Muscarinic Receptor Agonists and Antagonists

Question 1

Muscarinic agents-general considerations

Answer 1

Msucarinic cholinergic receptor AGONISTS can be divided into 2 groups:

1. AcH and several synthetic choline esters.
2. Naturally occurring cholinomimetic alkaloids and their synthetic congeners.

Question 2

Methacholine

Answer 2

Synthetic choline ester
QUATERNARY AMINE
Greater duration and selectivity of action than AcH
Added methyl group increases its resistance to hydrolysis by cholinesterase.
Slight nicotinic action and a predominance of muscarinic actions mostly in the CV system.
Used for diagnosis of bronchial airway hyperreactivity.
-Methacholine is given by inhalation via a nebulizer as a diluted powder.
-The test is for patients who do not have clinically apparent asthma.
-Drugs use shows intense bronchoconstriction and a reduction in vital capacity.
Contraindications for this test in some patients: if they have a severe airflow limitation, recent MI/stroke, uncontrolled hypertension, pregnancy.
Clincally used in the diagnosis of asthma.
Serious side effects: dyspnea (difficult or labored breathing)
Other side effects: lightheadedness, headache, pruritus (severe skin itching), throat irritation.
Contraindications: Recent heart attack or stroke, aortic aneurysm, uncontrolled hypertension.

Question 3

Carbachol

Answer 3

Synthetic choline ester
QUATERNARY AMINE
Unsubstituted carbamoyl ester
Completely resistant to hydrolysis by cholinesterase
Primarily muscarinic actions
Retains substantial nicotinic activity particularly in the autonomic ganglia.
Has a long half-life and is therefore distributed to areas of low blood flow.
Clinical applications in Glaucoma
Side effects: sweating, shivering, nausea, dizziness, increased frequency of urination, rhinitis (irritation of mucous membranes inside the nose) (oral formulations).
Contraindications: acute iritis or glaucoma after cataract extraction, narrow-angle (closure angle) glaucoma.
Carbachol cannot be used systemically because of its unpredictable nicotinic action at autonomic ganglia.
Topical application of carbachol to the cornea of the eye results in both pupillary contraction (miosis) and decreased intraocular pressure.
-Used topically in ophthalmology: reduces intraocular pressure in the treatment of glaucoma, induction of miosis during surgery.

Question 4

Bethanechol

Answer 4

Synthetic choline ester
QUATERNARY AMINE
Unsubstituted carbamoyl ester
Compeltely resistant to hydrolysis by cholinesterases
Primarily muscarinic action
Bethanechol has a long half life and is therefore distributed to areas of low blood flow.
Mainly muscarinic actions
There is some selectivity on the GI tract and urinary bladder motility.
Clinical application as a urinary tract motility agent.
Side effects: Sweating, shivering, nausea, dizziness, increased frequency of urination, rhinitis (oral formulations).
Contraindications: acute iritis or glaucoma after cataract extraction, narrow angle (angle-closure) glaucoma.
Almost completely selective for muscarinic receptors.
Bethanechol is used in the treatment of urinary retention and inadequate emptying of the bladder.
It is used if organic obstruction is absent in certain conditions: postoperative urinary retention, diabetic autonomic neuropathy, certain cases of chronic hypotonic, myogenic, or neurogenic bladder; this way, cauterization can be avoided.
In the GI tract, it stimulates peristalsis and increases motility.
It was formerly used to treat several conditions: postoperative abdominal distention, gastric atony (delay in food movement out of stomach), gastroparesis (prevents proper stomach emptying), adynamic ileus (failure of passage of enteric contents through the small bowel and colon), GERD; BUT MORE EFFICACIOUS THERAPIES FOR THESE DISORDERS ARE NOT AVAILABLE (GI ONES).

Question 5

Pilocarpine

Answer 5

Naturally occurring cholinomimetic alkaloids and their synthetic congeners
Pilocarpine has dominant muscarinic actions
It may cause anomalous (abnormal) CV pressor effects.
Sweat glands are sensitive to Pilocarpine.
Sialagogue (increased saliva flow rate) and miotic agent.
TERTIARY AMINE
Pilocarpine is used to treat xerostomia, associated with Sjogrens syndrome.
It enhances salivary secretion, ease of swallowing, improved oral cavity hydration.
Sweating is the MOST COMMON CHOLINERGIC SIDE EFFECT!!!
Pilocarpine is also used in the topical treatment of glaucoma and miotic agent.
Side effects: SWEATING, shivering, nausea, dizziness, increased frequency of urination, rhinitis (oral formulations).
Contraindications: acute iritis or glaucoma after cataract extraction, narrow angle (angle-closure) glaucoma.

Question 6

Quaternary Amines

Answer 6

1. Poorly absorbed after oral administration
2. Limited ability to cross the BBB
3. Generally resist hydrolysis
4. Short-acting agents are due to rapid elimination by the kidneys.

Question 7

Tertiary Amines

Answer 7

1. Readily absorbed
2. Cross the BBB
3. Excretion of the tertiary amines can be accelerated by acidification of the urine (the tertiary amine becomes quaternary with an added proton-acidic-and are rapidly eliminated by the kidney).

Question 8

Therapeutic Uses of Muscarinic Receptor Agonists

Answer 8

Muscarinic agonists are currently used in the treatment of urinary bladder disorders, xerostomia (dry mouth), and in the diagnosis of bronchial hyperreactivity.
Muscarinic agonists are also used in ophthalmology as miotic agents and for the treatment of glaucoma.

