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811 > Lecture 26/27 > Flashcards

Lecture 26/27 Flashcards

Cholinomimetics - Masserano

1
Q

Cholinergic Transmission Types

A
  1. Direct
  2. Indirect
  3. Irreversible
  4. Reversible
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2
Q

ACh Synthesis

A
  • Choline enters neuron via carrier-mediated transport
  • ChAT acetylates choline using acetyl coenzyme A
  • Stores in vesicles by carrier-mediated transport
  • Released by calcium exocytosis, 100-500 vesicles released per impulse
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3
Q

ACh Act on…

A

Muscarinic or nicotinic receptors

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4
Q

ACh is metabolized by…

A

ACh-terase. Occurs rapidly and breaks ACh into acetate and choline, the latter of which is taken back up into the neuron by carrier-mediated transport and reused.

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5
Q

Muscarinic Actions

A
  • Discovered in 1900 via adrenal gland extracts
  • Extracts increased blood pressure due to epinephrine content
  • Remove epinephrine and inject, blood pressure DROPS due to ACh in preganglionic terminal
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6
Q

ACh + Muscarinic Actions

A

-Occurs via post-ganglionic parasympathetic nerve endings

Exceptions:

  1. ACh causes vasodilation by vascular, endothelial cells released NO (not innervated)
  2. Sweat glands release ACh, part of sympathetic nervous system
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7
Q

Muscarinic v.s. Nicotinic Actions

A
  • ACh responses that were differentiated by Dale in 1914
  • Muscarinic actions are reproduced by injecting muscarine and abolished by low doses of atropine
  • Mimicked parasympathetic stimulation
  • After blocking these receptors and injecting higher doses of ACh, new set of effects similar to nicotine arose
  • These included stimulation to ALL autonomic ganglia, stimulation of voluntary skeletal muscles, increased release of epinephrine from adrenal medulla
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8
Q

Nicotinic ACh Receptor Classes

A
  1. Muscle-Skeletal - Neuromuscular Junction - (alpha1)2
  2. Ganglionic - transmits at sympathetic and presympathetic ganglia (alpha3)2(B4)3
  3. CNS types - (alpha4)B2 neuronal nicotinic receptors (Chantix - partial CNS nicotinic agonist)
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9
Q

Binding Sites of ACh

A
  • Two sites
  • Must both by occupied to activate channel
  • Interface between extracellular domain of each alpha subunits and its neighbor
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10
Q

Ligand Gated Channels

A
  • Control the fastest synaptic events in the NS
    1. Sodium ion influx - reaches peak in fractions of a millisecond, decays in a few milliseconds
    2. Fast Excitatory Post-Synaptic Potentials (EPSP) - occurs at nicotinic synapses due to rapid hydrolysis of ACh within milliseconds
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11
Q

ACh Agonists and Antagonists

A

Their actions at synapses MAINLY reflect differences between muscle and neuronal nicotinic ACh receptors.

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12
Q

ACh Muscle Receptor Antagonists

A
  • Tubocurarine
  • Pancuronium
  • Atracurium
  • Vecuronium
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13
Q

ACh Neuronal Receptor Antagonist

A

-Mecamylamine

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14
Q

ACh CNS Receptor Agonist

A

-Chantix (Varenicline)

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15
Q

M1 Receptors

A
  • Neural, mainly in CNS
  • M1 excitation causes a decrease in K+ conductance which causes membrane depolarization
  • Deficiency in M1 ACh-mediated effect in brain could be a possible connection to dementia
  • Inhibitors of ACh-terase used to treat Alzheimers increases ACh in the brain (Donepezil, Rivastigmine)
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16
Q

M2 Receptors

A
  1. Cardiac - ACh inhibition of heart causes and increase in K+ efflux and inhibiting of calcium and If channels
  2. Presynaptic terminals - PNS and CNS
  3. Coexpressed with M3 receptors in visceral smooth muscle which contribules to the smooth muscle stimulation seen with muscarinic agonists
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17
Q

