Adverse Drug Reactions (ADRs) Flashcards
What are the most common ADRs?
Wide range of frequency & severity:
- Irritation/redness – mild
- Hypersensitivity – mild
- Cataract – more severe – treatable through operation
- Glaucoma – extreme – visual impairment irreversible
o Using beta blockers to treat glaucoma carries risk of lowering pxs blood pressure – can lead to drop or fainting attack – lowers heart rate and can potentially lead to death (extremely rare)
Most ADRs seen in practice are mild, more severe ADRs are rarer.
Describe ADRs vs side-effects?
- A noxious & unintended response to a drug
o An undesired outcome for the px (can be mild or severe) - Side effects
o An unintended effect
Not necessarily undesirable – e.g. thickening, lengthening, darkening of eyelashes from glaucoma drugs
Describe irritation and hypersensitivity as ADRs
- Among the most common ADRs for topical (ocular) medications
- Particularly common with:
o Brimonidine (alpha 2 agonist)
o Dorzolamide (topical carbonic anhydrase inhibitor)
o Atropine (indications: cyclo refraction or treat severe anterior uveitis to break posterior synechiae)
o Lanolin (wool fat derivative – used in ocular lubricants for DED)
o Neomycin (antibacterial drug – not available in UK as standalone atm but incorporated in other drugs)
o Benzalkonium chloride (preservative, often in multi-dose preparations) - Delayed reaction: can be wks or mths of uneventful use
- Symptoms:
o Irritation, redness, stinging, burning - Signs:
o Hyperaemia, lid oedema, diffuse SPK
If hypersensitivity or allergy component (not always – can be chemical component instead) then likely to see lid oedema & conjunctival chemosis
Diffuse SPK: in epithelium of cornea (use optic section to determine this), dot-like scattered across cornea, keratitis – inflammation of cornea. Each dot represents an epithelial cell that has been lost – cornea has experienced a toxic reaction. Almost entire surface of cornea has been affected to same extent (shows it was an eye drop that caused this). Tear film here looks quite stable – uniform green glow across ocular surface - SPK in dry eye is more confined to inferior 1/3 of cornea (image) – unstable tear film – appears black and broken up
o VA: in diffuse SPK from ADRs may be reduced from 6/5 to 6/12 as SPK covering pupil (on visual axis). In the dry eye, VA may still be 6/5 as area of cornea affected is lower than pupil – VA in these pxs may be variable though and may need to blink more to spread the tears around - Severity is dose-dependent - & how often px is to use drug
Describe the mechanism of ADRs?
- Hypersensitivity: (allergy)
o Type IV hypersensitivity
o Mediated by T cells
o T cells release cytokines
o Cytokines promote inflammation – dilating BVs, leads to redness, tissue oedema etc - Chemical Toxicity:
o Direct irritation of ocular surface
o Irritation triggers inflammation
o Benzalkonium chloride – many pxs will say they are allergic to this but actually have a toxicity to it – in some pxs it is just sufficient amount of BAK to produce a toxicity reaction
They are sensitive to BAK no allergic
Describe benzalkonium chloride in ADRs?
- Used as a preservative in ocular medications
o Reduces bacterias ability to replicate in a multi-dose eye bottle
o Keeps eyedrop sterile - Found in up to 75% of ocular preparations available within the EU
- Mode of action: disrupts permeability of cell membrane
o Cell membrane lets nutrients and other good things in whilst also keeping out waste products, metabolites, CO2 etc
o BAK targets cell membrane, punctures it, cell then unable to function leading to cell death
o BAK needs to differentiate bacterial cell and a healthy host cell - May demonstrate a mild toxic effect on ocular surface
- Concentration-dependent irritation – some pxs are particularly sensitive to BAK and so even at low concs show toxic reaction and mild signs of ADR to BAK
- Picture:
o Comparison of effects of various lubricant eye drops on the in vitro rabbit corneal healing & toxicity
o Things seem to get much worse when BAK administered at sufficient conc to cause effect - Concs of BAK used are sufficiently low that in majority of pxs it will be fine
What is the management of irritation or hypersensitivity as ADRs?
