Exam 3: Cholinergic Neurotransmission and Cholinomimetics Flashcards

1
Q

What are the sites the of drug actions for cholinergic neurotransmission?

A
  1. Synthesis
  2. Storage
  3. Release
  4. Receptort binding
  5. Degradation
  6. Reuptake/ recycling
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2
Q

How does hemicholinium interfere with cholingeric site of action?

A

Blocks the reuptake of choline by CHT

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3
Q

How does Vesamicol interfere with cholingeric site of action?

A

Inhibits ACh reuptake into a synaptic vesicles

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4
Q

How does Botulinum toxin interfere with cholingeric site of action?

A

Inhibits Snaps from releasing synaptic vesicle containing the ACh

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5
Q

How does black widow venom toxin interfere with cholingeric site of action?

A

Increases the release of ACh into the neuromuscular junction

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6
Q

How does neostigime interfere with cholingeric site of action?

A

Inhibits ACh breakdown from cholinergic receptor

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7
Q

Where are M1 receptors found?

A

Nerves, CNS, ganglia, gastric parietal cells

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8
Q

What is the G protein associated with M1?

A

Gq

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9
Q

What secondary messengers are stimulated by Gq M1 receptors?

A

Increased IP3, depolarization from decreased K+ current

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10
Q

Where are M2 receptors the found?

A

Heart, nerves, smooth muscle

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11
Q

What secondary messengers are stimulated by Gi?

A
  1. Decrease in cAMP
  2. Increase K+ currents
  3. Decrease in Ca++ current
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12
Q

What is the G protein associated with M2?

A

Gi

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13
Q

Where are M3 receptors found?

A

Exocrine glands, smooth muscle, endothelium

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14
Q

What secondary messengers are stimulated by Gq M3 receptors?

A

Increased IP3
Increased Ca++ current

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15
Q

What G protein is associated with M4?

A

Gi

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16
Q

What G protein is associated with M5?

A

Gq

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17
Q

Describe the structure of a nicotinic receptor?

A
  1. 5 separate proteins subunits
  2. Cation selective the channels (Na+ and Ca2+)
  3. 2 ACh binding sites on alpha subunits
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18
Q

What protein subunits are found of muscle nicotinic receptors?

A

a1, b1, δ, y (e for y in fetus)

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19
Q

What protein subunits are found of neuronal nicotinic receptors?

A

a and b subunits (mostly a3/b4 and a4/b2)

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20
Q

Compare the response rates of nicotinic and muscarinic stimulation by ACh?

A

N: Fast (milliseconds)
M: Slow (seconds)

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21
Q

What are the types of ACh receptors?

A

Muscarinic and Nicotinic

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22
Q

What are the types of the muscarinic receptors?

A

M1-5
Various target tissues

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23
Q

What are the types of nicotinic receptors?

A

Muscle and neuronal

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24
Q

What receptors are associated with skeletal muscles?

