Ocular Adrenergic Agonist and Antagonist Drugs PDF

Ocular Adrenergic Agonist and Antagonist Drugs Jose M De Jesus, OD, MD, MA, FAAO Review of Nervous System (PNS) (CNS) Brain Spinal Chord (ANS) Ocular Autonomic Nervous System Efferent Innervation Somatic (voluntary) Autonomic (involuntary/ Visceral) Sympathetic Parasympathetic Ocular Au...

Ocular Adrenergic Agonist and Antagonist Drugs Jose M De Jesus, OD, MD, MA, FAAO Review of Nervous System (PNS) (CNS) Brain Spinal Chord (ANS) Ocular Autonomic Nervous System Efferent Innervation Somatic (voluntary) Autonomic (involuntary/ Visceral) Sympathetic Parasympathetic Ocular Autonomic Nervous System • Efferent (motor) and Afferent (sensory) • Efferent in the eye 1. Includes the sympathetic and parasympathetic 2. Three synapses in the sympathetic system a. Central b. Pre-ganglionic b. Post-ganglionic-organ effector • Afferent in the eye – parasympathetic only Ocular Autonomic Nervous System • Sympathetic Neurotransmitters 1. The neurotransmitter in the central and pre-ganglionic synapse is acetylcholine 2. For the sympathetic post-ganglionic synapse the neurotransmitter is norepinephrine, *adrenergic action 3. In some post-ganglionic site the neurotransmitter is still acetylcholine Ocular Autonomic Nervous System • Neurotransmitters Ocular Autonomic Nervous System • Physiologic Efferent Pupillary (Motor) Response 1. Iris Sphincter - constrict the pupil via parasympathetic innervation - the action is cholinergic (acetylcholine) 2. Iris Dilator - dilates the pupil via sympathetic innervation - the action is adrenergic (nor-epinephrine) Ocular Autonomic Nervous System • Post-ganglionic Receptors and Effector Structure - Alpha (a) 1 receptors 1. Dilation by dilator muscle contraction 2. Lid elevation by Mueller muscle contraction 3. Contraction of SM conjunctival arteriole Ocular Autonomic Nervous System • Post-ganglionic Receptors and Effector Structures - Alpha (a) 2 and receptors 1. Inhibitory response 2. Relaxation of dilator muscle – miosis 3. Decrease active secretion in aqueous (CBNPE) humor production - Beta (b) 2receptors – increase secretion in aqueous humor production (CBNPE) Efferent Oculosympathetic pathway Efferent Oculosympathetic Pathway • Oculo-sympathetic pathway 1st order neuron trajectory - Originates at the hypothalamus ( posterior and lateral nuclei) - Fibers descend through the lateral aspect of the brainstem and into the intermediolateral columns of the cervical aspect of the spinal cord - Synapses at a group of cell at the level of C-8 through T1-2 (Ciliospinal center of budge and Waller - Neurotransmitter is acetylcholine Efferent Oculosympathetic Pathway nd • Oculo-sympathetic pathway 2 order neuron trajectory - Fibers exit the spinal cord through the ventral roots and travel towards the sympathetic trunk via the white rami comunicante - Before passing by the apex of lung and around the subclavian artery fibers pass through the stellate ganglion - Then ascend parallel to the common carotid artery passing through the inferior and middle cervical ganglion and synapsing at the superior cervical ganglion approximately at the level of the bifurcation of the common carotid (hyoideum bone) - Neurotransmitter is acetylcholine Efferent Oculosympathetic Pathway • Oculo-sympathetic pathway 3rd order neuron trajectory - Some post-ganglionic fibers follow the trajectory of the external carotid (innervate sweat glands and arteries of that side of the face) - The rest of the fibers follow the trajectory of the internal carotid - In their ascendance some of the fibers traveling with the internal carotid leave the path and enter the middle ear and join the tympanic branch of the glossopharengeal nerve (IX) to form a tympanic plexus referred to as the carotico-tympanic nerve Efferent Oculosympathetic Pathway • Oculo-sympathetic pathway 3rd order neuron trajectory - These fibers then leave the plexus and rejoin the trajectory with the other post-ganglionic fibers before entering the cavernous sinus - Some of the fibers exiting the cavernous sinus join the ophthalmic nerve and enter the orbit through the superior orbital fissure - Inside the orbit they continue their course with nasociliary nerve and finally entre the globe in the long ciliary nerve -Once inside eye some fibers direct towards the ciliary body and the rest innervate the dilator pupillae Efferent Oculosympathetic Pathway • Oculo-sympathetic pathway 3rd order neuron trajectory - The rest of the fibers exiting the cavernous sinus continue the trajectory of the internal carotid and subsequently the branching-off of the ophthalmic artery and enter the orbit