Ocular Pharmacotherapeutics Flashcards
What drugs administered intracamerally induce miosis
carbachol, 0.01%, and acetylcholine, 1%
Acetylcholine is faster acting; however, carbachol is 100 times more effective and longer lasting. In addition, carbachol can lower intraocular pressure.
Which drug is shown to have significant effect on post operative endophthalmitis
Topical povidone-iodine solution (5%). ovidone-iodine can be safely given to patients with an allergy to contrast agents or shellfish; these patients have likely developed hypersensitivity reactions to specific proteins of the food itself (eg, seafood) or to the contrast medium rather than to the iodine in the compound
Effect of proparacaine on the cornea
Topical proparacaine reportedly does not inhibit the growth of Staphylococcus,Candida, or Pseudomonas; thus, it may be preferred to other drugs for corneal anesthesia before scraping a corneal ulcer for a culture
What happens in a Phase 1 drug trial
After animal and in vitro studies, human testing begins. This process involves trials with 10–80 people for collection of toxicology data and pharmacokinetic data on dosage range, absorption, and metabolism
What happens in a phase 2 drug trial
Randomized controlled clinical trials involving a minimum of 50–100 affected people are conducted to determine safety and effectiveness of the drug
What happens in a phase 3 drug trial
Controlled and uncontrolled trials evaluate the overall risk–benefit relation- ship and provide an adequate basis for physician labeling. The data gathered from these tests are then submitted as part of a new drug application for marketing
What is off label drug use
defined as prescribing a drug for an indication or employing a dosage or dose form that has not been approved through the FDA process, is common
What is Triamcinolone used for
the preparation Kenalog is used in intravitreal
and sub-tenon injections of triamcinolone acetonide for a variety of conditions, including macular edema, anterior/ intermediate uveitis, and retinal vein occlusions
Compliance vs Adherence
Medication compliance is the act of taking medication as prescribed, whereas medication adherence is the act of filling new prescriptions or refilling prescriptions on time
Where are cholinergic receptors found
1) Motor end plates of extraocular and levator palpebrae superioris muscles (somatic motor nerves)
2) Cells of superior cervical (sympathetic) ganglion and ciliary and sphenopalatine (parasympathetic) ganglia
3) Parasympathetic effector sites in iris sphincter and ciliary body and in the lacrimal, accessory lacrimal and meibomian glands (postganglionic PNS)
Summary of neurotransmitters released
Autonomic NS (SNS, PNS)
1) Pregnanglionic- Acetylcholine released at Nicotinic receptor
2) Postganglionic- SNS-Norepinehphrine at Adrenergic receptor , PNS Acetylcholine at Muscarinic receptor
Somatic NS Direct Acetylcholine at Nicotinic receptor
Types of adrenergic receptors
Alpha (1 and 2)
Beta (1 and 2)
Types of Cholinergic receptors
Muscarinic
Nicotinic
Agonists at Cholinergic receptors
Acetylcholine
Muscarine
Nicotine
Agonists at Adrenergic receptors
Norepinephrine
Phenylephrine (alpha 1)
Apraclonidine (alpha 2)
Tazolol (beta 1)
Albuterol (beta 2)
Antagonists at cholinergic receptors
Atropine (Muscarinic)
D-Tubocurarine (Nicotinic)
Antagonists at Adrenergic receptors
Prazosin, Thymoxamine, Dapiprazole (Alpha 1)
Yohimbine (Alpha 2)
Betaxolol (Beta 1)
Butoxamine (Beta 2)
What drugs cause miosis
Cholinergic agonists and adrenergic antagonists
What drugs cause mydriasis
Cholinergic antagonists and adrenergic agonists
Action of muscarinic direct acting agonists
Miosis
Contraction of circular fibres of ciliary muscle causing accommodation
Contraction of longitudinal muscles producing tension on scleral spur opening trabecular meshwork