A

Muscle nicotinic receptor

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25
What are the types of autonomic ganglia?
Sympathetic and parasympathetic
26
What receptors are associated with parasympathetic ganglia?
Neuronal nicotinic receptor
27
What are the receptors associated with autonomic tissue targets?
Muscarinic receptors
28
Describe the cholingeric system in the CNS?
1. Modulates neurotransmission 2. Role in cognition and learning 3. Both muscarinic and neuronal nicotinic
29
What is the function of cholinergic agonists?
1. Mimics the effects of ACh in PNS or NMJ 2. Increase ACh that binds to nicotinic and muscarinic 3. Inhibit the degradation of ACh increasing ACh in the synapse
30
What are examples of direct-acting cholinergic agonists?
Alkaloids and choline esters
31
What are the examples of indirect acting cholinergic agonists?
Reversible and irreversible
32
What are direct acting cholinergic agonists?
Drugs that bind directly to cholinergic receptors
33
How does direct acting cholinergic agonists affect the heart?
1. Decreases conduction 2. Slower contractions 3. Bradycardia
34
How does direct acting cholinergic agonists affect the vasculature?
1. Vasodilation 2. Decrease PVR
35
How does direct acting cholinergic agonists affect the visceral smooth muscle?
1. Increased GI motility 2. Increase in detrusors muscle tone 3. Decrease in sphincter tone 4. Bronchiolar constriction
36
How does direct acting cholinergic agonists affect the eyes after direct application?
1. Mitosis (constriction) 2. Ciliary muscle contraction and accommodation to near vision 3. Decrease in ocular pressure
37
How does direct acting cholinergic agonists affect the exocrine glands?
Increases secretion 1. Salivary 2. Sweat 3. Lacrimation 4. Gastric, intestinal, pancreatic 5. GIT mucous membrane
38
What are the types of choline esters?
1. Acetylcholine 2. Methacholine 3. Carbachol 4. Bethanechol
39
Describe the selectivity of acetylcholine?
Muscarinic and nicotinic
40
What is the clinical use for acetylcholine?
Ophthalmology (miochol)
41
What is the clinical use for methacholine?
Test bronchial hyper-reactivity (Provocholine)
42
What is the selectivity of methacholine?
More selective toward muscarinic than nicotinic but bind to both
43
What is the selectivity of carbachol?
Selective for both, slightly more the nicotinic
44
What is the clinical use for carbachol?
Ophthalmology
45
What is the selectivity of bethanechol?
Muscarinc
46
What is the clinical use for bethanechol?
Bladder and GI hypotonia (Urecholine)
47
Why are acetylcholine anad methacholine lousy for systemic use?
Susceptible to AChE hydrolysis
48
What are the types of alkaloid analogs?
1. Muscarine 2. Pilocarpine 3. Cevimeline 4. Nicotine
49
What is the selectivity of muscarine?
Muscarinic
50
What is the selectivity of pilocarpine?
Muscarinic
51
What are the clinical uses of pilocarpine?
1. Glaucoma 2. Xerostomia (dry mouth) 3. Causes excessive sweating
52
What is the selectivity of cevimeline?
Muscarinic (M3)
53
What are the clinical uses of cevimeline?
1. Xerostomia 2. Sojourn's syndrome
54
What is the selectivity of nicotine?
Nicotinic
55
What is the clinical use of nicotine?
Smoking cessation
56
How are the GIT and GUT affected by cholinomimetic toxicity?
Cramps Hypermotility Diarhea Vomiting Salivation Urination
57
How is the respiratory affected by cholinomimetic toxicity?
Excessive secretion Bronchoconstriction Dyspnea
58
How is the cardiovascular affected by cholinomimetic toxicity?
1. Bradycardia 2. Hypotension 3. Shock
59
What are the affects of nicotinic cholinomimetic toxicity?
Muscle fasciculation Weakness Paralysis
60
How is the CNS affected by cholinomimetic toxicity?
Convulsions Confusion Coma
61
How do you treat antimuscarinic actions?
Atropine (or muscarinic receptor antagonist)
62
How is the exocrine gland affected by cholinomimetic toxicity?
Perfuse sweating, flushed skin, and excessive lacrimation
63
In what ways does direct acting cholinergic agonist evoke SLUD?
