1. Cholinoceptor-activating & Cholinesterase-inhibiting drugs

2. Overview
Drugs affecting the ANS are divided into two groups according to the type of neuron involved in the mechanism of action:
The cholinergic drugs: they act on receptors that are activated by acetylcholine (Ach)
The adrenergic drugs: they act on receptors that are activated by norepinephrine or epinephrine
Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS

3. Neurotransmission at cholinergic neurons
Ca2+
Na+
Muscarinic
Receptor
ACh
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA +
Acetylcholine
Action Potential
Choline α β
Na+ H+
Nicotinic
Receptor
ACH
Choline
Acetate
Choline
Presynaptic neuron
Postsynaptic target

4. Cholinergic Receptors (Cholinoceptors)
Cholinoceptor denotes receptors that respond to acetylcholine
Two families/subtypes of cholinoceptors were named after the alkaloids originally used in their identification: muscarinic (M) and nicotinic (N) receptors

5. I. Muscarinic (M) receptors
These receptors, in addition to binding acetylcholine, also recognize muscarine, but show a weak affinity for nicotine
These receptors have been found in organs innervated by parasympathetic nerves as well as on some tissues that are not innervated by these nerves, eg, endothelial, and on those tissues innervated by postganglionic sympathetic cholinergic nerves

6. I. Muscarinic (M) receptors
Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5 have been identified
Muscarinic receptors are G-protein coupled receptors (seven transmembrane domains)
These receptors have different signal transduction mrchanisms based on the G-protein to which they are coupled

7. I. Muscarinic (M) receptors
M1/M3/M5 activations stimulate IP3 and DAG. These receptors are primarily responsible for activating Ca+2-dependent responses, such as secretion by glands and the contraction of smooth muscle
M2/M4 ativation inhibits adenylyl cyclase leading to decreased cAMP

8. II. Nicotinic (N) receptors
These receptors, in addition to binding ACh, also recognize nicotine, but show a week affinity for muscarine
N receptors are transmembrane polypeptide whose subunits form cation-selective ion channels
N receptors are located on plasma membranes of postganglionic cells in all autonomic ganglia, of muscles innervated by somatic motor fibers (i.e. Neuromuscular junction), and of some CNS neurons

9. II. Nicotinic (N) receptors
When the nicotnic AchR is stimulated, the channel opens and allows Na+ to rush into the cell
This triggers depolarization of the cell and elicits a neruronal action potential (in postganglionic nerve) or nuscle contraction (in skeletal muscles)
N receptors located at the neuromuscular junction are sometimes designated NM and the ganglionic (neuronal) receptors are designated NN

10. Subtypes and Characteristics of Cholinoceptors
Receptor Type
Other Names
Location
G protein
Post-receptor Mechanism M1
Nerves Gq
IP3, DAG cascade  M2
Cardiac M2
Heart, nerves, smooth muscle
Gi 
Inhibition of cAMP production, activation of K+ channels  M3
Glands, smooth muscle, endothelium M4
CNS Gi
Inhibition of cAMP production M5
IP3, DAG cascade NM
Muscle type, end plate receptor
Skeletal muscle neuromuscular junction
None
Na+, K+ depolarizing ion channel
NN 
Neuronal type, ganglion receptor
CNS postganglionic cell body, dendrites

11. Sympathatic innervation of adrenal medulla
Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems
Sympathatic innervation of adrenal medulla
Sympathatic
Parasympathatic
Somatic
Ganglionic transmittion
NN receptor
Adrenal medulla
NN receptor
NN receptor
Neuroeffector transmittion
Acetylcholine
Norepinephrine
Effector organ
α or β Adrenergic receptor
Effector organ
M receptor
Neuromuscular junction
NM receptor

12. Cholinergic drugs
Nonselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function
Selectivity of action is based on several factors:
Receptor selectivity: muscarinic vs. nicotinic
Pharmacokinetic selectivity: using appropriate routes of administration so that desired effects can often be achieved while while minimizing systemic effects

13. Cholinomimetic agents
Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces
Include agents that act directly (cholinoceptor agonists/stimulants) or indirectly acting mechanisms (cholinesterase inhibitors)

14. Neurotransmission at cholinergic neurons
Ca2+
Na+
Muscarinic
Receptor
ACh
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA +
Acetylcholine
Action Potential
Choline α β
Na+ H+
Nicotinic
Receptor
ACH
Choline
Acetate
Choline
Presynaptic neuron
Postsynaptic target

15. Direct acting cholinergic stimulants

16. Direct acting cholinergic stimulants
Cholinergic receptor agonists mimic the effects of ACh by binding directly to cholinoceptors
They differ in their spectrum of action (muscarnic vs. nicotinic stimulation) and in their pharmacokinetics

17. Cholinomimetic agents
The directly acting cholinomimetics can be subdivided into:
Parasympathomimetic drugs: agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuro-effector junctions
Agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction

18. Direct acting cholinergic stimulants
These agents can be divided into two groups:
Choline esters (acetylcholine, metacholine, carbachol, & bethanechol)
Naturally occurring cholinomimetic alkaloids (muscarine, nicotine, pilocarpine, & lobeline)

