Pharm - CH4: Cholinergic Agonists

Cholinergic Drugs

• Act on receptors that are activated by ACH

  • nicotinic

  • muscarinic

Adrenergic Drugs

• act on receptors that are activated by NE

  • alpha

  • beta

Cholinergic Agonists

• Drugs that: (at cholinergic receptors = muscarinic and nicotinic)

  • mimic ACH

  • have affinity

  • intrinsic activity 

Cholinergic Receptors

• located in all areas of PNS

  • except the sympathetic effector organ

Neurotransmission of ACH

1. synthesis of acteylcholine in the cytoplasm from choline (cholinergic neuron)

   1. choline ~ VitB; can be made in liver or found in some foods

      1. used for many bodily rxns; important for NS; development of brain function

   2. choline converted into acetylcholine

      1. helps muscles contracts, activates pain responses, plays a role in brain functions of memory + thinking

2. storage of acetylcholine in storage vesicles w/n cholinergic neuron

3. AP propagated by voltage sensitive Na+ channels arrives at nerve ending

   1. voltage sensitive Ca2+ channels on presynaptic membrane open 

   2. increase intracellular Ca2+ lvls

      1. promotes docking/fusing of storage vesicle

      2. release ACH into synaptic space

4. ACH released from synaptic vesicles into synaptic spaces diffuse across the synaptic space

   1. ACH binds to cholinergic receptors (nicotinic/muscarinic) 

5. ACH signal at post-junctional effector site rapidly terminated by acetylcholinesterase (ACHE) in synaptic space 

   1. which cleaves ACH into choline + acetate 

6. Choline is recaptured from the cytoplasm by Na+ coupled high affinity uptake system bk into the neuronal cytoplasm where it is acteyltated ag

   1. produces ACH

Cholinergic Receptor Types

• muscarinic

• nicotinic

Muscarinic

• Receptors are more sensitive and have a higher affinity to muscarine than both ACH and nicotine

• Muscarine is a naturally occurring plant alkaloids that bind + activates muscarinic subtypes of ACH receptors

• g-protein coupled receptors, bind to ACH, and recognize muscarine

  • located at PSN effector organ

  • can be either excitatory or inhibitory

  

Nicotinic

• Receptors are more sensitive + have a higher affinity to nicotine 

• nicotine is a toxic colorless/yellowish oily liquid that is the chief active constituent of tobacco. 

  • acts as a stimulant on ACHRs in small doses but in larger amts blocks the action of ACH on ACHRs in both autonomic nerve cells and skeletal muscle cells 

• ligand gated ion channel, binds to ACH and recognizes nicotine

  • located at a;; ganglia and NM junction

  • always excitatory

     

Direct Acting Cholinergic Agonist

• act on cholinergic receptors, mimic ACH

• “straightforward” 

Indirect Acting Cholinergic Agonists

• inhibits the effects of ACHE, thus maintains ACH levels in the synaptic space longer

• acts on the enzyme ACHE (inhibits the degradation of ACH + increases natural levels of ACH in synaptic cleft) 

Indirect and Direct Cholinergic Agonists

• Have the same final effect

Effects of Cholinergic Agonists

• rest and digest (parasympathetic)

  • eye - pupil constriction

  • heart - decrease HR and FOC

  • bronchiole smooth muscle - bronchoconstriction

  • GI - increase peristalsis + GI secretions (mucus, HCL, pepsin, pepinogen) 

  • Bladder - increase in contraction of the detrusor muscle, bladder empties

  • Blood vessels - there is no parasympathetic influence on vascular smooth muscle, but receptors on the endothelium respond and release nitric oxide second messenger, which goes on to vasodilate vascular smooth muscle (more later)

  • Secretions - all increase, saliva, mucus

Acronym for Parasympathetic Stimulation

SLUDGE BAM 

Salivation, Lacrimation, Urination, Defecation, GI Upset, Emesis

Bradycardia

Abdominal Cramps

Miosis

-chol

Cholinergic Agent

Direct Cholinergic Agonist Drugs

• acts directly on the receptor

1. acetylcholine

2. bethanechol tab (urecholine)

3. Carbachol (Isopto-Carbachol)

4. Pilocarpine (Isoptocarpine)

Acetylcholine (as a drug) 

• by itself — not specific enough — lacks therapeutic importance

Bethanechol Tab (Urecholine)

• not affected (hydrolyzed) by ACHE

• effect is at muscarinic receptor, used post-op to stimulate atonic (lacking muscular tone) bladder