1. Salivation and sweating 2. Lacrimation (miosis) 3. Urination 4, Defecation and diarrhea
64
What is the purpose of indirect cholinergic agonists?
Increases ACh in the synapse by inhibiting AChE allowing more ACh to bind to muscarinic or nicotinic receptors
65
Describe the mechanism of ACh neurons
1. Choline binds with Ac-CoA by choline acetyltranferase in presynaptic neuron 2. ACh is transferred in the synaptic vesicle and pushed to the synapse 3. ACh is released and binds to postsynaptic receptor 4. AChE degrades molecule to choline and acetic acid 5. Choline is recycled into presynaptic neuron through choline transporter
66
Describe how ACh hydrolysis occurs
1. ACh binds to th anionic and esteratic site (active center serine) 2. acetyl enzyme breaks of choline from site 3. Hydrolyses breaks of acetic acid from serine on esteratic site
67
Describe the types of AChE enzyme binding?
1. Simple alcohol binds to enzyme reversibly therefore short acting 2. Carabamates are medium to long lasting AChEI (30 min-hrs) 3. Organophosphates bind irreversibly and very long acting (many hours-days)
68
What are pharmacologic actions of ACHEI of heart?
Decreased conduction, velocity, and bradycardia
69
What are pharmacologic actions of ACHEI of visceral smooth muscle?
Bladder, GIT, bronchiolar constriction
70
What are pharmacologic actions of ACHEI of the CNS?
Alzheimer's disease
71
What are pharmacologic actions of ACHEI of the eyes?
1. Mitosis (Iris contraction) 2. Ciliary muscle contraction for near vision 3. Decreased intraocular pressure
72
What are pharmacologic actions of ACHEI of exocrine glands?
Increase 1. Salivary 2. Sweat 3. Lacrimal 4. Gastric, intestinal, pancreatic 5. Mucous membrane in GIT
73
What are the primary therapeutic targets of AChE inhibitors?
Skeletal muscle CNS Eyes
74
What is edrophonium (tensilon)?
1. Short-acting reversible indirect agonist to AChE 2. Quaternary nitrogen binds to anionic site (Glu) of the AChE enzyme 3. Hydrogen binding to imidazole nitrogen group of the histidine and hydroxyl group of active site serine (minor) 4. AChE can't degrade do to edrophonium binding
75
What is the site of action for edrophonium (tensilon)?
1. NMJ 2. Diagnosis myasthenia graves 3. 5-15 minute action
76
What makes edrophonium short acting?
Lack of carbamoyl makes it have rapid renal elimination
77
What is the function of carbamate AChEI?
Medium-acting AchE binding
78
What are the characteristics of carbamate AChEI?
1. Carbamate ester 2. Tertiary and quaternary amines 3. Reversible
79
What are the benefits of using carbamate as and AChEI?
More difficult and stable to hydrolysis than the acetylated enzyme therefore longer duration of 1-6hr
80
Why is Carbamate AChI considered a suicide inhibitor?
Parente compound is cleaved by enzyme to induce reversibility
81
Describe the mechanism to which neostigmine binds to AChE?
Binds to serine relatively fast, carbamate-serine hydrolysis slowly therefore inhibiting AChE
82
What are examples of medium-acting AChEI?
1. Neostigmine 2. Physostigmine 3. Pyridostigmine
83
What the duration of action for medium-acting AChEI?
Neostigmine and Physostigmine (1-2hrs) Pyridostigmine (3-6hrs)
84
What is the function of neostigmine (prostigmin)?
Used to reverse competitive neuromuscular block, oral treatment of myasthenia gravis
85
What is the function of pyridostigmine (mestinon)?
Used orally for myasthenia gravis. Better absorption and duration of action than Neostigmine
86
What is the function of physostigmine (antilirium)?
Used in eye drops for treatment of glaucoma, reversal of antimuscarinic overdose
87
Identify this drug?
Neostigmine (prostigmin)
88
Identify this drug?
Pyridostigmine (mestinon)
89
Identify this drug?
Physostigmine (antilirium)
90
What is myasthenia gravis?
Common chronic autoimmune neuromuscular disorder that causes flactuating weakness of voluntary muscle groups
91
Why does myasthenia gravis cause muscle weakness?
