CHOLINERGIC ANTAGONISTS

Prof. Dr. Aşkın TAŞ

 PARASYMPATHOLYTIC DRUGS

• Mechanism of Action: These drugs block muscarinic-type cholinergic

receptors on effector cells, including smooth muscle, secretion glands, and
heart cells.
• Selectivity: They typically do not block nicotinic-type receptors, with the
exception of certain quaternary amine derivatives, which weakly inhibit
nicotinic receptors as well.
• Physiological Effect: They reduce or eliminate parasympathetic tone on
effector organs.
 PARASYMPATHOLYTIC DRUGS

• Atropine, scopolamine, and other parasympatholytic drugs have equal

affinity for all muscarinic receptor subtypes.
• In organs with dual autonomic innervation, parasympatholytic drugs remove
parasympathetic tone, allowing sympathetic tone to dominate.
• Consequently, some effects of parasympatholytic drugs resemble those of
sympathomimetic drugs.
 PARASYMPATHOLYTIC DRUGS

• Dual Action: Some parasympatholytic drugs exhibit papaverine-like

activity, relaxing certain smooth muscles through two mechanisms:
• Neurotropic Effect: Blocking muscarinic receptors.
• Musculotropic Effect: Directly affecting contraction mechanisms.
• Selective Muscarinic Blockade: These drugs only block the muscarinic
effects of agents with both nicotinic and muscarinic actions, leaving the
nicotinic effects unaffected.
 PARASYMPATHOLYTIC DRUGS

• Tertiary Amine Derivatives: Drugs like atropine and scopolamine, which are
tertiary amines, can cross the blood-brain barrier and enter the CNS, where
they block muscarinic receptors, resulting in central effects.
• Quaternary Amine Derivatives: These parasympatholytics do not cross the
blood-brain barrier and, therefore, do not produce central effects.
 THE SENSITIVITY OF THE MUSCARINIC RECEPTORS OF THE
ORGANS TO THESE DRUGS IS DIFFERENT:
• Dose-Dependent Blockage Progression:
• Low Dose: Salivary glands, respiratory tract mucous glands, and sweat
glands are blocked first.
• Moderate Dose: Muscarinic receptors in the eye and heart are affected,
leading to noticeable symptoms.
• High Dose: Smooth muscles of the gastrointestinal tract and bladder are
affected.
• Resistance to Blockage: The acid-secreting parietal cells of the stomach are the
most resistant to the antimuscarinic effects of these drugs.
 MECHANISM OF ACTION AT THE RECEPTOR LEVEL

• Competitive Action: Parasympatholytic drugs compete with acetylcholine for

binding to muscarinic receptors.
• Sites of Action:
• Peripheral: They act at neuroeffector junctions in the peripheral nervous
system.
• Central Nervous System (CNS): For drugs that can cross the blood-brain
barrier, they also compete at muscarinic synapses in the CNS.
 PARASYMPATHOLYTIC DRUGS

• They can be grouped into 4 groups according to their source and chemical
structure:
• Belladon alkaloids
• Synthetic analogues of Belladon alkaloids
• Quaternary amine derivatives
• Selectively acting parasympatholytic drugs
 PARASYMPATHOLYTIC DRUGS
• Drugs: Atropine and scopolamine are tertiary amines.

• Chemical Forms:

• Atropine: D,L-hyoscyamine

• Scopolamine: L-hyoscine

• Source: These alkaloids are found in various parts of the belladonna (Atropa
Belladonna), henbane (Hyoscyamus niger), and jimsonweed (Datura stramonium) plants,
which belong to the Solanaceae family. These are collectively referred to as Solanaceae
alkaloids.