Why is acetylcholine not used topically
Poor penetration of corneal epithelium and rapidly degraded by acetylcholinesterase
What is an adies pupil
Pilocarpine, 0.12%, is used diagnostically to confirm an Adie tonic pupil, a condition in which the parasympathetic innervation of the iris sphincter and ciliary muscle is defective because of the loss of postganglionic fibers. Denervated muscarinic smooth muscle fibers in the affected segments of the iris exhibit supersensitivity and respond well to this weak miotic, whereas the normal iris does not
What is aqueous misdirection
anterior movement of the lens–iris diaphragm. This is a concern particularly in cases of secondary angle closure attributed to anterior rotation of the ciliary body and choroidal edema (eg, malignant glaucoma [also referred to as aqueous misdirection]
Complications of use of high concentration miotics
iris cysts and retinal detachment due to ciliary body contraction and traction on the pars plana
What is the near response
a synkinesis of accommodation, miosis, and convergence
Action of indirect agonists at muscarinic receptors
same actions as direct-acting muscarinic agonists, although they have a longer duration of action and are frequently more potent. 2 classes (reversible and irreversible inhibitors)
What are examples of reversible cholinesterase inhibitors
such as physostigmine (available as a powder for compounding and as a solution for injection), neostigmine, and edrophonium
What are examples of irreversible cholinesterase inhibitors
echothiophate diisopropyl phosphorofluoridate
Complications of patients receiving long term echothiophate
may experience toxic reactions from systemic absorption of local anesthetics containing ester groups (eg, procaine), which are normally inactivated by plasma cholinesterase. Administration of the muscle relaxant succinylcholine during induction of general anesthesia is also hazardous in these patients because the drug will not be metabolized and will prolong respiratory paralysis
Examples of muscarinic antagonists
Atropine
Cyclopentolate
Action of muscarinic antagonists in iridocyclitis
paralyze the ciliary muscles, which helps relieve pain
What are some adverse effects of miotic therapy
Miosis, cataractogenesis, and induced myopia. Although the broad range of retinal dark adaptation usually compensates sufficiently for the effect of miosis on vision during daylight hours, patients taking these drugs may be visually incapacitated in dim light
How do muscarinic antagonists like atropine work
react with postsynaptic muscarinic receptors and block the action of acetylcholine. Paralysis of the iris sphincter, coupled with the unopposed action of the dilator muscle, causes pupillary dilation, or mydriasis
Effects of systemic absorption of topical muscarinic antagonists
A combination of central and peripheral effects, including flushing, fever, tachycardia, constipation, urinary retention, and even delirium, can result
Examples of indirect acting nicotinic agonists
Edrophonium- a short- acting competitive inhibitor of acetylcholinesterase that binds to the enzyme’s active site but does not form a covalent link with it
Pathophysiology of Myasthenia Gravis
a neu- romuscular disease caused by autoimmunity to acetylcholine receptors (nicotinic receptors) in the neuromuscular junction and characterized by muscle weakness and marked fatigability of skeletal muscles. This disease may manifest primarily as ptosis and diplopia. In patients with myasthenia gravis, the inhibition of acetylcholinesterase by edrophonium allows acetylcholine released into the synaptic cleft to accumulate to levels that can act through the reduced number of acetylcholine receptors
What are some uses of nicotinic antagonists
Neuromuscular blocking agents that facilitate intubation for general anesthesia.