M3 Receptors

A
  • Glandular and smooth muscle excitation
  • Stimulates gland secretion and visceral smooth muscle contractions
  • Mediates relaxation of vascular smooth muscle due to release of NO form endothelial cells
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18
Q

Muscarinic Receptor Antagonists (M1, 2, and 3)

A
  • Atropine
  • Dicycloverine
  • Tolterodine
  • Oxybutynin
  • Ipratropium
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19
Q

PNS + Acid Secretion

A
  • ACh releases stimulations GI acid secretion
    1. M3 receptors of enterochromaffin-like cells release histamine which stimulates secretion
    2. M3 receptors directly on parietal cells stimulate secretion
    3. Directly on Antrum G cells - release gastrin to make parietal cells secrete
    4. ACh indirectly act on ACh receptors on Antrum D somatostatin-containing cells to inhibit its release which decreases the inhibition of gastrin release and stimulates secretion
  • Last two are via blood
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20
Q

Terminating Acid Secretion Response

A
  • Increase in intraluminal acids releases somatostatin onto Antrum G cell to inhibit gastrin release
  • Inhibition of gastrin release is enhanced by dietary peptides
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21
Q

Opposing ANS Innervation

A
  • PNS of Atria - ACh M2 receptor - inhibits Gi protein

- SNS of Atria - Beta 1 adrenergic receptors excitatory Gs protein that increases heart Rate

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22
Q

Function of Gs Protein

A
  1. Beta 1 activates Gs protein
  2. Gs protein goes on to activate adenyl cyclase
  3. Adenyl cyclase phosphorylates calcium channels on the membrane and phospholambin protein on sacroplasmic reticulum (usually removed calcium from cytoplasm)
  4. Causes a calcium influx and an increased heart rate
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23
Q

PNS + Lowering Heart Rate

A

3 Mechanisms:

  1. Gi - inhibited by Ach which increases calcium channel activity, decreases membrane potential and slowing the diastolic depolarization (also decreases Gs and adenylyl cyclase’s activity
  2. Decrease in phase 4 automaticity of If channel
  3. Decrease in calcium channel activity
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24
Q

ACh Muscarinic Antagonist

A
  • Muscarinic Receptor Blocker
  • Increases heart rate
  • May lead to tachycardia as side effect of antagonists (ex: Atropine)
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25
Q

Beta 1 Antagonist

A
  • Slows heart rate

- May lead to brachycardia as a side effect of antagonist (propranolol, esmolol)

26
Q

SNS + PNS + Genitalia

A
  • Specific cells in corpus cavernosum release NO in response to ACh
  • PNS - release NO from endothelial cells, relax smooth muscle blood vessels, dilates them, engorgment of corpus cavernosum, causes erection
  • SNS - contracts blood vessels, vasoconstriction, ejaculation (detumescence)
27
Q

PDE-5 Inhibitors

A
  • Viagra, Cialis, Levitra
  • Inhibit the breakdown of cGMP which prolongs cGMP effect
  • Relaxation, vasodilation, erection
28
Q

Therapeutic Uses of Cholinomimetics

A
  1. Opthalmic use - ACh (Miochol-E), Carbachol (Miostat), Pilocarpine (Isopto Carpine - Glaucoma)
  2. PNS + Salivary Glands/Tears - Pilocarpine (Salagen, oral), Cevimeline (Evoxac. oral)
  3. Bladder - Bethanechol (Duroid, Urecholine)
29
Q

Systemic Muscarinic Activity - Mushrooms

A
  • Amanita Muscarine - small amounts of muscarine, toxic through ibolenic acid (Gabaergic CNS depressant/hallicinogenic)
  • Cholinergic symptoms occur at higher doses
  • ACh-like muscarinic receptor agonist that isn’t metabolized by Ch-terase = longer duration of action
30
Q

