- M1 to M5, 1-3 are most commonly known - HIGH affinity for muscarine, LOW affinity for nicotine - found on autonomic effector organs (we cant control) -metabotropic

CHAPTER 4: CHOLINGERGIC AGONISTS/ DIRECT ACTING Flashcards by Daniella Erfanian

Stimulation of the parasympathetic nervous system (PSNS)

inc motility of GI tract
dec heart rate and contractility
constrict bronchi, inc gland secretion, bronchospasm
relax GI and urinary bladder sphincter
inc urination, inc pooping
pupillary constriction (miosis)

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4 basic cholinergic nerves

preganglionic in the ANS, postganglionic in the PSNS AND SNS, motor nerves in skeletal muscles and cholinergic in CNS

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what happens if the drug is able to pass the blood brain barrier?

it will bind to cholinergic receptors causing therapeutic AND adverse effects

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process of neurotransmission at cholinergic neurons (release of Ach steps)

1- choline is a cotransporter that goes into the cell also bringing in Na+. bind with the acetyl group from AcCoA to make acetylcholine
2- Ach goes into storage vesicles so it is stored and preserved
3- Action potential reached, depolarization of membrane induces influx of Ca2+ and fusion of synaptic vesicle to the membrane causing synaptic cleft
4- release Ach into presynpatic receptor for negative feedback and binds to receptor
5- degrade acetylcholine using acetylcholinesterase (AchE) into choline and acetate (waste)
6- choline is regenerated and used again

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different ways to alter neurotransmission

bind and activate receptors, inc Ca concentration to stimulate more vesicle fusion and more Ach binding, block the enzyme so Ach conc increases, or use a drug that acts on choline

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cholinergic receptors/cholinoceptors: 2 kinds

muscaranic receptors vs. nicotinic receptors

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muscarinic receptors

M1 to M5, 1-3 are most commonly known
HIGH affinity for muscarine, LOW affinity for nicotine
found on autonomic effector organs (we cant control)
-metabotropic

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metabotropic

g protein coupled

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nicotinic receptors

-NM (muscle) and NN (neurons)
- HIGH affinity for nicotine, LOW affinity for muscarine
-NN in the CNS, adrenal medulla, and autonomic ganglia
-NM in the neuromuscular junction in skeletal muscle
ionotropic

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ionotropic

ligand-gated ion channel

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which substrate is universal for both muscarinic and nicotinic receptors?

Ach

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mechanism of Ach signal transduction
- muscarinic receptor activation

M1 and M3: Gq protein activation results in inc of IP3 and inc DAG
- IP3 increases Ca2+–> inc contractility
-DAG activates protein kinase C–> phosphorylation

M2: Gi protein, inhibit adenylyl cyclase, dec cAMP

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mechanism of Ach signal transduction
- nicotinic receptor activation

-receptor is composed of 5 subunits that span the membrane and form a CHANNEL
- activated by Ach binding to receptor on ALPHA SUBUNIT–> CONFORMATIONAL CHANGE opens channel and allow flow of CHARGED MOLECULES (Na+ , K+) causing depolarization

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how many binding sites on the nicotinic Ach receptors

2 binding sites, indicate you need 2 Ach for it to function/activate

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A patient develops urinary retention after an abdominal surgery, urinary obstruction was ruled out in this patient. Which strategy would be helpful in PROMOTING urination?

you need stimulate the parasympathetic NS and RELAX the sphincters so….
you inhibit AchE (enzyme) from breaking down Ach.
Inc in Ach stimulates PSNS

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Cholinergic Agonists- 2 types

direct acting and indirect acting (reversible and irreversible)

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direct acting cholinergic agonists

mimic the effects of Ach by DIRECTLY binding to cholinoceptors, and prefer MUSCARINIC receptors w little specificity

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effect of directing acting choli agonists

increases stimulation of cholinergic receptor

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indirect acting cholinergic agonists

react with AChE and prevent it breaking down ACh released from the nerve

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effect of indirect acting cholinergic agonists

increases stimulation of ACh receptor sites

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pk of drug is the

plasma concentration of the drug in your system

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common direct acting cholinergic agonists

acetycholine, bethanechol, carbachol, cevimeline, pilocarpine

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different chemical structure of direct acting causes

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different PK of the drug in your system.

