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Unit 14 > Eye Pharmacology > Flashcards

Eye Pharmacology Flashcards

1
Q

What is phototransduction?

A

The sensory transduction process in the retina by which light is captured by receptors in the retina and converted into biochemical and neurological signals.

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2
Q

What are opsins?

A

Light-sensitive proteins function as a GPCR found in light-sensitive receptors in the retina.

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3
Q

What are the different opsins?
Where are they found?

A

Rhodopsin - high-sentivity rods
Long wave sensitivie opsin -1 = red cones
Medium wave sensitive opsin 1 = green cones
Short wave sensistive opsin 1 = blue cones

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4
Q

What is the functional importance of the different properties of the different opsins?

A

Detect different wavelengths of light - ability of cones to differentiate between colours, produce colour vision
Rods - rhodopsin - black and white
Break down at different intensities of light - rods are highly sensitivity, cones cells are less sensitive. (require high light intensities)

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5
Q

What is the link between retinoids and vitamin A?

A

Retinoids show structural and functional similarities to Vitamin A.
Derived from vitamin A.

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6
Q

What are the different retinoids?
How are they different?

A

Retinol - alcohol group - e.g all trans-retinol
Retinal - aldehyde - e.g all trans retinal
Retinoic acid - -COOH group e.g tretinoin

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7
Q

What makes up rhodopsin?

A

A protein (apoprotein) called opsin.
Bound to by a chromophore (11-cis-retinal), which forms covalent bond (a schiff base) to lysine residue in opsin

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8
Q

What is a chromophore?

A

A substance that absorbed light at particular wavelengths and releases colour as a result.

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9
Q

How does the retina respond to light?
(rhodopsin response)

A

Opsin + chromophobe

Double bonds in chromophobe are sterically restricted.
A photon of light can induce isomerisation of the the chromophore (11-cis-retinal) to all trans retinal - this causes a conformational change in the molecule.
in rhodopsin the efficiency of this change is 2 in 3.
This conformational change in retinal alters the structural reconfiguration of rhodopsin including cytoplasmic domains activitaing a signalling cascade.

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10
Q

What is the structure of transducin?
Related to cytoplasmic domain of rhodopsin

A

Cytoplasmic signalling molecule.
Consists of an alpha-GTPAse unit, Beta regualatory subunit and a gamma regulatory subunit.

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11
Q

What role does transducin have in phototransduction?

A

Rhodopsin activates transducin
Light activation results in release of GDP and binding a GTP to GtAlpha,
GTP-bound Gt alpha activates downstream signalling to activate cGMP phosphodiesterase, decrease cGMP levels improving visual perception.

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12
Q

What is the GPCR in rod cells?

A

Rhodopsin.

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13
Q

What is the link between Beta receptors and rhodopsin?

A

Are structurally similar both are GPCRs.

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14
Q

What are retinoids?

A

Drugs that similar in structure/dervied from vitamin A/retinoic acid.
1st gen - isomers of retinoic acid
2nd gen - synthetic derivatives of retinoic acid
3rd gen - structurally unrelated to retinoic acid, still active same receptors
4th gen - enhanced receptor selectivity.

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15
Q

What are nuclear hormone receptors?

A

Intracellular ligand-activated receptors that act as transcription factors to alter the transcription (either transactivation or transrepression)
Ligands include: steroids, thyroxine, vitamin D and retinoids.

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16
Q

What are the different retinoid receptors?

A

Retinoic acid recepotrs (RAR) with alpha, beta and gamma subtypes
Retinoic X receptors (RXR) with alpha, beta and gamma subtypes
Retinoic acid related orphans

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17
Q

What is an example use for retinoid drugs?

A

Reduce the pro-inflmmatory factors and disrupt the immunoinflammatory cascade associated with acen vulgaris .

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18
Q

What is mydriasis?

A

Have a large dilated pupil

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19
Q

What is miosis?

A

A small constricted pupil

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20
Q

What is Horners syndrome?

A

A defect in the sympathetic nervous supply in the eye
Results in a abnormally constricted pupil (miosis) in the affected side.

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21
Q

What is aniscoria?

A

Different sized pupils

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22
Q

What muscles and innervation is responsible for dilating the pupil? (mydriasis)

A

Sympathetic nervous system
Results in contraction fo the radial muscles

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23
Q

What muscles and innervation is resonsible for constricting the pupils? (miosis)

A

Parasympathetic nervous system
Results in contraction of the circular muscles

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24
Q

What signalling cascade is responsible for the contraction of the radial muscles?

