PCC2 Special Senses - The Eye

Large group of eye disorders with varying clinical features/causes that result in optic nerve neuropathy, leading to changes and loss of visual function and ultimately blindness. Glaucoma - Ocular Hypertension (OHT) - Primary glaucoma's What are the classifications of glaucoma ? - Secondary glaucoma's - Developmental glaucoma's Classifications of glaucoma: Ocular Hypertension (OHT) Elevated pressure Open angle - Obstruction to aqueous outflow through the trabecular meshwork Classifications of glaucoma: Primary glaucoma's Closed angle - Reduction of aqueous outflow due to angle closure Classifications of glaucoma: Secondary glaucoma's - Inflammation - Intraocular tumour - Developmental abnormalities Classifications of glaucoma: Developmental glaucoma's E.g., Primary congenital, Secondary retinopathy of prematurity Aqueous humour Clear watery fluid found in the space between the cornea and lens. What controls the level of pressure within The balance between the production and the eye ? drainage of aqueous humour. Intraocular pressure (IOP) Level of pressure within the eye Normal Intraocular pressure range 10-21mmHg 1 / 19 Intraocular pressure - Circadian cycle - Maximum levels occur between 8am and 11am - Minimum levels occur between midnight and 2am This can affect readings at out-patient clinic appointments What is usual diurnal variation range ? 3-5mmHG - this is wider in glaucoma patients What is the most important risk factor for glaucoma ? High IOP Produced behind the iris by the ciliary body Production of Aqueous humour - Aqueous humour flows through the pupil, drains away through the trabecular meshwork and back into the blood stream via Schlemm's Canal Conventional pathway - Aqueous humour - This is done at an angle between the cornea and iris (the drainage angle) Non-conventional pathway - Aqueous humour Some aqueous humour leave the eye through the ciliary body = called the uveo-scleral or non-conventional pathway. 2 / 19 - Most common type - Usually affects both eyes - Affects 1 in 200 people over 40yrs Epidemiology of Primary open-angle glaucoma (POAG) ? - Responsible for 20% of all blindness cases in UK - Both sexes affected equally - Frequently inherited condition How many Caucasians are affected by Primary open-angle glaucoma ? 1 in 1000 Caucasians over the age of 40yrs How many Asians and Hispanics are af1 in 400 Asians and Hispanics over the fected by Primary open-angle glaucoma age of 40yrs ? How many Inuits (Eskimos) are affected 2-4 per 100 Inuits over the age of 40yrs by Primary open-angle glaucoma ? - Occurs in pre-disposed eyes, generally Epidemiology of Primary angle-closure unilateral glaucoma ? - Ethnic variations in the disease - The rate of aqueous humour production What 2 factors determine how glaucoma - Resistance encountered in the outflow increases IOP ? channels - Secretion due to active metabolic process Describe the rate of aqueous humour production ? - Ultrafiltration: influenced by the level of blood pressure in the ciliary capillaries and the IOP 3 / 19 Describe the resistance encountered by - 80% through the trabecular meshwork aqueous humour in the outflow channels ? - 20% through the uveoscleral pathway - Primary site of damage = optic nerve head - Nerves are vulnerable to elevated IOP = may explain the progressive nature of Describe the pathophysiology of Primary the disease open-angle glaucoma ? - Channel resistance = causes rise in IOP - Trabecular meshwork is the main route of resistance for outflow - Chamber angle closure = causes rise in IOP This is due to muscle defects Potential theories: Describe the pathophysiology of Primary 1. Dilator muscle theory = contraction of angle-closure glaucoma ? the dilator muscle results in the peripheral iris obstructing the angle and causes rise in IOP 2. Sphincter muscle theory = Pupil sphincter precipitates angle closure - IOP greater than 21mmHG - An open angle Clinical presentation (signs & symp- Glaucomatous cupping (pushing back toms) of Primary open-angle glaucoma of the optic disc) ? - Suspicious or damaged optic nerve head - Visual field loss 4 / 19 - IOP usually between 50 and 80mmgHG - Sudden angle closure - Severe elevation in IOP - Rapidly progressive visual impairment Clinical presentation (signs & symptoms) of Acute Primary angle-closure glaucoma ? - Periocular pain (refer patient OTC) - Congestion of the eye - Nausea and Vomiting in severe cases - Corneal oedema - Vertically oval pupil and fixed in semi-dilated position - Pupil is unreactive to light and accommodation To prevent significant loss of sight by What is the aim of Glaucoma treatment lowering IOP as much as possible with ? minimal adverse effects using pharmacological therapy. First line treatment for Glaucoma NICE guidelines for the diagnosis and treatment of glaucoma ? Prostaglandin analogues - primarily for their comparative