ACh vs bethanechol, carbachol, and pilocarpine

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ACh, bethanechol, and carbachol contain ammonium compound–> N+, makes it more difficult to cross membranes
but, pilocarpine does not contain this compound allowing it to cross the BBB easily and go to the brain/cause unwanted effects

ACh- mechanism

ACh binds to the nicotinic or muscarinic receptors (its target)

ACh- inactivation

inactivated by cholinesterases (AChE)

ACh- therapeutic actions

dec heart rate, dec BP - vagus nerve controls heart rate, decreases heart rate by dec SA node firing - musc rec in smooth muscle relaxes vessels and dec BP

ACh- therapeutic uses/INDICATIONS

optho surgeries needing rapid miosis

ACh- Adverse effects (systemically)

bradycardia (DEC BPM/HEART RATE), hypotension , flushing, sweating, difficult breathing

why do we need to check if the patient is taking blood pressure medication when administering ACh systemically?

if the patient is taking medication for hypertension (high BP), their BP is already lowered and the adverse effects of ACh, hypotension, will cause BP to fall too low

difficulty breathing term-

bronchospasm

why does ACh have little therapeutic importance?

they act on BOTH nicotinic and muscarinic receptors, multiple actions make it less specific to what effect you are looking for

does ACh have adverse effects if administered locally?

NO! Only if administered systemically, then it will activate effects of the parasymp NS

Bethanechol-structure and mechanism

structural derivative of ACh -strong muscarinic activity, lack of nicotinic action muscarinic activity: action of SMOOTH MUSCLES BLADDER AND GI

bethanechol- duration of action longer or shorter than Ach?

longer than Ach, 1 hour, metabolized SLOWLY

Bethanechol- therapeutic actions

-inc GI intestinal motility/tone -inc detrusor bladder muscle tone -relax trigone and sphincter--> STIMULATE URINATION

Bethanechol- therapeutic uses/indications

urology, stimulate atonic bladder (urecholine)

atonic bladder

patient unable to urinate bc of insufficient destrusor muscle contraction

Bethanechol- adverse effects (systemically)

sweat, salvation, flushing, nausea, diarrhea, bronchospasm, hypotension/low BP

Carbachol- structure and mechanism

structural derivative of ACh, similar BOTH muscarinic and nicotinic actions

Carbachol- inactivation and duration of action?

LONG duration of action - not inactivated by AChE but is by other esterases

carbachol activates nicotinic and muscarinic receptors. what does this mean it stimulates?

since it activates nicotinic that means it ALSO stimulate the sympathetic NS

Carbachol- therapeutic actions

-stimulate THEN depress cardiovascular and GI systems - MIOSIS

Carbachol- therapeutic uses/indications

optho for treating glaucoma/miostat

Carbachol- adverse effects

little effects, it doesn't penetrate

Pilocarpine- structure, activity, inactivation

less potent that ACh and its derivatives (its a natural product and UNCHARGED) - not metabolized by AChE, ABLE to penetrate CNS -muscarinic activity

Pilocarpine- therapeutic actions

-topically induces miosis and contraction of the ciliary muscle -orally stimulates secretions (saliva)

Pilocarpine- adverse effects

CNS disturbances

Pilocarpine- indications

-optho for glaucoma -saliva production stimulator (salagen) in sjorgren syndrome

what counteracts pilocarpine CNS disturbances

atropine

types of glaucoma (2)

open-angle and angle-closure

Open Angle Glaucoma

-most common, no symptoms -damage optic nerve leading to blindness

what kinds of people are prone to OPEN ANGLE glaucoma?

ppl with high BP or diabetes are at higher risk

angle-closure glaucoma (narrow/acute glaucoma)

-considered a medical emergency -outer edge of the iris blocks fluid from draining out the front of the eye -if not treated, can cause blindness in days

what is Sjogrens Syndrome?

immune disease characterized by dry mouth and eyes

what is xerostomia?

dry MOUTH

treatment for sjogrens syndrome (2)

pilocarpine and cevimeline (in adults)

CHAPTER 4: CHOLINGERGIC AGONISTS/ DIRECT ACTING Flashcards

(57 cards)