through the superior orbital fissure - Inside the orbit vasomotor fibers pass through the ciliary ganglion enters the globe in the short ciliary nerve and innervate blood vessels of the uveal tract - The rest of the fibers do not enter the globe and innervate Muller’s muscle, lacrimal gland and sweat glands of the forehead Direct Adrenergic Agonists (Sympathomimetics) Direct Sympathomimetics ▪ Epinephrine a. Endogenous epinephrine is the counterpart of nor epinephrine b. Medulla of the adrenal gland c. hormone-like, aka as adrenaline d. mixed agonist e. inactivated almost immediately Direct Sympathomimetics ▪ Epinephrine e. conjunctival vasoconstriction d. Hypotensive effect – 1% (Eppy) for Tx POAG; increases uveal scleral outflow f. Dx of Horner’s syndrome – post-ganglionic Direct Sympathomimetics ▪ Epinephrine g. Ocular toxic side effect ( topical) - Maculopathy – 20-30% of aphakic patients; reversible Direct Sympathomimetics ▪ Epinephrine g. Ocular toxic side effect ( topical) - Madarosis – reversible - Pigment deposit on tarsal conjunctiva (oxidized epinephrine), mostly seen in elderly pts - Allergic reactions h. Topical side effects - Burning, ha’s, paradoxic conj. hyperemia Direct Sympathomimetics ▪ Epinephrine j. Not indicated in patients with narrow angles Direct Sympathomimetics ▪ Phenylephrine a. Synthetic, structurally similar to epinephrine b. virtually an alpha 1 agonists c. 0.12%, 2.5%, 10.0%* d. sodium bisulfite e. dilation, Mueller’s, conjunctival arterioles f. variable hypotensive effect Direct Sympathomimetics ▪ Phenylephrine h. Clinical uses - Partial dilation 1) 2.5% and 10%* 2) 45-60 min., 6-7 hrs. 3) No clinical cycloplegia 4) MEC 5% (no difference between 2.5% and 10% in dark eyes) Direct Sympathomimetics ▪ Phenylephrine h. Clinical uses - Posterior synechiae (10%) Direct Sympathomimetics ▪ Phenylephrine h. Clinical uses - Posterior synechiae (10%) - Pupillary cysts (2.5%) - Horner’s ptosis (0.125%) - Dx Horner’s (1%) - Conjunctival hyperemia (0.125%); caution with patients that have narrow angles (hyperreactive patients and cases of corneal abrasion can produce up to 1-1.5 mm mydrasis Direct Sympathomimetics ▪ Phenylephrine i. Ocular side effects - Lacrimation due to irritative effect - Pain, keratitis - Allergic dermatitis - Iris pigment drop out - Rebound miosis - Decrease in conjunctival and iris po2 with chronic use 1) Vasoconstriction of conjunctival and iris vasculature 2) Blood flow reduction 3) Hypoxia Direct Sympathomimetics ▪ Phenylephrine j. Systemic side effects - Episodes of rise in blood pressure have been seen (10%) 1) The National Registry of Drug Induced Ocular Side Effects a) age b) DMI, CD, advance arteriosclerosis, HTN c) One application/hr d) No prolonged contact time - Ventricular tachycardia, reflex bradycardia, subarachnoid hemorrhage Direct Sympathomimetics ▪ Phenylephrine k. Drug interaction (10%) - Tricyclic antidepressants and MAO inhibitors enhances its cardiovascular effect - Guanethedine - Methyldope potentiates the effect on adrenergic receptors - Atropine i. Contraindications (10%) - Idiopathic hypotension - Parkinson’s - History of hyper-reaction - Malignant hypertension - Aneurysm Indirect Adrenergic Agonists (Sympathomimetics) • Hydroxyamphetamine • Cocaine Indirect sympathomimetics • Hydroxyamphetamine a. 1% conc., paredrine b. mode of action - liberates nor epinephrine from the pre-synaptic vesicle at the neuromuscular junction c. very little effect on accommodation Indirect sympathomimetics ▪ Hydroxyamphetamine d. clinical uses - Partial dilation - 1% sol. 1) Comparable w/ 10% phenyl. 2) Paremyd (combo w/ .25% tropicamide) - Differentiate between central /2nd and 3rd neuron in Horner’s Syndrome Indirect sympathomimetics ▪ Hydroxyamphetamine e. Ocular side effects - moderate irritation f. Systemic side effects - Rare (little use as a mydriatic in comparison with phenylephrine) - Some cases of rise in blood pressure have been reported (but is characterized by tachyphylaxis) g. Contraindications similar to phenylephrine Indirect Sympathomimetics ▪ Cocaine a. Anesthetic action and blocks the reuptake of norepinephrine b. Not commercially available in ophthalmic solution c. Salt form (HCL) is diluted in aqueous solution for (1%, 4%, and 10%) for ophthalmic use d. Clinical uses - Force duction test - Dacryocystorhynostomy - Epithelial iodine cauterization - Horner’s syndrome Indirect Sympathomimetics ▪ Cocaine a. Anesthetic action and blocks the reuptake of norepinephrine X Blocks the re-uptake of NE Indirect Sympathomimetics ▪ Cocaine e. Adverse effects - Ocular 1) Grayish irregular depressions of corneal epithelium 