Cholinergic Pharmacology Pt1 Flashcards
Cholinergic neurotransmitter
Acetylcholine (primary NT from CNS to body)
Acetylcholine use as drug
- rarely used as drug bc effects too generalized and diffuse and its too short acting
- prototypic cholinergic agent for actions of cholinergic drugs
Cholinergic neurotransmission important for
- important for normal fx CNS and PNS
in periphery cholinergic transmission occurs in both
autonomic and somatic nervous systems
Aceetycholine transmission ANS
- in ganglia (including adrenal medulla) transmission= nicotinic cholinergic
- in parasympathetic neuroeffector junctions (and some symp junctions) transmission = muscarinic choliinergic
- heart smooth muscle, secretory glands
acetylcholine transmission somatic motor system
neuromuscular junction transmission is nicotinic cholinergic
muscarinic effects at neuroeffector junctions
- generally reflect parasympathetic respones
dramatic vasodilation due to stimulation of
noninnervated or sympathetically innervated muscarinic receptors in blood vessels
muscarine effects heart
Must know:
-decrease rate and contraction force
Additional:
- bradycardia bc depress pacemaker cells in SA node
- prolongs refractory period and conduction time through AV node and atria, at high doses can cause AV block
- negative inotropic effect decreasing force of contraction primarily in atria bc few muscarinic receptors in ventricles may -> slight decrease cardiac output
muscarinic effects GI tract
increase sections and peristalsis
decrease sphincter tone
overall effect- empty bowel
muscarinic effects urinary bladder
- contract detrusor and relax sphicter
- facilitate uriation
muscarinic effects bronchioles
- contract bronchiolar smooth muscle, decrease airways, increase secretions
muscarinic effects eye
- contraction sphincter muscle of iris -> iris contraction
- constrict ciliary muscle (acomidation near vision)
- opens canals scheme -> drainage intraocular fluids and decreasing intraocular pressure
muscarinic effects exocrine glands
- increase salivation (watery)
- lacrimation
- sweating (not horse)
bloodd vessels muscarinic effects
- indirect relaxation via increase nitric oxide synthesis in endothelial cells
- relax vascular smooth muscle and vasodilation decreasing peripheral vascular resistance -> decrease BP
- effect on vascular smooth muscle reflects activation primarily of noninnervated muscarinic receptor on blood vessel endothelial cells
nicotinic receptors generally
excitatory low does inhibitory high dose
muscarine receptors generally
excitatory or inhibitory depends on tissue
sweating inenrvtion
sweating sympathetic innervation but mediated by muscarinic effect (Ach released onto receptors)
nicotinic effects autonomic ganglia
- only evident at v high doses of ACh muscarinic effect on heart can be lethal unless muscarinic agonist present
- response to stimulation of autonomic ganglia reflects sum parasympathetic and sympathetic effects and general sympathetic responses predominate
exceptions to sympathetic effects predominating response to stimulation of autonomic ganglia
GI and urinary tracts
General effect nicotinic effect autonomic ganglia
- increase blood pressure
- tachycardia
- other sympathetic resposnes
in presence of atropine
only sympathetic effects seen
= atropine = muscarinic antagonist
nicotinic effects at neuromuscular junction
- ACh causes contraction skeletal muscle
- prolonged exposure and high doses -> tremors and fasciculations (twitches of muscle) terminating in depolarizing paralysis bc inactivation Na+ channels and desensitization nicotinic receptors
sympathetic ganglia
- synaptic terminals appear similar to those in CNS
- presynaptic terminal have cluster round, clear vesicles near membrane thickening
- cleft- 200 angstroms
- post synaptic membrane- has thickened apperance
parasympathetic ganglia
- preganglionic fibers- large termination on post synaptic cells
- terminal post ganglionic cholinergic innervation composed of long chains varicose fibers similar to adrenergic innervation
calyx
- single large termination of preganglionic fiber at parasympathetic ganglia on postsynaptic cell; covers almost half ganglion cells surface
transmission parasympathetic ganglionic synapses occurs
- chemically (via release acetylcholine)
