17 Cautions and contraindications Flashcards
Define caution
A situation in which additional care in the use of a medicinal product is required because the risk: benefit balance is altered
Define contra-indication
A situation in which a medicinal product should not be used because the risk outweighs potential benefits
Erythropoietin
- Stimulates red blood cell production
- Used to treat anaemia in cancer patients receiving chemotherapy
- 27 Feb 2008 Meta-analysis – increased risk of death in cancer patients.
- 7 March 2008 Amgen adds caution - Aranesp can speed up tumour growth and increase risk of death
- 13 March 2008 FDA allow continued marketing of Aranesp and Procrit but restrict use to incurable cancer
Contraindication occurs when..
expected ADR outweighs benefit
Situation or condition
• Increased expectation of ADR
• Decreased benefit of therapy
– If benefit outweighs risk but ADR is possible a caution may be appropriate instead
Contra-indications occur because..
• Drug exacerbates disease (“drug-disease interaction”) – Condition being treated orAnother pre-existing condition
• Adverse events are more likely due to an existing condition or demographic factor
– Drug creates a safety issue because of the condition • Pregnancy, Lactation, Age
• Subgroups of patients have a predisposition to ADR
• Immunological factors (e.g. allergy, hypersensitivity)
• Metabolic factors
• Drug-drug interaction should also be considered
Example of drug-disease interaction (1):
Sumatriptan and ischaemic heart disease
Sumatriptan contraindicated in patients with ischaemic
heart disease, previous MI, hypertension
Example Drug-disease interaction (2): β antagonists and Asthma
- Remember: β2 agonists (eg salbutamol) are used to treat Asthma –bronchodilator
- β antagonists used for heart conditions (angina, MI, arrhytmias) and open-angle glaucoma
- Non-selective β antagonist contraindication with asthma but cautioned in COPD
Example Drug-disease interaction (2): β antagonists and Asthma
Bronchiole..
Blocks bronchodilation, exacerbates asthma
Example Drug-disease interaction (2): β antagonists and Asthma
β2 receptor
Agonist -
Antagonist -
Agonist - dilation
Antagonist - constriction
Example Drug-disease interaction (2): β antagonists and Asthma
β Antagonist Levobunolol
Timolol
Eye - Reduced ocular pressure (glaucoma)
Example Drug-disease interaction (2): β antagonists and Asthma
β Antagonist
Nadolol, Sotalol Propanolol,
Heart - Decrease rate & bp (hypertension, anxiety, tachycardia)
Example drug-disease interaction (3):
amiodarone and thyroid dysfunction
Amiodarone
•Treat Arrhythmia ( 200 mg, 3 times daily; maintenance 200 mg daily)
•Inhibits K+ channels – prolong cardiac
- Interferes with thyroid hormone at several levels – can induce hypothyroidism
- Large iodine intake (exceeds r.d.a.)
- inhibition of thyroidal iodide uptake and thyroid hormone synthesis
- inhibition of fractional conversion of T4 to T3 intracellularly (inhibits 5’-deiodinase)
- inhibition of T4, T3 entry into cells
- T3 receptor antagonist
-Contraindicated in persons with thyroid dysfunction
Contraindications based on Patient Condition(1): pregnancy
- 1st trimester –congenital malformations (teratogenesis)
- 2nd & 3rd –growth & development
Examples
• Thalidomide and pregnancy
• SSRI – avoid if possible, compare risk to benefit
• Often drugs contraindicated without human testing Slide
Contraindication because of a condition (2): lactation
• Drugs in breast milk:
– Low amounts of drug may not be harmful or may cause hypersensitivity!
– Larger amounts may have a pharmacological effect
Examples:
• Hormone agonists and antagonists affecting the reproductive system may be contraindicated during lactation
– Fulvestrant
• estrogen receptor antagonist used in breast cancer
– Co-cyprindiol
• contains cyproterone-anti-androgen, used in severe acne
• Can cause feminization of male fetus
Contraindication because of a condition (3): Age
Examples
• Aspirin & Reyes Syndrome
– Reye’s syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver
– 1981 -1997, 1207 cases in children reported to the U.S. Centers for Disease Control and Prevention.
