Special Senses

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Glaucoma Classifications

  • Ocular Hypertension (OHT)
    • Elevated pressure
  • Primary glaucoma's
    • Open angle
      • Obstruction to aqueous outflow through the trabecular meshwork
    • Closed angle
      • Reduced aqueous outflow due to angle closure
  • Secondary glaucoma's
    • Inflammation, intraocular tumour, developmental abnormalities
  • Developmental glaucoma's
    • Eg. Primary congenital, secondary retinopathy or prematurity
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Eyes - aqueous humour

  • The fluid between the lens and cornea.
  • Intraocular pressure is controlled by the balance between production and drainage. 
    • Normal IOP is 10-21mmHg
    • Circadian cycle
      • Max levels between 8am-11am
      • Min levels between 12am-2am
    • Usual variation is between 3-5mmHg, which is wider in glaucoma patients 
  • High IOP is recognised as the most important risk factor
    • Can still occur in patients without high IOP
    • Not the only cause, but the only manageble parameter with pharmacological intervention.
  • Produced behind the iris by the ciliary body.
    • Flows through pupil
    • Drains through the trabecular meshwork at the angle between the cornea and the iris (conventional pathway)
    • Some drains through the ciliary body (uveo-scleral/non-conventional)
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Epidemiology of Primary open angle glaucoma

  • Most common
  • Both eyes
  • 1 in 200 >40
    • 1 in 1000 caucasians
    • 1 in 400 hispanics and asians
    • 2-4 per 100 inuits
  • Responsible for 20% of blindness in UK
  • Frequently inherited
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Epidemiology of Primary angle closure glaucoma

  • Occurs in predisposed eyes
  • Usually only affects 1 eye
  • Ethnic variations
  • Gives rise to an increased IOP
    • Imbalance between production and outflow
      • Production
        • Secretion due to active metabolic process
        • Ultrafiltration
          • Influenced by the level of blood pressure in the ciliary capillaries and the IOP
      • Outflow
        • 80% through the trabecular meshwork
        • 20% through the uveoscleral pathway
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Pathophysiology of POAG

  • Primary site of damage is the optic nerve head
    • They are vulnerable to elevated IOP, explaining why it is progressive
  • Channel resistance causes a rise in IOP
    • Trabecular meshwork is the main route of resistance for outflow.
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Pathophysiology of PACG

  • Closure of the chamber angle causes a rise in IOP.
    • Thought to be becuase of muscle defects
  • 2 potential theories
    • Dilator muscle theory - contraction of the dilator muscle results in the peripheral iris obstructing the angle.
    • Sphincter muscle theory - pupil sphincter precipitates angle closure
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Clinical presentation of POAG

  • IOP >21mmHg
  • Open angle
  • Glaucomatous cupping (pushing back of optic disc)
  • Suspicious or damaged optic nerve head
  • Visual field loss
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Clinical presentation of PCAG

  • IOP usually between 50-80mmHg
  • Sudden angle closure
  • Severe elevation in IOP
  • Rapidly progressive visual impairment
  • Periocular pain
  • Congestion of the eye
  • Nausea and vomiting (severe cases) 
  • Corneal oedema
  • Vertically oval pupil and fixed in a semi-dilated position
  • Pupil is unreactive to light and accomodation
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Treatment of glaucoma

  • Aim is to prevent significant loss of sight 
    • By lowering IOP as much as possible
    • With minimal adverse effects
  • Nice guidelines
    • Take into account any cognitive and physical impairments when making decisions about management and treatment
    • Check there are no relevent comorbities or potential drug interactions before offering pharmacological treatment
  • Generic prostaglandin analogue (PGA) to people with an IOP of 24mmHg or more
  • Second choice treatment for patients with IOP over 24mmHg
    • Beta blocker
  • Third choice
    • Non-generic PGA, carbonic anhydrase inhibitors, sympathomimetics, miotics or a combination
  • Offer preservative free eyedrops to patients with an allergy to preservatives
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Treatment of glaucoma 2

