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Unit 14 Week 4 (Tommy) > Eye Pharmacology > Flashcards

Eye Pharmacology Flashcards

1
Q

Explain the types of opsin receptors

A
  • Rhodopsin (between blue & green)
    • High-sensitivity rods
  • Long-wave-sensitive opsin 1
    • ‘Red’ cones
  • Medium-wave-sensitive opsin 1
    • ‘Green’ cones
  • Short-wave-sensitive opsin 1:
    • ‘Blue’ cones
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2
Q

Explain vitamin A (composition)

A
  1. Retin**ol**
    • aka: Vitamin A1, all-trans-retin_ol_
    • -ol = alcohol = -OH
  2. Retin**al**
    • aka: Vitamin A aldehyde, all-trans-retin_al_
    • -al = aldehyde = -CHO

β-carotene - conatins vitamin A

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3
Q

What is the composition of rhodopsin?

A

Rhodopsin = protein + chromophore

  • Protein (an apoprotein) = opsin
    • 7 trans-membrane domains
  • Chromophore = 11-cis-retinal
    • Covalently bound to lysine

Forming of 11-cis-retinal & lysine forms the SCHIFF base (C=N-H+) -> becomes unprotonated during photoactivation

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4
Q

Explain the response to light of 11-cis-retinal

A

In solution a single photon can induce isomerisation of 11-cis-retinal to all-trans-retinal with efficiency of 1 in 3 → structural change

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5
Q

Explain the response to light of rhodopsin

A
  • In rhodopsin a single photon can induce isomerisation of 11-cis-retinal to all-trans-retinal with an efficiency of 2 in 3→ structural change of retinal AND rhodopsin
  • Structural change to rhodopsin –> SIGNALLING –> Light perception

STRUCTURAL CHANGE –> FUNCTIONAL CHANGE

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6
Q

Explain signalling in light perception (and steps)

A

TRANSDUCIN (Gt) comprises 3 subunits:

  1. α-GTPase
  • Binds to GDP in inactive site
  • Binds to GTP in active state
  • N-terminal lipid link to membrane
  • C-terminal interacts with rhodopsin
  1. Beta - regulatory subunit
  2. Gamma - regulatory subunit
    • C-terminal lipid link to membrane

Steps in signalling in light perception:

  1. Rhodopsin activates transducin
  2. Light activation results in release of GDP and binding of GTP to Gtα
  3. GTP-bound Gtα activates downstream signalling → cGMP phosphodiesterase
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7
Q

Explain G protein signalling in general (& different types)

A
  • G protein-coupled receptor (GPCR) - seven transmembrane receptor
  • Interact with and signal through G proteins
  • G proteins form a heterotrimeric complex
    • Membrane-associated
    • α and βγsubunits
  • Gα subunits
  • Gαs: UP adenylate cyclase
    • UP cAMP –> UP PKA
  • Gαi/o:DOWN adenylatecyclase
    • DOWN cAMP –> DOWN PKA
  • Gαq/11: UP phospholipase Cβ
    • UP IP3 –> UP [Ca2+]i
    • UP DAG –> UP PKC
  • Transducin→ Gtα: INCREASE cGMP phosphodiesterase -> Decrease cGMP –> visual perception
  • Gβγ subunits
    • Inhibits: Gα,Ca2+channels
    • Activates: PLA2, GIRK
  • Rhodopsin is the prototypic G protein-coupled receptor
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8
Q

What do retinoid drugs do?

A

Retinoid drugs reduce the proinflammatory factors and disrupt the immunoinflammatory cascade associated with acne vulgaris

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9
Q

What is mydriasis?

A

Large pupil

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10
Q

What is miosis?

A

Small pupil

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11
Q

What is Horner’s syndrome caused by?

