Adverse Drug Reactions (ADRs) Flashcards

1
Q

What are the most common ADRs?

A

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.

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2
Q

Describe ADRs vs side-effects?

A
  • 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
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3
Q

Describe irritation and hypersensitivity as ADRs

A
  • 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
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4
Q

Describe the mechanism of ADRs?

A
  • 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
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5
Q

Describe benzalkonium chloride in ADRs?

A
  • 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
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6
Q

What is the management of irritation or hypersensitivity as ADRs?

A
  • 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
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7
Q

Describe tetracycline antibiotics and their ADRs?

A
  • 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
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8
Q

Describe topical corticosteroids and their ADRs?

A
  • 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
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9
Q

Describe steroid glaucoma?

A
  • 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
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10
Q

Describe other more uncommon ADRs with topical corticosteroids?

A
  • 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
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11
Q

Describe uncontrolled ocular inflammation and the risk?

A
  • 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
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12
Q

What is the advice on selecting a topical corticosteroid?

A
  • 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
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13
Q

Describe topical NSAIDs and ADRs of them?

A
  • 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)
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14
Q

Describe prostaglandin analogues (PGA) for glaucoma and ADRs?

A

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

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15
Q

Describe beta-blockers and ADRs?

A
  • 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
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16
Q

How do you report ADRs?

A
  • ADRs can be reported through the MHRA’s ‘yellow card’ scheme
  • Used to collect data about risk profile of medicines
  • Can be sent through BNF app, tear off from BNF paper copy or online website
  • May identify ‘new’ ADRs which were not detected during the clinical trial research phase
  • Particularly important for newer drugs (marked by black triangle in BNF) – so report to MHRA if any ADRs from these
  • MHRA are particularly interested in ADRs in elderly, children and ADRs which are listed as rare/uncommon