Drug interactions Flashcards
Drug interaction
Occurs when a substance alters the expected performance of a drug.
This substance can be a drug, food or toxin.
What are the two types of drug interactions?
Pharmacodynamic and pharmacokinetic.
Pharmacodynamic drug interactions
Occurs when drugs have an effect on the same target or physiological system.
Pharmacokinetic drug interactions
Occur when a drug affects the pharmacokinetics (ADME) of another drug.
Pharmacodynamic interactions are
Synergistic or antagonistic.
Due to drugs acting on the same drug receptor or system.
Generally predictable.
Highly selective drugs are less likely to be problematic.
Example of pharmacodynamic drug receptor synergistic interaction:
Amitriptyline for nerve pain.
Solifenacin for bladder spasm.
Solifenacin highly selective antagonist for M3 receptors.
M3 receptors widespread (bladder, CNS, salivary glands, GIT).
Amitriptyline increases serotonin and NA in synaptic cleft. Poor specificity for target, also antagonist at M3 receptors.
Amplified anticholinergic effects (dry mouth, constipation, flushed+dry skin, delirium).
Result - increased risk of adverse drug reactions.
Example of pharmacodynamic drug receptor antagonistic interaction
Atenolol - Beta antagonist
Salbutamol - Beta2 agonist
Salbutamol agonist at ß2 receptors (located in bronchial smooth muscle).
Atenolol cardioselective ß blocker (cardioselective antagonist at ß1 receptors but also antagonist at ß2).
Atenolol and salbutamol compete at ß2 receptors.
Results in incomplete agonist effect and reduced bronchodilation/increased bronchospasm.
Pharmacodynamic physiological system synergistic interaction
Morphine agonist at MOP, KOP and DOP.
Benzodiazepines potentiate actions of GABA.
MOP + KOP agonism and GABA transmission causes sedation.
Different mechanism within CNS -> increased risk of sedation.
Pharmacodynamic physiological system synergistic interaction.
Methadone agonist at MOP, KOP and DOP
Ciprofloxacin quinolone ABx.
Methadone and Cipro block VGPC= increased risk of QT prolongation and Torsade de Pointes.
Pharmacodynamic physiological system synergistic interaction: BENEFICIAL
Amlodipine: Calcium channel blocker - reduces Ca2+ influx into vascular smooth muscle.
Ramipril: ACE inhibitor
Both lead to reduced vasoconstriction -> increased risk of hypotension.
They are used together to lower BP.
A drug affects the rate of absorption of another drug:
It has limited clinical relevance - unless rapid effect required.
A drug affects the extent of absorption of another drug:
Can result in ineffective treatment - reduced steady state levels.
What are the mechanism of absorption interactions?
Drugs which alter the pH of GIT.
Formation of insoluble drug complexes.
P-glycoprotein induction/inhibition.
How do changes in the GIT pH affect absorption?
Changes in pH will alter the proportion of ionised and unionised drug
Famotidine (H2 antagonist) increases stomach pH and reduces absorption of ketoconazole (antifungal).
In practice: If taking famotidine, oral ketoconazole should be taken with an acidic drink
How does complex formation affect absorption?
Insoluble drug complexes will not be absorbed and will be retained in the GIT.
In practice: separate administration of doxycycline and oral iron by 2-3 hours.
How does P-glycoprotein induction/inhibition affect absorption?
P-glycoproteins (P-gp) are drug transporter proteins widely distributed in body.
Excretory function to remove toxic substances (incl drugs) out of cells.
Amongst other locations - situated in intestinal lumen to reduce absorption.
Activity can be altered by Pgp inhibitors and inducers leading to increased or decreased level of Pgp substrates.
Carbamazepine = Pgp inducer
Upregulates P-gp and therefore reduces the absorption of P-gp substrates.
Carbamazepine significantly reduces rivaroxaban levels (note interaction also occurs due to CYP3A4 induction).
How is distribution affected?
Only unbound drug will be distributed from plasma volume
Interactions can occur when drugs compete for protein binding.
Warfarin is highly protein bound (~99%)
1% unbound and pharmaceutically active
Amiodarone displaces warfarin from albumin to create unbound warfarin molecules
Change of 99% bound to 98% bound = free drug doubles from 1% to 2%
In practice: close monitoring of INR and decrease warfarin dose as necessary.
Pharmacokinetic interactions and metabolism
Kidneys excrete hydrophilic molecules
Lipophilic molecules are metabolised to create a hydrophilic metabolite
Cytochrome P450 (CYP450) enzymes are responsible for majority of phase 1 metabolic reaction
Most significant CYP enzymes for drug metabolism: 3A4, 2C9, 2C19, 1A2, 2D6.
Enzyme inducers
Increase the expression of the enzyme thus increase in metabolism of enzyme substrate.
Reduced levels of substrate - treatment failure.
Enzyme inhibitors
Decrease the expression of the enzyme thus decrease in metabolism of enzyme substrate.
Increased levels of substrate - ADRs and toxicity.
Pharmacokinetic drug interactions in elimination.
Limited clinical relevance in practice.
Competition for renal tubular secretion.
Drugs transported by OAT (organic anion transporters) and OCT (organic cation transporters).
Methotrexate
Methotrexate (MTX) is 80-90% excreted unchanged by the kidneys.
Secreted into renal tubule by OAT.
NSAIDs compete with MTX for secretion by OAT leading to reduced MTX elimination.
MTX toxicity: cirrhosis, fatal blood dyscrasias, renal damage (acute renal failure).
In practice: avoid NSAIDs and use alternative analgesia in patients taking MTX
Important drug-food interaction
Grapefruit juice is a CYP3A4 inhibitor (avoided by patients taking warfarin, statins).
Milk can affect absorption of some drugs due to insoluble complex formed with Ca (eg. doxycycline, levothyroxine, ciprofloxacin).
Action of warfarin (vitamin K antagonist) is opposed by foods high in vitamin K (kale, spinach, broccoli, avocado).
Cranberry juice is a CYP2C9 inhibitor (should be avoided by patients taking warfarin).
To avoid drug interactions; look out for high risk drugs by
Obtain complete drug history (DHx)
Enzyme inducers, inhibitors and substrates
Drugs with a narrow therapeutic index
High risk/critical medicines
New drugs (e.g. biologics) - little data
To avoid drug interactions look out for high risk patients
Polypharmacy
Kidney or liver impairment
Extremes of age
Red traffic light - avoid combination
Initiate an alternative drug
Temporarily suspend interacting drug
Permanently stop interacting drug
Yellow traffic light - proceed with caution
Additional monitoring (bloods, observations, vigilance for ADRs)
Green traffic light -
No action required
Mr K (86 year old male) is brought to A&E by his daughter after falling at home and hurting his wrist. He has recently started taking codeine for pain relief.
Which of his regular medicines would interact with codeine to increase his risk of falls?
Aspirin
Metformin
Morphine
Omeprazole
Ramipril
Morphine
