Eye pharmacology Flashcards
Opsin receptors in rod and cone cells
Opsin receptors:
Rods-
Rod cells are stimulated by light over a wide range of intensities and are responsible for perceiving the size, shape, and brightness of visual images. They do not perceive colour and fine detail, tasks performed by the other major type of light-sensitive cell, the cone.
- Rhodopsin- A biological pigment containing protein that sits in organelle membranes called discs.
Made up of a protein called an opsin and a photosensitive chemical called a chromophore derived from vitamin A- 11-cis-retinaldehyde.
Cones- come in different types reflecting the varying quantities of long, medium or short-wave sensitive opsins.
Long wave sensitive opsin 1- red cones
Medium wave sensitive opsin - green cones
Short wave sensitive opsin 1- blue cones
- Rhodopsin= apoprotein* (AKA opsin) + *chromophore (11 cis-retinal)
11-cis-retinal response to light with and without apoprotein opsin present
without opsin- In solution, 1 photon can induce isomerisation of 11-cis-transretinal to all-trans-retinal (structural change ) with an efficiency of 1/3.
In rhodopsin***, 1 photon can induce the same change with an ***efficiency of 2/3.
Signalling involved in light transduction
Transducin (Gt) is comprised of 3 subunits:
- a-GTPase
binds GDP in inactive state
Binds GTP in active state
Linked to membrane
C-terminal interacts with rhodopsin
B and y G subunits form a single regulatory functional unit
Rhodopsin activates transducin
Light activation results in release of GDP* and *binding of GTP to Gta
GTP bound Gta* is then f_ree to activates downstream signalling methods_* cGMP phosphodiesterase
Ga subunits and their effects
Gas
Ga1/0
Gaq/11
which one does transudcin have?
Gas- increases adenylate cylase –> increase cAMP –> incresae PKA
Ga1/0- decreases adenylate cyclase “”””
Gaq/11- increases phospholipase CB causing cGMP phosphodiesterase and decreased cGMP
Tansducin has a Ga subunit causing increased cGMP phosphodiesterase and decreased cGMP causing increased visual perception.
Term for large pupils?
term for constricted pupils?
mydriasis
miosis
Radial muscle
innervation
neurotransmitter
receptor
signalling proteins
function
- innervation- sympathetic
- neurotransmitter- Noradrenaline
- receptor- a1 receptor
- signalling proteins- Gq –> increase PLCB –> increase IP3–> increase Ca2+i
- function- contraction
Circular muscle
innervation- parasympathetic
neurotransmitter- acetylcholine
receptor- M3
signalling proteins- Gq –> increase PLCB–> increase IP3 –> increase Ca2+i
function- contraction- constriction of eye
Atropine
CLASS- antimuscarininc/ parasympatholytic
CHEM- natural
PHARM- target: muscarininc GPCR receptors effect: non-selective competitive antagonist
PHYS- mydriasis, cycloplegia
CLIN- lazy ey, anterior uveitits
symp> para –> blocks this:
Cyclopentolate
CLASS: antimuscarinic/ parasympatholytic
CHEM: synthetic
PHARM: target: muscarinic receptors (GPCR)
Action: non-selective, competitive antagonist
PHYS: multiple effects; myadriasis, cycloplegia (paralysis of ciliary body- can’t convex lens)
CLIN: used in eye examination
BLOCKS THIS
Tropicamide
CLASS: antimuscarinic/ parasympatholytic
CHEM: synthetic
PHARM: target: muscarinic receptors (GPCR)
Action: non-selective, competitive antagonist
PHYS: mydriasis, cycloplegia
CLIN: eye examination
blocks this vvvvvv
Phenylephrine
CLASS: sympathomimetic
CHEM: synthetic, adrenaline derivative
PHARM: target- a1 receptors
Action: full agonist
PHYS: mydriasis, vasoconstriction
CLIN: eye examination and surgery
oTHER drugs that can cause mydriasis
Hyoscine butylbromide— anticholinergic
L-dopa- precursor of adrenaline
Mydriasis reduced by carbidopa
Cocaine- sympathomimetic, drug abuse
opiates- diamorphine
CLASS: opiate
CHEM: semi-synthetic, morphine derivative
PHARM: target: u receptors (GPCR)
Action: full agonist
PHYS: stimulates oculomotor nerve miosis (constriction) among other things
CLIN: analgesic…
Para on
Pyridostigmine
CLASS: cholinesterase inhibitor
CHEM: synthetic
PHARM: target: acetylcholinesterase (enzyme)
Action: competitive reversible inhibitor
PHYS: increase [Ach] at cholinergic synapses increase niconitic activity at NMJ (myasthesia gravis) in overdose
increases muscarinic activity
CLIN: myasthesia gravis
Ciliary muscles are caused to contract by what innervation?
