Actions of Muscarinic Agonists

(aka Parasympathomimetics)

Miosis (contraction) of the Iris

Accomodation (Ciliary Muscle)

Blood vessel dilation, ↓ hr, ↓ bp [see charts for detailed actions on different parts of the heart]

 *Bronchoconstriction

↑ glandular secretion (lung, GI, bladder and glands).

↑ GI motility, ↓ Sphincter tone

↑ tone of the detrussor muscle, ↓ sphincter tone (voiding)

Examples: Ach Carbachol, Methacholine, Bethacholine, Cevimeline, Pilocarpine

Mydriasis (pupillary dilation)

Cycloplegia (paralasis of the ciliary muscle resulting in a loss of accomodation)

Initial ↓ then ↑ in hr (bradycardia then tachycardia)

Blocks the action of agonists on the blood vessels (prevents their dilatory effects)

Bronchodilation

↓ in secretions

↓ GI motility and tone

Relaxation of the detrussor muscle (retention)

CNS Effects: Sedation, anti-Parkinsons, Hallucination/euphoria (actions on Cerebral ctrs), prevention of motion sickness, may cause depression.

Ex: Atropine, Scopoline, Glycopyrrolate, Ipratopium, Oxybutynin, Trihexphenidyl, HCL, Beztropine, Topicamide

Inital ↑ (w sm doses) then ↓ in hr

Constriction of the vessels (through NE and Epi release form the adrenal medulla)

↑ GI motility and tone (nausea, vomiting, diarrhea)

In the CNS: +Vomiting Center (medulla:cardiac, resp, vomiting and vasomotor centers), +ADH release, Analgesia

Ex: Ach, Nicotine

Effects of Ganglionic Antagonists

(Block N1)

Mydriasis

Cycloplegia

Moderate ↑ hr and ↓ CO

Ortostatic hypoT, blood vessel dilation, ↑ in peripheral blood flow, ↓ in venous return.

↓ GI motility (constapation)

↓ contraction of the detrussor (retention)

↓ Secretions (Xerostomia, anhydrosis)

Relaxation of skeletal muscle

Ex: Hexamethonium, Mecamylamine

Thereputic uses: Tourette's syndrome

Muscarinic and Nicotinic Agonist

@ small doses IV: ↓ bp unless blocked by Atropine

@ large doses IV: ↓ bp

-w/ Atropine than will ↑ bp (release of Epi/NE)

-w/ Atropine + Hexamethonium: No effect on bp (blocking M and N1 receptors)

-w/ Atropine +Phentolamine: No effect on bp

-w/ Hexamethonium only: ↓ bp (direct action on M)

*Has no known treatment uses

Muscarinic Agonist

Has some Nicotinic action: Give w/ Atropine bp will ↑ due to nicotinic effects.

Not hydrolyzed by cholinesterase.

Tx Urinary retention,

post-op atony of the stomach or bowel (where there is no obstruction),

Glaucoma (topical administration, activates pupillary sphincter and ciliary m)

Muscarinic Agonist

Some N action (give w/ atropine and BP ↑)

Used to Dx asthma

Muscarinic Agonist

Activates smooth m of bowel and bladder.

Pure muscarinic actions (atropine has no effect on bp)

Not hydrolyzed by Achase

Oral or Parenteral

Tx: Urinary retention and postoperative atony of sotmach or bowel (when there is no obstruction).

Muscarinic Agonist

Pure M action (no N: give w/ atropine>No effect on bp)

Tx: Sjoren's Syndrome (dry mouth, dry eyes, arthritis),

Mikulicz Syndrome (bilateral enlargement of lacrimal and salivary glands),

Sicca Syndrome (xerostomia (dry mouth) and xeropthalmia (dry eyes))

 Pure Muscarinic Agonist (no N actions)

Topical

Rx: Closed angle glaucoma (↑ outflow of aqueous humor, activates pupillary sphincter and ciliary m),

Sjogren's Syndrome (stimulates salivation)

Muscarinic-specific Cholinergic Antagonist

Well-absorbed, crosses BBB

Effects are those of other muscarinic antagonists (bronchodilation, CNS effects due to stimulation then depression of medullary centers etc...)