  • Treatment for patients with suspected COAG
    • Do not offer to patients with COAG and IOP <24mmHg
    • Offer a generic PGA to patients with IOP >24mmHg
  • Treatment for patients with COAG
    • Generic PGA
    • Patients with advanced COAG can be offered surgery and pharmacological augmentation
  • Topical B adrenoreceptor antagonist and/or a prostaglandin analogue is the first line treatment
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Pharmacology of adrenoceptors

  • GPCRs 
  • Mediate the central and peripheral actions of noradrenaline and adrenaline.
    • Both play a part in the CV system (blood pressure, heart rate/force)
  • Regulate airway reactivity
  • Regulate a variety of metabolic and CNS functions.
  • Characterised by 7 hydrophobic membrane spanning helices and a glycosylated extracellular amino terminus
  • Ligand binding to a hydrophobic pocket promotes structural changes 
    • Leading to the modulation of second messengers within the cells.
  • Knowledge of the DNA sequences that encode adrenoceptors has enabled the isolation and identification of complementary DNA sequences.
  • Alpha 1 and 2 
    • Both further split into 3 subtypes
  • Beta
    • Further split into 4 subtypes
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a1 adrenoceptors

  • Expressed in both central and peripheral nervous systems.
  • In the CNS
    • Located post-synaptically 
    • Mediate an excitatory role,
  • All subtypes predominantly bind to phospholipase C
    • This activity produces 2 intracellular secondary messengers (IP3 and DAG)
    • The outcome of this is a rapid increase in the intracellular concentration of calcium ions
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a2 adrenoceptors

  • Located on both pre and post synaptic membranes
  • Mediate an inhibitor role in the central and peripheral nervous systems.
  • They are negatively coupled to adenylyl cyclase
    • They inhibit the production of cAMP
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B adrenoceptors

  • B1-B3
  • B1 is predominantly expressed in the heart and on adipose tissue
  • B2 is predominant on vascular, uterine and airway smooth muscle
  • B3 are atypical as they do not respond to commonly used beta antagonists
  • Coupled to heterotrimeric G proteins
    • Regulate the production of intracellular second messengers
    • Responses are mediated by increased production of cAMP through activation of Gs protein.
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B adrenoceptor antagonists

  • Timolol
    • Non selective
  • Carteolol HCl
    • Improved bioavailability 
    • Longer duration of half life
  • Levobunolol HCl 
    • Long duration of action (1 dose a day)
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Betaxolol

  • Selective third generation blocker or catecholamine stimulation of B1 adrenoreceptors
  • Can be given orally as a heart rate and blood pressure reducer, it is useful in hypertension
  • As an eyedrop it reduces IOP
    • Reduce the formation of aqueous humour from the ciliary body
    • Inhibit the synthesis of cAMP in the ciliary epithelium and lead to a decrease in aqueous secretion
  • Relitively selective for B1, low efficacy for B2
  • 0.5% solution eyedrops
    • Reduction of IOP by 13-30%
    • Transient localised stinging or irritation occurs in 25-40% of patients
    • Largely devoid of adverse bronchopulminary and cardiac effects
    • Has negligible local anaesthetic activity so corneal desensitisation doesn't occur with its use
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Prostaglandin analogues

  • Latanoprost
    • Ester prodrug converted to its active form by corneal hydrolytic enzymes
    • Not heat stable so requires refrigeration but can be stored out of the fridge for the 4 week use period 
    • Has preservatives (0.02%) so not all patients can use it
  • Bimatoprost
    • Thought to increase aqueous humour outflow by both uveoscleral and trabecular outflow pathways
  • Increase the uveosclearal outflow of aqueous humour
    • Increase in extracellular matrix metallproteinases in ciliary smooth muscle cells
    • Remodeling of the uveal meshwork
    • Increase in blood flow to the optic nerve, possibly contributing to neuroprotection in the retina
  • The reduction of IOP is greater than B antagonists
  • Have a long duration of action (1-2 days)
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Carbonic anhydrase inhibitors

  • CA-I, CA-II, CA-IV
  • Inhibition of CA-I_ slows the formation of bicarbonate ions and their secretions into the posterior chamber of the eye
    • Reduces the sodium transport into the posterior chamber and decreases aqueous humour production
  • Acetazolamide
    • Not useul long term due to side effects causing poor patient compliance 
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Sympathomimetic drugs