- electrically (direct current spread calyx to ganglion cell)
Varicosites
contain dense accumulation agranular vesicles assumed to release transmitter en passage
post junctional membrane (parasympathetic) lack
- obvious structural specialization seen in CNS, in ganglia, and in NMJ
Steps Cholinergic Activation
- Choline taken up into prejunctional nerve
- Acetylcholine synthesized
- Acetyl choline transported into synaptic vesicles
- Acetyl choline released into junction
- Acetylcholine activates nicotinic cholinergic receptors and muscarinic cholinergic receptors -> cell response
- Degredation (actively occurs during receptor activation as well)
What takes choline up into prejuncitonal nerve
high-affinity choline transporter (CHT1)
Acetylcholine synthesis
sythesized from choline and acetyl CoA; catalyzed by choline acetyltransferease
what transports acetylcholine into synaptic vesicles
H+-dependent vesiclar ACh transpoter (VAChT)
acetylcholine released into junction how
- quantal packets from vesicles
- some non-quantal release from cytoplasm
Nicotinic cholinergic receptors response
- in ganglia
- direct response is electrical biding acetylcholine -> opening cation channel -> rapid depolarization post synaptic membrane -> initiation action potential
Muscarinic cholinergic receptor
- in NEJ
- activation of receptor by acetylcholine -> activation of receptor by acetylcholine -> activation selective G-proteins -> transduce signal to various effector proteins
degradation acetylcholine
primarily by acetycholinesterase
- choline generated by hydrolysis transported into prejunectional nerve cell by CHT1 and recycled
Nicotinic receptors what type of receptor
ligand gated ion channel
activation nicotinic receptors description
- 2 acetylcholine bind
- Nonselective cat-ion channels open
- Depolarization postsynaptic or post junctional cell
Nicotinic receipts location and subtypes
Location: ganglionic synapses and neuromuscular junctions
Subtypes: two major families muscle (NMJ form) and neuronal receptors
structure nicotinic receptor
- 4 transmembrane domain
- M2 subunits face interior making pore for ion channel
where does Ach bind nicotinic receptor
binds to side Alpha subunit usually at y or s interface -> conformational change opening pore allowing through monovalent ions
Muscarinic acetylcholine receptors what type receptor
- GPCR (therefore 7 membrane spanning domain)
Muscarinic acetylcholine receptor activation steps
- Acetylcholine binds to receptor
- Coupling to and activation of G proteins induced ->
- inhibition adnenylyl cyclase
- activation phospholipase C-> DAG and IP3 formation and/or changes ion channel activity
Muscarinic acetylcholine receptors found where
- parasympathetic effector junctions
- a few sympathetic NEJ
subtypes muscarinic receptors
- M1-M5
- M1,M3,M5: couple to Gq -> activate phospholipase
- M2,M4 couple to Gi -> inhibit adenyl cyclase and stimulate K+ channels and inhibit voltage gated Ca2+ channels
pathways -> muscarinic smooth muscle contraction
Pathway 1:
1. Acetylcholine -> M3 receptor -> Gq -> activate PLC (phospholipase C) ->cleaves PIP2 -> DAG and IP3 -> IP3 stimulates Ca2+ release -> contraction smooth muscle
Pathway 2:
Acetylcholine -> M2 receptor -> Gi -> inhibition adenylyl cyclase (AC) -> reduce levels fo cAMP -> decrease relaxation (ie contraction)
sympathetic system and parasympathetic system adenycyclase
sympathetic system stimulates adenycyclase increasing levels cAMP increasing smooth muscle relaxation?
parasympathetic system decreases relaxation and decreases sympathetic effect by inhibiting adenylyl cyclase via Gi via M2 receptor
Characteristics of nicotinic muscle cholinergic receptors
- 2 alpha subunits
- 1 beta subunit
- 1 y subunit
- 1s subunit
Characteristics of neuronal cholinergic receptors
- 2 alpha subunits
- 3 beta subunits
M2
primary receptor type in heart mediating contraction reduction (on smooth muscle, stimulates contraction)
M3
- secretory glands, increase secretions
- on smooth muscle stimulates contraction
CNS contains which subtypes muscarinic receptors
CNS contains all subtypes muscarinic receptors
what causes relaxation sphincters in urinary and GI tracts
- release dilatory peptides from intrinsic ganglia or parasympathetic nerves
blood vessels relax how
consequence of release of nitric oxide form endothelium