Reduction in nicotinic receptor sites is caused by the an antibody that destroys or blocks receptor sites (at least 80% reduction in ACh receptor sites)
92
How is myasthenia gravis treated?
Anti-ACh agents (mestinon) allow Ach to remain at neuromuscular junction longer so that more receptor sites can be activated
93
What is dementia?
1. Decline in memory 2. Decline in intellectual functioning 3. Behavioral and personality changes
94
What are the types of dementias?
Irreversible and reversible
95
What are examples of irreversible dementia?
1. Alzheimer's (50-70%) 2. Vascular dementia 3. Lewy bodies dementia 4. Frontotemporal dementia (Pick's) 5. Parkinson's 6. Creutzfeldt-Jakob 7. Huntington's
96
What are examples of reversible dementia?
1. Delirium 2. Depression 3. Alcohol 4. Infections 5. Normal Pressure hydrocephalus (NPH)
97
What is an example drug that is associated with delirium?
Diphenhydramine (Anticholinergic activity)
98
What causes Alzheimers
1.Production of b-amyloid1-42 linked to APP mutations 2. thNeurofibrillary tangles and hyperphosphorylated tau leading to neuronal cytoskeletal degredation
99
What are the results of plaques and tangles?
1. Loss of dendritic and synapses 2. Neuronal atrophy and loss of cortical neurons causing enlarged ventricles in the brain
100
What are the neurochemical changes associated with Alzheimers
1. Decline in choline acetyltransferase and cholinergic activity in the nucleus basalts/medial septal nucleus affects cholinergic neurons of cerebral cortex, amygdala, hippocampus 2. Loss of cholinergic neurons are linked to the cognitive & memory deficits seen in Alzheimer's Disease 3. Loss of nicotinic receptor subtypes
101
What are the two forms of choline esterase's?
AChE and pseudocholinesterase (BuChE)
102
What is the difference between AChE and BuChE?
A: targets the CNS to increase ACh B: Butyrylcholinesterase (plasma)
103
What are the drug used to treat dementia?
Reversible cholinesterase inhibitors 1. Tacrine 2. Rivastigmine 3. Donepezil 4. Galantamine
104
What are the benefits of treating Alzheimers with AChEI?
1. May improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild to moderate AD 2. Don't alter the neurogenerative processes
105
What is the dosage schedule for someone with mild to moderate AD?
Donepezil (5 or 10 mg) for 38 weeks Rivastigmine (6-12 mg) for 38–42 weeks Galantamine (24 mg) for 52+ weeks
106
What is the disadvantage of delaying Alzheimers treatment?
Loss of potential benefit
107
What is the mechanism of action for Donepezil (Aricept)?
1. Reversible and noncompetitive inhibitor of AChE 2. Highly selective for CNS AChE minimizing systemic adverse effects
108
What is the adverse effect ofDonepezil?
Gastrointestinal including N/V, diarrhea, & anorexia.
109
Describe the pharmacokinetics of Donepezil?
1. 100% oral bioavailability, 96% protein bound (75% to albumin) 2. Metabolized by CYP 2D6 and 3A4 and cleared renally 3. T1/2 is 60 hours in younger adults, but can be up to 100 hours in the elderly
110
Identify this drug?
Donepezil (Aricept)
111
What is the mechanism of action for Rivaastigmine (Exelon)?
1. Carbamate AChEI (semi-reversible) 2. Selective towards AChE and BuChE 3. Preferentially inhibits the G1 isoform of AChE that is selective for cortical and hippocampal AChE
112
What are the adverse effects of Rivastigmine (Exelon)?
1. GI including N/V, diarrhea, abdominal pain, anorexia. 2. Increased REM sleep density with decreased quality and quantity of sleep
113
Describe the pharmacokinetics of Rivastigmine (Exelon)?
1. 40% oral bioavailability 2. Food slows absorption 3. Metabolized primarily by cholinesterase-mediated hydrolysis to the decarbamylated metabolite and eliminated via kidneys
114
Identify this drug?
Rivastigmine (Exelon)
115
What is the mechanism of action for Galantamine (Razadyne)?
Found in bulbs of daffodils and snowdrop 1. Competitively and reversibly inhibits AChE in peripheral and central cholinergic synapses and PNS 2. Allosterically modulates nAChR that potentiates a response