Question 9

Acetylcholine

Answer 9

Used topically for the induction of miosis during ophthalmologic surgery.
Given topically into the eye as a 1% solution.
Clinical applications in producing miosis during ophthalmic surgery.
Side effects: hypotension, bradycardia, flushing, breathing difficulty, corneal edema and clouding.
Contraindications: NONE
Safety and efficacy has not been established in children.

Question 10

Cevimeline

Answer 10

High affinity for M3 muscarinic receptors.
The receptor is present in lacrimal and salivary gland epithelia.
Cevimeline has a long-lasting sialogogic action; may have fewer side effects than pilocarpine.
It enhances lacrimal secretions in Sjogrens syndrome.
Serious side effects: sweating, shivering, nausea, dizziness, increased frequency of urination, rhinitis (oral formulations).
Contraindications: acute iritis or glaucoma after cataract extraction, narrow-angle (angle-closure) glaucoma.
M1 and M3 agonist.
Treats xerostomia in Sjogrens syndome.

Question 11

Contraindications, Precautions, and Adverse Effects of Muscarinic Receptor Agonists

Answer 11

-Important contraindications: Asthma, COPD, urinary or GI tract obstruction, acid-peptic disease, CV disease accompanied by bradycardia, hypotension, may cause atrial fibrillation in hyperthyroid patients.
-Common adverse effects: diaphoresis (excess sweating), diarrhea, abdominal cramps, nausea/vomiting, other GI side effects, sensation of tightness in the urinary bladder, difficulty in visual accommodation, hypotension (can severely reduce coronary blood flow).
Contraindications and adverse effects are of LITTLE CONCERN WITH TOPICAL APPLICATION.

Question 12

Toxicology of Muscarnic Agonists

Answer 12

Poisoning from the ingestion of plants containing pilocarpine, muscarine, or arecoline: exaggeration of their various parasympathomimetic efffects.
Treatment: HIGH ENOUGH DOSES OF ATROPINE SO IT CROSSES THE BBB, support of the respiratory and CV systems.

Question 13

Action of muscarinic receptor ANTAGONISTS

Answer 13

-Blocks ACh binding to muscarini cholinergic receptors at neuroeffector sites.
Smooth muscle
Cardiac muscle
Gland cells
-Blocks ACh binding to muscarinic cholinergic receptor in peripheral ganglia and the CNS.
-MUSCARINIC RECEPTOR ANTAGONISTS CAUSE LITTLE BLOKCADE AT NICOTINIC RECEPTOR SITES.
Quaternary ammonium antagonists exhibit a greater degree of nicotinic blocking activity; therefore more likely to interfere with ganglionic and neuromuscular transmission.
MECHANISM OF ACTION:
Compete with agonists for a common binding site on the muscarinic receptor
-Atropine is a competitive antagonist: it cane be overcome if the concentration of ACh at the receptor sites is increased.

Question 14

Cholinergic Transmission

Answer 14

High or toxic doses of atropine and related drugs
-Central effects are observed; generally causes CNS stimulation followed by depression.
Parasympathetic neuroeffector organs:
-Different organs vary in sensitivity to muscarinic receptor antagonists like atropine
Small doses of atropine depress salivary and bronchial secretion and sweating.
Large doses of atropine: pupil dilates, accommodation of the lens to near vision is INHIBITED, vagal effects on the heart are blocked so that the heart rate is increased, antagonize parasympathetic control of the urinary bladder, inhibiting micturation (urination), antagonize parasympathetic control of the GI tract decreasing gut tone and motility.
Even LARGER doses of atropine: required to inhibit gastric motility and particularly secretion; doses that depress gastric secretion then almost invariably affect other systems.
This is the DOSE HIERARCHY FOR ATROPINE; NOT A CONSEQUENCE OF DIFFERENCES IN THE AFFINITY OF ATROPINE FOR RECEPTOR SUBTYPES.
-It is more likely due to the degree to which the functions of end organs are regulated by parasympathetic tone, involvement of intramural neurons and reflexes.
The actions of clinically available muscarinic receptor antagonists differ only quantitatively from those of atropine.
-No antagonist in the receptor-selective category is completely selective; balance on receptor subtypes.

Question 15

Prototypical alkaloids Atropine and Scopolamine

Answer 15

Atropine and Scopolamine differ quantitatively in antimuscarinic actions, particularly in the CNS.
Atropine has almost no detectable effect on the CNS in doses that are clinically used.
In contrast, Scopolamine has prominent central effects at low therapeutic doses (greater permeation across the BBB than atropine).
FOR THIS REASON, ATROPINE IS PREFERRED TO SCOPOLAMINE FOR MOST PURPOSES.