  • Stimulants which mimic the effects of neurotransmitters
  • Usually selective a2 adrenoceptor agonists
    • alpha 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
  • Brimonidine tartrate
    • Selectivity results in reduced side effects
    • Structuarly similar to adrenaline
  • Side effects related to a1 adrenoceptors:
    • Pupil dilation
    • Vasoconstriction of microvessels
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Dry eyes syndrome

  • Causes eye irritation causing varying degrees of discomfort
  • Prevelent in around 3% of adults and increases with age
  • More common in women
  • Caused by either a reduction in tear volume or an alteration in tear composition
    • Underproduction can be the result of increase evaporation, increased tear drainage and a decrease in tear production by the lacrimal gland
  • Tear composition
    • Innermost mucin layer
      • Allows tears to adhere to the conjunctival surface
    • Middle aqueous layer
      • Contains 90% of tear thickness
    • Outermost lipid layer
      • Helps slow aqueous layer evaporation
  • A reeduction in any layer of tears can result in dryness
    • Frequently, the mucin layer is affected due to a reduction in goblet cells which produce mucin
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Signs and symptoms and treatment of dry eyes

  • Usually effects both eyes
  • Symptoms include burning, tired eyes, itchiness, irritated, gritty with symptoms worsening through the day
    • The conjunctiva is not red unless irritated
  • Management is the instillation of artificial tears and lubricating ointments
    • Hypromellose 0.3-1%
      • Hourly admission
    • Polyvinyl alcohol
      • 1.4% acts as a viscosity enhancer
      • 4 times a day
      • Can cause temporary blurred vision
    • Carmellose
    • Carbomer 980
      • Better tolerated
      • Can cause temporary blurred vision
    • Sodium hyaluronate 
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Bacterial eye infection

  • 35% of eye problems are infective conjunctivitis 
  • No gender differences or age factors
    • Although age doesnt influence it, its more common in children and adults
  • Most common bacteria involved
    • Adults: Staphlococcus, Streptococcus pnuemoniae, Moraxella species, Haemophilus influenzae
    • Children: Streptococcus, Moraxella and Haemophilus
  • Signs and symptoms include red eye.
    • Usually starts in one eye first
    • Redness of the sclera is often generalised and more severe away from the iris
    • Gritty sensation
    • Mucuplurent discharge
  • Chloramphenicol is the first line treatment 
    • Can cause transient irritation and temporary vision blurring
  • Symptoms tend to resolve spontaneously without the need for eyedrops
  • Ciprofloxacin can be used in superficial infections as eye drops
  • Sodium fusidate can be used in the treatment of penicillin-resistant staphlococcal infections
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Motion Sickness

  • Exact prevalence of motion sickness is unknown
    • Ages between 2-12 are most commonly affected
    • Affects women more than men
  • Believed to be caused by the brain being unable to process conflicting information received from sensory nerve terminals (the sensory conflict hypothesis)
  • Symptoms
    • Nausea, pallor, vague abnominal discomfort, vomiting (common)
    • Fatigue, weakness and inability to concentrate (rare)
  • Treatment
    • First generation antihistamines
      • cyclixine, cinnarizine, promethazine
    • Anticholinergics
      • Hyoscine, scopolamine (hyoscine hydrobromide)
      • Can cause dry mouth and sedation
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Hyoscine hydrobromide

  • No evidence of a benefit once motion sickness is established.
  • Both hyoscine and acetylcholine possess a basic nitrogen and ester group.
    • The distance between these two groups is similar
  • Hyoscine is larger than atropine (agonist)
    • This allows it to bind to areas in the receptor that acetylcholine does not, causing antagonist effects instead of agonist effects.
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Type I & II Hypersensitivity reactions

  • Type I
    • Immediate or anaphylatic hypersensitivy
    • T-helper cells will convert into Th2 cells
      • Resulting in the stimulation of B cells that will begin to produce IgE antibodies
        • This is done instead of using cell-mediated responses from Th1 cells and macrophages
    • These individuals express more IgE antibodies, which are associated with allergy
    • Localised type I responses result in problems such as hay fever, urticaria (hives), triggering asthma attacks.
    • Generalised responses can cause anaphylactic shock.
  • Type II
    • Antibody dependent cytotoxic hypersensitivity
    • Immune reactions are directed against an individuals cells that have the appearance of being non-self 
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Type III & IV Hypersensitivity reaction