What are the 2 types of Nicotinic antagonists
*non-depolarizing agents, including curare-like drugs such as rocuronium, vecuronium, gallamine, and pancuronium, which bind competitively to nicotinic receptors on striated muscle but do not cause contraction
* depolarizing agents, such as succinylcholine and decamethonium, which bind competitively to nicotinic receptors and cause initial receptor depolarization and muscle contraction
Summary of neurotransmitters released
Autonomic NS (SNS, PNS)
1) Preganglionic-Acetylcholine released at Nicotinic receptor
2) Postganglionic- SNS-Norepinehphrine at Adrenergic receptor , PNS Acetylcholine at Muscarinic receptor
Somatic NS Direct Acetylcholine at Nicotinic receptor
Why should depolarising agents not be used to induce general anaesthesia for operations on open globes
because the force of extraocular muscle contractions on the eye, occurring with use of these drugs, could expel intraocular contents
Where are receptors of adrenergic activity found in the eye
1) cell membranes of the iris dilator muscle, the superior palpebral smooth muscle of Müller, the ciliary epithelium and processes, the trabecular meshwork, and the smooth muscle of ocular blood vessels (supplied by postganglionic autonomic fibers from the superior cervical ganglion)
2) presynaptic terminals of some sympathetic and parasympathetic nerves, where the receptors have feedback-inhibitory actions
What do alpha 1 receptors do
generally mediate smooth muscle contraction
What do alpha 2 receptors do
mediate feedback inhibition of presynaptic sympathetic (and sometimes parasympathetic) nerve terminals
What do beta 1 receptors do
found predominantly in the heart, where they mediate stimulatory effects
What do beta 2 receptors do
mediate relaxation of smooth muscle in most blood vessels and in the bronchi
What do beta 3 receptors do
found on fat cells mediating lipolysis
What is the primary clinical use of direct acting alpha 1 adrenergic agonists
such as phenylephrine, is stimulation of the iris dilator muscle to produce mydriasis. Because the parasympathetically innervated iris sphincter muscle is much stronger than the dilator muscle, the dilation achieved with phenylephrine alone is largely overcome by the pupillary light reflex during ophthalmoscopy. Co-administration of a cycloplegic drug allows sustained dilatation.
What is the primary function of alpha 2 adrenergic agonists
Apraclonidine hydrochloride (para-aminoclonidine) is a selective α2-adrenergic agonist and a clonidine derivative that prevents release of norepinephrine at nerve terminals. It decreases aqueous production as well as episcleral venous pressure and improves trabecular outflow
How is apraclonidine used to diagnose Horner syndrome
Apraclonidine can also be used to diagnose Horner syndrome, characterized by denervation hypersensitivity of the α1-receptors in the iris. Under normal conditions, as a weak α1-adrenergic agonist, apraclonidine has no effect on pupil dilation; however, in cases of Horner syndrome, instillation of the drug results in dilation of the affected pupil
Limitation of long term use of apraclonidine
Tachyplaxis
Brimonidine vs Apraclonidine
Brimonidine tartrate is another selective α2-adrenergic agonist. Compared with apraclonidine, brimonidine tartrate is more α2 selective, is more lipophilic, and causes less tachyphylaxis during long-term use. The rate of reactions, such as follicular conjunctivitis and contact blepharodermatitis, is also lower (less than 15% for brimonidine but up to 40% for apraclonidine). Cross-sensitivity to brimonidine in patients with known hyper- sensitivity to apraclonidine is minimal.