A

By a defect in the sympathetic nervous supply

Results in anisocoria (different sized pupils)

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12
Q

Explain what the iris muscles do

A
  • Radial muscle (dilator pupillae)
    • Sympathetic - noradrenaline (NA) –> alpha 1 adrenergic receptor
    • Gq –> UP IP3 –> contraction
    • ​LARGER pupil
  • Circular muscle (sphincter pupillae)
    • Parasympathetic - acetylcholine –> M3 muscarinic receptor
    • Gq –> UP IP3 –> UP [Ca2+]i –> contraction
    • SMALLER pupil
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13
Q

Explain the pharmacology of atropine

A

CLASS

  • Antimuscarinic/parasympatholytic

PHARMACOLOGY

  • Target: muscarinicreceptors(GPCR)
  • Action: non-selective, competitive antagonist
  • Very long lasting

PHYSIOLOGY

  • Mydriasis, cycloplegia (paralysis of ciliary muscle = no accomodation), unilateral amblyopia (‘lazy’ eye) → in good eye; anterior uveitis
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14
Q

Explain the pharmacology of cyclopentolate

A

CLASS

  • Antimuscarinic/parasympatholytic

PHARMACOLOGY

  • Target: muscarinicreceptors(GPCR)
  • Action: non-selective, competitive antagonist long-lasting action (up to 24 hours)

PHYSIOLOGY

  • (multiple effects) incl. mydriasis, cycloplegia

CLINICAL

  • Eye examination; unilateral amblyopia (‘lazy’ eye) → in good eye; anterior uveitis; ↓posterior synechiae
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15
Q

Explain the pharmacology of tropicamide

A

CLASS

  • Antimuscarinic/parasympatholytic

PHARMACOLOGY

  • Target: muscarinic receptors(GPCR)

PHYSIOLOGY

  • Action: non-selective, competitive antagonist
  • Short-acting (up to 6 hours - as less potent) mydriasis, cycloplegia

CLINICAL

  • Eye examination (funduscopy)
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16
Q

Explain the pharmacology of phenylephrine

A

CLASS

  • Sympathomimetic

PHARMACOLOGY

  • Target: α1receptors (GPCR)
  • Action: full agonist
  • Signalling: Gq/11

PHYSIOLOGY

  • Mydriasis, vasoconstriction

CLINICAL

  • Eye examination and surgery
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17
Q

Explain pharmacology of heroin/diamorphine

A

CLASS

  • Opiate
  • PHARMACOLOGY
  • Target: μ receptors(GPCR)
  • Action: full agonist

CLINICAL

  • Stimulates nuclei oculomotor (CNIII) → miosis, (respiratory depression, analgesia etc…) analgesic etc…
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18
Q

What is the pharmacology of pridostigmine?

A

CLASS

  • Cholinesterase inhibitor

PHARMACOLOGY

  • Target: acetylcholinesterase(enzyme)
  • Action: competitive reversible inhibitor

​PHYSIOLOGY

  • ↑ [ACh] at cholinergic synapses →↑ nicotinic activity at NMJ (myasthenia gravis)
  • In overdose
    • →↑ muscarinic activity (many side effects!) incl. miosis

CLINICAL

  • Myasthenia gravis
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19
Q

Explainn the ciliary muscles (anatomy & innervation)

A
  • Anatomy
    • Smooth & circular
  • Innervation
  • Parasympathetic
    • (sympathetic ??)
  • Receptors
    • M3 - acetylcholine (neurotransmitter)
    • β2 - adrenaline (circulating)
  • Signalling
    • M3 - as in iris Gq →↑[Ca2+]i
    • β2 - Gs →↑AC →↑[cAMP]
  • Function
    • M3 - as in iris = contraction
    • β2 - as in bronchi = relaxation
20
Q

Explain signalling in cardiac & smooth muscle

A
21
Q

Explain how smooth muscle contraction happens

A
22
Q

Explain how smooth muscle relaxation happens

A
  • PKA phosphorylates:
    • PLCbeta
    • IP3 receptor
    • MLCK (myosin light chain kinase)
23
Q

