Drug interactions

Question 1

Drug interaction

Answer 1

Occurs when a substance alters the expected performance of a drug.

This substance can be a drug, food or toxin.

Question 2

What are the two types of drug interactions?

Answer 2

Pharmacodynamic and pharmacokinetic.

Question 3

Pharmacodynamic drug interactions

Answer 3

Occurs when drugs have an effect on the same target or physiological system.

Question 4

Pharmacokinetic drug interactions

Answer 4

Occur when a drug affects the pharmacokinetics (ADME) of another drug.

Question 5

Pharmacodynamic interactions are

Answer 5

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.

Question 6

Example of pharmacodynamic drug receptor synergistic interaction:

Answer 6

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.

Question 7

Example of pharmacodynamic drug receptor antagonistic interaction

Answer 7

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.

Question 8

Pharmacodynamic physiological system synergistic interaction

Answer 8

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.

Question 9

Pharmacodynamic physiological system synergistic interaction.

Answer 9

Methadone agonist at MOP, KOP and DOP

Ciprofloxacin quinolone ABx.

Methadone and Cipro block VGPC= increased risk of QT prolongation and Torsade de Pointes.

Question 10

Pharmacodynamic physiological system synergistic interaction: BENEFICIAL

Answer 10

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.

Question 11

A drug affects the rate of absorption of another drug:

Answer 11

It has limited clinical relevance - unless rapid effect required.

Question 12

A drug affects the extent of absorption of another drug:

Answer 12

Can result in ineffective treatment - reduced steady state levels.

Question 13

What are the mechanism of absorption interactions?

Answer 13

Drugs which alter the pH of GIT.

Formation of insoluble drug complexes.

P-glycoprotein induction/inhibition.

Question 14

How do changes in the GIT pH affect absorption?

Answer 14

Changes in pH will alter the proportion of ionised and unionised drug

Question 15

Famotidine (H2 antagonist) increases stomach pH and reduces absorption of ketoconazole (antifungal).

Answer 15

In practice: If taking famotidine, oral ketoconazole should be taken with an acidic drink

Question 16

How does complex formation affect absorption?

Answer 16

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.

Question 17

How does P-glycoprotein induction/inhibition affect absorption?

Answer 17

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).

Question 18

How is distribution affected?

Answer 18

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.

Question 19

Pharmacokinetic interactions and metabolism

Answer 19

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.

Question 20

Enzyme inducers

Answer 20

Increase the expression of the enzyme thus increase in metabolism of enzyme substrate.

Reduced levels of substrate - treatment failure.

Question 21

Enzyme inhibitors

Answer 21

Decrease the expression of the enzyme thus decrease in metabolism of enzyme substrate.

Increased levels of substrate - ADRs and toxicity.

Question 22

Pharmacokinetic drug interactions in elimination.

Answer 22

Limited clinical relevance in practice.

Competition for renal tubular secretion.

Drugs transported by OAT (organic anion transporters) and OCT (organic cation transporters).

Question 23

Methotrexate

Answer 23

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

Question 24

Important drug-food interaction

Answer 24

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).

Question 25

To avoid drug interactions; look out for high risk drugs by

Answer 25

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

Question 26

To avoid drug interactions look out for high risk patients

Answer 26

Polypharmacy

Kidney or liver impairment

Extremes of age

Question 27

Red traffic light - avoid combination

Answer 27

Initiate an alternative drug
Temporarily suspend interacting drug
Permanently stop interacting drug

Question 28

Yellow traffic light - proceed with caution

Answer 28

Additional monitoring (bloods, observations, vigilance for ADRs)

Question 29

Green traffic light -

Answer 29

No action required

Question 30

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

Answer 30

Morphine