Question 16

Atropine

Answer 16

Therapeutic dosses…
-Causes only mild vagal excitation; results of stimulation of the medulla and higher cerebral centers.
Toxic doses…
-Central excitation becomes more prominent: restlessness, irritability, disorientation, hallucinations of delirium.
Even larger doses…
-Stimulation is followed by DEPRESSION: this leads a period of paralysis and coma, followed by circulatory collapse and respiratory failure.
-Conventional systemic doses of atropine have little ocular effect.
-Locally applied atropine produces ocular effects of considerable duration; accommodation reflexes may not fully recover for 7-12 days.
Effects on heart in the CV system:
At clinical doses…
Main effects on the heart is tachycardia
There are NO CHANGES in BP or cardiac output.
At larger doses intramuscularly…
Causes progressively increasing tachycardia
Blocks vagal effects on M2 receptors in the SA nodal pacemaker.
If it is given to healthy adults…the influence of atropine is most noticeable due to high vagal tone.
It it is given to infants and elderly…larger doses may fail to accelerate the heart.
Atropine often produces cardia arrhythmia without CV systems.
Effect on he circulation in the CV system in toxic (sometimes therapeutic) doses…
-Can dilate cutaneous blood vessels, especially those in the blush area causing “atropine flush”
Effects on the GI tract:
-Vagal activity modulates gastrin-elicited histamine release and gastric acid secretion.
-Histamine H2 receptor antagonists and proton pump inhibitors have replaced nonselective muscarinic antagonists as inhibitors for acid secretion.
-At low doses…atropine blocks M1 receptors to prevent ACH reuptake, so negative feedback happens and there is more ACh, so you get bradycardia.
Effect on the biliary tract…
-exerts a mild antispasmodic action on the gallbladder and bile ducts
-Atropine can’t overcome the spasm and increase in biliary duct pressure caused by opioids (nitrites more effective than atropine).
Half-life is 4 hours.
The liver metabolizes and eliminates half of the atropine dose, the rest is excreted unchanged in the urine.
Used in amnesia; given to block vagal reflex responses induced by surgical manipulation of visceral organ.
Atropine or glycopyrolate is used with neostigmine:
-Blocks parasympathomimetic effects of neostigmine (reverses anti cholinesterase inhibition).
-Combination used when neostigmine is used to reverse skeletal muscle relaxation after surgery.
-Serious cardia arrhythmias have occasionally occurred: possibly due to combination effects: initial bradycardia produced by atropine, cholinomimetic effects of neostigmine.
ANTICHOLINESTERARSES POISONING
Large doses of atropine for treatment of poisoning by anticholinesterae organophosphorus insecticides.
Atropine antagonizes the parasympathomimetic effects of pyridostigmine or anti cholinesterase agents; drugs are administered in the treatment of myasthenia gravis.
Will not interfere with the salutary (beneficial) effects at the skeletal NMJ.
Most useful in early therapy when poisoning occurs, before tolerance to muscarinic side effects has developed.

Question 17

Scopolamine

Answer 17

Therapeutic doses…
-Causes CNS depression with drowsiness, amnesia, fatigue, and dreamless sleep (reduction in REM sleep).
-It causes euphoria, so it is subject to some abuse.
It was previously used as an adjunct to anesthetic agents or for preanesthetic medication.
-Desirable depressant and amnesic effects.
-The same dose of scopolamine can be complicated by the presence of sever pain; can occasionally cause excitement, restlessness, hallucinations, or delirium (THESE EXCITATORY EFFECTS RESEMBLE THOSE OF TOXIC DOSES OF ATROPINE).
-Scopolamine is effective in preventing motion sickness (action on cortex or vestibular apparatus).
Clinical applications in motion sickness and nausea/vomiting.
Serious side effects: alteration in heart rate, drug-induced psychosis.
Other side effects: Somnolence (sleepiness), xerostomia, blurred vision.
Contraindications: narrow-angle glaucoma.
Scopolamine has significant CNS effects
It is delivered via a transdermal patch
It has a faster onset of action than atropine.
-Doses of scopolamine equal to conventional systemic doses of atropine cause definite mydriasis (big pupils) and loss of accommodation.
-Locally applied Scopolamine produces ocular effects of considerable duration; accommodation and pupillary reflexes may not fully recover for 7-12 days.
-Shorter duration of action agents preferred as mydriatics in ophthalmological practice.
Effects on heart in CV system…
Scopolamine has less vagal blocking effects than atropine.
Scopolamine is the most effective prophylactic agent in treating MOTION SICKNESS for short (4-6 hours) exposure to severe motion, probably unto several days.
-Transdermal preparation: highly effective, drug is incorporated into a multilayered adhesive unit and applied to the post auricular mastoid region.
Side effects: dry mouth is common and drowsiness is frequent, blurred vision may occur in some people, mydriasis and cycloplegia can occur from inadvertent transfer of the drug to the eye from the fingers, rare but severe psychotic episodes have been reported due to CNS activity.
-Scopolamine also used to produce tranquilization and amnesia in many cases like labor.
Although, its use is declining and of questionable value.
Untoward (unexpected and innappropriate or inconvenient) effects: given alone in he presence of pain or severe anxiety may induce outbursts of uncontrolled behavior.

Question 18

Belladonna alkaloids and related muscarinic receptor antagonists

Answer 18

These are used in the treatment of parkinsonism; they are effective adjuncts to treatment with levodopa.
They are used in treatment of side effects of conventional antipsychotic drug therapy; used to treat extrapyramidal symptoms (movement).
Certain antipsychotic drugs are relatively potent muscarinic receptor antagonists; these drugs cause fewer extrapyramidal side effects (because have both, muscarninic receptor antagonist action).

Question 19

Muscarinic Receptor antagonists and Ganglia and Autonomic nerves

Answer 19

Cholinergic neurotransmission in autonomic ganglia
-Generation of action potentials: mediated primarily by activation of nicotinic ACh recepors.
-Modulation of transmission: mediated by ganglionic M1 muscarinic receptors.
Blockage of parasympathetic ganglia: may contribute to the response to muscarinic antagonists in the lung and heart.
-Presynaptic muscarinic receptors: present on terminals of sympathetic and parasympathetic neurons.
Blockade generally increase neurotransmitter release due to negative feedback mechanisms.