19. Direct acting cholinergic stimulants Pharmacokinetics
Choline esters
Poorly absorbed and poorly distributed into the CNS because they are hydrophilic and susceptible to esterase hydrolysis in the GIT
Methacholine is more resistant to hydrolysis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action

20. Direct acting cholinergic stimulants Pharmacokinetics
Natural cholinomimetic alkaloids
Tertiary amines (pilocarpine, nicotine, lobeline) is well absorbed from most sites of administration, and it can cross the BBB
Quaternary amine (Muscarine) is less completely absorbed from the GIT than the tertiary amines but is toxic when ingested and it even enters the brain

21. Muscarinic agonists: Parasympathomimetics
Cholinergic receptor agonists (also called acetylcholine-like agonists) mimic the effects of ACh by binding directly to cholinoceptors
They show relatively few selectivity for M2/M4 vs. M1/M3/M5

22. Acetylcholine chloride
Pharmacology of acetylcholine-like agonists
Choline Ester
Susceptibility to Cholinesterase
Muscarinic Action
Nicotinic Action
Acetylcholine chloride
++++
+++
Carbachol
Negligible ++
Methacholine +
None
Bethanechol
Muscarine
Pilocarpine

23. Direct acting cholinergic stimulants Organ system effect
Cardiovascular system
ACh has four primary effects on the cardiovascular system:
Vasodilation*
Decrease in heart rate (negative chronotropic effect)**
Decrease in the conduction velocity in the atrioventricular (AV) node (negative dromotropic effect)**
Decrease in the force of cardiac contraction (negative inotropic effect)**
* activation of endothelial M3
** activation of M2 receptors

24. Direct acting cholinergic stimulants Organ system effect
Eye
Muscarinic agonists cause contraction of the smooth muscle of the:
Iris sphincter*: resulting in miosis
Ciliary muscle*: resulting in accommodation of the eye for near vision
* activation of M3 receptor

26. Direct acting cholinergic stimulants Organ system effect
Other Organ Systems
Respiratory system*: bronchoconstriction & increase tracheobronchial secretion
GIT***: stimulation of salivation and acid secretion, increased intestinal tone and peristaltic activity, and relaxation of most sphincters
Genitourinary tract: stimulation of the detrusor muscle* and relax the trigone and sphincter muscles of the bladder**, thus promoting urination
* M3 activation ** M2 activation ***M2 and M3 activation

27. Direct acting cholinergic stimulants Organ system effect
Other Organ Systems
Miscellaneous Secretory Glands*: stimulation secretion by thermoregulatory sweat, lacrimal, and nasopharyngeal glands
CNS: Muscarinic agonists are able to produce marked CNS owing to activation of M1- receptors in the brain areas involved in cognition
* M3 activation

28. Clinical uses of the direct acting cholinomimetics
Glaucoma: cholinomimetics reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor (e.g pilocarpine and carbachol)
Bladder and bowel atony after surgery: Bethanechol
Xerostomia associated with Sjögren's syndrome and that caused by radiation damage of the salivary glands: pilocarpine & cevimeline

29. Toxicity
Potentially severe adverse effects can result from systemic administration of cholinomimetic drugs and the comsumption mushrooms of the genus Inocybe (Muscarine)
Overdosage is characterized chiefly by exaggeration of the various parasympathomimetic effects: NVD, urinary urgency, salivation, sweating, hypotension with reflex tachycardia, cutaneous vasodilation, and bronchial constriction

30. Toxicity
Pilocarpine can cross the BBB and affect cognitive function especially among the elderly
Cholinomimetics elicit miosis and spasm of accommodation, both of which disturb vision
Treatment consists of the parenteral administration of atropine in doses sufficient to cross the BBB and measures to support the respiratory and CV systems and to counteract pulmonary edema

31. Nicotinic drugs
Drugs that modulate nicotinic receptors have very limited application because of the localization of these receptor subtypes
Pharmacological stimulation of ganglionic neuronal receptors (NN) has limited utility because this receptor affect both branches of the ANS
The tissue and organ effect depend on the autonomic innervation of the organ involved

32. Nicotinic drugs
Excessive stimulation of NM receptors can cause depolarization block: loss of electrical excitability due to inactivation of voltage-gated sodium channels
If repeated doses of the agonist is used, the nicotinic cholinergic receptors can quickly become desensitized leading to fasciulations and paralysis

33. Nicotinic drugs
In the brain, the α4β2 oligomer is the most abundant nicotinic receptor in the brain
Activation of α4β2 nicotinic receptors is associated with greater release of dopamine in the mesolimbic system: mild alerting action and the addictive property of nicotine absorbed from tobacco

34. Nicotinic drugs
Sustained desensitization may contribute to the benefits of nicotine replacement therapy in smoking cessation regimens
In high concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center
At still higher levels, nicotine causes convulsions, which may terminate in fatal coma

35. Nicotinic drugs
Direct acting nicotine agonists have no therapeutic applications exept in smoking sessation (nicotine and varenicline) and producing skeletal muscle paralysis (succinylcholine)

