Drug-drug interactions

Question 1

What is the exact definition of DDI?

Answer 1

When effects of one drug taken by a patient are changed by another drug, food or drink also taken by the patient

Question 2

What are the outcomes of DDI’s?

Answer 2

they can be beneficial e.g. treating hypertension
they can be clinically insignificant
they can be harmful- worsen the outcomes

Question 3

How do warfarin and clarithromycin interact?

Answer 3

clarithromycin will increase warfarin levels which can leads to increase in INR( prothrombin time) and so a bleed in the brain

Question 4

What are patient risk factors for a DDI?

Answer 4

• age
• neonates and children
• gender
• co-morbidities
• diet
• smoking
• illicit drugs

Question 5

How is age a risk factor for DDI?

Answer 5

• if older there is more drug use
• with age there is more change in body composition so more fat and less muscle
• co-morbidities
• <28 days- hepatic function reduced
• older children have a rapid improvement in drug elimination

Question 6

How is sex a risk factor for DDI?

Answer 6

women - eliminate drugs more rapidly and are more subject to some ADRs

Question 7

what is polymorphic enzyme expression? what does it mean for metabolism?

Answer 7

when a single base pair changes in the DNA sequence
have drug metabolising enzymes
- rapid metabolisers
- the wild type is the most common

Question 8

how is comorbidites a risk factor? and what is an example relating to liver failure?

Answer 8

• increases DDI risk
• liver failure/malnutrition reduces albumin levels leading to changes in availability of protein bound drugs
• liver/renal dysfunction -> accumulation leading to potentially severe toxicity

Question 9

How does illicit drugs act as a risk factor for DDI?

Answer 9

• acute effects: warfarin and metronidazole
• cannabis can enhance drug clearance and tachycardia
• respiratory depression with heroin - accentuated by opiates

Question 10

What is the percentage of pharmacodynamic and pharmacokinetic of DDI’s?

Answer 10

92% is pharmacodynamics ; receptor level interactions and tissue/organ impact
5% pharmacokinetic; biotransformational changes -> enzyme induction/enzyme inhibition

• distribution changes and protein binding

Question 11

What are the pharmacokinetic interactions of an DDI?

Answer 11

• when one drug impacts on the biotransformation or distribution of a drug

Question 12

What does the pharmacokinetic interactions graph look like?

Answer 12

It is conc. vs time
It has a steep increase with onset time being first and then reaches peak where Cmax and tmax are reached. After this peak the graph steadily decreases until it plateaus eventually.
The graphs peak time is the duration of action and the MTC and MEC difference is the therapeutic range

Question 13

Explain the induction of biotransformation. What does it lead to and how long does it last?

Answer 13

• drug entry constant
• increased biotransformation -> premature loss of drug -> reduce/abolish clinical effect
  time frame- day and week s

Enzyme induction of biotransformation will happen over days and weeks and lead to clinical effect failure

Question 14

explain the inhibition of biotransformation. What does it lead to and how long does it last?

Answer 14

• drug entry constant
• removal of drug inhibited -> drug accumulation -> off-target effects and toxicity

time frame- hours and days

Question 15

Explain the P-glycoprotein - efflux pump . Give an example of what it does

Answer 15

• major efflux system
• uses ATP to transport many absorbed drugs to gut
• e.g. transports digoxin back into gut

Question 16

What are influx pumps and how do they work? What do they contain

Answer 16

they contain Organic Anion Transporting Polypeptides (OATPs)- liver cell membranes and gutt
these pumps are solute carriers for nutrients- diverse range of water soluble drugs are carried by OATPS; fexofenadine absorption prevented by grapefruit juice

Question 17

what drugs can inhibit OATPs?

Answer 17

rifampicin inhibits OATP

atorvastatin does not enter liver cells so there is 7-fold increase in plasma conc.

Question 18

How are some organs involved in first pass metabolism?

Answer 18

Absorption from the gut will occur and this will enter the liver through the hepatic portal vein.
The drug will be distributed to the body through the vena cava
From the liver the drug can also be metabolised

Question 19

Define first pass metabolism?

Answer 19

this is when the concentration of a drug is greatly reduced before reaching the systemic circulation
this fraction of the drug is lost in absorption from gut or the liver

Question 20

How does the cytochrome P450 system work?

Answer 20

• can manipulate any chemical
• can change the shape and physiochemical properties of a molecule
• used to build and destroy
• drugs/toxins caught up in destruction process
• poorly water soluble -> water soluble
  major focus of biotransformation

Question 21

Name the Major CYPs drugs that work on them?
CYP3A4
CYP3A5
CYP2D6
CYP2C9.CYP2C8
CYP2C19
CYP1A2
CYP2E1

Answer 21

CYP3A4- half of metabolic capability
CYP3A5- similar, increased prevalence in Afro-caribbean
CYP2D6- antidepressants, SSRIs, opiates, beta-blockers
CYP2C9.CYP2C8- warfarin, anticonvulsants
CYP2C19- PPI, clopidogrel
CYP1A2- clozapine, SSRI, warfarin
CYP2E1- paracetamol and in ethanol

Question 22

What occurs when CYP induction by drug happens? How long does it last for?

Answer 22

happens within hours- full effect 2-3 weeks
for 2-3 weeks it will be stable but after will need a higher dose
when drug conc falls outside of therapeutic window a higher dose might be needed for fast metabolised drugs
stop inducer when inductive effect is lost in days

a break in drug therapy put patients at overdose risk