• Natural Form: The living plant contains L-hyoscyamine, which converts to atropine
through processes like drying.
Atropa Belladona
 PARASYMPATHOLYTIC DRUGS
Pharmacokinetic Properties

• Atropine and scopolamine are quickly absorbed orally, with effects

beginning within 1 hour and lasting 3–4 hours.
• Atropine: 50% is metabolized in the liver by esterase, with the rest
excreted unchanged in urine.
• Scopolamine is used as a transdermal patch behind the ear, provides
extended protection against motion sickness.
• Rabbits are resistant to belladonna poisoning due to the enzyme atropine
esterase, which humans lack, increasing sensitivity.
 PARASYMPATHOLYTIC DRUGS

Pharmacological properties:
• Glandular and Eye Effects: Scopolamine is more effective than atropine on sweat,
salivary, airway mucous glands, and in the eye (iris and ciliary muscle).
• Smooth Muscle Effects: Atropine is stronger and longer-acting in the heart,
gastrointestinal tract, and bronchi.
• CNS Effects: Atropine, at clinically used doses, does not depress the CNS or cause
drowsiness, making it preferable in many cases. Scopolamine, however, causes
significant sedation in addition to its parasympatholytic effects.
PARASYMPATHOLYTIC DRUGS
Pharmacological properties:
Cardiovascular system:
• Heart Rate:
• Tachycardia: Caused by blocking M2 muscarinic receptors, removing inhibitory
vagal tone.
• Bradycardia: Occurs at low doses by blocking M1 autoreceptors, reducing ACh
release.
• A-V Node Conduction: Reduces vagal tone on the A-V node, accelerating transmission,
with significant positive chronotropic (heart rate) and dromotropic (conduction)
effects.
• Clinical Use: Atropine is used to prevent temporary slowing of the heart (bradycardia)
and cardiac arrest (asystole) during medical procedures that may inadvertently trigger
the vagal reflex. This reflex can occur due to baroreceptor stimulation (e.g., during
carotid artery manipulation or pressure on the carotid sinus) or other triggers such as
respiratory tract irritation, handling of the peritoneum, or cardiac catheterization.
Atropine helps by blocking vagal effects on the heart, ensuring heart rate stability
during these procedures.
• Vascular Effects: Minimal impact on vascular resistance and blood pressure, as most
vascular beds lack parasympathetic innervation.
 PARASYMPATHOLYTIC DRUGS
Pharmacological Effects:

Eye:
• Mydriasis and Photophobia: By blocking parasympathetic tone on the iris
sphincter muscle, sympathetic activity becomes dominant, causing pupil
dilation (mydriasis) and sensitivity to light (photophobia).
• Accommodation Paralysis (Cycloplegia): Relaxation of the ciliary muscle
reduces lens curvature, impairing near vision. This effect, known as
cycloplegia, can last about one week.
• Risk of Acute Glaucoma: These drugs may trigger an acute glaucoma crisis,
especially in individuals with narrow-angle glaucoma.
 PARASYMPATHOLYTIC DRUGS
Pharmacological Effects:
Glands of external secretion:
• Sweat and Salivary Glands: Even at low doses, belladonna alkaloids inhibit
sweat and salivary glands, causing dry skin (anhidrosis) and dry mouth
(xerostomia). They reduce or stop secretion in eccrine (common) sweat glands
but do not affect apocrine sweat glands, which are sympathetically innervated.
• Risk of Hyperthermia: By inhibiting sweating and reducing heat loss, these
drugs can raise body temperature.
• Respiratory Secretions: Parasympatholytics inhibit water and mucus secretion in
the trachea and bronchi, which impairs mucociliary transport (except for
ipratropium and tiotropium bromide).
• Gastric Mucosa: Parietal cells (acid-secreting) are resistant to these drugs, while
mucin- and pepsin-secreting cells are more affected.
 PARASYMPATHOLYTIC DRUGS
Pharmacological Effects:

Gastrointestinal smooth muscles:

• Antagonistic Effect: These drugs partially counteract parasympathetic nerve
stimulation and fully block the effects of injected parasympathomimetic or
anticholinesterase drugs.
• Effects on Peristalsis and Muscle Tone: They reduce the frequency and
amplitude of spontaneous peristaltic movements and decrease the muscle
tone in the intestinal wall. Sphincter relaxation becomes difficult, leading to
delayed gastric emptying, slower passage of intestinal contents, and prolonged
transit time, which may cause constipation.
• Antispasmodic Use: In cases of gastrointestinal spasm, these drugs reduce tone
and motility more effectively in the spasmodic areas, making them useful as
antispasmodics.
 PARASYMPATHOLYTIC DRUGS
Pharmacological Effects:
Other smooth muscular structures:
• Bladder Effects: These drugs relax the detrusor muscle of the bladder and
increase the tone of the sphincter and trigone muscles, leading to urination
difficulty and increased bladder capacity.
• Ureter Effects: At sufficient doses, they reduce the tone and motility of the
ureters, expanding the renal pelvis and ureters.
• Biliary Tract Effects: They weakly inhibit the tone and motility of the bile ducts
and gallbladder, making them ineffective as antispasmodics for biliary spasms.
• Bronchodilation: Causes mild bronchodilation by removing parasympathetic
tone in bronchial smooth muscles.
• Limitations in Asthma Treatment: Not typically used for asthma because it
dries bronchial mucosa and reduces mucociliary transport.
• Asthma-Specific Alternatives: Ipratropium bromide and tiotropium
bromide are used as aerosol treatments in asthma patients.
 PARASYMPATHOLYTIC DRUGS
Pharmacological Effects:
CNS effects:
• Atropine: Does not significantly depress the CNS or cause drowsiness at
therapeutic doses.
• Scopolamine: Causes CNS depression when administered parenterally, leading
to sedation, drowsiness, fatigue, euphoria, amnesia, and sometimes a hypnotic
effect. It can prevent motion sickness by depressing the vestibular system if
taken before symptoms appear.
• Toxicity: High doses of atropine and scopolamine can lead to coma, convulsions,
respiratory center paralysis, and death.
• Antagonistic Effect: Both drugs counteract CNS excitation and respiratory
depression caused by physostigmine and organophosphate anticholinesterases.
Physostigmine can reverse central symptoms of atropine poisoning but is
avoided due to side effects.
 PARASYMPATHOLYTIC DRUGS
1. ATROPINE

• Injectable solutions prepared from atropine sulfate salts sc or im can be

used.

• The maximum one-time dose of atropine is 1 mg parenterally, 2 mg orally.

In organic phosphate insecticide poisoning, these limits can be crossed.

• Atropine and scopolamine can be used orally in the form of tablets. Their
usual dose is 0.5-0.6 mg.
 PARASYMPATHOLYTIC DRUGS
1. ATROPINE
• The dose and frequency of administration of atropine sulfate in the
treatment of bradycardia arrhythmias vary depending on the severity of
the condition.
• Adults:
• The usual starting doses are 0.5 - 1.0 mg (0.5 - 1 ml) intravenously
(i.v.).
• In less severe cases, the total dose may be repeated up to 0.03 mg/kg
(approximately 2 mg) (2 ml). The recommended dose range may range
from 3-5 minutes to 1-2 hours.
• In severe cases, a total dose of 0.04 mg/kg (approximately 3 mg) (3 ml)
may be given.
• Some experts recommend that this total dose be divided into three (1
mg) at intervals of 3-5 minutes, while others prefer to administer the
total dose of 3 mg as a single dose.
 PARASYMPATHOLYTIC DRUGS
1. ATROPINE
• As an antidote:
• Doses of up to 1-2 mg (1-2 ml) by the sc im or iv route are used in the
treatment of overdosage with parasympathomimetic agents.

• In the treatment of irreversible anticholinesterase poisoning such as

organophosphorus insecticides: Higher doses (at least 2-3 mg) may be
required.

• These doses are repeated until the symptoms of cyanosis disappear or the
heart rhythm is 80-90/min. Dose intervals are adjusted according to the
patient's heart rate. This practice should be continued until there is a
definite recovery. This period can be 2 days or more.

• In mushroom poisoning with rapid signs of intoxication, adequate doses

should be administered to control parasympathomimetic signs before
coma and cardiovascular collapse are seen.
 PARASYMPATHOLYTIC DRUGS
1. ATROPINE

Preanesthetic medication:
• To reduce the risk of vagal inhibition of the heart and to decrease saliva
and bronchial secretions before general anesthesia, 0.3 - 0.6 mg of
atropine sulfate (commonly 0.5 mg) can be administered subcutaneously
or intramuscularly 30-60 minutes prior to anesthesia.

• Alternatively, the same dose may be given i.v. immediately prior to

induction of anaesthesia.