ACh-Like Muscarinic Molecule Features

A
  1. Does not cross BBB (PNS symptoms)
  2. Onsets of symptoms occurs in minutes to hours after ingestion, stops in 6-24 hours
  3. Symptoms = Salivation, lacrimation, urination, defacation (SLUD), can also experience miosis, emesis, bronchoconstriction, bradycardia, and bronchorhea (DUMBELS + 2Bs)
  4. Atropine used for severe toxicity that decreases pulmonay secretions/constrictions and blocks bradycardia
31
Q

Glaucoma

A

-Increases intraocular pressure (IOP) in eye
Causes by:
1. Impaired outflow of aqueous humor resulting from an abnormal draining system (open-angle glaucoma), most patients have this type, from a block or dysfunction of meshwork and decreased drainage
2. Impaired access of humor to drainage system, close-angle glaucoma), blocks flow in pupil, pathway is blocked and angle is closed, pressure builds and pushes on iris

32
Q

Glaucoma Treatment Options

A
  1. Decrease aqueous humor coming into eye

2. Increase amount of humor leaving the eye

33
Q

Aqueous Pathways in Eye

A
  • Supplies nutrition to vascular structure
  • Fluid produced by ciliary body behind iris, moves up and over lens into posterior chamber, through pupil to anterior chamber
  • Goes into angle (cornea + iris), iridocorneal angle, and out the trabecular meshwork (filter) and into the canal of Schlemm draining into the circulation
34
Q

End Result Damage of Glaucoma

A
  1. Eye Disease
  2. Pressure not tolerated by eye
  3. Optic nerve damage
  4. Visual field damage
  5. Blinding
35
Q

Cholinergics + Glaucoma

A

Mechanism - Increase outflow of humor from eye
Side effects - brow ache, cataract formation, retinal detachment
Pregnancy Class - C

36
Q

ACh Intraocular Solution

A
  • Increases outflow
  • Miosis of iris in seconds after delivery of lens in cataract surgery and other anterior segment surgery
  • Done to intact eye and causes no discernible response as Ch-terase destroys the molecule rapidly
  • Rare side effects - Bradycardia, hypotension, flushing, sweating, and breathing differences
37
Q

Pilocarpine Opthalmic Solution

A
  • Decreases IOP by facilitating outflow of aqueous humor
  • Decreases resistance so IOP drops
  • Can use in combination with other medicines like beta blockers
38
Q

Pilocarpine Mechanisms

A
  1. Pilocarpine contracts the ciliary muscle which opens the meshwork to facilitate outflow of humor
  2. Produces miosis through iris sphincter contraction which relieves appositional angle narrowing and closure
39
Q

Pilocarpine Uses

A
  1. Decreased IOP with open-angle glaucoma or ocular hypertension
  2. Prevents post-operative IOP associated with laser surgery
  3. Induction of miosis
40
Q

Pilocarpine Rare Side Effects

A
  • Headache
  • Blurred Vision
  • Eye irritation
  • Vision impairment
  • Eye Pain
41
Q

Carbachol (Miostat) Solution

A
  • Contracts iris sphincter muscle and ciliary body to increase outflow and decrease IOP
  • Onset ~2-5 minutes
42
Q

Carbachol Therapeutic Uses

A
  • Miosis during surgery

- Decreases the intensity of IOP increase the first 24 hours after surgery

43
Q

Carbachol Side Effects

A

Systemic: Flushing, swelling, epigastric distress, stomach cramping, bladder tightness

44
Q

Carbachol Cautions

A

-Use with caution in patients with asthma, COPD, Acute cardiac failure, peptic ulcers, G.I. spasm, urinary tract obstruction, Parkinsons

45
Q

Other Therapies for Glaucoma

A
  • Decrease the aqueous humor production by ciliary bodies

- B-adrenergic antagonists - Timolol and Betaxolol

46
Q

Timolol

A
  • Beta 1 and 2 (non-selective) antagonists
  • Decrease normal and elevated IOP whether glaucomic or not
  • Side effects: wrose asthma/emphysema, bradycardia, decreased BP, fatigue
47
Q