  • Type III
    • Complex-mediated hypersensitivity 
    • Antibodies and soluble antigens react and form complexes
      • Which then can activate complement or attach to mast cells to cause inflammatory mediators to be released
  • Type IV
    • Cell-mediated hypersensitivity 
    • Activation, proliferation and mobilisation of antigen-specific T cells
    • This takes time to occur so can be called delayed-type hypersensitivity.
    • Large amounts of cytokines get released from the activated T cells
      • They recruit large numbers of leukocytes that can go on to cause damage
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Histamine production and storage

  • Mast cells are involved in the release of inflammatory mediators. 
    • They can be stimulated when they come into contact with allergens
    • One of the main mediators released is histamine
  • Histamine is formed from the essential amino acid histidine by histidine decarboxylase.
  • It is found in most body tissues, stored as granules in mast cells and basophils.
    • It is also found in stomach histaminocyes and CNS histaminergic neurones.
  • It has several diverse actions
    • Contraction of gut smooth muscle
    • Bronchoconstriction
    • Stimulation of sensory nerves
  • H1 = smooth muscle and inflammatory effects
  • H2 = mostly gastric acid production 
  • H3 = CNS actions
  • H4= immune response regulation
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The triple response and H1 receptors

  • Within 10 seconds reddening occurs at the site
    • Resulting from small arteriolar vasodilation
  • Local oedema then occurs
    • Due to increased postcapillary venule permeability
  • A diffuse, mottled reddening develops around the area
    • Due to arteriolar dilation caused by a sensory nerve reflex.
  • The above effects are due to histamine acting on H1 receptors in tissues
    • In normal circumstances these responses are useful
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Antihistamines

  • First generation (non selective)
    • Cross the BBB
    • Cause drowsiness and sedation 
    • Can have antimuscarinc actions (dry mouth, blurred vision)
    • Chlorphenamine (piriton) is the most commonly used. 
      • It is a halogenated alkylamine antihistamine and so exhibits optical isomerism.
  • Several classifications of antihistamine share structural similarities
    • 2 aromatic rings connected to a central C, N or CO
      • Chirality of this central atom was seen to increase potency and selectivity for H1 receptors
    • Amine is substituted with small alkyl groups
    • A spacer between the central X and the amine
    • Ethylenediamines (meyramine)
    • Ethanolamines (clemastine)
    • Piperazines (meclizine)
    • Tricyclics and tetracyclics (promethazine)
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Antihistamines 2

  • Second generation (selective, non sedating)
    • Selectivity makes them less drowsy
    • Do not cross the BBB or affect muscarinic receptors
      • Can't cross BBB due to their zwitterionic properties making them polar
    • Cetirizine
    • Loratadine
      • Prodrug
  • Can be administered orally, topically, transnasally and intravenously
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Bacterial ear infection

  • Most likely in children
    • 3/4 children by the age of 3
  • Eustachian tubes become clogged with fluid and mucus.
    • These tubes regulate air pressue in the middle ear, refresh air in the ear and drain normal secretions
  • Clinical presentation in children
    • Ear pain, tugging/pulling ear, difficulty sleeping, crying more, more irritable, diffculty hearing or responding to sound, loss of balance, high temperature, drainage of fluid from ear, headache, loss of apetite
  • Clinical presentation in adults 
    • Ear pain, drainage from the ear, diminished hearing
  • Antibiotics are a first line treatment 
  • A large number of cases resolve after 48-72 hours
  • Antibiotic ear drops can be used to treat otitis externa (outer ear infection)
    • Gentamycin or ciprofloxacin
  • Oral antibiotics can be used to treat otitis media (middle ear infection)
    • Amoxicillin
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Herpes simplex

