Drug-drug and drug-disease interactions Flashcards
(36 cards)
1
Q
Types of drugs to consider
A
- Prescribed drugs
- Herbal remedies
- OTC medications
- Dietart factors
- Lifestyle factors
2
Q
What is drug interaction?
A
Modification of one drug’s actions by another
3
Q
Individual variations to drugs
A
- Loss of efficacy
- Unexpected side-effects or toxicity
- Types of variability are pharmacokinetic (different conc. of drug reaching site of action) and pharmacodynamic (different degree of response)
4
Q
Effect on medication of being child
A
- Drug metabolism slower - organs are immature
- Renal excretion less efficient
- Drug sensitivity changes
- Body fat to mass changes
5
Q
Effect on medication of being elderly
A
- Failing organ function decreases drug metabolism
- Renal excretion less efficient
- Drug sensitivity changes as receptor numbers deplete
- Poly-pharmacy and co-morbidities
- Body fat and mass changes
6
Q
Effect on medication of being pregnant
A
- Decrease in plasma protein binding
- Increased plasma volume and extracellular fluid
- Increased cardiac output - increased renal blood flow and GFR = increased renal drug elimination
7
Q
Pharmaco-genetics
A
how different individual genotypes relate to different drug responses
8
Q
Pharmaco-genomics
A
pharmaco-genetics applied to whole human genome
9
Q
Mixed function oxidases
A
- Found in liver, often referred to as cytochrome P450 family
- Good at breaking down meducations
- Changes toxicity and effectiveness of drug
10
Q
Ethnicity and drug response
A
- Genetic differences account for some variations
- Diet also important
- ACEi not used in afro-caribbean background because of angio-oedema
11
Q
CYP 1A2
A
Increases/decreases anti-psychotic drugs metabolism
Increases adverse reaction of traduce dyskinesia
12
Q
CYP 2C9
A
Increases/decreases warfarin, phenytoin and losartan metabolism
Increases adverse reaction of bleeding, toxicity, ataxia and confusion
13
Q
CYP 2C19
A
Increases/decreases diazepam, omeprazole metabolism
Increases adverse effects of prolonged sedation and acid suppression
14
Q
CYP 2D6
A
Increases/decreases B-blockers metabolism
Increases adverse reaction to excessive bradycardia
15
Q
Har,ful drug interactions
A
- 15% of adverse drug reactions
- Elderly, hepatic/renal impairment, polypharmacy (on multiple drugs) and pts on drug with narrow therapeutic range (phenytoin) are at increased risk
16
Q
Pharmacodynamics
A
- Agonism at receptor - 2 drugs of same/similar class (e.g. opioids competing for receptor)
- Antagonism at receptor - opiate analgesics and naloxone, B-blockers and beta2 agonists
- Non-selective nature of drug - antidepressants intercta with many receptor subtypes
- Enhanced effect by other means - increased digoxin toxicity by hypokalaemia caused by loop diuretic e.g. furosemide
17
Q
Pharmacokinetics
A
- ADME - 4 stages of pharmacokinetics (absorption, distribution, metabolism, excretion)
- Parenterally = passes first pass metabolism
- Excreted in urine and bile
18
Q
Absorption
A
- Changes in gut motility - opiates and atropine slow gut down - Cmax and Tmax
- Metoclopramide speeds gut up - Cmax and Tmax
- Interfere with absorption and enterhepatic circulation - calcium salts bind tetracyclines in gut, cholestyramine binds warfarin and digoxin, activated charcoal binds drugs in gut after overdose
19
Q
Distribution
A
- Many drugs alter distribution by displacing another drug from plasma or tissue binding sites
- Causes transient increases in unbound drug
- Subsequently corrected by increased elimination
- Total drug concentration reduced but free value recovers at steady state
20
Q
Metabolism
A
- 2 phase metabolism for many drugs
- Liver is main site of metabolism
- Drug → derivative → conjugate
- Phase 1: CYP450 family, low substrate specificity metabolises a wide range of drugs
- Phase 2: e.g. glucuronidation increases solubility and allows easier renal elimination , converted to active metabolite
21
Q
Enzyme inducing drugs
A
- Warfarin and carbamezapine
- Increased activity of cytochrome family
- Warfarin metabolised quicker = failure of treatment
- Drugs that induce CYP450 increase metabolism of other drugs and increase own metabolism
- Carbamezapine induces CYP3A4 - warfarin is metabolised and carbamezepine causes faster warfarin clearance, reduced anticoagulant activity, therapy failure
22
Q
CYP 450 induction
A
- Slow onset (1-2 weeks) because new enzyme production induced
- Induction persists some time after stopping inducing drug and whilst enzyme levels normalise
- Removing inducer will disturb equilibrium
- Warfarin may have been adjusted so INR is stable despite interaction
- Removal leads to reduced CYP3A4 activity - warfarin metabolism slows over 1-2 weeks, warfarin levels climb, risk of over-anticoagulation and bleeding
23
Q
Herbal remedy for depression
A
St John’s Wort
24
Q
Why is St John’s Wort dangerous
A
increases metabolism of oral contraceptive, digoxin, phenytoin, warfarin
25
CYP 450 inducers
```
Anticonvulsants
Antibiotics
Steroids
Alcohol
St John's Wort
HIV therapies
```
26
Macrolide antibiotics and warfarin
- All antibiotics kill gut bacteria - vit K falls, increased anticoagulant effect, increased INR
- Macrolide antibiotics (clarithromycin) - inhibit CYP450, warfarin metabolism reduced, increased INR
27
CYP 450 inhibition
- Relatively quick onset
- Related to half life and clearance of drug and plasma concentration at time of interaction
- Usual effect is reduced metabolism of drugs - increased effect and toxicity
28
CYP 450 inhibitors
```
Anti-arrythmics
Antibiotics
Anti-ulcers
Antidepressants
HIV drugs
Statins
Sodium valproate
```
29
QTc interval prolongation
- Increased risk of lethal cardiac arrhythmia
- Drugs may prolong this interval and cause torsade des pointes
- Leads to PEA
- Genetic and acquired forms
- Ion channels and sympathetic abnormalities
- QTc lengthened by anti-arrythmics
- Another drugs prolong QT
- Any drug impairs metabolism of QTc prolonging drug may cause long QT
30
Drugs increasing risk of long QTs
- Anti-arrythmics - quinidine, aotalol
- Antibiotics - macrolides (erythromycin, clarithromycin)
- Anti-fungal agents
- Anti-histamines
- Psychotropic drugs
- Motility agents
31
Hepatic disease
Decreased clearance of hepatically metabolised drugs
Decreased CYP450 activity
Increase half life and toxicity - classic is opiates in cirrhotic patients
32
Renal disease
Reduced clearance of renal excreted drugs - digoxin
Increased electrolyte and fluid distributions = increased toxicity
Nephrotoxic drugs worsen renal function
33
Cardiac disease
Decreased metabolism of drugs dependent on hepatic blood flow
Increased response to cardiovascular drugs
34
Other diseases
Exacerbation of asthma by beta-blockers and NSAIDs
| Decreased seizure threshold with some antibiotics like ciprofloxacin
35
Grapefruit juice
- Inhibits CYP450 isoenzymes
- Decreased clearance of many drugs - simvastatin, amiodarone and terfenadine (long QT)
- May lead to increased exposure of drugs
36
Cranberry juice
- Treats urinary sepsis
- Inhibits bacterial adherence to urothelium
- Inhibits CYP2C9 isoform - decreased clearance of warfarin, increased anticoagulant effect, increased risk of haemorrhage, pt should be advised not to drink if on warfarin