- Switch to unpreserved preparation, if possible
o Single dose units/filtered multi-dose bottles
o Preservative free prescribing?
Hx of severity of preservatives
Very frequent dosing (6x day +)
Preservative free usually more expensive so need to use when clinically appropriate - Change to alternative medication
o E.g. allergic to lanolin so change to med w/o lanolin in it - Symptomatic relief:
o Cold compresses
o Artificial tears – preservative free
o Topical steroid – preservative free (IP OPTOMS ONLY)
A range of corticosteroids are available, with significant differences in potency
This would be in more severe cases
Non-Penetrating/Soft: - Episcleritis
- Pingueculitis
- Inflamed pterygium
- Marginal keratitis – inflammatory conditions – no infection here just inflammation
- The above four are all ocular surface inflammations, all relatively superficial in location – so non-penetrating steroid is suitable
- E.g. Fluorometholone (FML) 1 drop, 4x a day for 1 week (then taper)
- The ADR showing irritation & hypersensitivity would be treated with soft steroid if needed as relatively superficial
Penetrating/Hard: - Penetrating = abiltiy of drug to cross corneal epithelium, enter aqueous humour & come into contact with other structures such as iris & ciliary body
- Anterior Uveitis
- E.g. Prednisolone
o Topical (ocular) Antihistamines:
Azelastine, oloptdine
Not suitable in this case of ADR as mechanism is different
o Mast cell stabilisers:
Sodium cromoglicate, lodoxamide
Not suitable in this case of ADR as mechanism is different - Refer back to original prescriber – if you were not the one who prescribed the drug – if original prescriber was ophthalmologist could call hospital
- Don’t withdraw a medication, unless its safe to do so
Describe tetracycline antibiotics and their ADRs?
- An effective 2nd-line tx for blepharitis
- Highly effective against chlamydia (but this needs urgent referral)
- Doxyclycline 100mg
- Minocycline 50/100mg
- Oxytetracycline 500mg
- Tetracycline 500mg
- ADRs:
o Photosensitivity:
Advise against prolonged sun exposure
Advise use of sun protection (more frequently than usual)
o Tooth discolouration:
Contraindicated in under 12s, pregnancy (can cross placenta) & breast-feeding
Can cause discolouration & malformation of teeth & bones
o GI Disturbance:
Nausea
Diarrhoea
Vomiting - Advise px of the above GI disturbances – ask them to return if it becomes problematic
o Headaches – ask them to come back if becomes problematic
o Stevens-Johnson Syndrome – v severe inflammatory disease which causes inflammation and scarring in multiple mucous membranes throughout body
o Kindey/Liver Damage:
Avoid in pxs with renal/hepatic impairment
Before issuing Rx to px is check BNF – quick cross check of contraindications – check kidney/liver function, pregnancy etc – tick off all these important points before prescribing medication to px
Describe topical corticosteroids and their ADRs?
- Effective short-term measure to control ocular inflammation
o Uveitis
o Allergic eye disease
o Marginal keratitis - Often used intensively (e.g. every hour)
- ADRs:
o Suppress immune response & ability to fight infection
Exclude infectious cause (1st pic = wrong drug been prescribed – geographic ulceration (end stage of herpes simplex infection) - Ocular infections MUST be managed by anti-bacterial, anti-viral or anti-fungal medications
o Cataract development
Particularly posterior sub-capsular cataract – small size but can affect vision as quite small but near nodal point of eye – near vision may be particularly affected and when pupil is misosed e.g. looking at oncoming car-headlights
o Delayed wound healing
A corneal abrasion may take longer to recover than usual
o Corneal/scleral thinning
Conditions where this is associated e.g. scleritis are usually managed by opthalmologist
Describe steroid glaucoma?