  • There are two main catagories
    • HSV1
      • Cold sores
    • HSV2
      • Genital lesions
  • More than 50% of people show symptoms of being infected with HSV1, although not all have symptoms
    • Estimated that 20-50% of people will experience a cold sore at some time.
    • Most people have recurrant cold sores will have fewer than 2 episodes per year
      • 5-10% of people affected have a minimum of 6 reoccurances per year
  • Infection is spread by viral shedding into saliva and results from direct mucous membrane contact at sites of abraded skin between an infected and uninfected individual.
    • The virus then infects the epidermal and dermal cells, causing skin vesicles. 
    • Following primary infection the virus travels to the sensory ganglia where it lies dormant in the dorsal root ganglia of the trigeminal nerve until reactivation.
    • Once reactivated the virus migrates from these sensory ganglia to the outer layer of the skin and lips to cause cold sore leisions.
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Signs and symptoms of herpes simplex

  • Prior to vesicle eruption - from a few hours to a couple of days before the lesion develops
    • Itching
    • Burning
    • Pain
    • Tingling
  • Lesions appear as bilsters and vesicles with associated redness on the outer lip.
    • They crust over usually within 24 hours
    • Tend to be itchy and painful and might bleed
    • They spontaneously resolve in 7-10 days, so most outbreaks last 14 days from the recognition of symptoms to the resolution of lesions
  • Many patients can identify a cause of their cold sore
    • 20% induced by UV light
    • Recurrence is common and lesions tend to occur in the same location.
    • Immunocompromised patients or patients on immunosuppressive medication can experience severe symptoms.
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Treatments and side effects of herpes simplex

  • Antivirals
    • Aciclovir
      • Evidence for topical administration is less conclusive, but is very effective orally
        • Topical administration during the prodromal stage reduces the healing time of subsequent lesions bu 1/2 a day to a day.
    • Penciclovir
    • Inhibit the herpes virus DNA polymerase
    • Trial data has shown topical antivirals not to have a preventative effect
  • Side effects
    • Transient stinging on application
    • Aciclovir is a chain terminator and acts as a false substitute during viral DNA replication
      • It contains a guanine base allowing it to pair with cytosine on growing DNA chains
      • A triphosphate group is added to it in viral infected cells to allow it to mimic guanine
      • The sugar unit is incomplete and lacks the required hydroxyl group at the 3' position, terminating the chain
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Eczema

  • Itchy red eruption consiting of patches or papules
  • Atopic is the most common found in children
    • Affects between 10-20% of all school age children
    • Affects both sexes equally
    • Combination of environmental, genetic and immunological factors that cause it.
  • Can be catagorised as acute or chronic
    • Acute is an inflammatory process, which leads to oedema in the epidermis. 
      • The fluid collects into tiny blisters which can then join together
    • In normal skin, the cells are closely packed together to create a natural barrier
      • During an acute eczema flare up, fluid is lost through the skin causing the cells to separate
        • This allows for the ingress of chemicals, allergens and pathogens to cause inflammation and a defective skin barrier.
    • Chronic results in a thickened epidermis due to prolonged rubbing and scratching.
      • The skin appears thick, scaly and leathery. 
  • Both acute and chronic eczema there is heavy inflammatory cell infiltration
    • Consequently the main symptom is itching
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Clinical presentation of eczema

  • Various forms
    • Atopic, contact dermatitis, seborrheic dermatitis, discoid, stasis and asteatotic.
  • Usual areas affected with age
    • Infant
      • Usually facial lesions but patchy elsewhere
    • Older child
      • Lesions on inner elbows and knee flexures
      • Also on wrists and ankles
    • Mid teens
      • May clear, persist or change pattern
  • A number of factors exacerbate eczema
    • Extremes of temperature, irritants such as soap and bubble bath, stress, bacterial/viral infection and contact/food/inhaled/airborne allergens.
  • Emollients are the first line treatment for eczema
    • Aqueous cream, E45, diprobase
    • Followed by topical corticosteroids
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Topical corticosteroids

  • The main therapeutic activity is the non specific anti inflammatory effect
    • Due to their effect on chemical mediators of inflammation
  • They have been shown to be antimitotic
    • May be relevent in the treatment of scaling dermatoses and their dermal thinning effect resulting from inhibition of fibroblasts.
  • Combinations of corticosteroids with antibacterial and antifungal agents have been shown to be very effective in flexural eruptions and secondary infected dermatoses.
  • Glucocorticoid signalling pathways contribute to many features of the causes of psoriasis and other inflammatory disorders.
    • The inhibition of these signalling events provides an explaination for the long term clinical effects of topical corticosteroids.
  • Topical use can deliver high concentrations to a target site, reducing side effects from systemic administration.
    • Significant systemic absorbtion can occur at higher doses 
      • Therefore a low potency corticosteroid must be used in continuous use.
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Potency of steroid creams