• given orally to treat urinary retention 

  • results from gen. anesthesiac, diabetic neuropathy of bladder, side effect of antidepressants, treat GI atony (lack of muscular tone)

• the muscarinic receptors on the bladder and GI tract stimulate contraction of the bladder (detrusor muscle) + expulsion of urine, _ increased GI motilit

  • SLUDD

Sum: increase urine output

Carbachol (Isopto-Carbachol) Drops

• has both nicotinic +muscarinic actions 

• pupil constriction

  • used as an eyedrop to constrict the eye (para. pupil ciliary muscle constriction part of rest + digest) to increase drainage of aqueous humor + decrease pressure on the retinal nerve for glaucoma

Sum: used to treat glaucoma

Aqueous Humor

• clear fluid filling the space in front of the eyeball b/n the lens + cornea

• bathes and nourishes the lens and maintains pressure in the eye

Vitreous Humor

• transparent gelatinous tissue filling the eyeball behind the lens

Glaucoma

• abormality in the eye’s drainage system

  • excess aqueous flu. can buildup —> excess pressure that damages the optic nerve 

• damage in the optic nerve + retina

• can cause vision loss

• Risk Factors: increasing age, high pressure in eye, a family history of glaucoma, use of steroid medication

Pilocarpine (Isoptocarpine)

• muscarinic activity only

  • acts on subtype of muscarinic receptor (M3) found at the iris sphincter muscle, causing the muscle to contract — resulting in pupil constricting (miosis) 

• action facilitates the rate aqueous humor leave the eye to decrease intraocular eye pressure (IOP)

• stable to ACHE

• DOC for emergent decrease in IOP for glaucoma

• cholinergic agents increase conventional outflow by constricting longitudinal portion of ciliary muscle

• cause immediate stop in IOP = increase drainage of aqueous humor (onset ~ few minutes, duration ~ 4-8 hours) 

  • drug of choice for narrow angle/wide angle glaucoma

Reversible Indirect Acting Cholinergic Agonists

• drugs bind to and block the actions of ACHE

  • prolongs the effect of ACH in the synaptic space to affect the receptors that remain intact

• reversible; reversibly binds to ACHE + blocks its actions on ACH, providing more ACH in the synaptic cleft

1. Physotigmine

2. Nestigmine

3. Pyridostigmine (Mestinon)

4. Rivastigmine ( Exelon)

5. Donepezil ( Aricept )

Physostigmine

• indirect acting cholinergic agent

• wide range activity at muscrinic, nicotinic, and neuromuscular junction

• increases intestinal + bladder motility 

• used to treat glaucoma + delayed gastric emptying

  • enhances transmission of ACH signals in brain and can cross BBB

• physostigmine salicylate is used to treat anticholinergic poisoning

Neostigmine

• greater effect/selectivity at the NMJ than physidtigmine

  • used in treating muscle weakness associated w/ myasthenia gavis

    • antibodies block, alter, destroy, ACH receptors at N/M juction

Pyridostigmine ( Mestinon)

• has greater effect at NMJ

• used for myasthenia gravis at NMJ

• preferred for treatment of myasthenia gravis b/c has longer duration of action + less likely to cause unwanted effects

Myasthenia Gravis

• chronic autoimmune disorder —> antibodies target + destroy ACH at NMJ (somatic NS)

  • decrease comm. b/n nerves + muscle, resulting in diverse weakness of skeletal muscles

  • less ACH receptors

• affects voluntary muscles of the body, esp. control of eyes, mouth, throat, limbs

Symptoms of Myasthenia Gravis

• weakness of eye muscles

• difficulty swallowing 

• drooping of one or both eyes (ptosis) 

• change in facial expressino

Irreversible Indirect Cholinergic Agonists

• permanently inactivates ACHE

• restoration of ACHE requires the synthesis of new enzyme

1. Echothiophate (Phospholine Iodide)

Echothiophate (Phospholine Iodide)

• Organophosphate

• used as an eyedrop to decrease IOP in the treatment of chronic glaucoma

Indirect Cholinergic Agonists also used Centrallyfor Alzheimer's Dx

• bind to central ACHE

• pts w/ alzheimer’s dx have deficiency of cholinergic (ACH producing) neurons in CNS

• despite the ability to delay the progression of alzheimer’s disease, none can stop progression

1. Rivastigmine (Exelon)

2. Donepezil (Aricept)

Summary Drugs

Pyridostigmine ( Mestinon)