Explain what happens after muscle relaxation for muscle contraction to occur

A
24
Q

Explain how theophylline causes brochial smooth muscle relaxation

A
  • Theophylline is a non-selective competitive antagonist of adenosine receptors (A1, A2A, A2B, A3)
  • Adenosine induces bronchoconstriction and production of inflammatory mediators and cytokines
  • Some hypotheses:
    • A1 and A3 may contribute to clinical signs and therapeutic effect
    • A2B activation by autocrine adenosine may desensitise β2 receptors
    • Alternative signalling pathways for A2B (i.e., Gq/11) may be present
  • Theophylline is also an inhibitor of PDE, so may increase cAMP

INCLUDE IMAGE

25
Q

How can sildenafil cause visual disturbances?

A
  • As inhibits phosphodiesterases (usually PDE5)
  • PDE6 is found in the cones hence, affects vision (COMMON)
26
Q

What is glaucoma & explain it

A
  • Visual impairment
    • Progressive optic neuropathy, optic nerve cupping
  • Classification
    • Primary (unknown cause) vs secondary (known cause)
    • Acute vs chronic
    • Open-angle vs closed-angle (between iris & cornea)
    • Primary open-angle glaucoma (POAG) is most common (and chronic)
  • Intra-ocular pressure (IOP) often raised – a significant risk factor
  • IOP regulated by production and drainage of aqueous humour
    • Impaired drainage (↓outflow) is a common cause of raised IOP
    • Increased production (↑inflow) is a rare cause of raised IOP
27
Q

Explain the production of aqueous humour & where it goes

A
  • Ciliary body synthesises aqueous humour
    • Turnover ≈ 1% of the anterior chamber volume per minute
  • Aqueous humour flow:
    • INFLOW: Ciliary body→posterior chamber→pupil→anterior chamber→
    • OUTFLOW:
      • ~90%: trabecular meshwork→Schlemm’s canal→scleral and episcleral veins (pressure SENSITIVE)
      • ~10%:uveoscleral route(pressure INSENSITIVE)
  • Production via three processes
    • Passive diffusion of solutes down concentration gradients
    • Filtration of fluid from fenestrated capillaries into interstitium of ciliary stroma (passive)
    • Active secretion of solutes against gradients (80-90% production)
  • Two important biochemical mechanisms
    • Sodium pump: Na+/K+-ATPase
    • Carbonic anhydrase (CA)
28
Q

Explain what the ciliary body contains

A
  • Ciliary Muscles: 3 types
    • Longitudinal (LCM): most external, connects scleral spur and trabecular network anteriorly to choroid sclera posteriorly. Contraction opens trabecular network and Schlemm’s canal.
    • Circular (CCM): anterior, inner muscles. Contraction → accommodation
    • Radial (RCM): intermediate, connects LCM and CCM.
  • Epithelia: double layer on inner surface of ciliary processes
    • Inner layer: non-pigmented adjacent to aqueous
    • humour in posterior chamber
    • Outer layer:pigmentedadjacenttostroma/vessels
  • Stroma, incl. mesenchymal cells and connective tissue in ciliary processes
  • Vessels, incl. major arterial circle (E) and ciliary process capillaries
  • Nerves, incl. parasympathetic and sympathetic to vessels, muscles and stroma/epithelia
29
Q

Explain how CA & Na+/K+ ATPase work in the eye

A

On diagram

30
Q

Explain the pharmacotherapy of glaucoma

A
  • PHARMACOLOGY
    • Targets: α1, α2, β1, β2, M3, FP, CA
    • Action: agonists, partial agonists, antagonists, inhibitors…
    • Location: smooth muscle, vessels, epithelia, stroma cells, nerve endings…
  • PHYSIOLOGY
    • Increasing aqueous drainage (↑outflow)
      • FP receptor agonists (-prost) → via uveoscleral route
      • Cholinomimetics → via trabecular/Schlemm route
    • Reducing aqueous production (↓inflow)
      • β-blockers (-olol)
        • Carbonicanhydraseinhibitors (-zolamide)
        • α2-adrenergicagonists (-onidine)
31
Q

