
Volume of distribution (Vd)
Apparent volume in which a drug is dissolved in the body
Regimens
Convenient dosing to obtain stable plasma concentration within window
How does the presence of food affect stomach?
Prescence of food increases time in stomach
Acid stable drugs
Slowed absorption
Acid labile drugs
Stay longer + more readily broken down
Example of Acid labile drugs
PPIs - they are given in gastro-resistant capsules
Half life
Time for plasma concentration to decrease by 50%
Calculate half life
t1/2 = 0.693 / K = 0.693Vd / Cl
K
Rate constant = fraction eliminated per unit time
K = Clearance / Vd
Calculate dose given
Dose given = Amount needed / F
Where does absorption take place
After taken an oral dosage form: it crosses gastrointestinal tract to blood stream
What alters absorption
Food / gastric emptying
First order kinetics
Rate of elimination is proportional to concentration of drug
Ct = Coe^-kt
Ct (in first order of kinetics)
Conc at t=t
Co (in first order of kinetics)
Conc at t=0
K (in first order of kinetics)
Rate constant
T (in first order of kinetics)
Time
Resources to find out drug interactions
BNF
Stockley’s drug interactions
Computer alerts
What inhibits CyP450
Cimetidine Antifungal agents (Ketoconazole) Erythromycin / clarithromycin (macrolide) Ciclosporin Psolaralen
What is the speed of the onset of CYP450 inhibition
1-2 days = Rapid onset
Reverses quickly on stopping
What makes clopidogrel less effective
Omeprazole
- therefore avoid omeprazole and esomeprazole
Types of drug interactions
Drug - drug
Drug - food
Enzyme induction
Increase activity of metabolising enzyme
What drugs have an effect on metabolism
Metoprolol - enhance action of poor metabolisers
Fluoxetine
Codeine - reduced response in poor metabolisers ( needs to be metabolically converted)
Tamoxifen -
GI tract interactions
- pH (drugs are passively absorbed best unionised; rise in pH can influence absorption of other drugs)
- Absorption (2 drugs may alter absorotion)
- GI motility/emptying (affect - absorption = metoclopramide acclerates absoription of other drugs)
- Binding (colestyramine binds bile in GI Tract to prevent its reabsorption)
What can increase pH
Antacids, PPIs, H2RAs
MDR 1 (+other known names)
multiple drug resistance is an efflux transporter or pump which pumps drugs out into lumen (P-glycoprotein / ATP binding cassette = ABC)
- Digoxin is a substrate
- Rifampicin = inducer
- Verapamil = inhibits (also psoralen
Why does omeprazole make clopidogrel less effective
Due to being biotransformed by same Cyt P450
- includes esomeprazole
- clopidogrel no longer converted to active metabolite
What is the current advice to take clopidogrel
Use another H2RA / PPI
- not cimetidine
- pantoprazole does not affect Cyt P450 + evidence suggest that it does not interact
Most common polymorphism
SNP - single nucleotide polymorphism
- mutations
- lead to amino acid substitution (sickle cell)
Therapeutic monitoring window for induction + inhibition
Inhibitor
Therapeutic window
Inducer
What drugs are enzyme inducers + what do they do
Barbiturates Rifampicin Griseofulvin Phenytoin Ethanol Carbamazepine - autoinduction St John's wort
They reduce conc of a range of drugs as the increase metabolism of OCs
How long is the onset of enzyme inducers
1-2 weeks
- effects can still continue after stopping inducer
What increases drug interactions
Polypharmacy
Conditions e.g. renal impariment
- problem for drugs with narrow therapeutic window
CYP2D6
Genetic polymorphism - poor metaboliser of debrisoquine - homozygous for recessive genes Extensive metaboliser = wild type Ultrarapid metabolisers = multiple copies of CYP2D6 gene
How do you report an ADR?
Yellow card Scheme
In BNF, submit to CSM (committee on safety of medicines) who monitor ADRs
- especially new meds + ADRs resulting in hospital admission
Report all black triangle drugs
Type A ADR
Augmented responses - Undesirable pharmacological response
Dose-related
Predictable
Type B ADR
Bizarre Unrelated to pharmacology Unpredictable Rare Severe Related to genetic or immunology
Ulcerogenic effects of NSAIDs
NSAIDs + corticosteroids associated with peptic ulceration/damage
State how ulcerogenic effects of NSAIDs can be minimised
Use paracetamol instead for pain-relief
Use PPI with Misoprostol (stable PGE1 analogue, acts on prostanoid receptors to inhibit gastric H+ secretion)
Example of an immunological
Penicillin allergy
- Treat with H1 - antagonist
- allergic to one means likely to be allergic to all
NSAIDs
Non-steroidal anti-inflammatory drugs
- aspirin, ibuprofen, diclofenac
- inhibit cyclooxygenase
- pain-relief
- anti-platelet
- aniti-pyretic
- anti-inflammatory
How can you manage Type A
Managed by dose adjustment
Most important ADR
NSAIDs
% of hospital admissions ADR-related
5%
% of hospital patients that suffer an ADR
10-20%
% of patients who die from ADR
0.1%
