Safety - ADRs & Interactions

Question 1

Most significant ADR

Answer 1

NSAIDs
29.6% 
GI bleeding
Renal impairment 
Wheezing

Question 2

What is a Type A response

Answer 2

Augmented response

Normal pharmacological response is undesirable
Dose related
Predictable
Usually managed by dose adjustment

Question 3

Adverse side effects of: TCAs

Answer 3

Antimuscarinic effects 
Dry mouth
Blurred vision
Constipation
Urinary retention

Question 4

Adverse side effects of: beta blockers

Answer 4

Cold extremities
Bradycardia

Contraindicated in asthma - bronchospasm risk

Block effects of salbutamol

DONT GIVE WITH CALCIUM CHANNEL BLOCKERS
Beta blocker + verapamil = risk of bradycardia/ asystole
Could be fatal, avoid

Avoid with DILTIAZEM - another non DHP Ca channel blocker

Much less of a problem with DHP Ca channel blockers

Question 5

Adverse side effects of: Cimetidine/ spironolactone

Answer 5

Gynaecomastia

Reduced testosterone synthesis or oestrogenic

Question 6

Adverse side effects of: Opioids

Answer 6

Constipation
Nausea and vomiting
Sedation
Low blood pressure

Question 7

Adverse side effects of: Antibiotics

Answer 7

Diarrhoea

Question 8

Adverse side effects of: NSAIDs

Answer 8

GI Bleeding/ damage/ peptic ulceration
Usually oral NSAIDS (sometimes corticosteroids, esp WITH NSAIDs)
Annually 10,000 hospital admissions and 2000 deaths
1:2000 risk for long term users

Renal impairment
Inhibit renal PGs
Reduce renal blood flow, reduced GFR (esp in CHF patients)
May lead to acute renal failure (7% all cases)
May also cause acute interstitial nephritis

Contraindicated in asthma - risk of bronchospasm (b2 receptor blocking), even risk in “selective” b1 antagonists (poor selectivity)
Caution in COPD

CV Disease
May cause fluid retention
May exacerbate HTN/ CHF
Low dose aspirin less of a problem

With methotrexate –> leads to methotrexate toxicity

Question 9

Adverse side effects of: Digoxin

Answer 9

Nausea and vomiting
Visual disturbances

INTERACTS WITH: Amiodarone & verapamil

Question 10

Adverse side effects of: Cytotoxics

Answer 10

Myelosuppression

Question 11

Mechanism of ADRs ADME

Answer 11

Pharmacokinetic.

ABSORPTION
2 drugs may interact to alter rate of uptake e.g. Tetracycline and Fe2+ salts or Ca2+ (milk)
pH: passive absorption of drugs best in UNCHARGED form, governed by pKa value. Rises in pH (antacids, PPI, H2antags) may influence absorption of other drugs. Separate drugs by several hours.
Binding: colestyramine
GI motility: changes in motility/ gastric emptying may affect absorption. Metoclopramide accerlerates absorption of other drugs (use in anti migraine drugs).

ELIMINATION
Renal and hepatic
Change sis rate of elimination, leading to increased plasma concentration, are the most important causes of ADRs.
E.g. Reduced renal function (especially in elderly and neonates)

METABOLISM
Reduced metabolism may lead to increased plasma concentration

Neonates conjugate at a slow rate
Microsomal enzyme activity decreases variably with age
Genetic differences: 10% population have defective isoenzyme of cytochrome P450
Hepatic failure: LFTs poorly predict ability to metabolise.

Question 12

Digoxin. Mechanism of ADR

Answer 12

2/3 is renally cleared
Therefore in the renal impaired the plasma concentration graph is much raised, above the safe therapeutic window. Digoxin has a narrow window and so increased concentrations lead to toxicity.

Toxic effects: nausea, visual disturbances, heart block, arrhythmias

Patients tend to be elderly with impaired renal function.

Monitor renal function: eGFR from plasma creatinine

If toxic, stop for a time

Question 13

What is a type B reaction?

Answer 13

Bizarre/ Idiosyncratic (uncommon reaction due to genetic predisposition)

Unrelated to pharmacology
Unpredictable
Rare
Often severe
Often related to genetics or immunology

Question 14

Immunological ADR

Answer 14

PENICILLINS
Penicillin couple to proteins, forming immunogens (hypersensitivity reaction)
Treat with H1 antagonist

CEPHALOSPORINS
Recent evidence - cross reactivity is less (0.5-6.5%) than originally thought, some may be used if no alternative is available.

Remember Co-amoxiclav too

Question 15

Haematological ADR

Answer 15

Agranulocytosis - absence of neutrophils
Mouth ulcers
Severe sore throat
Infections
Caused by clozapine/ carbimazole/ carbamazepine

Thrombocytopenia
Bruising/ bleeding

Question 16

How to minimise NSAID GI damage

Answer 16

Paracetamol for analgesia

Identity risky patients
Over 65
Ulcer history

PPI Prophylaxis
H2 antagonists less or ineffective
Misoprostol - a stable PGE1 analogue ( prostaglandin E1)

Question 17

Adverse side effects of: Statins

Answer 17

MYOPATHY
Rarely statins may cause muscle damage/ myopathy leading to pain

Often due to a drug interaction

Myopathy rarely progresses to rhabdomyolysis - may result in renal damage

Question 18

ADRs Skin reactions

Answer 18

Most commonly affected organ, trivial to serious

Urticaria
Erythematous eruptions- reddening, may resemble measles or maculopapular
Toxic epidermal necrolysis- rare, often fatal, blistering and skin peels off (upper layer)
Stevens Johnson syndrome- fever/ rash/ blisters