lack of ocular side-effects. - Cognitive and Physical impairments should be taken into account when making decisions about management and treatment - Check there are no relevant co-morbidities or potential drug interactions before offering pharmacological treatment 5 / 19 - Offer a generic prostaglandin analogue (PGA) to people with IOP of 24mmHG or more if they are at risk of visual impairment within their lifetime NICE guidelines - treatment for people with Ocular hypertension ? - Offer another pharmacological treatment who cannot tolerate their current treatment. The first choice should be an alternative generic PGA Not tolerated = offer a beta-blocker. If none of these options are tolerated = offer carbonic anhydrase inhibitors, sympathomimetics, miotics or a combination of treatments. - Offer a drug from another therapeutic class (beta-blocker, carbonic anhydrase inhibitor or sympathomimetic) to people with IOP of 24mmHg or more whose current treatment is not reducing IOP sufficiently to prevent the risk of progression to sight loss. - Refer people whose IOP cannot be reduced sufficiently with pharmacological - Offer preservative-free eye drops to people who have an allergy to preservatives - Treatment should NOT be offered to people with suspected COAG and IOP less than 24mmHG NICE guidelines - treatment for people - Offer a generic PGA to people with with COAG (Chronic open-angle glaucosuspected COAG and IOP of 24mmHg or ma) ? more, in line with the recommendations on treatment for people with OHT - Offer a generic PGA 6 / 19 - Advanced COAG = surgery with pharmacological augmentation What class of receptors do Adrenoceptors belong to ? G-protein coupled receptors Adrenoceptors - G-protein coupled receptors - Mediate the central and peripheral actions: The neurotransmitter = noradrenaline and The hormone/neurotransmitter = adrenaline Where are adrenoceptors found ? In nearly all peripheral tissues and on many neuronal populations within the CNS. Both endogenous agonists play a role in Role of noradrenaline and adrenaline in the cardiovascular system through: the CVS ? - the control of BP - the rate of myocardial contraction Characterised by 7 hydrophobic membrane spanning helices and a glycosylated extracellular amino terminus. Structure of adrenoceptors ? Describe what happens when a ligand binds to a hydrophobic pocket on an adrenoceptor ? Describe ±1Adrenoceptors ? Promotes structural changes leading to the modulation of second messengers within cells. - Three ±1adrenoceptor subtypes further confirmed by the molecular cloning of receptor genes that are expressed in both the central and peripheral nervous systems 7 / 19 - Located post-synaptically in CNS = they mediate an excitatory role - All subtypes predominantly couple to phospholipase C. This produces 2 intracellular second messengers = inositol trisphosphate (IP3) and diacylglycerol (DAG) Describe the interaction between ±1-adrenoceptor subtypes and phospholipase C ? A major outcome of this pathway = rapid increase in the intracellular concentration of Ca2+, this underlies many of the physiological functions of ±1adrenoceptor activation. - Located on both pre- and post-synaptic membranes to mediate an inhibitor role in both central and peripheral nervous systems Describe ±2Adrenoceptors ? - They are negatively coupled to adenylate cyclase = inhibit the production of second messenger cAMP (cyclic adenosine monophosphate) ²1-adrenoceptor - dominant receptor in heart and adipose tissue, equally sensitive to noradrenaline and adrenaline. What are the 2 major subtypes of B-adrenoceptors ? ²2-adrenoceptor - responsible for relaxation of vascular, uterine and airway smooth muscle. Less sensitive to noradrenaline. Distribution of ²1-adrenoceptors within the CNS ? There is a high density of ²1-adrenoceptors located in the striatum, this is predominantly expressed in the heart and on adipose tissue. Distribution of ²2-adrenoceptors within the CNS ? Predominant on vascular, uterine and airway smooth muscle. 8 / 19 ²receptors are coupled to heterotrimeric What proteins are ²receptors coupled to, G proteins that regulate the production of and what is their role ? intracellular second messengers. - Timolol - Carteolol HCl Examples of ²-adrenoceptor antagonists ? - Levobunolol HCl - Betaxolol Timolol - Introduced in 1978 - Non-selective ²-adrenoceptor antagonist (²-blocker) inhibiting both ²1and ²2 adrenergic activity. Timolol side effect - Eye discomfort - Eye disorders - Eye inflammation - Vision disorders Carteolol - Showed equivalent IOP lowering efficacy with Timolol - Has improved bioavailability and longer duration of action = due to 2-3 fold increase in half life of its active metabolite (8-hydroxycarteolol) Levobunolol Was as effective as timolol and carteolol - has a long duration of action = once daily dose Structure activity relationship of first gen