Question 20

Muscarinic Receptor antagonists and the Eye

Answer 20

-Block the cholinergic responses of the pupillary sphincter muscle of the iris: causes dilation of the pupil (mydriasis).
-Block the cholinergic responses of the ciliary muscle controlling lens curvature: paralyzes accommodation (cycloplegia); no contraction.
These effects can occur after either local or systemic administration of the alkaloids; SYSTEMICALLY GIVEN ATROPINE AND SCOPOLAMINE HAVE LITTLE EFFECT ON INTRAOCULAR PRESSURE!!! Must also be treated with a first glaucoma attack.
-One exception is in patients predisposed to narrow angle glaucoma; pressure may occasionally rise to dangerous levels.
-Muscarinic antagonists rarely precipitate a first glaucoma attack.

Question 21

Muscarinic Receptor antagonists and the Respiratory Tract

Answer 21

-The PNS plays a major role in regulating bronchomotor tone; a diverse set of stimuli cause a reflex increase in parasympathetic activity and contributes to bronchoconstriction.
Normal vagal fiber activity: synapse and activate nicotinic and M1 receptors in parasympathetic ganglia located in the airway wall.
Short postganglionic fibers release ACh; acts on M3 receptors in airway smooth muscle and on M3 receptors on submucosal glands.
Ipratropium and tiotropium are more often used in this anticholinergic therapy.
Effects: dry the mucous membranes of the respiratory tract.
-Atropine, belladonna alkaloids and synthetic analogs
Reduce secretion in both the upper and lower respiratory tracts.
-Probable action of antihistamines employed in “cold” mixtures (antimuscarinic properties)
Systemic administration of belladonna alkaloids or their derivatives
-Use: bronchial asthma or COPD
-Disadvantages: reduced bronchial secretions (material is difficult to remove from the respiratory tree, it can obstruct airflow and predispose patient to infection).

Question 22

Muscarinic Receptor antagonists and the GI Tract

Answer 22

Have use as antispasmodic agents; for the treatment of GI disorders and treatment of peptic ulcer disease; however, doses used produce pronounced side effects, so H2 receptor antagonists and proton pump inhibitors are now the current drugs of choice to reduce gastric acid secretion.
SECRETIONS:
-Salivary secretions is mediated through M3 receptors and is particularly sensitive to inhibition by muscarinic antagonists; mouth becomes dry and swallowing and talking become difficult.
-Gastric secretions are reduced markedly by muscarinic receptors antagonists.
MOTILITY:
-Produce prolonged inhibitory effects on the motor activity: stomach, duodenum, jejunum, ileum, and colon.
-Reduce tone and amplitude and frequency of peristaltic contractions; relatively large doses are needed to produce such inhibition.

Question 23

Muscarinic Receptor antagonists and other smooth muscle effects

Answer 23

URINARY TRACT:
-Decrease the normal tone and amplitude of contractions in ureter and bladder.
-Control of bladder contraction is mediated by muscarinic receptor subtypes.
BILIARY TRACT
SWEAT GLANDS AND TEMPERATURE:
-Small doses of atropine or scopolamine; inhibit the activity of sweat glands innervated by sympathetic cholinergic fibers.
-Sweating may be depressed enough to raise the body temperature (normally a heat dissipating mechanism); only notable after large doses or at high environmental temperatures.

Question 24

Ipratropium Bromide

Answer 24

Quaternary ammonium compound
-BLOCKS ALL SUBTYPES OF MUSCARINIC RECEPTORS!
Lacks appreciable action on the CNS
More potent than atropine: greater inhibitory effects on ganglionic transmission.
Therapeutically important property with local or parenteral administration.
Minimal inhibitory effect on mucociliary clearance relative to atropine (ipratropium is better at clearing than atropine is).
-In patients with airway disease, it lessens increased accumulation of lower airway secretions compared to atropine.
-Given by inhalation; action is confined almost exclusively to the mouth and airways; dry mouth is the only side effect reported frequently; does not produce adverse effect on mucociliary clearance.
-Anticholinergic properties can also be used in the treatment of airway disease.
-Ipratropium often used with inhalation of long-acting adrenergic receptor agonists (little evidence of true synergism).
-The principal clinical use of ipratropium and tiotrpium is in the treatment of COPD; less effective in most asthmatic patients.
-Ipratropium is FDA approved for perennial and common cold-associated rhinorrhea existing for a long time period.
Ipratropium is administered as an aerosol or solution for inhalation.
Ipratropium effects last for 4-6 hours.
Clinical applications in COPD and asthma
Serious side effects: paralytic ileus, anaphylaxis, oropharyngeal edema.
Other side effects: abnormal taste in mouth, xerostomia (nasal spray).
Contraindications: hypersensitivity to ipratropium or tiotropium.
-Ipratropium is more effective than beta adrenergic receptor agonists in the treatment of COPD, but less effective at treating asthma.

