Exam 4 - Lecture 35, Cholinergic Agonists and Cholinesterase Inhibitors Flashcards
Direct Acting drugs
Agonist at muscarinic receptors (M type GPCRs)
Agonist at nicotinic receptors (nAChR ion channels)
Indirect acting drugs
Inhibitors of cholinesterase = increase ACh
M1, M3,M5
Gaq
Mechanism: IP3, DAG cascade
M2 or Cardiac M2
Gai/o
Mechanism: Inhibition of cAMP production, activation of K+ channels
M4
Gai/o
Mechanism: Inhibition of cAMP production
Nm and Nn ion channels
Mechanism: Na, K depolarizing ion channel
Nicotinic acetylcholine receptors
Pentameric channel, conducting Na,K,CA2+
Activation of receptor depolarizes membrane potential, initiating action potentials in neurons and contraction of muscle
Binding 1 ACh molecule results in modest increase in open probability; simultaneous binding gives significant increase in Po
Single nAChR channels
Fetal (immature) channels
Mature channels
Fetal (immature) channel
consists of 2 X a1 subunits and one each of beta, delta, and gamma-subunits. This channel has low amplitude currents with long open time
Mature channels
Gamma subunits are replaced with E-subunits.
Open time decreases but current amplitude increases
Whole-cell nAChR channels
some isoforms are pentamer of a7-subunits
activations results in fast, rapidly decaying currents
In response to continued activation, nAChR channels will….
Desensitize
Increase in Ca2+ will cause an increase in PKC (phosphorylates proteins that facilitate Desensitization of channels)
Active -> Desensitization -> resting state
Example action of activated nAChRs
Ach will bind to receptor, activate channel and they will pass Na and depolarize membrane…leads to EPSP (if large enough) and it will cause action potential and contraction
M1, M3, M5 detailed pathway
- Activates PLCB
- PLCB metabolizes PIP2 to DAG and IP3
- DAG activates PKC
- IP3 activates IP3 receptors on ER
- NOTE: decrease of PIP2 also has cellular effect (inhibition of M-current
M2 and M4 detailed pathway
- Gai inhibits Adenylate Cyclase -> decrease cAMP
- Gbg activates GIRK channels, made of Kir3-subunits, increase K+ flux and decrease excitability
- Gbg inhibits activity of specific Cav channels; decrease Ca2+ flux and decreasing excitability
Organophosphates
Irreversible , covalent inhibitors of AChE
most common type of chemical pesticide
Ex. DDT, banned by most countries in 70s and 80s and superseded by parathion
Toxicity of direct & indirect cholinomimetic drugs
DUMBBELSS
D- diarrhea, defacation (muscarinic) U- Urination (M) M - Miosis (M) B - Bronchospasm (M) B - Bradycardia (M) E - Excitation (N...followed by block) L - Lacrimation (M) S - Salivation (M) S - Sweating (M)
Medical use of cholinomimetic agents
Glaucoma
Ileus or Urinary retention
Myasthenia Gravis
Glaucoma
often caused by high ocular pressure
Drugs constriction pupil and ciliary muscle, increasing outflow of humor form eye and reducing ocular pressure
ILeus (Loss of peristaltic activity) or Urinary Retention
can occur after surgery or neurological injury
Myasthenia Gravis
Autoimmune degradation of SM nAChRs, causing weakness treated with cholinesterase inhibitors
Short acting (15 min, used to diagnose) Long-acting for treatment (4hr, neostigmine...8hr, pyridostigmine)
Neostigmine
Used in treatment of Myasthenia graves
Used to treat Ogilvile syndrome
Used to treat envenomation from snake bite, particularly kraits
Physostigmine
Reversible cholinesterase inhibitor
Used to treat glaucoma and delayed gastric emptying, mydiasis
Crosses BBB so can be used as antidote for OD with anticholinergics such as Atropine and Belladonna
Can cause death by respiratory arrest and paralysis of cardiac muscle
Acetylcholinesterase enzymes
Found in high conc at chemical synapses and neuromuscular junctions
Required to terminate action of ACh
Inhibitors augment the action of ACh so are cholinomimics
Some AChE-inhibitors have medial utility, some are dangerous toxins
Action of nicotinic cholinomimetics
Autonomic ganglia:
Both sympathetic and parasympathetic ganglia are activated; downstream action on innervated organs is unpredictable
SM neuromuscular junctions:
Depolarization due to opening of nAChR channels, causes muscle contraction. Maintained stimulation desensitizes nAChRs, leading to paralysis
Action of muscarinic cholinomimetics on eye
contract pupillary constrictor and ciliary muscle; the pupil is biotic and focus is on near vision
Action of muscarinic cholinomimetics on airway
contracts smooth muscle of airway, causing wheeing
Action of muscarinic cholinomimetics on blood vessels
smooth muscle in most vessels has few cholinoreceptors; endothelium has M-receptors
if activated, endothelial cells produce NO, it diffuses into adjoining smooth muscle causing relaxation, BP falls and baroreceptors maybe evoked
Action of muscarinic cholinomimetics on heart
Activation of vagal nerve causes bradycardia and slowed A-V conduction
Indirect cholinomimetics amplify effects of endogenous ACh
Direct cholinomimetics cause sufficient hypotension to evoke tachycardia
Action of muscarinic cholinomimetics on exocrine gland
Lacrimal, salivary and thermoregulatory (eccrine) sweat glands stimulated
Action of muscarinic cholinomimetics on GI and GU tract
smooth muscle contracts and motility increases, sphincters relaxed
Recycling of GPCRs
Continued activation of GPCR can lead to B arresting binding which causes desensitization or internalization. It can be recycled back into membrane or it can be degraded
Vagal regulation of the sinoatrial node
M2 receptors, coupled to Gai are activated when ACh is released by vagus nerve (parasympathetic)
Gbg is released and activates Kir3.1/3.4 (GIRK1/4) channels, hyper polarizing the membrane potential
Inhibition of adenylate cyclase reduces generation of cAMP -> decrease PKA -< decrease voltage gated Ca2+ current -> contraction
Decreased activation of HCN channels (funny current channels)
** Note: Activation of B-receptors -> Gas increases AC activity -> increase cAMP
Gai and Gas often in complex together
Adenylate cyclase is in complex, trying to make cAMP with it being up and down regulated by Gai and Gas
Cholinergic (sympathetic)
M2 and M4 receptors are Gai coupled
Adrenergic (parasympathetic)
a2 adrenoceptors are Gai coupled
B1-3 adrenoceptors are Gas coupled
** M1, M3, M5, and a1 not couple to either Gai or Gas but to are coupled to Gaq **