ß-blockers 9 / 19 Practolol - Second gen ß-blocker - Selective ß1-blockers antagonist = helps alleviate side effects caused by interactions with ß2 receptors - Safer for asthmatics = due to increased polarity, leading to fewer CNS effects Why was Practolol withdrawn ? Due to unexpected, serious side effects: - Skin rashes - Eye problems - Peritonitis ß1 activity is lost - this implied that there What happens if the the amido group on was an additional hydrogen-bonding inPractolol is moved to the ortho or meta teraction taking place in ß1 receptors position of the ring system ? which was not taking place in ß2 receptors. How was Betaxolol formed ? Betaxolol Replacement of the original acetamido group on Practolol with other groups capable of hydrogen-bonding led to a series of selective ß1-blockers. - Selective 3rd gen blocker of catecholamine stimulation of ß1-adrenoceptors - Lipophilic ß-adrenoceptor antagonist = relatively selective for ß1-adrenoceptors with weak ß2-blocking activity 10 / 19 Betaxolol - Oral administration Administered orally as a traditional beta-blocker to reduce HR & BP in the management of hypertension ('cardioselective') given its selectivity to ß1. - Reduces IOP in conditions e.g., ocular hypertension and chronic open-angle glaucoma (0.5% solution) - Produces a reduction in intraocular pressure between 13 and 30% - Can be combined with other types of anti-glaucoma agents Betaxolol - Eye drops MOA: - Reduces the formation of aqueous humour by the ciliary body - Inhibit the synthesis of cyclic adenosine monophosphate (c-AMP) in the ciliary epithelium - This leads to a decrease in aqueous secretion and reduction in IOP Most noticeable = transient local stinging Betaxolol - adverse effects (Ocular ador irritation occurring in 25-40% of paministration) tients - Following ocular administration appears to be largely devoid of adverse bronchopulmonary or cardiac effects Why can betaxolol be considered as a therapeutic option for the management of chronic open-angle glaucoma and oc- Has negligible local anaesthetic activity ular hypertension ? = corneal desensitisation does not occur with its use Why is betaxolol a great drug for the treatment of ocular disorders? - Its apparently lower propensity to affect the cardiopulmonary system represents a significant advantage over other ocular ²-adrenoceptor antagonists. - It is selective to ²-1 =exhibits fewer side effects (e.g., effects mediated by the inhibition of ²2receptors) 11 / 19 Examples of Prostaglandin analogues ? Latanoprost - Latanoprost - Bimatoprost They are analogues of naturally occurring prostaglandins F2±. - An ester pro-drug = converted to its active free acid form by corneal hydrolytic enzymes - The first prostaglandin analogue to be launched for the treatment of elevated IOP and is the market leader - Not heat-stable, requires refrigeration = Stable enough to be stored at room temperature for 4-week in-use period Increases the uveoscleral outflow of aqueous humour = reducing IOP This may be due to: 1. An increase in extracellular matrix metalloproteinases in ciliary smooth muscle Latanoprost MOA - Glaucoma treatment cells 2. Remodelling of the uveal meshwork 3. Increase in blood flow to the optic nerve - may contribute to neuroprotection in the retina Uveal meshwork A sponge-like tissue located near the cornea and iris that functions to drain aqueous humour from the eye into the blood. Latanoprost side effects - Eye discolouration - Eye discomfort - Eye disorders 12 / 19 - Eye inflammation - Vision disorders Bimatoprost - A prostamide (prostaglandin-ethanolamide) - Pharmacologically similar to ethanolamide prostaglandin F2±1- Bimatoprost MOA - glaucoma Increases aqueous humour outflow via both uveoscleral and trabecular outflow pathways. - Better at reducing IOP (in comparison Advantages of Prostaglandin analogues to ß-adrenoreceptor antagonists) ? - Have a longer duration of action = 1-2 days - CA-I Examples of carbonic anhydrase enzyme forms present in the ocular tissue ? - CA-II - CA-IV - Slows the formation of bicarbonate ions and their secretions into the posterior chamber of the eye What happens if CA-II is inhibited in the - This reduces the sodium transport into ciliary epithelium ? the posterior chamber and decreases aqueous humour production = reducing IOP - Carbonic anhydrase inhibitor - Most potent ocular hypotensive agent Acetazolamide - Use is limited in long-term management of glaucoma = due to poor patient compliance resulting from occurrence of side-effects 13 / 19 What are Sympathomimetic drugs ? Stimulants that mimic the effects of neurotransmitters of the sympathetic nervous system. MOA of Sympathomimetic drugs - Selective ±2adrenoreceptor agonists that mimic the effects of neurotransmitters of the sympathetic nervous system - ±mediated vasoconstriction of the ciliary body results in reduced aqueous humour production and - increased outflow due to a dilation of the aqueous and episcleral veins What sympathomimetic drug was the first adrenergic agonist ? Apraclonidine - Sympathomimetic drug - Selective ±2adrenoreceptor agonists - Works better than Apraclonidine Brimonidine - Structural modification and resulting selectivity towards ±2receptors eliminated certain side effects resulting from ±1agonist activity including mydriasis (dilation of the pupil) and vasoconstriction of microvessels. - Mimics the neurotransmitter adrenaline Dry eyes syndrome 14 / 19 Chronic condition where the surface of the eye becomes inflamed and sore due to imbalance/insufficient tear film. - Exact prevalence is unclear - It is common - Almost 3% of older adults will develop dry eye each year - Prevalence increases with increasing age - More common in women than men Dry eyes syndrome - Epidemiology A reduction in tear volume or alteration in tear composition causes dry eyes Underproduction of tears is a result of: - increased evaporation from the eye - increased tear drainage - a decrease in tear production by the Explain the Pathophysiology of Dry eyes lacrimal gland syndrome ? Tear film is made up of 3 layers = Innermost mucin layer, Middle aqueous layer, Outermost lipid layer - Reduction in any of these layers can lead to dryness - Most common cause is Chronic inflammation of the eyelids (Blepharitis) Describe the structure of Tear film ? Made up from 3 distinct layers: - Innermost mucin layer = allows tears to adhere to the conjunctival surface - Middle aqueous layer = contains 90% of the tear thickness - Outermost lipid layer = helps to slow aqueous layer evaporation What can cause an underproduction of tears ? - increased evaporation from the eye - increased tear drainage - a decrease in tear production by the lacrimal gland 15 / 19 Why is the innermost mucin layer in tear This is due to a reduction in the mucin film affected more frequently in dry eyes producing goblet cell. syndrome ? What is the most common cause of Dry Chronic inflammation of the eyelids (bleeyes syndrome ? pharitis) Usually affecting both eyes: - Burning sensation in eyes - Eyes feel tired - Itchy - Irritated - Gritty Symptoms worsen through the day Signs and Symptoms of dry eyes syndrome ? Instillation of artificial tears and lubricating ointments e.g.,: - Hypromellose (0.3-1.0%) - Polyvinyl alcohol How can dry eyes syndrome be treated - Carmellose pharmacologically ? - Carbomer 980 - Sodium hyaluronate - Ocular lubricants - Possess film-forming and emollient properties Hypromellose - Lack ideal wetting characteristics = results in up to hourly administration to provide adequate relief - Lack of published data confirming efficacy 16 / 19 - Ocular lubricants - Acts as a viscosity enhancer in a concentration of 1.4% = product now has the same surface tension as normal tears Polyvinyl alcohol - Therefore has optimal wetting characteristics and hence less frequent dosing - Administered about 4x a day - Lack of published data confirming efficacy Carbomer - Ocular lubricants - Shown to be more efficacious than placebo and as safe as, but better tolerated than polyvinyl alcohol - Ocular lubricants Sodium hyaluronate - Showed a reduction in symptom severity - When compared with carbomer products and carboxymethylcellulose, found to be equally effective Side effects of Ocular lubricants ? - Transient stinging and/or burning - Blurred vision after instillation of carbomer and polyvinyl alcohol has also been reported - Exact prevalence is unknown - GP statistics show that eye problems account for up to 5% of their workload, Describe the epidemiology of conjunc35% of this are for infective conjunctivitis tivitis ? - Affects sexes equally - May present in any age of patient, more common in children and the elderly 17 / 19 In adults = Staphylococcus species (0ver 50% of cases), Streptococcus pneumoniae (20%), Moraxella species (5%) and Explain the pathophysiology of Bacterial Haemophilus influenza (5%) conjunctivitis ? In children = Streptococcus, Moraxella and Haemophilus are most common - Red eye is the major symptom, often starts unilaterally before spreading to the second eye - Redness of the sclera is often generSigns and Symptoms of bacterial conalised and more severe away from the junctivitis ? iris - Gritty sensation - Mucopurulent discharge - Chloramphenicol = first line treatment, available as eye ointment and drops - Quinolone ciprofloxacin = treatment of superficial bacterial infections , broad-spectrum antibiotic that is available as eye drops Bacterial conjunctivitis treatment - Sodium fusidate = treatment of penicillin-resistant staphylococcal infections, an example of a bacterial protein synthesis inhibitor 18 / 19 - Drops = can cause transient irritation - Ointment = can cause temporary blurring of vision Bacterial conjunctivitis treatment - Chloramphenicol side effects 19 / 19