receptors?
signalling?
parasympathetic
M3- acetylcholine contraction . B2- adrenaline relax
M3 in iris- Gq- increased Ca2+i
B2 Gs–> increased AC– increased cAMP
Gq Smooth muscle contraction pathway of signalling
Gq is the key pathway that can be coupled to multiple kinds of receptors (M3, a1, H1).
Gaq can be activated by things like opsins,,,,,,,,,
Calmodulin binds to elevated levels of calcium.
This complex activates MLC kinase, which in turn ohosphorylates MLC, which then triggers muscle contraction
Gas activation to cause smooth muscle relaxation
Glaucoma
Visual impairment
Progressive optic neuropathy, optic nerve cupping
Classification:
Primary/ secondary, acute/ chornic, open angle/ closed
IOP increased
IOP regulated by production and drainage of aqueous humor
impaired drainage through the trabecular meshwork (canal of Schlemm)
production of aqueous humor
Ciliary body synthesises aqeous humour
Flow path:
INFLOW: ciliary body –> posterior chamber –> pupil –> anterior chamber
OUTFLOW: 90% trabecular meshwork –> Schlemm’s canal –> scleral and episcleral veins. (pressure sensitive)
UVEOSCLERAL ROUTE (PRESSURE insensitive)
production of aqueous humor by 3 methods
- Passive diffusion of solutes down pressure gradient
- Filtration of fluid from fenestrated capillaries into interstitium of ciliary stroma (passive)
- Active secretion of solutes against gradient 80-90%)
2 important biochemical mechanisms
sodium potassium ATPase pump
Carbonic anhydrase
Drugs for galucoma work by:
increasing aqueous drainage:
x
x
x
reducing aqueous production:
xxx
increasing drainage
- Fc receptor agonists (-prost) –> via uveoscleral route
- cholimemtics –> via trabecular/ schlemm route
reducing aqueous production
- B blockers -olol
- carbonic anhydrase inhinbitors -zolamide
- A2 adrenergic agonists -onidine
*
Prostaglandin
CHEM- all prodrug analogues of PGF2a
Free acid forms are most active (esters and amide)
PHARM- target- FP receptor (GPCR)
Action- agonist
1* signalling- Gq/11
PHYS-
Increase permeability of sclera
Increase aqueous outflow via the uveoscleral route
No effect on aqueous production
CLIN- 1st line treatment for glaucoma in many cases
Topical application
trepostinil
Synthetic analogue of PGI2
IP receptor agonist
Vasodilation
Pulmonary art hypertension
B blockers
CLASS: B blockers (-olol)
CHEM: all small molecules
PHARM: all competitive antagonists
PHYS: decrease sympathetic tone of ciliary body
Decrease aqueous humour formation (decrease inflow)
CLIN: chronic open-angle glaucoma, ocular hypertension
apraclinidine
CLASS: sympathomimetic
CHEM: synthetic
PHARM: target- a2-adrenergic receptor GPCR
Action- full agonist
1* signalling- Gi/o
PHYS:
Decreased sympathetic tone (pre-synaptic) decreased aqeous formation
Increased uveoscleral drainage causing increased outflow
Also: mydriasis, disruption of accommodation
CLIN: glaucoma
clonidine
CLASS: sympathomimetic
CHEM: synthetic
PHARM:
Target- a2-adrenergic receptor (GPCR)
Action- partial agonist
1* signalling: Gi/o
PHYS:
Can enter CNS
Direct action on ventral medulla
Pre-synaptically decreases cAMP decreases Ca2+ influx and NA release
Decreases sympathetic tone
CLIN:Hypertension
adrenoreceptor classification and signalling
acetolazamide
carbonic anhydrase in ciliary processes
Carbonic anhydrase in ciliary processes
Ca –> increases [HCO3-]I –> more Na+ transport
Formation of intracellular HCO3- by CA contributes to the movement of Na+ into the cell, ensuring Na+i is sufficiently high to supply sodium pump with substrate.