A

Sympathetic innervation
Noradrenaline
Binds to alpha 1 adrenergic receptors
Actives GPCR, Gq alpha subunit activates PLCbeta, increase IP3 leading to increased Ca2+ resulting in muscle contraction
Radial muscles contraction
Mydriasis

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25
Q

What signalling cascade is responsible for the contraction of circular muscles?

A

Parasympathetic innervation
Acetylcholine
Acts on muscarininc M3 receptors
Activates GPCR Gq/11 subunit increases PLCbeta activity, results in increase IP3 and Ca2+
Results in circular muscle contraction
Results in miosis

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26
Q

What is the MOA of atropine in the eye?

A

Class - antimuscarinic
Chem - originate from deadly nightshade, small molecule
Pharm - Target: Muscarininc receptors (GPCR), action: non-selective, competitive antagonist, effect lasting up to 7 days
Physiology: prevents ACh binding to M3, GPCR is not activated (no PLCbeta, IP3 inc Ca2+) inhibits circular muscle contraction, causes mydrasis (unopposed dilation)
Clinical: unilateral amblyopia, anterior uveitis, posterior synechiae

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27
Q

What are the different antimuscarinics that act in the eye?
What is different in their pharmacology?

A

Atropine - very long lasting up to 7days
Cyclopentolate - long lasting up to 24hrs
Tropicamide - short-acting, up to 6hrs.

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28
Q

What is the MOA of phenylephrine in the eyes?

A

Class - sympathomimetic
Chem - synthetics, adrenaline derivative
Pharm - targets alpha 1 receptors (GPCRS) full agonist, signals via Qq/11.
Physi - contracts radial muscle of the eye, myadrasis (also cause HTN systemically)
Clinial - eye examination and surgery.

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29
Q

What drugs can cause drug-induced mydriasis?

A

Hycoein butylbromide (or any parenteral anticholinergic) - anticholinergic used got GI spasm.
L-DOPA : precursor for noradrenaline, mydrasis effect is reduced if pre-treated with carbidopa (inhibits dopa decarboxylase)
Cocaine: sympathomimetic, drug of abuse

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30
Q

What is the effect (MOA) of opiates in the eye?

A

Aka diamorphine/heroin
Class - opiate
Chem - semi-synthetic, morphine derivative
Pharm - targets mu and kappa recepotrs (GPCRS), acts as a full agonist
Phys - stimulates oculomotor nucleus (CN3), parasympathetic efferents cause contraction of circular muscles -> miosis.
Clinical - analgesics

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31
Q

How does pyridostigmine (-stigmine) affect the pupil? (MOA)

A

Class - anti-cholinesterase
Chem - synthetic, small molecule.
Pharm - Targets acetylcholinesterase, competitive reversible inhibitor
Phyio - Inc ACh levels in synapse, In overdose - binds to M3 receptors, contraction of circular muscles leads to pupillary contraction - miosis.
Clinical - beneficial at nicotinic receptors in myasthenia gravis.

32
Q

How can novichok poisoning be detected in the pupils?

A

Class - organophosphates (OP)
Chem - synthetic, small molecule
Pharm - target: acetylcholinesterase (enzyme), action irreversible inhibitor.
Phys - Inc ACh at cholinergic synapses inc muscarinic activity (multiple effects including miosis) and nicotinic activity leading to respiratory paralysis and death.
Clinical - none.

33
Q

What is the effect of malathion on the pupils?

A

Malathion
Class - organophosphate (OP)
Chem - synthetic, small molecule
Pharm - acetylcholinesterase, irreversible inhibitor,
Phys - inc ACh at cholinergic synapse in lice -> increase nicotinic activity -> cause neuromuscular paralysis
_> inc muscarinic in humans cause pupil constriction
Clinical: topical use for head lice

34
Q

What are the ciliary muscles in the eye?

A

Intrinsic muscle of the eye formed by caring of smooth muscle, responsible for lens accommodation.
Recieves both parasympathetic (ACh neural) and sympathetic (adrenaline - hormonal) input

35
Q

How does sympathetic innervation affect the ciliary muscles in the eye?
What is the effect of this?

A

Circulating adrenaline binds to Beta 2 receptors in the smooth muscle.
Activates GPCR - Gs - activates adenylyl cyclase to increase levels of cAMP - smooth muscle relaxation
Relaxed circular ciliary muscles flattens the lens, allows to focus on more distant objects.

