CHAPTER 4: CHOLINGERGIC AGONISTS/ DIRECT ACTING Flashcards
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)
4 basic cholinergic nerves
preganglionic in the ANS, postganglionic in the PSNS AND SNS, motor nerves in skeletal muscles and cholinergic in CNS
what happens if the drug is able to pass the blood brain barrier?
it will bind to cholinergic receptors causing therapeutic AND adverse effects
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
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
cholinergic receptors/cholinoceptors: 2 kinds
muscaranic receptors vs. nicotinic receptors
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
metabotropic
g protein coupled
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
ionotropic
ligand-gated ion channel
which substrate is universal for both muscarinic and nicotinic receptors?
Ach
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
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
how many binding sites on the nicotinic Ach receptors
2 binding sites, indicate you need 2 Ach for it to function/activate
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
Cholinergic Agonists- 2 types
direct acting and indirect acting (reversible and irreversible)
direct acting cholinergic agonists
mimic the effects of Ach by DIRECTLY binding to cholinoceptors, and prefer MUSCARINIC receptors w little specificity
effect of directing acting choli agonists
increases stimulation of cholinergic receptor
indirect acting cholinergic agonists
react with AChE and prevent it breaking down ACh released from the nerve
effect of indirect acting cholinergic agonists
increases stimulation of ACh receptor sites
pk of drug is the
plasma concentration of the drug in your system
common direct acting cholinergic agonists
acetycholine, bethanechol, carbachol, cevimeline, pilocarpine
different chemical structure of direct acting causes
different PK of the drug in your system.
ACh vs bethanechol, carbachol, and pilocarpine
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)