116
What are the adverse effects of galantamine?
1. Gastrointestinal including N/V, diarrhea, & anorexia 2. CNS (~10%) – dizziness (37%), HA, tremor, depression, insomnia, agitation 3. Long-term clinical benefit is debatable after “loss of benefit”.
117
Describe the pharmacokinetics of galantamine?
Metabolized by CYP2D6 and CYP3A4 and renal excretion
118
What are the drug interactions of galantamine?
Increased donepezil and galantamine plasma concentration by inhibitors of CYP 3A4 and CYP 2D6
119
What are the types of reversible indirect cholinergic agonists?
Endophonium and carbamates
120
What are examples of irreversible indirect cholinergic agonists?
Organophosphate and insecticides
121
What is the general structure of organophosphate AChEI?
1. Phosphate 2. R1 and R2 can vary (Alkyl, alkoxy, halides, aryloxy) 3. AChE enzyme cleaves the “leaving” group 4. X defines the family of the agent: a good leaving group such as: halogen, cyanide, thiocyanate, alkylthio, alkoxy, aryloxy thiophosphate, pyrophosphate, quaternary ammonium
122
What is the mechanism for organophosphate inhibition of AChE?
Organophosphates form a covalent bond between the phosphate and the hydroxyl group of the active site serine OH on phosphate group is hydrolyed
123
What are examples of AChEI that are long-acting and irreversible?
1. Isoflurophate (DFP, Dyflos) 2. Echothiophate (Phospholine) 3. Parathion
124
What is isoflurophate (DFP, Dyflos)?
1. Highly toxic and potent 2. Long acting inhibition 3. Once used for glaucoma 4. Related to nerve gases
125
What is echothiophate (phospholine)?
1. Eye drops for glaucoma 2. Prolonged duration of action 3. Can cause systemic effects if swallowed 4. Only therapeutic agent in this class
126
Identify this drug?
Isoflurophate (DFP Dyflos)
127
Identify this drug?
Echothiophate (Phospholine)
128
What are examples of nerve gas agents that are irreversible ACHEI?
1. Tabun 2. VX 3. Sarin 4. Soman
129
What are examples of insecticides that are irreversible AChEI?
1. Parathion 2. Chlorpyrifos (CPF)
130
What receptors are affected by organophosphates?
1. Muscarinic in the PNS 2. Nicotinic at NMJ 3. Neuronal nicotinic and muscarinic receptors in CNS
131
What are the symptoms of organophosphate overexposure at muscarinic receptors at PNS?
1. Bronchospasm 2. Hypotension 3. Bronchorrhea 4. Bradycardia 5. Miosis 6. Vomiting 7. Sweating 8. Urination 9. Diarrhea 10. Salivation/Lacrimation
132
What are the symptoms of organophosphate overexposure at nicotinic receptors at NMJ?
1. Muscle weakness 2. Fasciculations 3. Eventual paralysis
133
What are the symptoms of organophosphate overexposure at muscarinic and nicotinic receptors in the CNS?
1. Confusion 2. Agitation 3. Respiratory failure 4. Coma
134
What are the general symptoms of organophosphate exposure?
1. Cholinergic crisis (PNS overstimulation and intermediate syndrome) 2. Respiratory failure from diaphragm paralysis at NMJ
135
What is intermediate syndrome?
1. A delayed-onset of muscular weakness and paralysis following acute cholinesterase inhibitor poisoning. (cholinergic toxidrome) 2. Recirculation of lipid soluble cholinesterase inhibitors from lipid and fat compartments
136
How can we reactivate AChE from organophosphate toxicity?
Oximes 1. 2-PAM 2. Obidoxime 3. HI-6
137
What structure does oxides have in common?
HON=HC
138
Why's is pralidoxime 2-Pam considered an organophosphate antidote?
cleaves the phosphate ester bond to the active site serine, reactivating the enzyme
139
Describe the structure of 2-PAM?
1. The quaternary N+ of 2‑PAM has affinity for the anionic site of the cholinesterase 2. The oxime’s -OH is basic and can react with the phosphate ester. 3. The oxime is oriented to exert a nucleophilic attack on the electrophilic phosphorus. 4. The oxime-phosphonate complex is released, reactivating the enzyme.
140
How must 2-pam be used?
1. Quickly 2. Chronically 3. With atropine
141
What is the purpose of using atropine with 2-pam?