Question 25

Tiotropium bromide

Answer 25

Longer duration of actions agent
Shows some selectivity for M1 and M3 receptors (lower affinity for M2 receptors; blocking these stimulates more ACH release)-minimizes presynaptic effect on ACH release.
-Produces bronchodilation, tachycardia, and inhibition of secretion.
-Similar to atropine, it is administered parenterally.
Tiotropium lacks appreciable action on the CNS.
It is more potent than atropine; greater inhibitory effects on ganglionic transmission.
Therapeutically important property with local or parenteral administration: better at mucociliary clearance than atropine.
In patients with airway disease, tiotrpoium lessens increased accumulation of lower airway secretions compared to atropine.
Give by inhalation: the action is confined almost exclusively to the mouth and airways.
-Tiotropium does not produce adverse effects on mucocilirary clearance
Anticholinergic properties can be used in the treatment of airway disease.
Agents often are used with inhalation of long-acting adrenergic receptor agonists (little evidence of true synergism).
Dry mouth is the only side effects reported frequently.
The principal clinical use of tiotropium is the treatment of COPD; less effective in most asthmatic patients.
Tiotropium is administered as a dry powder.
Slower onset.
Tiotropium effects permit for 24 hours-amenable for once daily dosing.
Clinical applications in COPD and Asthma
Serious side effects: paralytic ileus, anaphylaxis, oropharyngeal edema.
Other side effects: abnormal taste in the mouth, xerostomia (nasal spray).
Contrindications: hypersensitivity to ipratropium or tiotropium.
-Relative to ipratropium, tiotropium has been shown to have similar, and possibly superior, efficacy as a bronchodilator in the treatment of COPD.

Question 26

Absorption, fate, and excretion of muscarinic antagonists

Answer 26

-Belladonna alkaloids and the tertiary synthetic and semisynthetic derivatives
Absorbed rapidly from the GI tract
Enters the circulation when applied locally to the mucosal surfaces.
Absorption from intact skin is limited; efficient absorption does occur in post auricular region for some agents (ear/earlobe)-allows for the use of transdermal patches.
-Inhaled or orally ingested quaternary muscarinic receptor antagonists; systemic absorption is MINIMAL.
-Belladonna alklaoids quaternary ammonium derivatives: penetrate the conjunctiva less readily, central effects are lacking; DO NOT CROSS THE BLOOD BRAIN BARRIER.
Drugs administered by inhalation: about 90% of the dose is swallowed and appears in the feces.
Maximal responses usually develop over 30-90 minutes.

Question 27

Umeclidinium

Answer 27

Long-acting, antimuscarinic agent recently approved for ORAL INHALATION.
NONSELECTIVE for subtypes of muscarinic receptors M1 to M5.
COMPETITIVE AND REVERSIBLE ANTAGONISM.
IN THE AIRWAYS, it inhibits M3 receptors in the smooth muscle, which leads bronchodilation.
-Umeclidinium is used for maintenance treatment of airflow obstruction in patients with COPD; includes chronic bronchitis and/or emphysema; for long-term, once daily use.
-Should not be used for acute symptoms.
-Avoid coadminsitration with other anticholinergic-containing drugs.
-Ellipta mixes; but can be used alone as well.
Clinical applications in LONG TERM treatment of COPD.
Serious side effects: paradoxical bronchospasm, urinary retention, exacerbation of narrow angle glaucoma.
Other side effects: Nasopharyngitis, upper respiratory tract infection, cough, arthralgia (pain in a a joint).
Contraindication: severe hypersensitivity to milk proteins.

Question 28

Aclidinium

Answer 28

Long-acting, antimuscarinic agent recently approved for ORAL INHALATION.
NONSELECTIVE for subtypes of muscarinic receptors M1 to M5.
COMPETITVE AND REVERSIBLE ANTAGONISM
In the airways, it inhibits M3 receptors in the smooth muscle, which leads bronchodilation.
-Aclidinium is used for the maintenance treatment of airflow obstruction in patients with COPD; includes chronic bronchitis and/or emphysema.
-For long-term use, TWICE DAILY (NOT AS LONG ACTING AS UMECLIDINIUM).
Serious side effects: paradoxical bronchospasm, urinary retention, exacerbation of narrow angle glaucoma.
Other side effects: headache, nasopharyngitis, and cough.
Contraindications: NONE!!!
Should not be used for acute symptoms, long term twice daily use only.
Avoid coadministration with other anticholinergic containing drugs.

Question 29

Tolterodine

Answer 29

NONSPECIFIC Muscarinic receptor antagonist used to treat overactive urinary bladder disease.
-Synthetic substitute for atropine
-Tolterodine lowers intravesicular (in detrusor muscle in the urinary bladder) pressure and increases the capacity of the bladder.
-Reduces the frequency of contractions by antagonizing parasympathetic bladder control.
Indicated for overactive bladder
Side effects: dry mouth and dry eyes limit the tolerability of these drugs, constipation, diarrhea, nausea, application-site erythema (superficial reddening of the skin), pruritus (severe itching of skin).
Tolterodine may cause less dry mouth than oxybutynin.
Clinical applications in hyperreflexic and overactive bladder, urge incontinence.
Contrindications: narrow-angle glaucoma.
Reported increased flexibility of dosing with fesoterodine versus tolterodine.
Converts to active 5-HMT by cyp2D6 (in the liver); potent muscarinic antagonist; shows selectivity for the urinary bladder, but no unique receptor subtype selectivity.
Antispasmodic drug

Question 30

Fesoterodine

Answer 30

Synthetic substitude for atropine
Lower intravesciular pressure and increase capacity in the bladder.
Reduce the frequency of contractions by antagonizing parasympathetic bladder control.
Indicated for overactive bladder.
Side effects: dry mouth and dry eyes limit the tolerability of these drugs, constipation, diarrhea, nausea, application-site erythema (skin reddening), pruritus (severe itchy skin).
Clinical applications in hyper reflexive and overactive bladder, urge incontinence.
Contraindications: Narrow-angle glaucoma.
Reported increased flexibility of dosing with festerodine versus tolterodine.
Converts to active 5-HMT by non-specific esterases; does not depends on cytochrome liver function; potent muscarinic antagonist, but no unique receptor subtype activity.