Tx: After exposure to Achase inhbitors/organophosphates (to ↓ Ach effects),

↓ slavation and resp secretions for endotrach tubing,

Acute MI (w/bradycardia and hypotension but no arrhythmia),

to tx digitalis toxicity (conteracts overstim by vagus n)

Muscarinic Antagonist

Well absorbed, crossess BBB

Tx: Motion sickness

Muscarinic Antagonist

Tx: gastric hypermotility

Muscarinic Antagonist

Inhaled (*Is a quarternary compound: not absorbed from the GI and does not cross BBB)

Tx: asthma/COPD

*Note that M blockers are not as effective as beta agonists in tx asthma due to the fact that the density of M receptors decreases from the trachia>bronchioles and density of B2 receptors ↑ towards the bronchioles*

Muscarninc Antagonist

Tx: Hyperactive bladder

Muscarinic Antagonist

Tx: Parkinsonism

Muscarinic Antagonist

Tx: Parkinsonism (CNS effects)

Muscarinic Antagonist

Used for fundoscopic examination

Actions have even shorter duration than atropine.

Actions can be reversed with Pilocarpine

Nicotinic Agonist

↑ in bp (release Epi and NE)

 -w/ Hexamethonium (N1): No effect on bp

-w/ Phentolamine: No effect on bp

Nicotinic (N1) Antagonist

Causes PNS, SNS, adrenal and sweat responses.

Is a quarternary amine and thus does not cross BBB (No CNS symptoms).

*Not used clinically

Inhibits the sotrage of Ach in vesicles.

Not used clinically

Alpha 1/2, Beta 1 Agonist

↑ bp

-w/ Phentolamine: No effect on bp

An irreversible Ach inhbitor

Rx: Glaucoma

Should not be used in older individuals (cataracts).

Blocks the Sodium-mediated uptake of Choline into the neuronal terminal of cholinergic neurons (the rate-limiting step in Ach synthesis).

Indirect inhibtion of Ach synthesis and anticholinergic effects.

Inhbits the storage of Ach in vesicles after it is synthesized from choline.

Not used clinically

*Sidenote: Ach vesicles also contain peptide P, ATP and proteoglycans.

Protease activity of botulinium targets SNAP-25 and VAMP (key members of the membrane fusion machinery that allows exocytosis of Ach from vesicles at the presynaptic membrane) thereby inhibitng Ach release.

Tx: Wrinkles,

Strabismus (misalignment of the eyes),

Blepharospasm (twitch of m around the eye),

Meige's Syndrome (unilateral spasm due to inflammation of the facial n.),

Spasmodic Torticollis (involuntary movement of the neck m. with spasms of the elbow, wrists and fingers),

Underarm sweating,

Migranes

Muscarinic antagonist

Muscarine> Ach >>Nicotine

Muscarine> Ach >>Nicotine

Actions blocked by Atropine (M-selective block)

Muscarine receptors located on effectors of postgang parasympatetics, endothelial cells of blood vessels, Glands (incl sweat: postgang sympathetic inn).

M1 and M3 action is through a GPCR where a Gq protein couples the M receptor to a membrane-bound Phospholipase C leading to the activation of and IP3 (triggers Ca release from storage in sm m) and DAG (modulates PKC actions).

M2 action is primarily thorugh the coupling of M receptors to adenylyl cyclase via an inhbitory Gi

Alternately, M2 can be coupled to K+ channels in the heart and agonists can cause the opening of these channels.

RECAP

M1,3,5 act through Gq to ↑IP3/DAG

M2,4 act through Gi to ↓cAMP

*Major roles of M4 and M5 receptors in the periphery have not been noted.

N receptors present in the sympa and parasympa ganglia, adrenergic nerve termials and adrenal medullary cells (so-called Ganglion Receptors, N_N/1) which differ slightly from those in the NMJ (N_M/2)

N Ach receptor is located on a Na+ and K+-selective channel protein.