- Significant elevation of IOP associated with corticosteroid use in approx. 35% of pxs (known as steroid responders)
o Damage to NRR and associated VF loss – these signs will present in steroid glaucoma too
o Impossible to predict which pxs will go on to develop this reaction to corticosteroids - Guidance on IOP Monitoring:
o Measure baseline IOP – initial examination
o Recheck at 2 weeks – of steroid use
o Recheck every 4 weeks for 2-3 months
o Then 6 monthly if therapy is to continue - Management:
o IOP elevation typically subsides within 1-4 weeks (when corticosteroid is withdrawn)
o Urgent referral back to original prescriber
They can then decide if they want to: - Change to alternative medication
o If we were original prescriber: can decide if want to stop corticosteroid (dependent on condition), change to alternative
If e.g. anterior uveitis & not yet under control cannot stop corticosteroid tx yet - & px has steroid glaucoma, may need to add glaucoma medication – referral to ophthalmologist for this - Specific CMG on steroid glaucoma
Describe other more uncommon ADRs with topical corticosteroids?
- Rare (development of Central Serous Chorioretinopathy (not just CSR) with corticosteroid use – not sure why it happens)
- Mechanism unclear increased choroidal permeability – allowing fluid to escape into sub-retinal space
o Thought there may be linked between use of topical corticosteroids and development of central serous chorioretinopathy (px likely have blurred vision, metamorphopsia (distorted vision)) - Recent (stay up-to-date)
- Px advice: report blurred vision immediately & present for EE
- Optom advice: be aware
- If px presents with sudden blurred vision & in hx is on corticosteroids – exclude possibility that px has CSR (using dilated fundus exam & OCT scan)
- Corticosteroids administered via:
o Inhaled
o Intranasal
o Epidural
o Intra-auricular
o Topical dermal
o Periocular - Report instances of this ADR that we see in pxs via MHRA Yellow Card Scheme
Describe uncontrolled ocular inflammation and the risk?
- Severe ocular inflammation (e.g. uveitis) carries risk of:
o Posterior synechiae – can block angle leading to rise in IOP
o Secondary glaucoma – may be secondary open-angle as drainage meshwork has become clogged up with inflammatory debris OR could be secondary closed-angle glaucoma secondary to posterior synechiae & resulting iris bombé
o Cataract
o Cystoid macular oedema – blurred vision & metamorphopsia (distorted vision) - More risk from with-holding tx than px is from ADRs
- Topical steroid use should be tapered, not abruptly stopped – even when sxs disappeared
o Risk of inflammatory ‘flare-up’ or ‘rebound’ effect
What is the advice on selecting a topical corticosteroid?
- Consider a ‘non-penetrating’ corticosteroid (ADRs risk is lower than ‘penetrating corticosteroids)
o Fluorometholone (FML)
o Loteprednol (Lotemax)
Use above in ocular inflammation confined to ocular surface – episcleritis, pingueculitis, inflamed pterygium - Reduced potency & corneal penetration reduces risk of ADRs – THEREFORE SELECT CORRECT CORTICOSTEROID FOR THE CONDITION PRESENT
- Hard steroids e.g. Prednisolone 1% are required in certain situations e.g. anterior uveitis (FML or Loteprednol would not penetrate far enough to relieve px of sxs & signs of anterior uveitis)
- Higher the steroid potency, the greater the ocular hypertensive response
- The ophthalmic steroids dexamethasone and prednisolone acetate are more likely to result in clinically significant increases in IOP when compared to fluorometholone & loteprednol
o Risk of steroid glaucoma is related to increase in IOP – risk of steroid glaucoma being associated with the greatest rise in IOP
o Risk of steroid glaucoma as an ADR and therefore irreversible vision loss is greatest with penetrating steroids - Consider a topical Non-Steroidal Anti-Inflammatory Drug (NSAID) (i.e. not using a corticosteroid at all in certain clinical scenarios)
o Diclofenac Sodium (Voltarol Ophtha)
Topical NSAID will NOT be effective in anterior uveitis (must use topical steroid here). NSAIDs can provide relief in cases on mild superficial ocular inflammation e.g. episcleritis, pingueculitis
Describe topical NSAIDs and ADRs of them?