Question 31

Oxybutynin

Answer 31

NONSPECIFIC MUSCARINIC RECEPTOR ANTAGONISTS.
Marketed as a transdermal system
Lowers the incidence of side effects than oral immediate-or ER preps.
Clinical applications in hyper reflexive and overactive bladder, urge incontinence.
Side effects: contripation, diarrhea, nausea, dry mouth, application-site erythema, pruritus.
Contraindications: narrow-angle glaucoma.
-Tolterodine may cause LESS dry mouth than oxybutynin.
Antispasmodic drug

Question 32

Trospium chloride

Answer 32

Synthetic substitues of atropine
Quaternary amine
NONSPECIFIC MUSCARINIC RECEPTOR ANTAGONISTS!!!
EFFECTIVE AS OXYBUTYNIN WITH BETTER TOLERABILITY!!!
Trospium lowers intravesicular pressure and increases the capacity in the bladder.
Reduces the frequency of contractions by antagonizing parasympathetic bladder control.
Indicated for overactive bladder.
Side effects: dry mouth and dry eyes limit the tolerability of the drug, constipation, diarrhea, nausea, application-site erythema, pruritus.
Clinical applications in hyperreflexic bladder and overactive bladder, urge incontinence.
Contraindications: narrow-angle glaucoma.
Antispasmodic drug

Question 33

Solifenacin

Answer 33

SELECTIVE M3 RECEPTOR ANTAGONISTS; THESE NEWER M3 SELECTIVE AGENTS MAY CAUSE LESS DRY MOUTH AND CONSTIPATION THAN NONSELECTIVE AGENTS; more specificity, less side effects.
NEWLY APPROVED WITH A FAVORABLE EFFICACY:SIDE EFFECT RATIO (high efficacy and low side effects).
Indicated for overactive bladder.
Side effects: dry mouth and dry eyes limit tolerability of these drugs, constipation, diarrhea, nausea, application-site erythema, pruritus.
Clinical applications in hyperreflexic and overactive bladder, urge incontinence.
Conraindications: narrow angle glaucoma.

Question 34

Darifenacin

Answer 34

Indicated in overactive bladder
Side effects: dry mouth and dry eyes limit tolerability of these drugs, constipation, diarrhea, nausea, application-site erthyma, pruritus.
SELECTIVE ANTAGONIST FOR M2 AND M3 MUSCARINIC RECEPTORS
Potential utility.
Clinical applications in hyperreflexic and overactive bladder, urge incontinence.
Contraindications: narrow angle glaucoma.
Darifenacin is a selective M3 receptor antagonist.
This newer agent darifenacin may cause less dry mouth and constipation than the nonselective agents.

Question 35

Muscarinic Receptor antagonists and the genitourinary tract

Answer 35

Muscarinic antagonists are used for treating this increasingly common disorder (overactive urinary bladder disease).
Used for treating enuresis in children (involuntary urination).
Used in spastic paraplegia; they reduce urianry frequency and increased bladder capacity.

Question 36

Belladonna alkaloids and sedative combinations in the GI tract

Answer 36

-Atropine, l-hyoscyamine sulfate, scopolamine
These can reduce tone and motility when administered in maximal tolerated doses (you are going to see side effects).
They are expected to be useful in conditions involving excessive smooth muscle contraction; often may not be the case; M3 selective antagonists might achieve more selectivity.
They have major effects on salvation, bronchiolar secretion/contraction, and bladder motility.
-Atropine, l-hyoscyamine sulfate, and scopolamine are used in combination with other agents: sedatives (phenobarbital or butabarbital), anti anxiety agents (chlordiazepoxide), ergotamine (migraine headaches).
-Diarrhea treatment associated with irritative conditions of the lower bowel: mild dysenterys and diverticulitis: MAY RESPOND TO ATROPINE-LIKE DRUGS.
-Diarrhea treatment associated with more severe conditions: salmonella dysentery, ulcerative colitis, Crohn’s disease: REPOND POORLY TO ATROPINE-LIEK DRUGS.
-Belladonna alkaloids and synthetic substitues (atropine, l-hyoscyamine, scopolamine) are effective in reducing excess salivation: drug induced salivation, heavy-metal poisoning, and parkinsonism.

Question 37

Muscarinic Antagonists and their uses in Ophthalmology

Answer 37

Local administration
Limits effects to the eye
PRODUCE MYDRIASIS AND CYCLOPLEGIA (loss of accommodation).
CYCLOPLEGIA: not attainable without mydriasis; requires higher concentrations or more prolonged application of a given agent.
Complete cycloplegia may be necessary for some procedures for accurate measurement of refractive errors; treatment of iridocyclitis (inflammation of iris and ciliary body of eye) and choroiditis (inflammation of retina and choroid).
MYDRIASIS: often is necessary for thorough examination of the retina and optic disc; often necessary in therapy of iridocyclitis and keratitis (inflamed cornea).
Belladonna mydriatics may be alternated with miotics: this breaks or prevents the development of adhesions between the iris and the lens.
WHEN COMPELTE CYCLOPLEGIA IS REQUIRED: ATROPINE OR SCOPOLAMINE; NOT TROPICAMIDE (SHORTER ACTING).
-Homatropine, cyclopentolate hydrochloride, and tropic amide ARE PREFERRED TO TOPICAL ATROPINE AND SCOPOLAMIDE USED IN OPHTHALMOLOGICAL PRACTICE BECAUSE OF THEIR SHORTER DURATION OF ACTION.

