Eye Pharmacology Flashcards
(45 cards)
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
2
Q
Explain vitamin A (composition)
A
-
Retin**ol**
- aka: Vitamin A1, all-trans-retin_ol_
- -ol = alcohol = -OH
-
Retin**al**
- aka: Vitamin A aldehyde, all-trans-retin_al_
- -al = aldehyde = -CHO
β-carotene - conatins vitamin A
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
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
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
6
Q
Explain signalling in light perception (and steps)
A
TRANSDUCIN (Gt) comprises 3 subunits:
- 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
- Beta - regulatory subunit
-
Gamma - regulatory subunit
- C-terminal lipid link to membrane
Steps in signalling in light perception:
- Rhodopsin activates transducin
- Light activation results in release of GDP and binding of GTP to Gtα
- GTP-bound Gtα activates downstream signalling → cGMP phosphodiesterase
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
8
Q
What do retinoid drugs do?
A
Retinoid drugs reduce the proinflammatory factors and disrupt the immunoinflammatory cascade associated with acne vulgaris
9
Q
What is mydriasis?
A
Large pupil
10
Q
What is miosis?
A
Small pupil
11
Q
What is Horner’s syndrome caused by?
A
By a defect in the sympathetic nervous supply
Results in anisocoria (different sized pupils)
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
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
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
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)
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
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…
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
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
How can ***sildenafil*** cause visual disturbances?
* As inhibits ***phosphodiesterases*** (usually PDE5)
* *_PDE6_* is found in the cones hence, affects vision (COMMON)
26
What is ***glaucoma*** & explain it
* ***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
Explain the *production* of ***aqueous humour*** & where it goes
* ***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
Explain what the ***ciliary body*** contains
* ***_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 cana_*l.
* *_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
Explain how **CA** & **Na+/K+ ATPase** work in the eye
On diagram
30
Explain the ***pharmacotherapy*** of glaucoma
* ***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
Explain MOA of ***prostaglandins*** in the eye
* **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
Explain the *physiology* of different **prostaglandins**
33
Explainn the MOA of **Beta-blockers** (in the eye)
**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
Explain MOA of **apracl_onidine_** (in the eye)
* **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
Explain the MOA of **cl**_onidine_****
* **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
Explain the ***adrenoceptor*** classification & signalling
37
Explain the MOA of **acetazolomide**
* **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
Explain the role of **carbonic anhydrase** in the *ciliary process*
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
2. 3. 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
What is the MOA of **dorz**_olamide_****
* **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
What is the MOA of **pilocarpine**?
* **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
What is **age-related** **macular degeneration**? & what are the *classifications & drugs available?*
* 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
* Bevac**_izumab_**
* Ranib**_izumab_**
* Aflibercept
42
What is the MOA of **VEGF-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
What is the MOA of **bevacizumab**?
* **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
What is the MOA of **Ranib**_izumab_****?
* **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
What is the MOA of **aflibercept**?
* **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)