- Anti-inflammatory action
- Analgesic action – pain-relief
- E.g. use in corneal abrasion – reduces severity of px’s sxs, can also be used in episcleritis and mild allergic conjunctivitis
- Reduced ADRs:
o No concern about steroid glaucoma
o No cataract
o Damper effect on immune response – px maintains ability to fight infection
o Wound healing – corneal abrasion would still be expected to heal
o Pxs may still experience:
Ocular irritation, burning, stinging and dryness - Systemic ADRs:
o Indirect administration
o ADRs: gastric, ulceration (& peptic bleeding), aspirin hypersensitivity (risk of cross-sensitivity to NSAIDs – best avoided)
Describe prostaglandin analogues (PGA) for glaucoma and ADRs?
o Low risk of systemic ADRs – may be headaches, upper respiratory tract sxs
o Majority are local to the ocular region
Local ocular irritation & conjunctival hyperaemia
* Common, prevalence: 6.3-58%
* 63% of glaucoma pxs who stopped or switched medication did so because of hyperaemia – may need to enquire about changing glaucoma med if possible
o ADRs:
Iris hyperpigmentation (darkening of iris):
* Common, prevalence: 7-50%
* More likely with mixed colour irides (than uniform irides)
* Typically within yrs 1 & 2 of tx
o 90% of pxs who develop iris hyperpigmentation have done so by end of yr 2
* Irreversible – even if prostaglandin analogue is stopped
* Cosmetic change only – reassure pxs that no implications on underlying health of eye
Eyelash & Eyelid Changes:
* Increase in lash length, thickness & pigmentation
* Common, prevalence: up to 50%
* Associated increase in eyelid skin pigmentation – periocular region appears darker
o Less common, prevalence up to 7%
* Reversible – when med is discontinued
* Cosmetic change only – reassure pxs that no sinister implications for ocular health
o May cause problems in monocular tx e.g. eyelashes will get longer and darker in one eye only
Cystoid Macular Oedema (CMO) – inflammation: intraretinal swelling
* Causes px to have painless, blurred and distorted vision
* Considerably rarer (significantly less than 1%)
* Typically in pseudophakic/aphakic pxs, particularly if surgery was complicated
o Complications during surgery can provide a route for drug to diffuse past crystalline lens (or its replacement), reach the vitreous humour and come into contact with retina in significant concs
* Macular oedema resolves following cessation of PGA
o 71-year-old female, Latanoprost (L PIC), Cataract surgery with torn capsule, VA = 6/60 , Cease latanoprost & 12 months later (VA 6/12)(R PIC)
Anterior Uveitis:
* Rare
* Reports of exacerbation/flare-up of existing cases
* Also reports of new cases (w/o any hx of previous anterior uveitis)
* This association remains controversial: other studies have found no link
Herpes Simplex Keratitis:
* Rare
* Risk of reactivation with PGA use – which may then trigger another episode of HSK
* Supported by animal work – severrity of HSK exacerbated when PGA introduced
* BNF contraindications (latanoprost):
o Active HSK
o History of recurrent HSK associated w/ prostaglandin analogues
Describe beta-blockers and ADRs?
- Several systemic, few ocular
- Dry eye:
o Beta blockers reduce IOP by inhibiting synthesis of aqueous humour
o Beta blockers reduce production of aqueous component of tear film
o Common: prevalence 10-25%
o Lower risk with preservative-free: 16% v 35%
At least some cases thought to be dry eye caused by drug itself are actually toxic reaction to preservative
o Topical beta blockers induce dry eye by 2 mechnisms:
Toxic reaction to preservatives – common to almost all preserved eye drops
Reducing aqueous component of tear film - Sympathetic ANS: Flight or flight
o Increase heart rate
o Bronchial dilation – allows more air into lungs - Beta-blockers: Block Sympathetic ANS:
o Bradycardia – abnormally slow heart rate <60bpm – risk of fainting/collapsing
o Obstructive airway disease/asthma – may be clinically significant in pxs with COPD/asthma – breathlessness sxs - Contraindications:
o Bradycardia (<60bpm)
o Heart block
o Uncontrolled heart failure
o Asthma
o Obstructive airway disease - Other ADRs:
o CNS:
Depression
Loss of libido (sex drive)
Confusion
o Peripheral Vascular: these meds reduce px’s BP & induce vasoconstriction in peripheral vascular system
Migraine
Raynaud syndrome – poor circulation to extremities e.g. hands and feet