Explain MOA of prostaglandins in the eye

A
  • PHARMACOLOGY
    • Target: FP receptor (GPCR)
    • Action: agonist
    • 1° signalling: Gq
  • PHYSIOLOGY
    • ↑permeability of sclera
    • ↑aqueous outflow via uveoscleral route • No effect on aqueous production
  • CLINCAL
    • 1st line treatment for glaucoma in many cases
    • Topical application

Prostaglandins are prodrugs and are either:

  • ‘prost’ = agonists
  • ‘iprant’ = antagonists
32
Q

Explain the physiology of different prostaglandins

A
33
Q

Explainn the MOA of Beta-blockers (in the eye)

A

CLASS

  • B-blockers (-olol)

PHARMACOLOGY

  • Non-selective (propranolol)
  • B1 selective
  • B2 selective

PHYSIOLOGY

  • Sympathetic tone DECREASE in ciliary body
  • DECREASE aqueous humour formation

CLINICAL

  • Open-angle glaucoma
  • Ocular hypertension
34
Q

Explain MOA of apracl_onidine_ (in the eye)

A
  • CLASS
    • ​ Sympathomimetic
  • PHARM
    • Target: α2-adrenergic receptor (GPCR)
    • Action: full agonist
    • 1° Signalling: Gi
  • PHYS
    • ↓sympathetic tone (pre-synaptic) →↓aqueous formation
    • ↑uveoscleral drainage →↑ outflow
    • also: mydriasis, disruption of accommodation
    • Limited access to CNS (cf. clonidine)
  • CLIN:
    • Glaucoma
35
Q

Explain the MOA of clonidine**

A
  • CLASS
  • Sympathomimetic
  • PHARM
    • Target: α2-adrenergic receptor (GPCR)
    • Action: partial agonist
    • 1° Signalling: Gi/o
  • PHYS:
    • Can enter CNS (cf. apraclonidine)
    • Direct action in ventrolateral medulla (rich in α2) →↓ABP
    • Pre-synaptically: Gi/o →↓[cAMP] →↓Ca+ influx (VGCC) →↓NA release
    • Acts on central I1 sites →↓sympathetic tone
  • CLIN
    • ​Hypertension
36
Q

Explain the adrenoceptor classification & signalling

A
37
Q

Explain the MOA of acetazolomide

A
  • CLASS
    • ​Carbonic Anhydrase Inhibitor
  • PHARMACOLOGY
    • Target: carbonic anhydrases
    • Action: Competitive inhibitor
  • PHYSIOLOGY(complex!)
    • ↓Na+ reabsorption in PCT → ↑urine flow (~3 ml.min−1)
    • ~1⁄3 PCT Na+ reabsorption is through Na+/H+ antiporter
    • Diuretic effect is mild and self-limiting
    • → ↓ preload → ↓ venous congestion → symptomatic relief
    • Heavy loss of HCO3− → alkaline urine/metabolic acidosis → ↓diuresis
    • ↑Na+ at DCT → ↑K+ loss → hypokalaemia
    • acetazolamide
  • CLINICAL
    • First ‘modern’ diuretic, superseded mercurials, now obsolete as diuretic
    • Still in use for glaucoma: I.V. for acute ↑IOP as topical treatment cannot enter the eye across cornea

Is given IV (intravenously) - otherwise is NOT absorbed

38
Q

Explain the role of carbonic anhydrase in the ciliary process

A
  1. CA →↑[HCO3−]i
  2. ↑[HCO3−]i →↑Na+ transport

Proper steps (detail):

  1. Formation of intracellular HCO3− by CA contributes to movement of Na+ into cell, ensuring [Na+]i is sufficiently high to supply sodium pump (5) with substrate
    1. HCO3− also enters via co-transporter with Na+. CA facilitates rapid transport/diffusion of HCO3− (as CO2) between epithelial layers. HCO3− passes into aqueous