Decreases Ach binding synapse once 2-PAM removes organophosphate
142
What is organophosphate aging?
1. Phosphorylated cholinesterases may undergo hydrolysis (or dealkylation) of the organophosphorus moiety leading to an "aged" enzyme 2. Aging strengthens the interaction so that the enzyme cannot be regenerated 3. Rate of aging varies by OP and is dependent on the OP chemical structure
143
What are the factors that determine organophosphate recovery?
1. The degree of aging dictates effectiveness of oxime treatment 2. Aged AChE can't be reactivated by treatment
144
Describe the nerve gases' onset?
Soman: <10 min (rapid aging) Sarin: 3-5hr Dimethyl OPs: At 3 hrs post-exposure, ≈50% of AChE will be aged At 12 hrs, ≈94% of the AChE will be aged Diethyl OPs (parathion): At 33 hrs ≈50% of the AChE
145
Describe the long-term management for organophosphate toxicity?
1. Highly lipophilic and stored in fat 2. Well absorbed from lungs, GI tract & skin 3. Peak levels may occur in minutes 4. Many organophosphates (particularly pesticides) degrade rapidly by hydrolysis on exposure to sunlight, air, and soil
146
How does carbamates differ from organophosphates?
1. Carbamates undergo hydrolysis and reverse relatively quickly 2. Shorter half-life and decreased toxicity 3. Do not undergo “aging”
147
Can carbamates be treated with 2-PAM?
No just atropine management especially in children
147
Can carbamates be treated with 2-PAM?
No just atropine management especially in children
148
What are potential sources of ACh-like compounds?
Pesticides, Nerve gas, etc. Poisonous mushrooms Drug overdose
149
What are the GI symptoms of ACh-like compounds?
Cramps, hypermotility, colic, diarrhea, vomiting, salivation, urination
150
What are the respiratory symptoms of ACh-like compounds?
Excessive secretions, bronchoconstriction, dyspnea With AChEIs: Failure of the muscles of Respiration is the 1° cause of death
151
What are the cardiovascular symptoms of ACh-like compounds?
Bradycardia (especially @ higher doses), hypotension, shock
152
What are exocrine gland symptoms of ACh-like compounds?
Perfuse sweating & flushed skin Excessive lacrimation Muscle fasciculations, weakness and paralysis CNS: convulsions, confusion & coma Depending on nicotinic and muscarinic selective binding
153
What is the treatment for ACh-like compounds and organophosphate intoxications respectively?
1. Atropine 2. Pralidoxime
154
What is glaucoma?
ACh-like compounds
155
What happens is glaucoma is untreated?
Permanent damage of the optic nerve and resultant visual field loss and blindness
156
What is the leading cause of blindness?
catarcts
157
How is glaucoma controlled?
1. Topical beta blocker therapy may use cholinergic agonists and acetylcholinesterase inhibitors to reduce intraocular pressure 2. Reduce the production of aqueous humor 3. increase the outflow of aqueous humor
158
How do we increase drainage of aqueous humour in eye?
Mechanically open trabecular meshwork
159
What is normal anterior chamber angle glaucoma?
1. Drainage is impaired 2. Slow rising pressure
160
How do we treat open anterior angle glaucoma?
By opening the iris, this helps to mechanically reduce the possibility of the iris blocking the opening of the canal of Schlemm By contraction of the ciliary body, this can mechanically “stretch” and open the trabecular meshwork
161
How do we treat closed anterior angle glaucoma?
1. Rapidly rising pressure 2. Medical emergency
162
What are the symptoms of closed anterior angle glaucoma?
1. Severe eye pain 2. Headaches 3. Nausea vomiting 4. Mid dilated pupil 5. Irritation 6. Blurred vision 7. Halos around lights
163
What are the advantages of eyedrops?
Achievement of adequate concentration of drug without incurring or minimizing systemic side effects
164
What are the limitations of eyedrops?
Very little retained (small surface area) Volume of Lacrimal fluid present (held by eyelids) Reflex tearing and blinking Corneal epithelium and endothelium