How does Brimonidine work to lower intraocular pressure
involve both decreased aqueous production and increased uveoscleral outflow. As with β-blockers, a central mechanism of brimonidine, 0.2%, may account for some IOP reduction
Is Brimonidine neuroprotective
brimonidine may have neuroprotective properties that are independent of IOP reduction. the pro- posed mechanism of neuroprotection is upregulation of a neurotrophin, basic fibroblast growth factor, and cellular regulatory genes
Why is Brimonidine contraindicated in infants
Severe systemic toxicity, with hypotension, hypothermia, and bradycardia, has been reported in infants
What are some indirect acting adrenergic agonists
cocaine, 4% or 10%, and hydroxyamphetamine, 1%
What is the sympathetic pathway for iris muscle dilation
pupil response fibers originating in the hypothalamus pass down the spinal cord to synapse with cells in the intermediolateral columns. In turn, preganglionic fibers exit the cord through the anterior spinal roots in the upper thorax to synapse in the superior cervical ganglion in the neck. Finally, postganglionic adrenergic fibers terminate in a neuroeffector junction with the iris dilator muscle
Examples of adrenergic antagonists
Thymoxamine hydrochloride (moxisylyte), an α1-adrenergic blocking agent, acts by competitively inhibiting norepinephrine at the receptor site. Thymoxamine inhibits α-adrenergic receptors of the dilator muscle of the iris and causes pupil constriction; however, it has no significant effect on ciliary muscle contraction and therefore does not induce substantial changes in anterior chamber depth, facility of outflow, IOP, or accommodation in POAG
Ciliary muscle function
anterior chamber depth, facility of outflow, or accommodation
Action of beta 2 agonists
lower IOP by improving trabecular outflow and possibly by in- creasing uveoscleral outflow. The beneficial effect on outflow more than compensates for a small increase in aqueous inflow as detected by fluorophotometry. The effect on outflow facility seems to be mediated by β2-receptors
How is norepinephrine synthesiszed
1) Hydroxylation of tyrosine
2) Tyrosine–>DOPA–>Dopamine.
3) Dopamine–> Norepinephrine
4) Norepinephrine methylated by COMT and oxidised by MAO (to break it down post action)
Examples of beta adrenergic antagonists
β-blockers, lower IOP by reducing aqueous humor production by as much as 50%. Six β-blockers are approved for use in the treatment of glaucoma: timolol maleate, levobunolol, metipranolol, carteolol, betaxolol, and timolol hemihydrate
How are beta adrenergic antagonists thought to work
it is likely that the site of action is the ciliary body, it is not known whether the vasculature of the ciliary processes or the pumping mechanism of the ciliary epithelium is primarily affected. A possible mechanism may be an effect on the β-adrenergic receptor–coupled adenylate cyclase of the ciliary epithelium.
Symptoms of beta blockade
inhibit the increase in pulse and blood pressure that is exhibited in response to exertion. Nonselective β-blockers inhibit the pulmonary β2-receptors that dilate the respiratory tree. The induced bronchospasm may be significant in patients with asthma or chronic obstructive lung disease
beta 1 vs beta 2 blockers on aqueous secretion
β2-antagonists have a greater effect on aqueous secretion than do β1-antagonists.comparative studies have shown that the specific β1-antagonist betaxolol, 0.5%, is approximately 85% as effective as timolol in lowering IOP
Examples of carbonic anhydrase inhibitors
acetazolamide and methazolamide are approved for the treatment of glaucoma and idiopathic intracranial hypertension (IIH, also known as pseudotumor cerebri), in addition to other systemic conditions
Onset and duration of action of Diamox
Onset 1-1.5hrs
Duration 8-12 hours
How do carbonic anydrase inhibitors work
In addition to lowering IOP by inhibiting ciliary body carbonic anhydrase, each drug at high doses further lowers IOP by causing renal metabolic acidosis. The mechanism by which acidosis lowers secretion is uncertain, but it probably involves reduction in HCO–3 formation and activity of Na+,K+-ATPase.
Side effect of carbonic anhydrase inhibitors
loss of Na+, K+, and HCO–3. In patients receiving CAI therapy concurrently with diuretics, steroids, or adrenocorticotropic hormone (ACTH), severe hypokalemia can result. This situation may be dangerous for patients using digitalis, in whom hypokalemia may elicit arrhythmias.
Kidney stones ++
Examples of topical CAI
dorzolamide and brinzolamide
Adverse effects of topical CAI’s
burning on instillation, punctate keratitis, local allergy, and bitter taste
Examples of prostaglandin analogues
Latanoprost, bimatoprost, travoprost, and tafluprost are administered once daily, with nighttime dosing; unoprostone is used twice daily.
How do prostaglandin analogues work
interact with the prostaglandin FP receptor. In contrast, bimatoprost is not a prodrug, and it acts on the prostamide receptor