36
Q

How does parasympathetic innervation affect the ciliary muscles in the eye?
What is the effect of this?

A

ACh released from parasympathetic nerve fibres
Neurotransmitter binds to M3 activates GPCR. activates Gq - increasePLC beta activity - inc Ca2+ ions - ciliary muscle contraction
The lens becomes more convex in shape - allow to focus on closer objects.

37
Q

What is the second messenger of M2 and alpha 2 adrenergic receptors?

A

Gai
Inhibition of adenylyl cyclase

38
Q

What is the second messenger of beta 1 and beta 2 adrenergic receptors?

A

Gas
Activation of adenylyl cyclase
Inc cAMP inc PKA

39
Q

What is the second messenger for M3 and alpha 1 receptors?

A

Gaq
Activation of PLC beta.

40
Q

How does PKA result in smooth muscle relaxation?

A

Phosphorylates and inactivates PLC beta
Decreases IP3 mediataited Ca2+ influx into cytoplasm
Phosphorylates and inactivates MLCK.

41
Q

What are the visual effects of Sildenafil?

A

Cause visision disorders as a common/very common side effect such as blurred vision and light sensitivity
Phosphodisterases have many subtypes.
Sildenafil targets PDE5, however PDE5 has a similar catalytic site to PDE6 found in the rods and cones in the eyes. Also has a lower pIC50
Partial inhibition of PDE6
Overdose or differential sensitivity may cause visual disturbances.

42
Q

What are the different acetylcholinesterases that effect the pupil?
How are they different?

A

Pyrostigmine - reversible
Novichok poisoning - organophosphate - irreversible
Malathion - organophosphate - irreversible

43
Q

What is the key anatomy underpinning glucoma?

A

The eye is made from an anterior and pasterior cavity (vitreous cavity) separated by the lens.
The anterior cavity consists of the anterior and posterior chamber separated by the iris and connected by the pupil.
The chamber angle is between the iris and the conrea.

44
Q

What is the anatomy of aqueous humour production/circulation?

A

Synthesised in ciliary bodies and secreted into posterior chamber. Passes round equator of iris and through the pupil into the anterior chamber.
Produce 1% of anterior chamber volume per minute.

45
Q

What is glaucoma?

A

A visual impairment resulting from chronic degeneration of the optic nerve.
The neurotinal rim of the optic nerve becomes progressively thinner, resulting in optic nerve cupping.
intra-ocular pressure is often raised - a significant risk factor.
Patches of vision loss and potentially total blindness

46
Q

What is the difference between open and closed-angle glaucoma?

A

Open angle - angle between iris and cornea is open so aqueous humour can still access, drainage however, drain in partially blocked so is slower, fluid and pressure builds up gradually. Sympatoms are gradual starting from periphery often not detected until central vision is lost.

Closed angle - sudden blockage of aqueous humour drainage, example lax iris, sticks to the lens when pupil dilated,blocks drainage into anterior chamber, inc pressure in posterior chamber pushes iris forward decreases the chamber angle.

47
Q

What are the different classifications of glaucoma?

A

Acute vs chronic
Primary vs secondary
Open angle vs closed angle

48
Q

What is the most common type of glaucoma?

A

Chronic Primary open-angle glaucoma

49
Q

What regulates intraocular pressure in glucoma?

A

Balance of production and drainage of aqeous humour from the anterior cavity.
Raised when drainage is impaired (most common in glaucoma) or when production is increased (rare in glaucoma)

50
Q

What is the anatomy of aqeous humour drainage in the eye?

A

Circulates the anterior chamber then 90% drains into the trabecular meshwork into the canal of schlemm into scleral and episcleral veins - this method is pressure sensitive.
10% drains via the uveoscleral route which is pressure insensitive.

51
Q

What are the three biological processes by which aqueous humour is produced in the eye?

A

Passive diffusion of solute down a concentration gradient
Filtration of fluid from fenestrated capillaries into interstitium of ciliary stroma (passive)
Active secretion of solutes against gradient (80-90% production)
This is mainly mediated by Sodium Postassium pump and carbonic anhydrase.

52
Q

What is meant by the ciliary body of the eye?

A

Made from the ciliary musucles, epithelial, stroma, blood vessels and nerves.

53
Q

What composes the ciliary muscles?