2) Epithelial corneal erosion - Systemic 1) Restlessness and anxiety 2) Nausea, vomiting, abdominal pain 3) Rapid irregular pulse 4) Respiratory failure > death f. Drug interaction 1) Monoaminoxidase inhibitors 2) Tricyclic antidepressant 3) Methyldope Physiological Differential Diagnosis of a Miotic Pupil Post-ganglionic Neural Activity in Horner’s Central Lesion Pre-ganglionic Lesion Nerve ending NE NE Dilator muscle Intact OculoSympathetic system NE NE NE NE NE Post-ganglionic Lesion NE Pharmacological Differential Diagnosis of a Miotic Pupil MIOTIC PUPIL 10% COCAINE INSTILLATION (2 POSSIBILITIES) NORMAL DILATION Dx: PHYS. ANISOCORIOA NO DIALTION Dx: SUGGESTS HORNER’S SYNDROME 1% HYDROXYAMPHETAMINE DILATION Dx: 1ST OR 2ND ORDER NEURON HORNER’S SYNDROME NO DILATION OR MINIMAL Dx: 3RD ORDER NEURON HORNER’S SYNDROME Study on Dx of Horner’s “We found that simply measuring the postcocaine anisocoria provided a better prediction of Horner's syndrome than taking the trouble to calculate the net change in anisocoria.” A postcocaine anisocoria value of 0.8 mm was is indicative of Horner's syndrome. Critical Evaluation of the Cocaine Test in the Diagnosis of Horner's Syndrome Randy H. Kardon, MD, PhD; Chad E. Denison; Carl K. Brown, MS; et alH. Stanley Thompson, MD Arch Ophthalmol. 1990;108(3):384-387. doi:10.1001/archopht.1990.01070050082036 Selective Adrenergic Agonist Selective Adrenergic Agonist • Aproclonidine 1) Iopidine 0.5% 2) mainly alpha 2 agonist 3) 1% concentration pre and post-operatively in anterior segment laser procedures 4) mode of action – decreases aqueous humor production, may have some effect in the uveo-scleral outflow 5) exhibits tachyphylaxis – primarily used as short term therapy on patients awaiting on glaucoma surgery 6) minimal side effects Selective Adrenergic Agonist • Brimonidine tartrate 1) Alphagan P 0.2% 2) alpha 2 agonist primarily 3) mode of action – decreases aqueous production 4) mode therapy – bid 5) IOP reduction similar to Timoptic 6) side effects a. may cause increased blood pressure in some patients b. blanching test before prescribing Selective Adrenergic Agonist • Brimonidine tartrate 0.025%ophthalmic solution 1) Lumify - over-the-counter (OTC) brimonidine tartrate for the treatment of conjunctival hyperemia 2) 1 drop in the affected eye(s) every 6-8 hours Ophthalmic Adrenergic Antagonists Dapiprazole (Mydriolytic agent) • Rev-eyes 0.5% • Listed in the “Discontinued Drug Product List” section of the Orange Book since 2013 • Effect on mydriasis 1. Reversably blocks ά-receptors (1) on in dilator muscle 2. Dilator muscle relaxation 3. Almost complete reversal on phenylephrine 4. Partial reversal on tropicamide •Side effects 1. Transient hyperemia 2. Superficial punctate keratitis (stability for 3 weeks) 3. Ptosis • Contraindicated in inflammatory processes Ophthalmic Beta Blockers • Reversible blockage of beta receptors at CBNPE • Ocular hypotensive effect by decrease active secretion in aqueous humor production - IOP • 20-22% IOP reduction, approx. 10% on the fellow eye • All except one are non-selective (the remaining is cardio selective) Ophthalmic Beta Blockers • Non-selective 1) Timolol Maleate a. Timoptic 0.25, O.5; XE 0.5%, ocudose PF ; Betimol 0.5% b. new mode of therapy – 0.25% qd AM c. maximum effect in 3 weeks d. washout period 1-2 months e. liposoluble substance f. Cosopt Ophthalmic Beta Blockers • Non-selective 2) Levobunolol a. Betagan 0.25%, 0.5% b. same indications as Timoptic c. more effective in some patients d. more side effects in some patients 3) Carteolol a. Ocupress 1% b. mode of therapy – bid c. equally as effective as Timoptic d. less effective than Betagan in some patients e. hydrosoluble substance (less side effects) f. increases the ratio of high density lipids to total cholesterol Ophthalmic Beta Blockers • Cardio-selective - Betaxolol a. Betoptic S 0.25 % suspension b. beta-1 blocker (safer in asthmatic patients) c. mode of therapy – qd AM d. calcium channel blocker activity e. careful with sulfa allergies Ophthalmic Beta Blockers • Systemic side effects 1) mask of hypoglycemic effects in patients under diabetic treatment 2) bronchial asthma (non-selective) 3) bradycardia (hypotension) 4) mental depression (except Ocupress) • Ocular side effects 1) allergic conjunctivitis 2) transient burning and irritation 3) corneal hypesthesia causing dry 4) ocular myasthenia 5) superficial punctate keratitis (SPK) Ophthalmic Beta Blockers • Contraindications 1) chronic obstructive pulmonary disease (COPD) 2) bronchial asthma 3) congestive heart failure (CHF) 4) bradycardia 5) hypotension Combo Alpha Agonist/Beta Blocker