Activation of the N receptor triggers channel opening and depolarization of the cell as a direct result of Na+ influx →EPSP (and if large enough an AP).

M2 cholinergic receptors are the effectors of parasympathetic outflow to the heart.

Binding of Ach to M2 > opening of K+ channels in the heart.

Ach on M2 receptors on Atrial Cells: ↓ contractile force, ↑ conduction velocity, ↓ absolute refractory per.

Ach acting on M2 receptors at the AV node: ↑ rel. refractory period and ↓ conduction velocity = ↓ HR

NET EFFECT, parasympathetics on the heart: ↓ HR, ↓ conduction velocity at the AV node and (↑/↓?) excitability of latent pacemakers 

Vasodilation

↓ BP

Ach is an endothelium-dep vasodilatior that binds to Muscarinic receptors on endothelial cell surfaces > Influx of Ca (via actions of IP3/DAG second messengers) > Ca activates NADPH-dep NOS > ↑ NO > NO diffuses out and causes relaxation of smooth muscle and vasodilation.

Note that vasodilation is not a parasympathomimetic effect as it results from the release of NO down the line and not directly from parasympathetic discharge.

Muscarinic receptor type

Found on Nerves

Acts through IP3/DAG > ↑ Ca

Muscarinic Receptor

On the Heart, Nerves, and Smooth muscle

Acts to inhbit the production of cAMP and to activate K+ channels.

Muscarinic receptor

Located on Glands, smooth muscle and Endothelium

Actions are through IP3/DAG > Ca release

Orthostatic hypotension, syncope,

Exacerbation of asthma (in asthmatics),

Substernal pain,

Gut or urinary urgency, belching, abdominal cramps,

Sweating,

Salvation,

Cardiac arrhythmias,

Alterations in vision/accomodation.

Asthma,

Hyperthyroid conditions (can result in atrial fib),

coronary insufficency/hypotension,

Peptic ulcer dz

In order of increasing sensitivity to block:

Mydriasis for examination of fundus and optic disc,

↓ salvation and respiratory secretions,

in an acute MI when bradycardia is assoc w hypoTN (w/o an arrhythmia),

Digitalis toxicity (causing a heart block),

to ↓ GI tone/motility to counter drugs that ↑ motility,

tx mild dysentary,

anticdote to mushroom poisoninig by anticholinesterases,

tx Parkinsonism

Receptor distribution*

-Blood vessels are innervated mostly by SNS and therefore nicotinic receptor activation results in vasoconstriction mediated by sympathtetic postganglionic nerves.

-The gut is innervated mostly by the PNS so N receptor activation causes increased motility and secretion due to postsympathtic parasympathetic discharge

-N receptors are at the NMJ and when activated directly cause fasciculations and spasm.

Rapid-onset (similar to cyanide poisoning)

Nausea, vomiting, diarrhea, (↓ bp, in notes but not listed on wiki), mental confusion

Death is caused by respiratory paralysis.

Tx with gastric lavage with a solution of KMNO4 accompanied by ventilatory support and anticonvulsant therapy.

*Note that these symptoms are distinct from those caused by chronic use of tobacco.

Nicotine

Thereputic uses and SE

Nicotinic Agonist (@N1 and N2)

Crosses the BBB

Thereputic Uses: analgesia, cognitive enhancement, neuroprotection, anxiolytic (anti-anxiety), antipsychotic

SE: GI distress, hypothermia, emesis, HTN*, seizures, respiratory distress, addiction.

Nicotinic (N1-specific) Antagonist

Crosses BBB

PNS effects everywhere except for in the vessels and sweat glands are blocked.

Tx: Severe HTN and hypertensive crises,

Tourette's sndrome.

Orthostatic hypotension,

Uriniary retention,

Mydriasis, cytoplegia,

Impaction,

Impotence,

CNS effects (with those that cross BBB),

Tolorance

Renal, cerebrovascular, or coronary insufficiency*

Because with marked hypotension (as may be caused by ganglionic blockade) blood will pool away from these organs resulting in ischemia.