• Gastrointestinal radiography: 1 mg (1 ml) administered i.m. route.

 PARASYMPATHOLYTIC DRUGS
1. ATROPINE
Atropine poisoning
• Dryness of the mouth, throat and skin, then tachycardia, palpitations and eye
manifestations, photophobia due to mydriasis, deterioration of near vision.
Difficulty urination and defecation, skin red, dry, hot. Memory loss, toxic
psychosis (delirium, hallucinations, hyperexcitation, agitation...)
Reminder tip for anticholinergic toxicoma
• Mad as a hatter
• Blind like a bat (pupils don't fit well)
• Red like beets
• Dry as a bone
• Hot like Hades (underworld, god of fire in mythology)
• Therapy:
• If taken orally, gastric lavage, activated charcoal.
• If psychic excitation and convulsions are present, i.v. diazepam.
• Application for hyperthermia (cool place, sheets soaked in a water-
alcohol mixture, ice).
• Mechanical respiration and oxygen administration for respiratory
paralysis.
 SYNTHETIC ANALOGUES OF BELLADON ALKALOIDS
2. TERTIARY AMINE DERIVATIVES

• These analogues have weaker parasympatholytic effects than atropine but can
enter the CNS.
• Ophthalmic Use: Homatropine, eucatropine, cyclopentolate, and tropicamide
are used in eye solutions. They provide rapid, short-term mydriasis and
cycloplegia with minimal irritation.
• Oral/Parenteral Antispasmodics: Oxyphencyclimine, piperidolate, dicyclomine,
and solifenacin are general antispasmodics.
• Urinary Antispasmodics: Oxybutynin, flavoxate, propiverine, and tolterodine
target the bladder and urethra.
• Papaverine-like Effect: Adifenine, dicyclomine, and flavoxate also act as
antispasmodics with papaverine-like properties.
SYNTHETIC ANALOGUES OF BELLADON ALKALOIDS
3. QUATERNARY AMINE DERIVATIVES
• Quaternary Amine Derivatives: These are semi-synthetic or synthetic drugs derived
from belladonna alkaloids. They do not cross the blood-brain barrier, avoiding CNS
side effects. They can also block nicotinic receptors in ganglia and may induce
neuromuscular block at high doses. Their gastrointestinal absorption is poor, and
parenteral doses are typically 1/4 of the oral dose.
• Primary Uses: Used to treat gastrointestinal spasms, hypermotility, biliary colic, and
renal colic. They inhibit tone and motility in the GI tract more than gastric acid and
other secretions.
• Examples:
• Hyoscine-N-butylbromide: Used for GI spasms, hypermotility, biliary, and renal
colic; preferred parenterally due to low oral absorption.
• Propantheline: Strongly reduces GI tone, motility, and gastric acid secretion.
Also used in enuresis and neurogenic bladder.
• Fenpiverinium Bromide: Used in combination with pitofenone (antispasmodic)
and dipyrone (analgesic) rather than alone.
 4. SELECTIVE PARASYMPATHOLYTIC DRUGS
• Ipratropium, Tiotropium, Aclidinium Bromide: Used in asthma and COPD
treatment, administered locally (aerosol, dry powder inhaler, or nebulizer)
targeting the M3 receptor in the lower respiratory tract.

• Glycopyrrolate Hydrobromide: More effective than atropine at inhibiting

salivary secretion; commonly used in preanesthetic medication.

• Pirenzepine Dihydrochloride: Selectively blocks M1 muscarinic receptors on

neurons and is gastroselective. It significantly inhibits gastric acid secretion but
is no longer used clinically.
SIDE EFFECTS AND CONTRAINDICATIONS OF
PARASYMPATHOLYTIC DRUGS
• Contraindications:
• Narrow-angle glaucoma (risk of glaucoma crisis due to increased intraocular
pressure).
• Bowel and gastric atony, ileus, organic pyloric stenosis.
• Conditions such as kidney and liver failure, hyperthyroidism, coronary heart
disease, congestive heart failure, tachycardia, and arrhythmia.
• Use with caution in elderly, pregnant and lactating women, and in acute
myocardial infarction cases.