  • Glucocorticoid receptor agonists
    • Hydrocortisone
      • Less potent
    • Betamethasone
      • More potent
    • Clobetasol 
      • Very potent
  • Improved dermal absorption is achieved via esterification of one or more hydroxyl groups
    • Most corticosteroids are given as phosphate esters
  • Esterification of the C-21 hydroxyl group determines the extent of hydrophobicity within the molecule and controls the depoistion of the compound.
  • Introduction of C-16 substituent counteracts mineralocorticoid activity
    • This explains increased potency observed over that of hydrocortisone which lacks a C-16 substituent. (Clobetasone)
    • Unlike others, clobetasone lacks the C-11 OH group of cortisol.
      • Usually this replacement with a keto group results in a prodrug with reduced activity.
      • Introduction of substituents elsewhere such as the introduction of halogens at C-9 and C-21 restored activity.
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Psoriasis

  • Chronic relapsing inflammatory disorder characterised by a variety of morphological lesions that present in a number of forms.
    • The most common form is plaque psoriasis (80-90% of cases)
  • Depending on the extent and severity of lesions, psoriasis can have a profound effect of the person's work and social life
  • Estimated prevalence between 1-3% 
  • Affects 1-2% of the UK population
    • This is probably an underestimate as many patients with mild psoriasis do not go to the doctor.
  • Can present at any time in life, but is more prevelent in the 2nd and 5th decade.
    • It's rare in infants and uncommon in children.
    • Sexes are equally affected
    • More common in caucasians 
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Pathophysiology, signs and symptoms of psoriasis

  • The cause is unclear but is now recognised as an immune mediated disorder with a genetic influence.
  • Studies have identified a region on chromosome 6 as a contributor to psoriasis susceptibility.
    • This has been associated with at least 50% of cases
      • Genetic predisposition does not necessarily mean disease expression
  • Lesions also develop at sites of skin trauma, such as sunburn and cuts, following streptococcal throat infection and during periods of stress. 
  • Plaque psoriasis presents with characterist salmon pink lesions with silvery white scales and well defined boundaries. 
    • On darker skin this characteristic colour is not apparent, the skin darkens.
    • Lesions can be single or multiple and vary in size from pinpoint to covering extensive areas.
    • If the scales on the surface are gently removed and the lesion then rubbed it reveals pinpoint bleeding from the superficial dilated capillaries.
      • Auspitz sign
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Treatment of plaque psoriasis

  • Topical treatments are first line treatments.
    • Emollients, keratolytic, coal tar
  • Systemic treatments are available but generally reserved for extensive psoriasis or those patients non responsive to topical therapy.
    • Vitamin A and D analogues and steroids. 
  • Emollients are used to help soften scaling and soothe skin 
    • Reducing irritation, cracking and dryness. 
    • May have to try severeal until finding an effective one.
  • Keratolytics (salycilic acid, lactic acid) have been added to emollients to aid clearing scale.
    • No published evidence for their efficacy 
    • Clinical practice suggests that they should be used first when significant scaling is present before using other treatments. 
  • A number of study have confirmed the benefits of coal tar on psoriasis.
    • Negative is the variability in preparations composition
    • Starting on the lowest possible concentration and gradually increasing the concentration until improvement is noticed.
  • Improvement upon use of vitamin D analogues is usually seen in 2 weeks and continues for at least 8 weeks.
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Side effects of treatments

  • Emollients - Well tolerated, with very few side effects; if experienced generally related to sensitisation reactions caused by excipients.
  • Coal tar - Unpleasant smell, skin irritation, folliculitis and stains clothes
  • Dithranol - Skin irritant, stains skin and hair
  • Vitamin D analogues (e.g. Calcipotriol; calcitriol; tacalcitol) – Skin irritation and photosensitivity. High usage (> 100 g weekly has been associated with depression of serum parathyroid)
  • Vitamin A analogues - Skin irritation, burning and erythema. Must not be used for pregnant or breastfeeding women
  • Steroids - Skin atrophy and telangiectasia
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Formulation of ocular dosage forms