36. Nicotin replacement therapy
To help patients stop smoking
Available in the form of gum, transdermal patch, nasal spray, or inhaler
Sustained desensitization of α4β2 receptors in the CNS and reduces the desire to smoke and the pleasurable feelings of smoking

37. Varenicline (Chantix®)
Is a partial agonist at α4β2 nicotinic receptors
Varenicline prevents the stimulant effect of nicotine at presynaptic α4β2 receptors that causes release of dopamine
ADRs: nausea, insomnia, and exacerbation of psychiatric illnesses, including anxiety and depression

38. Indirect acting cholinomimetics

39. Indirect acting cholinomimetics
Acetylcholinesterase (AChE) is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its action
Inhibitors of AChE indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine in synapses where acetylcholine is released physiologically (i.e. they have both muscarinic and nicotinic effets)

40. Indirect acting cholinomimetics
There are three chemical groups of cholinesterase inhibitors:
Simple alcohols bearing a quaternary ammonium group, eg, edrophonium
Carbamates (eg, neostigmine)
Organophosphates (eg, echothiophate)

41. Therapeutic Uses and Durations of Action of Cholinesterase Inhibitors
Approximate Duration of Action
Alcohols
Edrophonium
Myasthenia gravis, ileus, arrhythmias
5–15 minutes
Carbamates and related agents
Neostigmine
Myasthenia gravis, ileus
0.5–2 hours
Pyridostigmine
Myasthenia gravis
3–6 hours
Physostigmine
Glaucoma
Ambenonium
4–8 hours
Demecarium
4–6 hours
Organophosphates
Echothiophate
100 hours

42. Indirect acting cholinomimetics
The anti-ChE agents potentially can produce all the following effects:
Stimulation of muscarinic receptor responses at autonomic effector organs
Stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions)
Stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS

43. Indirect acting cholinomimetics Organ system effect
Central nervous system (CNS)
In low concentrations, the lipid-soluble cholinesterase inhibitors cause diffuse activation on the electroencephalogram and a subjective alerting response
In higher concentrations, they cause generalized convulsions, which may be followed by coma and respiratory arrest

44. Indirect acting cholinomimetics Organ system effect
Eye, Respiratory Tract, GIT, & Urinary Tract
The effects of the cholinesterase inhibitors are qualitatively quite similar to the effects of the direct-acting cholinomimetics

45. Indirect acting cholinomimetics Organ system effect
Neuromuscular junction
Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction
At higher concentration, with marked inhibition of acetylcholinesterase, depolarizing neuromuscular blockade occurs and that may be followed by a phase of nondepolarizing blockade (i.e. nicotinic receptors can quickly become desensitized)

46. Clinical uses of the indirect acting cholinomimetics
Glaucoma: physostigmine, demecarium, echothiophate, isoflurophate
Gastrointestinal and Urinary Tracts: Neostigmine is most commonly used anticholinesterase agents in the treatment of adynamic ileus and atony of the urinary bladder, both of which may result from surgery

47. Clinical uses of the indirect acting cholinomimetics
Myasthenia gravis
Anticholinesterase agents help to alleviate the weakness by elevating and prolonging the concentration of ACh in the synaptic cleft, producing a greater activation of the remaining nicotinic receptors
Anticholinesterase agents play a key role in the diagnosis and therapy of myasthenia gravis, because they increase muscle strength

48. Clinical uses of the indirect acting cholinomimetics
Myasthenia gravis
Carbamates (Pyridostigmine, neostigmine , and ambenonium): anticholinesterase agents used in the long-term therapy for myasthenia gravis
Edrophonium (IV) is used for the diagnosis of myasthenia gravis and in differentiating myasthenic crisis from cholinergic crises (adequecy of treatment)

49. Clinical uses of the indirect acting cholinomimetics
Antimuscarinic Drug Intoxication
To treat overdoses of drugs with antimuscarinic actions, such as atropine
Physostigmine (cholinesterase inhibitor) has been used for this application because it enters the CNS and reverses the central as well as the peripheral signs of muscarinic blockade

50. Clinical uses of the indirect acting cholinomimetics
Alzheimer’s Disease
Tacrine, donepezil, rivastigmine, & galantamine are approved for the palliative treatment of Alzheimer’s disease
These agents can cross the BBB to produce a reversible inhibition of AChE in the CNS
They produce modest but significant improvement in the cognitive function of patients with mild to moderate Alzheimer’s disease, but they do not delay progression of the disease

51. Toxicity
Major cause of toxicity is accidental intoxication from the use pesticide use in agriculture and in the home
With increasing inhibition of AChE and accumulation of ACh, the first signs are muscarinic stimulation, followed by nicotinic receptor stimulation and then desensitization of nicotinic receptors
CNS symptoms include agitation, dizziness, and mental confusion (compounds of extremely high lipid solubility)

52. Toxicity
Excessive inhibition can ultimately lead to a cholinergic crisis that includes:
GIT distress: NVD & excessive salivation
Respiratory distress: bronchospasm & increased bronchial secretions
CV distress: bradycardia
Visual disturbance: miosis, blurred vision
Sweating
Loss of skeletal motor function: progressing through incoordination, muscle cramps, weakness, fasciculation, and paralysis