• Side Effects:
• Prostatic hypertrophy may lead to micturition difficulty and urinary retention.
• Hyperthermia and heat stroke risks, particularly in feverish patients, those
working in hot environments, or under sunlight, due to inhibition of sweating.
 PAPAVERIN-LIKE SPASMOLYTIC DRUGS
• Mechanism: Papaverine is a musculotropic antispasmodic that relaxes smooth
muscles directly without targeting specific receptors. The term "papaverine-like
action" refers to smooth muscle relaxation without receptor specificity.
• Effect: These drugs relax all smooth muscle structures, including blood vessels,
the gastrointestinal (GI) tract, biliary tract, genitourinary system, bronchi, and
the ciliary muscle in the eye. They do not have antimuscarinic effects.
• Clinical Use: In cases of smooth muscle spasms, papaverine and its analogues
are particularly effective. They can enhance the effects of parasympatholytic
drugs, often used together or in combination for GI and genitourinary
conditions.
• Additional Uses: Peppermint oil can be applied for abdominal colic relief,
especially in irritable bowel syndrome (IBS).
 PAPAVERIN-LIKE SPASMOLYTIC DRUGS
Mechanism of Action of Papaverine:
• Phosphodiesterase (PDE) Inhibition:
• Papaverine inhibits phosphodiesterase enzymes, increasing intracellular
cyclic adenosine monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP) levels. This elevation leads to the relaxation of
smooth muscles.
• 2. Reduction of Calcium Ion Influx:
• Papaverine decreases intracellular calcium levels, preventing smooth
muscle contraction. The reduction of calcium, which is essential for
contraction, facilitates muscle relaxation.
• 3. Direct Action on Smooth Muscle Cells:
• Papaverine directly acts on smooth muscle cells, reducing their tone and
inducing relaxation. This effect is particularly evident in blood vessels, bile
ducts, urinary tracts, and the gastrointestinal system.
PAPAVERIN-LIKE SPASMOLYTIC DRUGS

• Papaverine
• Mebeverine
• Pinaverium bromide
• Trimebutine maleate
• Alverine citrate
• Peppermint oil
 PAPAVERIN-LIKE SPASMOLYTIC DRUGS

Uses of Papaverine-Like Spasmolytic Drugs:

• Gastrointestinal Tract: Relieves diarrhea, abdominal cramps, pyloric and cardia
spasms, and biliary colic. Used in radiological exams of the GI tract to
distinguish between functional and organic disorders; functional spasms resolve
with medication.
• Other Smooth Muscles:
• Combined with anti-inflammatory analgesics for renal colic.
• Effective against dysmenorrhea.
• Reduces frequent urination in cystitis.
• Used for nocturnal enuresis and neurogenic bladder disorders; aids in
urinary control and storage.
• Effective in urge incontinence.
CLINICAL PHARMACOLOGY OF PARASYMPATHOLYTIC
DRUGS
Uses of Short-Acting Parasympatholytics:
• Ophthalmology: Used in fundus exams to dilate pupils, but sympathomimetics
are preferred for stronger mydriasis without cycloplegia. Also applied to detect
refractive errors in children, induce ciliary paralysis, and prevent iris adhesions
in uveitis.
• Preanesthetic Medication: Drugs like atropine are administered to reduce
respiratory secretions, preventing bronchial obstruction and laryngospasm
during anesthesia.
• Cardiovascular Diseases: Atropine can relieve bradycardia and A-V block caused
by excessive vagal activity. It may improve A-V block due to vagal stimulation,
but careful evaluation is needed as it accelerates the heart rate.
CLINICAL PHARMACOLOGY OF PARASYMPATHOLYTIC
DRUGS

Uses of Atropine and Related Tertiary Amines:

• Antidote for Poisoning: Atropine is the primary antidote for poisoning by
parasympathomimetic, anticholinesterase drugs, and certain mushrooms.
• Central Effects: Atropine and other tertiary amines, such as biperidene,
trihexyphenidyl, benztropine mesylate, and bornaprine hydrochloride, are used
to treat Parkinson's disease symptoms (tremor, rigidity) and to alleviate
extrapyramidal side effects of neuroleptic drugs.