Obtain drug history
Usually stop the drug
Treat symptoms with anti histamine/ soothing cream

Question 19

Adverse side effects of: Sumatriptan

Answer 19

2007 operation - patient found to bleed dark green blood

ADR, rare, leads to sulphahaemoglobinaemia (a sulphur atom incorporated in the haem group)

Reversed on stopping to sumatriptan

Question 20

General signs that indicate ADRs, look out for:

Answer 20

Changes in renal and liver functions

Blood counts (associated symptoms)

Rashes

Allergy/ anaphylaxis

CNS effects

Visual disturbances

Muscle pain (e.g. Statins +/- fibrates)

Question 21

ALARM BELLS, WATCH OUT

Answer 21

NSAIDs in elderly (even low dose aspirin has risks)

NSAIDs in ulcers

Beta blockers in Asthma/COPD

Corticosteroids

Question 22

Define a drug interaction

Answer 22

An interaction occurs when the effects of one drug are changed by the presence of another food/drink/drug/environmental chemical agents.

May increase toxicity
Or reduce activity - failure of therapy

Be aware of food/ OTC/ renal impairment/ narrow TIs.

Question 23

CYP Mediated Metabolism. ADR

Answer 23

Multiple CYPs

ENZYME INDUCTION - (reduced plasma conc)
Barbiturates/ Rifampicin/ Griseofulvin/ Phenytoin/ Ethanol/ Carbamazepine (autoinduction)/ St John’s Wort
Reduce plasma concentration of range of drugs (e.g. Rifampicin increases metabolism of OCP)
May take 1/2 weeks for effect
Effect may persist on stopping inducer

CYP450 INHIBITION (raised plasma conc)
Cimetidine/ Antifungal agents/ Erythromycin/ Ciclosporin/ Psoralen
Rapid onset: 1-2 days
Often reverse quickly on stopping

Question 24

Simvastatin Interactions

Answer 24

Contraindicated with macrolides

Interaction with: amlodipine/ verapamil/ diltiazem

Amlodipine & Statin
Use 10mg atorvastatin
Pravastatin does not interact
Use 20mg simvastatin as max. dose.

Question 25

Renal elimination Drug interactions

Answer 25

Competition for weak acid/ base transports

Aspirin and methotrexate complete for elimination and NSAIDs in general may reduce renal perfusion - SEVERE INTERACTION.

• Counsel patient taking methotrexate NOT to take OTC ibuprofen or aspirin
• NSAIDs prescribed with care in RA

pH and renal elimination

• secretion related to pH, increase pH: increase excretion of weak acids
• in aspirin, barbiturate poisoning increase pH of urine with NaHCO3 to increase their elimination

Question 26

Fluid and electrode interactions

Answer 26

Diuretics. 
Lead to volume depletion. 
When first adding ACEI, increased risk of severe first dose HTN
- stop diuretic?
- separate in time?
- take ACEI before bed?

Diuretics - loop& thiazides
Cause hypokalaemia - so increase toxicity of digoxin

Question 27

K sparing diuretics

Answer 27

E.g. Spironolactone, amiloride

Increase K
May be a problem if patient takes K supplement of ACEIs (which also increase K)
Risk hyperkalaemia

Question 28

Adverse side effects of: Theophylline (treat resp disease)

Answer 28

Augments salbutamol

Theophylline is a phosphodiesterase inhibitor which raises intracellular cAMP
(Beta2 adrenoceptor agonists also raise cAMP)

Question 29

Warfarin indications

Answer 29

Post surgery
Patients with replaced heart valves
AF
PE
DVT

Takes several days to act

Question 30

Warfarin - risks and interactions

Answer 30

Narrow TI
Many interactions
(Inducers lead to therapy failure)
(Inhibitors lead to increased bleeding)

Increased bleeding with aspirin/ NSAIDs

Warfarin and Anitbiotics (esp erythromycin and ciprofloxacin) lead to increased bleeding

Question 31

What is INR

Answer 31

Internal normalised ratio
Prothrombin time: normal control
Should be around 1

Question 32

Consequences of warfarin interactions

Answer 32

Increased actions lead to bleeding:

Gastric
Cerebral
Haemoptysis 
Blood in faces
Blood in urine
Easy bruising

Question 33

Herbal interactions

Answer 33

St. John's wort
ENZYME INDUCER
AVOID WITH:
OCP
SOME HIV drugs
Ciclosporin
Warfarin
Simvastatin 

Serotonergic syndrome: avoid with MAOIs and SSRIs

Question 34

Food interactions

Answer 34

Cranberry juice potentiates warfarin

Grapefruit juice interacts with:
Terfenadine
Simvastatin
Some Ca antagonists

Question 35

Alcohol interactions

Answer 35

Labels 2&4 (avoid if affected or avoid)

Mostly CNS depressants/ sedating actions enhances
E.g. TCAs/ Sedating antihistamines/ benzodiazepines

Few antibiotics actually interact
Metronidazole leads to disulfiram-like effect

Gastric effects
Avoid aspirin containing products for a hangover

Question 36

OCP interactions

Answer 36

Watch out for inducing agents that will accelerate OCP metabolism

Rifampicin
Carbamazepine
phenytoin

Question 37

ADRs statistics

Answer 37

5% hospital admissions
10-20% hospital patients suffer ADRs
0.1% medical patient mortality

Many patients receiving poly pharmacy, increased interactions/ reaction risk.