"-cur-"

Occupy skeletal muscle Nicotinic receptors and thereby prevent Ach-meidated depolariation of the fiber.

Provide a competitive, reversible block.

No AP can be generated (hence non-depolarizing) and relaxation/paralysis of the muscle ensues.

All are given Parenterally, none cross BBB (none have analgesic effects).

Competitve block is reversed by by Achase inhbitors (anti-cholinesterases) which ↑[Ach] allowing it to outcompete the competitive NM blockers.

Non-depolarizing/Competitive NM blocker

Some cross-rxn with N, ganglionic, receptors.

Short onset (min), long duration (hours)

Low bioavail (quarternary ammonium), ltd. hepatic metabolism, renal elim.

Triggers Histamine release (hypoT, ↓ CO, bronchospasm, uticaria) and Muscle paralysis (face and neck>limbs>trunk > intercostal m > diaphragm (difficulty breathing).

*Note that m. recover in opposite order(diaphragm 1^st).

Tx: Used w general anesthesia to allow lower doses to be used,

Convulsions (Tetanus, epilepsy, electroshock therapy),

SE: HypoT, bronchospasm, uticaria, difficulty breathing

CI: Pt w/ cardiac ischemia

OD: Tx OD of D-tubocuarine with assisted ventilation and Achase inhibitors.

Non-depolarizing/Competitive NM blocker

Short onset, long duration

Renal degradation

Does not release histamine (>does not cause hypoT)

Used: as a m. relaxant in endotrachial intubation.

Non-depolarizing/Competitive NM blocker

Short onset, Intermediate duration

Hepatic/renal degredation

No CV fxn (does not release histamine)

Non-depolarizing/Competitive NM blocker

Short-onset, Intermediate duration

Undergoes spontaneous (Hoffman) degradation

CV effects are due to minimal release of histamine

Non-depolarizing NM blocker

Short-onset, Intermediate duration

Hepatic/renal degradation

No CV fxn (does not release Histamine)

Tx: used (more commonly than those agents that do cause CV effects) to aid in endotrachial intubation.

Non-depolarizing/Competitive NM blocker

Short onset, Short duration

Degraded by pseudocholinesterase*

*Some Pt are genetically deficient in pseudocholinesterase. These pt have effects that are severely prolonged and can be toxic.

Act like N2 nicotinic agonists and depolarize the muscular end plate.

Phase 1 of Depolarizing Block: Accompanied by fasiculations.

Antagonized by curare or other non-depolarizing NM blockers and intensified by Achase inhibitors.

Phase 2 Desensitized Block: Continuous depolarization results in m relaxation/paralysis because tension can't be maintained in m w/o periodic repol and depol of the end plate.

*Desensitizes receptors to Ach and other cholinergic agonists. During Phase 2 desensitization varies with the dose and m affected.

Depolarizing NM blocker

Some action @ N1 (ganglionic), and M receptors.

Rapid onset, Ultra-short duration

IM admin

Metabolized by cholinesterase in liver and plasma.

Phase 1: action @ N2, depolarizing block→muscle activation (fasciulations) in action similar to a potent Ach, can be antagonized by cuarare and intisifiedy by Achase inhbitors.

Phase 2: @N2, Desensitized block of N2 receptors. Antagonized by Achase inhbitors and intensified by curare*

SE: Hyperkalemia (depol), Cardiac dysrhythmias, Masseter spasm, Malignant hyperthermia*, Myalgias (m pain), ↑ ICP, IOP, and IGP (Cranial, Ocular, and Global P)

Is both a competitive and depolarizing NM

Synthetic, quarternary amine with considerable Achase inhbitory activity.

Inhalation anesthetics (Ether, Halothane, Isoflurane) have curare (non-depol NM blocker)-action and cross the BBB, CNS effects of relaxation.

Synergizes with competitive NM blockers.

*You must ↓ dosage of curare if administered with these.

Streptomcin, Neomycin, Polymyxin etc... cause competitive N blockade and ↓ release of Ach*

You see similar effects with colistin and Kanamycin

Typically includes Achase inhbitors to ↑ Ach effects by ↑ [Ach] in the NMJ. Commonly used agents are Neostigmine or Pyrdostigmine.