  • Most common forms are solution, suspension or semisolid ointment.
  • Major barrier is tear production and drainage
    • Only 1-10% of topically applied dose is usually absorbed
    • The majority of the remainder is drained into the nose and absorbed
      • Potentially systemically absorbed leading to unwanted side effects
  • Most of the drug is lost due to tear turnover, drainage, metabolism or binding to protein.
  • The cornea acts as a protective barrier and limits drug permeation into the eye
    • Most topical treatments are for treating issues on the surface of the eye
    • Other methods are used to deliver a drug into the eye
      • Intravitreal, intracameral and periocular injectios
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Formulation of ocular dosage forms considerations

  • Volume
    • Too little and the drug may be too concentrated and lead to irritation
    • Too much and the drops will spill out of the eye
    • The eye can accomodate 20-30 microlitres
  • Osmolarity
    • Preparations must be isotonic so as to not dehydrate or irritate the eye.
    • Irritation leads to increased tear production.
    • Solutions with osmotic pressure equivalent to 0.6-1.3% sodium chloride are well tolerated. 
  • pH
    • Tears have a pH between 7.2-7.4
    • pH of eye drops is determined by several factors
      • Stability of the drug in preparation and storage, What pH the drop is most stable in, Activity of the API, What pH the drug is most active, Patient comfort
    • The eye can tolerate pH 3.5-9
      • Still important to make the pH as close as possible to neutral so the eye isnt irritated.
    • pH can be modified to control the ionisation of drugs (buffering)
    • Buffers include borate, citrate and phosphate buffers.
    • On occasion a change in pH is needed for treatment 
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Formulation of ocular dosage forms considerations

  • Surface tension
    • Normal tear fluid = 43.6-46.6 mN m-1
    • Administration of fluids with a lower surface tension acts to destabalise the tear film.
      • This leads to the formulation of lipid droplets, irritating the eye
      • Surfactants are added to solubilise the drug and prevent this.
        • Non ionic are favoured (polysorbate 20) since they are less irritating
  • Viscosity
    • They need to remain in contact with the eye as long as possible to enhance absorbtion.
    • Most eyedrops are between 15-25 millipascal per second
    • Enhanced viscosity will increase the contact time
      • However, drops are drained within 30 seconds
    • Viscosity enhancers include hypromellose and polyvinyl alcohol and carbomers (also lubricate)
  • Eye drops should be isotonic with tears that have the tonicity of 0.9% sodium chloride solution.
    • Tonicity can be increased by the addition of sodium chloride
    • The eye will tolerate tonicities between 0.7-15%.
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Components of eye drops

  • API
  • Vehicle (usually aqueous and water based)
  • Antimicrobial preservitives
  • Adjuvants
    • Adjust tonicity, viscosity of pH
    • Increase the comfort of the product in use and the stability of the API
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Components of eye drops

  • API
  • Vehicle (usually aqueous and water based)
  • Antimicrobial preservitives
  • Adjuvants
    • Adjust tonicity, viscosity of pH
    • Increase the comfort of the product in use and the stability of the API
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Sterility of ophthalmic products

  • Its a legal requirement for all preparations and inserts to be sterile.
    • Terminal sterilisation using heat or radiation is advised. 
    • Thermally unstable products are advised to be filtered under aseptic conditions.
    • They must be labelled with a duration of use once opened. 
  • Preservatives are included in multidose containers to prevent the growth of microorganisms introduced after opening.
    • They must be efficacious, well tolerated by the eye, able to withstand steralisation and compatible with the API
    • Benzalkonium chloride, chlorhexidine acetate, chlorbutanol, phenylmercuric salts, thiomersal
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Ophthalmic packaging

  • Can be made from glass or plastic 
  • Can be single or multidose
  • The container should
    • Protect the contents from microbial contamination, air and moisture 
    • Not shed or leach into drops
    • Not permit adsorption or absorption
    • Be able to withstand sterilisation
  • Single dose units (SDU) have been developed to avoid contamination as they can be disposed after use and not require preseratives. 
    • Packaging costs are higher
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