Question 38

Homatropine

Answer 38

TERTIARY AMINE
Preferred in topical ophthalmology because of short duration of action than atropine (12-24 hours).
Semisynthetic derivative of atropine.
Clinical application in mydriasis and cycloplegia for refraction, acute inflammatory conditions for the uveal tract.
Serious side effects: increased intraocular pressure, systemic anticholinergic effects with repeated dosing.
Other side effects: Local irritation, vascular congestion, edema, exudate (fluid emitted through pores or wound, eczema.
Contraindications: Narrow-angle glaucoma.
HOMATROPINE METHYLBROMIDE:
-Quaternary derivative of homatropine.
-Less potent than atropine in antimuscarinic activity.
-FOUR TIMES MORE POTENT than atropine as a ganglionic blocking agent.
-Available in combination with hydrocodone as an antitussive (suppress coughing) combination.
-Relief of GI spasms and adjunct in peptic ulcer disease..

Question 39

Cyclopentolate hydrochloride

Answer 39

TERTIARY AMINE
Preferred to atropine in topical ophthalmic use because of shorter duration of action.
Often used in pediatric formulations.
Clinical applications in producing mydriasis and cycloplegia.
Cycloplegic and mydriatic effect that is maximal in 15 to 60 minutes; recovery usually occurs within 24 hours.
Serious side effects: increased intraocular pressure, systemic anticholinergic effects with repeated dosing.
Other side effects: local irritation, vascular congestion, edema, exudate (fluid emitted through pores or wound), eczema.
Contraindications: narrow-angle glaucoma.

Question 40

Tropicamide

Answer 40

Preferred to atropine in topical ophthalmic use because if its shorter duration.
In instances when complete cycloplegia is required, atropine or scopolamine are preferred to tropic amide because of its shorter duration of action.
Clinical application in mydriasis for fundus (interior surface of the eye) examination, cycloplegia for refraction.
Serious side effects: increase in intraocular pressure, CV events and death (use with hydroxyamphetamine).
Other side effects: stinging, blurred vision, photophobia (extreme sensitivity to light).
Contraindications: Narrow-angle glaucoma
Cycloplegia may require 2 doses and study within 30 minutes.
Much shorter half life than atropine (15-60 minutes).

Question 41

Muscarinic Receptor Antagonists and the CV system

Answer 41

Of limited clinical application in treatment of CV diseases.
These agents are generally used in coronary care units for short-term interventions or in surgical settings.
ATROPINE
-May be considered the initial treatment of patients with acute myocardial infarction.
-May prevent further clinical deterioration in cases go high vagal tone or AV block: restores heart rate to a level sufficient to maintain adequate hemodynamic status, eliminates AV nodal block, the dosing must be done carefully (too low of doses can cause a paradoxical bradycardia, excessive doses will cause bradycardia.

Question 42

Muscarinic Receptor Antagonists and the Central Nervous System

Answer 42

Belladonna alkaloids and synthetic substitutes were the only agents helpful in the treatment of parkinsonism for years.
Levadopa or levodopa along with carbidopa now is the treatment of choice.
Alternative or concurrent therapy with muscarinic receptor antagonists, however, may still be required in some patients.
Drugs to treat parkinsonism and extrapyramidal (motor) side effects of antipsychotic agents: efficacious in preventing dystonias (muscles contract uncontrollably) or parkinsonian symptoms.
-TERTIARY AMINE MUSCARINIC RECEPTOR ANTAGONISTS
Benztropine mesylate
Procyclidine
Trihexphenidyl hydrochloride
Ethanolamine antihistamine: diphenhydramine (strong anticholinergic activity).
Belladonna alkaloids were the first drugs to be used for prevention of motion sickness.
All motion sickness drugs are much less effective after severe nausea or vomiting has already developed.
Muscarinic Antagonist use in anesthesia:
Relatively nonirritating to the bronchi
Eliminated the need for prophylactic use of muscarinic receptor antagonists.

Question 43

Trihexyphenidyl

Answer 43

TERTIARY AMINE
Muscarinic Receptor Antagonist
Clinical applications for being an adjunct for parkinsonism.
Serious side effects: angle closure glaucoma, increased intraocular pressure, psychosis.
Other side effects: Dizziness, blurred vision, nervousness, nausea, xerostomia, urinary retention.
Contraindications: Narrow angle glaucoma, younger than 3 years of age, tardive dyskinesias.
Reduces tremor more than bradykinesia and therefore effective in treating patients for whom TREMOR is the major clinical manifestation of Parkinsons disease.
May worsen dementia and cognitive impairment in the elderly.

Question 44

Benztropine mesylate

Answer 44

TERTIARY AMINE
Muscarinic antagonist
Clinical application as an adjunct for parkinsonism
Serious side effects: angle closure glaucoma, increased intraocular pressure, psychosis, hyperpyrexia (fever with extreme elevation in body temperature), paralytic ileus.
Other side effects: dizziness, nausea, nervousness. blurred vision, xerostomia, urinary retention.
Contraindications: narrow angle glaucoma, younger than 3 years of age.
Benztropine reduces tremor more than bradykinesia and therefore effective in treating patients whom tremor is the major clinical manifestation of parkinsonism.
May worsen dementia and cognitive impairment in the elderly.