Betaxolol

A
  • Selective Beta 1 antagonist

- Less cardic/pulmonary side effects than others

48
Q

Beta Blockers

A
  • Decrease aqueous humor production
  • Side effects: bradycardia, asthma exacerbation, hypotension
  • Pregnancy class: C
49
Q

Pilocarpine Tablet Uses

A
  • Pilocarpine tablets - treat dry mouth from salivary gland hypofunction from chemotherapies at head and neck
  • Treats Sjogren’s Syndrome dry mouth as well
  • Onset: 20 minutes, peak: 1 hour, duration: 3-5 hours
  • Side effects: sweating (65%), nausea, dyspepsia, rhinitis
50
Q

Sjogern’s Syndrome

A
  • Chronic autoimmune disease
  • WBC attack moisture-producing glands that make tears and saliva (dry eyes and mouth)
  • Can also effect joints, brain, blood vessels, etc.
51
Q

Pilocarpine Tablet Warnings

A
  1. Administer with caution with asthma, chronic bronchitis, or chronic COPD
  2. Caution with significant cardiovascular disease that would be unable to compensate for transient changes
    * *Systemic side effects**
52
Q

Cevimeline Capsules

A
  • TID
  • Dry mouth with Sjogren’s Syndrome
  • Cholinergic muscarinic receptor agonists, increase exocrine gland secretions and smooth muscle tone in GI tract and urinary tracts
  • Side effects: Excressive sweating (18.7%), nausea, rhinitis, and diarrhea
  • Cardiac conduction alteration can also occur which can decrease heart rate, use epinephrine if too severely depressed
53
Q

Cevimeline Cautions

A
  • Can increase airway resistance and bronchial secretions
  • Administer with caution in those with asthma, COPD
  • Atropine = antidote in overdose
54
Q

Alternatives of Cholinergic Therapy

A
  • Prescription Saliva Substitutions - Aquoral and Caphosol

- OTC - Biotene products, Aquoral, Moi-Sure, Saliva Sure

55
Q

Urination Control

A
  • PNS - innervates bladder wall, contracts bladder musculature to empty
  • CNS - innervates bladder and internal sphincter, closes internal urinal sphincter, inhibits bladder wall contraction
56
Q

Mirabejron (Myrbetriq)

A
  • Relaxes bladder

- B3 agonist

57
Q

Moderate distension of bladder…

A

Inhibits PNS activity and allows SNS activity to take over and urine to accumulate.

58
Q

Full Bladder

A
  • Afferent activity conveyed centrally
  • Increases PNS function and decreases SNS acitivity to relax muscles and contract bladder
  • Voluntary system - holds in urine by micturition center in brain stem
  • Paraplegic patients - reflex still initiated by sufficient bladder distention, usually not COMPLETE emptying though which increases their risk of UTIs
59
Q

Betanechol

A
  • Muscarinic Agonist
  • Increases tone of detrusor muscle to product contraction and empty bladder
  • Increases gastric motility and tone to restore rhythmic peristalsis
60
Q

Betanechol Therapeutic Uses

A
  1. Treatment of acute post-operative and post-partum non-obstructive (functional) urinary retention
  2. Neurogenic atony of bladder with retention - destruction of sensory nerves from bladder to spine, absence of bladder control, bladder overstimulation and abnormal residual urine amounts
61
Q

Betanechol Features

A
  • NOT broken down by Ch-terase
  • Duration ~2 hours
  • Doesn’t cross BBB
  • Minimal effects on heart rate and BP
  • Adverse effects: cholinergic usually - digestive (cramps, salivation, diarrhea), decrease BP, sweating, asthma attacks
62
Q

MAIN Betanechol Precaution

A

In urinary retention, if sphincter fails to relax as bethanechol contracts the bladder, urine may be forced up the ureter into kidney pelvis which can cause reflux infections.

811 (38 decks)

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