A

The longitudinal - most external, connects scleral spur and trabceular network anterior to the choird sclera posteriorly. Contractions open trabecular network and schlemms canal
Radial - intermediate
Circular - anterior inner muscles, contraction is responsible for lense accommodation,

54
Q

What is the epithelial of the ciliary bodies like?

A

Double layer on inner surface of ciliary processes
Inner layer - non pigmented cells and next to aqueous humour in poster chamber
Outer layer - pigmented and next to stroma/vessels
Therefore has two basement membranes and uses carbonic anhydrase pumps within both layer and Na+/K+ pumps in the non-pigmented layer to secretes aqueous humour into posterior chamber.

55
Q

What makes up the stroma,vessels and nerves of the eye ciliary bodies?

A

Includes mesenchymal cells and connective tissue in ciliary processes
Vessels - major arterial circle and ciliary process capillarires
Nerves - in parasympathetic and sympathetic to vessels, muscles and stroma/epithelium.

56
Q

What glaucoma drugs increase aqueous drainage?

A

Increase aqueous drainage (outflow) such as FP receptors agaonist (-prost) via utersocleral route and cholimoimmetics via trabecular/schlemm route

57
Q

What glaucoma drugs reduce aqueous production?

A

Beta blockers (olol)
Carbonic anhydrase inhibitors (-zolamide)
Alpha 2 adrenergic agonist - (onidine)

58
Q

What are the different glaucoma drugs listed on the BNF?

A

Prostaglandins - all PGF2alpha analogues (-prost)
Beta blockers - (olol)
Carbonic anhydrase inhibitors - (-zolamide)
Sympathomimietics (-nindine)
Muscarininc agonsts such as pilocarpine.

59
Q

How are prostaglandins used to treat glucoma?

A

Chem - analogues of PGF 2 alpha, all are prodrugs either esters or amides, free acid forms are most active
Pharm - target FP receptors (GPCR), agonist that activates Gq/11 signalling
Physio - inc permeability of sclera, into aqueous outflow via the uveosclera route, no effect on aqueous production
Clinical - 1st line treatment for glaucoma in many cases, topical application.**

60
Q

How can beta blockers be used to treat glaucoma?

A

Class - beta blocker (olol)
Chem - all small molecules
Pharm - all competitive antagonists at adrenergic receptors
Beta 2 increases section and alpha 2 decreases secretion, therefore a beta 2 selective beta blocker is most effective.
Phys - decrease sympathetic tone in the ciliary body, decrease aqueous humour formation (hence lowers IOP)
Clinical - chronic open angle glaucoma, ocular hypertension

61
Q

What is the role of apraclonidine in treating glaucoma?

A

Class - sympathomimetic
Chem - synthetic small molecule
Pharm - full agonist at alpha 2 adrenergic receptors, triggers signalling via Gi/o - inditis adenylyl cyclase
Phyio - decrease aqueous formation, increase uversoscleral draininage, inc outflow
Can have side effects of mydraiasis and disruption of accommodation
Clinial - glaucoma.

62
Q

What is the role of clonidine with hypertension?

A

Class - sympathomimetic
Chem - synthetic small molecule
Pharm - targets alpha 2 adrenergic receptors (GPCR), partial agaonist, activates Gi/o signalling
Physio - can enter CNS, direct action in ventrolaterla medullar rich in alpha 2 to reduce ABP by inhibiting Noradrenaline release
Also Presynapticiallt decreases NA release via Gi/o/
Acts on central I1 sites to decrease sympathetic tone.
Clinical use: treatment for hypertension.

63
Q

What are the different adrenoreceptors classification and signalling?

A

Alpha 1 - type A,B,D - Gq/11 - inc Ca2+ conc
Alpha 2 - type A,B,D - Gi/o - decrease cAMP
Beta - type 1,2,3 - Gs - increase cAMP

64
Q

What is the role of carbonic anhydrase in aqueous fluid production in the ciliary bodies?

A

Carbonic anhydrase is found within the pigmented and non-pigmented epithelium.
1. Intracellular HCO3- formation contributes to the movement of Na+ into the pigmented epithelium, which then travels along into non-pigemented and ensures a sufficient sodium supply for the sodium potassium pump.
2. HCO3- is also produced in ECF and enters pigmented epithelium via co-transporters with Na+. CA facilates rapid transport/diffusion of HCO3- as CO2 between epithelial layers than passes out into aqueous as HCO3-.

65
Q

What is the role of dorzolamide in treatment of glaucoma?