HCO3- also enters via the co-transporter with Na+. CA facilitates rapid transport/ diffusion of HCO3- as CO2 between epithelial layers. HCO3- passes into aqueous.
dorzolamide
CLASS: carbonic anhydrase inhinbitor
CHEM: synthetic
PHARM: target- carbonic anhydrases
Action- competitive inhibitor
PHYS:
Decreases [HCO3-] in ciliary epithelia
Decreased HCO3 decreased Na+ substrate for NA+/K+-ATPase
“ decreases pH decreases action of NA+/K+-ATPase
“ decreases co-transport into aqueous with Na+ decreased aqueous formation
CLIN: open-angle glaucoma
pilocarpine
CLASS: parasympathomimetic
CHEM: natural small molceule
PHARM:
Target- muscarinic receptors (GPCR)
Action- non-selective, partial agonist
1* signalling: M1, 3, 5
PHYS:
M3 on ciliary muscle contraction of LCM opening of trabecular meshwork/Schlemm’s canal decreases outflow resistance increases ocular aqueous outflow
Miosis, disruption of accommodation, headache
CLIN: acute closed angle glaucoma
Age related macular degneration
Progressive degeneration of central retinal cells –> vision loss
Classification
Dry (non-neovascular): degeneration without formation of new blood vessels
Wet (neovascular): new vessels form and damage retina
Active- may benefit from treatment
Inactive- changes probably irreversible- unlikely to benefit from treatment
Available drugs all target VEGF pathway
VEGF-A – vascaulr endothelial growth factor
CHEM: homodimer
PHARM: binds to VEGF receptors- receptor tyrosine kinase
PHYS:
Endothelial cell proliferation
Promotes cell migration
Inhibits cell migration
Inhinits apoptosis
Induces permeabilization of blood vessels
CLIN: ANTI-VEGF used in tumours, AMD and diabetic eye disease
Bevacizumab
CLASS: angiogenesis inhibitor
CHEM: IgG
PHARM: target- VEGF-A
Action- blocking
PHYS:
VEGF promotes angiogenesis
Decreased blood vessel formation slows degeneration of retina
CLIN:
Wet-type age related macular degeneration
Ranibizumab
CLASS: angiogenesis inhibitor
CHEM: fab fragment of bevacizumab
PHARM: target- VEGF-A
Action- binding/ blocking
PHYS: VEGF promotes angiogenesis
Decreased blood vessel formation slows degeneration of retina
CLIN: Wet-type age related macular degeneration
Aflibercept
CLASS: angiogenesis inhibitor
CHEM: fusion protein of human IgG Fc and ligand binding domain of VEGRF-1 and VEGRF-2 receptors
PHARM:
Target- VEGF-A and B growth factors
Action- binding/ blocking
PHYS:
VEGF promotes angiogenesis
Decreased blood vessel formation slows degeneration of retina
CLIN: Wet-type age related macular degeneration