LESS CA = LESS [HCO3-]i = LESS Na+ transport = LESS aqueous humour formed

39
Q

What is the MOA of dorzolamide**

A
  • CLASS
    • Carbonic anhydrase inhibitor (CAI)
  • PHARM
    • Target: carbonic anhydrases
    • Action: Competitive inhibitor
  • PHYS:
    1. CAI →↓[HCO3−]i in ciliary epithelia
    2. ↓[HCO3−]→↓[Na+]i →↓substrate for Na+/K+-ATPase
    3. ↓[HCO3−]→↓pH →↓ Na+/K+-ATPase activity
    4. ↓[HCO3−] →↓ co-transport into aqueous with Na+
    5. →↓ Na+ movement into aqueous →↓ aqueous formation
  • CLIN
    • ​Open-angle glaucoma (eye drops - topically)
40
Q

What is the MOA of pilocarpine?

A
  • CLASS
    • ​Parasympathomimetic
  • PHARM
    • Target: muscarinic receptors (GPCR)
    • Action: non-selective, partial agonist
    • 1° Signalling: M1, M3, M5 → Gq; M2, M4 → Gi
  • PHYS
    1. M3 on ciliary muscle → contraction of LCM →
    2. opening of trabecular meshwork/Schlemm’s canal →
    3. ↓outflow resistance → ↑ocular aqueous outflow
    4. also: miosis, disruption of accommodation, headache!
    5. (also: vasodilation → blood flow to ciliary body - partial agonist ??)
  • CLIN
    • ​Glaucoma (in use since 1877!); acute closed-angle glaucoma
41
Q

What is age-related macular degeneration? & what are the classifications & drugs available?

A
  • Progressive degeneration of central retinal cells → vision loss
  • Classification
    • Dry (non-neovascular): degeneration without formation of blood vessels
    • • Wet (neovascular): new vessels form and damage retina
      • Active – may benefit from treatment
      • Inactive – changes probably irreversible – unlikely to benefit from treatment
  • Drugs – all target VEGF pathway
    • Bevacizumab
    • Ranibizumab
    • Aflibercept
42
Q

What is the MOA of VEGF-A?

A
  • PHARM
    • ​Binds to VEGF receptors (in blood vessels)– receptor tyrosine kinase (RTKs)
  • PHYS
    1. Endothelial cell proliferation
    2. Promotes cell migration
    3. Inhibits apoptosis
    4. Induces permeabilization of blood vessels
  • CLIN:
    • ANTI-VEGF used in tumours, AMD and diabetic eye disease
43
Q

What is the MOA of bevacizumab?

A
  • CLASS:
    • Angiogenesis inhibitor
  • CHEM:
    • IgG
    • -mab = monoclonal antibody
    • -zu- = humanized
    • -ci- = cardiovascular
  • PHARM:
  • Target:VEGF-A (growth factor)
  • Action: binding/blocking
  • PHYS:
    1. VEGF promotes angiogenesis
    2. ↓ blood vessel formation slows degeneration of retina
  • CLIN:
    • Multiple types of solid tumour (licensed)
    • Wet-type age-related macular degeneration (unlicensed)
44
Q

What is the MOA of Ranibizumab**?

A
  • CLASS:
    • Angiogenesis inhibitor (HAS NO Fc fragment thus, much smaller)
  • PHARM:
    • Target: VEGF-A (growth factor)
    • Action: binding/blocking
  • PHYS:
    1. VEGF promotes angiogenesis
    2. ↓ blood vessel formation slows degeneration of retina
  • CLIN:
    • Wet-type age-related macular degeneration (licensed)
45
Q

What is the MOA of aflibercept?

A
  • CLASS
    • Angiogenesis inhibitor
  • PHARM:
    • Target: VEGF-A and VEGF-B (growth factors)
    • Action: binding/blocking
  • PHYS:
    1. VEGFs promotes angiogenesis
    2. ↓ blood vessel formation slows degeneration of retina
  • CLIN:
    • Wet-type age-related macular degeneration (licensed)

Unit 14 Week 4 (Tommy) (5 decks)

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