AutonomicsAutonomics

Claro M. Isidro M.D.

Parasympathetic DrugsParasympathetic Drugs

Drugs Affecting the ANS:

1.Cholinergic drugs – act on the receptor that is activated by acetylcholine

2.Adrenergic drugs – acts on the receptor that are stimulated by norepinephrine or epinephrine

Cholinergic NeuronsCholinergic Neurons

Preganglionic fibers terminating in the adrenal medulla

Preganglionic fibers of both parasympathetic & sympathetic nervous system

Postganglionic fibers of the parasympathetic nervous system

Voluntary muscles of the somatic nervous system

Neurotransmission at Cholinergic neurons

Synthesis of acetylcholineStorage of acetylcholine in vesiclesRelease of acetylcholineBinding to receptorDegradation of acetylcholineRecycling of choline

Cholinergic Receptors Muscarinic : M1 – nerves M2 – heart, nerves, smooth muscles M3 – glands, smooth muscles Endothelium M4 - ? CNS M5 - ? CNS

Nicotinic: Nm – skeletal muscles Neuromuscular junction Nn – Preganglionic parasympathetic & sympathetic

Effector Organs Receptors Action

Eye sphincter m.

ciliary m.

M3

M3

Contraction (meiosis)Contraction(accomodation)

Heart SA node AV node Contractility

M2

M2

M2

↓ Heart rate

↓ conduction velocity & ↑ refractory period

↓ contraction

Lung bronchial m. M3 contraction

Effector Organs Receptor Action

Blood Vessels most BV skeletal m.

--

Small doses – vasodilatation Large doses – vasoconstriction

GIT sphincter motility & tone

M3

M3

RelaxationIncrease

GUT trigone & sphincter m. bladder wall & detrusor m.Penis, seminal v.

M3

M3

M

Relaxation

Contraction

Erection

Effector Organs

Receptor Action

Secretory glands sweat intestinal bronchial lacrimal

M

M3

MM

Generalized secretion↑ secretion↑ secretionProfuse secretion

Cholinomimetics / Parasympathetic Agonist/Cholinergic Agonist Drugs that have effects producing parasympathetic dominance

Direct-Acting Cholinoceptor Stimulants

A. Esters of Choline: Synthetic

1. Acetylcholine 3. Carbachol

2. Metacholine 4. Betanechol

B. Alkaloids: Naturally occurring

1. Muscarinic

Muscarine, Pilocarpine, Oxotremorine

2. Nicotinic

Nicotine, Lobeline,

Dimethylphenylpiperazinium (DMPP)

Direct-Acting (Choline Esters)::

Acetylcholine quarternary ammonium compound muscarinic & nicotinic receptors equally Actions:

↓ HR and CO, ↓ BP ↑ salivary & intestinal secretion and GI motility Enhances bronchiolar secretions ↑ detrussor muscle tone stim. Ciliary m. → near vision miosis

Susceptibility to

Cholinesterase

Muscarinic Effects

Nicotinic Effects

Therapeutic Use

Ach + +++ +++ Miotic

Metacholine

+ ++++ + Dx of bronchial hyperactivity

Carbachol - +++ ++ Miotic

Betanechol - ++ - Non-obstructive urinary retention

Direct-Acting (Choline Esters):

Naturally-occurring:

Pilocarpine• tertiary amine

• dominant muscarinic action• resistant to acetylcholinesterase• Use as topical eye drop. Produce rapid meiosis & contraction of

ciliary muscle• Increase gastric acid secretion & bronchoconstiction• Potent stimulator of secretions (sweat, tears, saliva)• Therapeutic Use:

• DOC in emergency lowering of IOP in glaucoma• Adverse Effects: CNS disturbances, profuse sweating and salivation

ARECOLINE• chief alkaloid of areca or betel nuts• muscarinic & nicotinic receptors• enhances salivary secretion• no therapeutic indication

MUSCARINE• quarternary amine• muscarinic receptors• found in mushrooms (Amanita muscaria)• small amounts edible• large amounts poisonous• effects: fall in BP, temporary cessation of heart beat,

diaphoresis• antidote: ATROPINE

Indirect-Acting : AnticholinesteraseIndirect-Acting : Anticholinesterase

REVERSIBLE (Anticholinesterases)

IRREVERSIBLE (Organophosphate)

AnticholinesteraseAnticholinesterase

AcetylCholine Choline + Acetic acid

Cholinesterase-

Indirect-Acting :REVERSIBLE (Anticholinesterases):

Physostigmine Neostigmine Pyridostigmine Ambenonium Edrophonium Tacrine, Donezepil, Rivastigmine, Galantamine

IRREVERSIBLE1. Organophosphates

• Isoflurophate• Echothiophate• Malathion, Parathion

2. Chemical Warfares• Sarin, Soman

PHYSOSTIGMINE• Alkaloid, tertiary ammmonium grp.• Enters the CNS• DOA: O.5 to 2 hrs.• Therapeutic Uses:

1. Atony of intestines and bladder2. Glaucoma lowers IOP3. Antidote atropine, phenothiazines, TCA4. NDMR (tubocurarine) reversal

• Adverse effects: convulsions, bradycardia, CO

NEOSTIGMINE• Quarternary ammonium grp.• Does not enter the CNS peripheral• DOA: 0.5 to 2 hrs• Therapeutic Uses:

1. Atony of intestines and bladder2. Myasthenia gravis3. NDMR (tubocurarine) antidote

• Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm

PYRIDOSTIGMINE and AMBENONIUM

• DOA: PYRIDOSTIGMINE - 3 to 6 hrs• AMBENONIUM – 4 to 8 hrs• Therapeutic Uses:

1. Myasthenia gravis2. NDMR (tubocurarine) antidote

• Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm

EDROPHONIUM • Quarternary amine• DOA: 5 to 15 mins• Therapeutic Uses:

1. Diagnosis of Myasthenia gravis2. NDMR (tubocurarine) antidote3. Arrhythmias (SVT)

• Antidote: Atropine• Adverse effects: salivation, flushing, ↓ BP, nausea,

abdominal pain, diarrhea, bronchospasm

Tacrine, Donezepil, Rivastigmine,Galantamine

• Alzheimer disease deficiency of cholinergic neurons in the CNS

• Tacrine – hepatotoxic• Adverse effect: GI distress

Indirect-Acting IRREVERSIBLE : ORGANOPHOSPHATES

ISOFLUROPHATE tx of open angle glaucoma

ECHOTHIOPHATE Produce intense miosis tx of open angle glaucoma

PARATHION, MALATHION Insecticides

ORGANOPHOSPHATE POISONING:

Signs & Symptoms1. miosis2. salivation, frothy secretions3. sweating4. bronchial constriction5. vomiting and diarrhea6. muscle fasciculation

ORGANOPHOSPHATE POISONING:

Therapy:• maintenance of VS respiration• Decontamination• Drugs: Atropine + Pralidoxime ATROPINE sulfate

• 1 to 2 mg IV every 5-15 min until muscarinic effect disappears (maximum of 1 gm per day)

PRALIDOXIME

• A cholinesterase enzyme regenerator compound

• - 1 to 2 gm given over 30 min by IV infusion

Parasympathetic Antagonists/Cholinergic Antagonist (Parasympatholytics)

ANTIMUSCARINIC

Tertiary Amines:a. Natural – atropine, scopolamine

b. Semisynthetic – tropine, homatropine

c. Synthetic – dicyclomine, oxybutyrine, oxyphencyclimine

Quarternary Amines:a. Anisotropine

b. Propantheline

c. Methanteline

ATROPINE• prototype• Belladona alkaloid• high affinity for muscarinic receptors• central and peripheral muscarinic blocker

causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors

Unopposed sympathetic action

ATROPINEActions:1. CNS

• minimal stimulant effect2. Eye

• mydriasis, unresponsiveness to light• cycloplegia inability to focus for near-vision

3. GIT• antispasmodic reduce GIT activity

4. GUT • reduce urinary bladder hypermotility

5. SECRETIONS• blocks salivary glands antisialogogue• decrease also lacrimal & sweat glands secretion

ATROPINE

6. CVSdivergent effects depending on

dose

Low dose – (-) M1 ↑ Ach release

Higher dose – (-) M2 on SA node ↑ CR

Effects in relation to dose:

Dose Effects

0.5 mg Slight cardiac slowing some dryness of mouth inhibition of sweating

1.0 mg Definite dryness of mouth; thirst acceleration of heart, sometimes preceded by slowingmild pupillodilatation

Dose Effects

2.0 mg Rapid HR; palpitations marked dryness of mouth Dilated pupils; some blurring of vision

5.0 mg All of the above symptoms marked; difficulty in speaking and swallowing;Restlessness and fatigue;Headache; dry, hot skinDifficulty in micturitionReduced intestinal peristalsis

Dose Effects

10.0 mg and more Above symptoms more markedPulse rapid and weakIris practically obliteratedVision very blurredSkin flushed, hot, dry, and scarletAtaxia, restlessness and excitementHallucinations and deliriumComa

ATROPINETherapeutic Uses:1. Ophthalmic

• Permits measurement of EOR

2. Antispasmodic3. Antidote for cholinergic agonists

• Organophosphate poisoning• Mushroom poisoning• acetylcholinesterase inhibitors

4. Antisecretory agent

SCOPOLAMINE• Belladona alkaloid• Peripheral effects similar to atropine• Greater and longer CNS action• Action:

• Anti-motion sickness• Blocks short-term memory• Produces sedation, • excitement

Therapeutic Uses: anti-motion sickness adjunct in anesthesia procedures > in obstetrics, + morphine sedation & amnesia

IPRATROPIUM• Quarternary derivative of atropine• Does not enter CNS • Therapeutic Uses:

• Treat asthma in patients who are unable to take adrenergic agonists

• Management of COPD

GANGLIONIC BLOCKERS

Specifically act on NICOTINIC receptors No selectivity towards PNS or SNS Blocks entire ANS output

GANGLIONIC BLOCKERSA. NICOTINE

B. TRIMETHAPHAN

C. MECAMYLAMINE

D. HEXAMETHONIUM

The End

Write A if cholinergic agonist

B if cholinergic antagonist

1. Bethanicol

2. Scopolamine

3. Isoflurophate

4. Trimethaphan

5. Arecoline

6. Main neurotransmitter of PNS

7. Amino acid precursor of Ach

8. Drug of choice in emergency lowering of IOP

9. Antidote for organophosphate poisoning

10. Aids in the diagnosis of myasthenia gravis

Short QuizShort Quiz

1. Describe the pharmacodynamic difference between direct and indirect acting cholinomimetics

2. Describe the effects of acetylcholine on the major organs

3. Describe the effects of atropine on the major organ system

4. Clinical uses of atropine & scopolamine

A. NICOTINE Low dose :

ganglionic stimulation by depolarization CNS: euphoria, arousal, relaxation

improves attention, learning, problem solving & reaction time

Peripheral: ↑ BP & HR, vasoconstriction

High dose ganglionic blockade BP falls, blocks GIT & bladder activity