Adjunctive corticosteriod therapy (to suppress autoimmune systems)

Plasmaphresis to remove autoreactive Abs.

Thymectomy (cures remission in 25% of pt and improvement in 75%)

Reversible inhibtor of Achase

Binds at anionic and esteratic sites on Achase.

Rapid onset, short duration.

Used: to diagnose MG (actions too short to use as tx)

Reversible Achase Inhbitor

Has high affinity for Achase at anionic and esteratic sites

Readily absorbed from GI, SubQ, and mucous membranes

Acts on M and N sites

CNS actions: Stimulation followed by depression.

Tx: Glaucoma, Dementia and Alzheimer's Dz.

Physostigmine, Donepezil, Rivastigmine, Galantamine.

Centrally-acting Achase Inhbitors

Reversible Achase Inhbitor

Has both N and M effects including 'direct' effects on skeletal muscle.

No CNS effects.

Rx: Dx and Tx of Myasthenia gravis,

Post-operative atony of the gut and bladder,

Tx curare OD

Reversible Achase Inhbitor

Has loger duration of action and fewer SE than other drugs of this class*

Tx: Myasthenia Gravis

Irreversible Achase Inhibitors

Phosphorylates Achases causing irreversible inhbition.

Has both N and M effects.

Are hydrolyzed by phosphorylphosphatases.

Readily absorbed by all routes (lipid-soluble, crosses BBB to exert CNS effects).

Incl Insecticides and Neve gases.

Tx: Glaucoma

Toxicity: Manifests as N, M and Nicotinic effects caused by the excessive amouts of Ach present in the synaptic cleft when Achases are blocked.

Toxic effects are due to excessive Ach (builds up when organophosphates block Achases) at sites of N/M receptors and in the CNS.

Tx: Remove source of poisoning,

Administer Atropine (competitive antagonist @ M Ach receptors),

Administer Pralidoxome (cholinesterase reactivator),

Assist in ventilation (resp collapse caused by exhaustive paralysis of the diaphragm),

Administer Trimethadone (anticonvulsant),

Administer Thiopental (barbituate anesthetic).

A cholinesterase recativator.

aka 2-PAM

Combines with the anionic site on the Achase enzyme (by electrostatic attraction).

Binding of Pralidoxime causes a reorientation of the inhbited Achase which results in hydrolysis of the organophosphate group and reactivation of the Achase enzyme.

Ach

[Beth Cevim Carries Methylated Pillows]

Bethanechol,

Cevimeline,

Carbachol,

Methacholine,

Pilocarpine.

M-only actions: Bethanechol, Cevimeline, and Pilocarpine.

N and M actions: Carbachol, Methacholine.

Not hydrolyzed by Achases: Bethanechol and Carbachol

After Trying a hex, Ipra ate pye while
Scooping up the Oxygen of the Tropics.

Atropine,

Trihexphenidyl HCl,

Ipratropium,

Glycopyrrolate,

Scopolamine,

Oxybutynin,

Tropicamide

Atropine and Scopolamine are naturally occuring, well absorbed and widely distributed.

Quarternary amines (Ipratropium, must be inhaled) are not well absorbed and have ltd distribution.

*This mneumonic is bunk...let me know if you have another one!

GI distress,

Hypothermia,

Emesis,

HTN,

Seizures (caused by release of Glu in the brain),

Respiratory Distress.

Advantages: rapid-onset, ultra-short duration of action, IM administration.

Disadvantages/SE: Hyperkalemia,

Cardiac dysrhythmias (due to hyperkalemia),

masseter spasm,

Malignant Hyperthermia (Occurs in genetically susceptible individuals who have a big release of Ca and an overwhelming activation of oxidative metabolism which depletes the body's stores, potentially fatal),

Increased ICP, IOP, IGP

Remember that these are the ones that have CV effects!

S.T.A.M.

Succinylcholine, Tubocurarine, Atracurium, Mivacurim

V.A.R.

Vecuronium, Atracurium, Rocuronium