A

Is a carbonic anhydrase inhibitor.
Chem - small molecule, synthetics
Pharm - is a competitive inhibitor of carbonic anhydrase
Physio - decrease conc HCO3- in ciliary epithelial, therefore decreases Na+ in transport reducing substrate for Na+K+ pump.
Also low HCO3- decreases pH impariting Na+K+ ATPase activity
Less ECF HCO3- so less co-transport of Na+ into the epithelium.
Reduced movement of Na+ into aqueous leads to reduced aqueous formation
Clinical - reduced IOP in open-angle glaucoma. (given topically as eye drops)

66
Q

What is the use of pilocarpine in glaucoma?

A

Class - parasympathomimetic
Chem - natural, small molecule
Pharm - non-selective partial agonist at muscarinic receptors
Physio - acts on M3 receptors on ciliary muscle - causes contraction of LCM -> this opens the trabecular meshwork/schlemms canal
This increase ocular aqueous outflow reducing IOP in glaucoma
Clinical - side effects include miosis, disruption of accommodation and headache,
Used for acute closed -angle glaucoma.

67
Q

What is age-related macular degeneration?
What are the different types?

A

The progressive degeneration of central retinal cells resulting in vision loss
Can be classified as:
Dry (non-neovascular) - degeneration without formation of blood vessels
Wet (neovascular) - new vessels form and damage the retina

68
Q

What are the subcategories of wet age related maculear degeneration?
How does this link to the pharmacology?

A

Active - may benefit from treatment as blood vessels are still forming
Inactive - changes probably irreversible, unlikely to benefit from treatment.

69
Q

What are the different drugs available for wet age-related macular degeneration and what is common about them?

A

All drugs target the VEGF pathway
Bevacizumab
Ranibizumab
Brolucizumab
Afilbercept
Faricimab (bisopecic also targets angiopoteine-2).

70
Q

What is VEGF-A and how does it relate to glaucoma pharmacology?

A

Chem - protein homodimer (linked by disulphide bonds)
Pharm - binds to VEGF receptors - recepotr tyrosine kinase (RTK)
Phsyio - cause angiogenesis, endothelial cell proliferation, promotes cell migration, inhibits apoptosis, induces permeabilization of blood vessels
Clincal - ANTI- VEGF used in tumours, AMD and diabetic eye disease.

71
Q

What is the usefulness of bevacizumab in glaucoma?

A

Class - angiogenesis inhibitor
Chem - whole IgG antibody, humanized monoclonal antibody
Pharm - blocking/neutralising VEGF-A
Physio - Anti-VEGF decreases blood vessel formation and slow degeneration of the retina
Clinical - multiple solid tumours (licened) and Wet type AMD (unlicensed)

72
Q

What is the usefulness of ranibizumab in the treatment of glaucoma?

A

Class - angiogenesis inhibitor
Chem - Fab fragment of bevacizumab, humanized monoclonal antibody
Pharm - neutralising VEGF-A
Physio - ANTI-vegf decrease blood vessel formation and slows degeneration of the retina
Clinical - wet AMD (licensed)

73
Q

What is the usefulness of brolicizumab in the treatment of glaucoma?

A

Class - angiogenesis inhibitor
Chem - single chain variable fragment, from a humanized monoclonal antibody
Pharm - neutralising VEGF-A
Physio - ANTI-VEGF decreases blood vessel formations and slower degeneration of the retina
Clinial - wet AMD (licensed)

74
Q

What is the usefulness of Afibercept in treatment of glaucoma?

A

Class - angiogenesis inhibitor
Chem - recombinant fusion protein containing the ligand binding domains for VEGFR-1 and VEGFR-2
Pharm - targets VEGF-A and VEGF-B, neutralising effect
Physio - Anti-VEGF decreases blood vessel formation, slows degeneration fo the reina
Clinical - wet AMD. (licensed)

75
Q

What is the usefulness of faricimab in the treatment of glaucoma?

A

Class - angiogenesis inhibitor
Chem - IgG1 bispecific antibody, engineered to not interact with Fc receptors.
Pharm - Neutralisation of VEGF-A and Angiopoietin-2.
Physio - Anti-VEGF and Anti-Ang-2 - decreases blood vessel formation and slows degeneration of the retina.
Clinial - licensed route of wet AMD.

76
Q

What is the feature of V1 as a cortex?

A

Has a topographical map - vision is projected onto it in an upside and left to right pattern.

Unit 14 (17 decks)

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