– >80% associated with aspirin treatment – mechanism unknown but mitochondrial toxicity
– Contraindication - Children who are under 16 years of age should not take aspirin, unless for Kawasaki syndrome and prevention of thrombus formation after cardiac surgery
Cautions/Contraindications because of changes in ADME
• Liver Disease
– Reduced elimination
– Reduced production of serum binding proteins
– BNF
• Increased Sensitivity to CNS drugs often seen
• Coagulation impaired–increased sensitivity to anti-coagulants
– Avoid drug or dose reduction
• Renal disease
– Reduced excretion
– BNF
• Avoid drug or dose reduction according to renal function (glomerular filtration rate)
• BUT – drugs also may be contraindicated in liver/renal disease because they can potentially worsen the disease eg ACE inhibitors and impaired renal perfusion
ACE inhibitors and renal disease
• ACE inhibitors used in treatment of hypertension
• Prevent AngII →vasoconstriction & aldosterone release
• Contraindicated in patients with significantly reduced renal perfusion
-
Slide 29
• Vasodilation further reduces renal pressure driving glomerular filtration
How do ACE inhibitors work?
ACE inhibitors work preferentially on efferent rather than afferent arteriole. Hence lowers glomerular pressure and filtration rate
Types of Cautionary label
• How to take/use the medicine
– Eg dissolve in water, dissolve under tongue, suck, chew, swallowed whole, spread thinly
• When to take/use the medicine
– Eg regular intervals, Before or after food, Not to stop taking medicine, completing
course of treatment, maximum amount in a period
• Potential adverse events & effects on driving or work – Eg drowsiness, avoid driving & machinery, blurred vision, coloured urine
• Food, medicine to be avoided
– Eg indigestion remedies, Fe, Zn, milk; avoid alcohol, sunlight; avoid aspirin,
paracetamol
• Storage
– Flammable, fridge
Example drug-drug interaction (PD): antagonistic effects (2)
• Histamine H1 antagonists
– Eg used to treat hay fever, rash
• Histamine H1 agonists – Betahistine
– Used to treat vertigo because it has an effect on the blood supply to the ear
– Vasodilation of arteries supplying inner ear.
Example drug-drug interaction (PD): additive effects
- Amiodarone and sotalol
- Both prolong cardiac action potential – risk of additive QT prolongation •Found in 2/1135 patients. Drug Safety 2005 28 67
•Triptans and Ergot alkaloids cause vasoconstriction and hypertension if taken together
Triptans
- 5HT agonists
- Sumatriptan
- Rizatriptan
- Zolmitriptan
Ergot Alkaloids
- 5 HT, & DA, NA
- Ergotamine (Migraine)
- Bromocriptine (Parkinsons)
Example: drug-drug interaction (PK)
Azole Antifungals (eg Ketoconazole Fluconazole Itraconazole) inhibit cytochrome P450 3A4
- Cyp 3A4 most abundant in liver and metabolizes largest number of drugs •Azole antifungals can inhibit metabolism of some benzodiazepines •Increased benzodiazepine in plasma
- Increased sedation – may lead to contraindication.
Balancing risks & benefits of
off-label use
• Risk for adverse effects
– Unknown adverse effects
– Use of (older) drugs with data available,
but more adverse effects
• Risk for suboptimal efficacy
– Use of (older) drugs with data available,
but lesser effect
– Underdosing, if data for correct dosing not
available
Example drug-drug interaction (PD): antagonistic effects (1)
dopamine
agonist
Eg bromocriptine - Parkinson’s disease
dopamine antagonist Eg chlorpromazine Schizophrenia
Some examples of why cautionary labels
are required
6 Do not take indigestion remedies or medicines containing iron or zinc 2 hours before or after you take this
medicine - Ofloxacin
M2+ (Quinolone – metal complexes have altered PK & PD properties)
21 Take with or just after food - Sporanox capsules
30 Contains Paracetamol. Do not take anything else containing paracetamol while taking this medicine - Co-dydramol.