Question 45

Glycopyrolate

Answer 45

This or atropine is used with neostigmine
-Block parasympathomimetic effects of neostigmine when neostigmine is used to reverse skeletal muscle relaxation after surgery (reverses acetylcholinesterase inhibition).
-Serious cardiac arrhythmias have occasionally occurred; possibly due to combination effects, initial bradycardia by atropine and cholinomimetic effects of neostigmine.
Clinical applications in peptic ulcer disease, surgically induced or vaguely induced bradycardia.
Serious side effects: cardia arrhythmias, malignant hyper thermia, anaphylaxis, seizure.
Other side effects: constipation, xerostomia, urinary retention, decreased sweating.
Contraindications: narrow angle glaucoma, GI obstruction.
Glycopyrolate is an alternative or additive agent to standard peptic ulcer disease therapies; has delayed but measurable CNS and cognitive anticholinergic effects.
-Employed orally to inhibit GI motility.
-Used parenterally to block the effects of vagal stimulation during anesthesia and surgery.
-Used in combination with formoterol fumarate (long acting beta 2 agonist) for COPD.
Antispasmodic properties
Appear to exert some nonspecific direct relaxant effect on smooth muscle.
Therapeutic doses decrease spasm of the GI tract, biliary tract, ureter, and uterus.

Question 46

Methscopolamine bromide

Answer 46

QUATERNARY AMMONIUM DERIVATIVE OF SCOPOLAMINE
-Lacks the central actions of scopolamine.
-Methscopolamine use has been limited chiefly to GI diseases.
-Less potent than atropine and is poorly absorbed, although action is more prolonged than atropine.
Clinical application in peptic ulcer disease.
Serious side effects: cardiac arrhythmias, malignant hyperthermia, anaphylaxis, seizure.
Other side effects: constipation, xerostomia, urinary retention, decreased sweating.
Contraindications: narrow angle glaucoma, GI obstruction.
Methscopolamine is an alternative or additive agent to standard peptic ulcer disease therapies.
It has delayed but measurable CNS and cognitive anticholinergic effects.

Question 47

Mepenzolate bromide

Answer 47

QUATERNARY AMINE with peripheral actions similar to those of atropine.
Adjunctive therapy of peptic ulcer disease.
Mepenzolate has been used as an antispasmodic for the relief of GI disorders.
Serious side effects: increased intraocular pressure, tachycardia, palpitations.
Other side effects: dryness of the mouth, urinary hesitancy and retention, blurred vision, mydriasis.
Contraindications: narrow angle glaucoma, myasthenia gravis, intestinal atony of the elderly or debilitated patient.
Mepenzolate diminishes gastric acid and pepsin secretion and also suppresses spontaneous contractions of the colon.

Question 48

Dicyclomine

Answer 48

Tertiary amine
Antispasmodic drug
Clinical applications in irritable bowel syndrome and minor diarrhea.
Serious side effects: increased intraocular pressure, tachycardia.
Other side effects: urinary retention and confusion.
Contraindications: narrow angle glaucoma, GI obstruction, urinary obstruction, myasthenia gravis.
Dicyclomine has a short half life (1.8 hours), BUT ACTION LASTS UP TO 6 HOURS.

Question 49

Flavoxate

Answer 49

Tertiary amine
Antispasmodic drug
Clinical applications in dysuria, urgency, and incontinence.
Side effects: nausea, vomiting, dry mouth, nervousness.
Contraindications: GI obstruction, obstruction uropathies, achalasia.

Question 50

Propantheline bromide

Answer 50

One of there widely used of the synthetic NONSELECTIVE muscarinic receptor antagonists.
At high doses…
Produces symptoms of a ganglionic blockade.
At toxic doses…
Blocks the skeletal NMJ.
Duration of action: comparable to that of atropine, repeated doses may be needed.
-Treatment of marked excitement.
BENZODIAZEPINE is the most suitable agent for sedation and for control of convulsions.
Phenothiazines or agents with antimuscarinic activity should not be used, antimuscarinic action is likely to intensify toxicity.
Support of respiration and control of hyperthermia may be necessary: ice bags and alcohol sponges help to reduce fever especially in children.
Clinical applications of propantheline in hyperreflexic and overactive bladder, urge incontinence.
Side effects: constipation, diarrhea, nausea, dry mouth, application-site erythema, pruritus.
Contraindications: narrow angle glaucoma.
NONSPECIFIC MUSCARINIC RECEPTOR ANTAGONISTS

Question 51

Metoclopramide

Answer 51

Muscarinic Receptor Sensitizer
Mechanism: acts as a dopamine antagonist
Clinical application in GI motility disorders GERD, prevention of chemotherapy induced emesis.
Serious side effects: extrapyramidal effects (tardive diskenesia).
Other side effects: restlessness, drowsiness, fatigue, nausea, xerostomia, diarrhea/constipation.
Contraindications: pheochromocytoma (hormone secreting tumor that can occur in the adrenal gland), seizure disorders, patients taking antipsychotic drugs possibly causing extrapyramidal effects (phenothiazines, butyrophenones).
Chronic use of metoclopramide has been linked to tradeoff dyskinesia.

Question 52

L-hyoscyamine sulfate

Answer 52

Belladonna alkaloid
Can reduce tone and motility when administered in maximal tolerated doses (going to see side effects).
Expected to be useful in conditions involving excessive smooth muscle contraction (often may not be the case).
M3 selective antagonists might achieve more selectivity: major effects on salivation, bronchiolar secretion/contraction and bladder motility.
Clinical application in peptide ulcer disease, irritable bowel syndrome, hyeprmotility disorders (GI and bladder), infant colic.
Serious side effects: increased intraocular pressure, tachycardia, palpitations.
Other side effects: dry mouth, urinary hesitance and retention, blurred vision, mydriasis.
Contraindications: narrow angle glaucoma, myasthenia gravis.
LONGER DURATION OF ACTION THAN DICYCLOMINE.