ANS drugs

Question 1

Main neurotransmitter of parasympathetic system

Answer 1

Acetylcholine
Released:
1. Parasympathetic nerve endings
2. Some sympathetic nerve endings
- Sweat glands except hand and palm NA
- Piloerector muscles
- Arterioles of smooth muscles
- Adrenal gland
3. ALL ganglia
4. CNS - memory
5. Skeletal muscle - not parasympathetic or sympathetic

Question 2

Cholinergic receptor

Answer 2

Muscarinic
M1 gastric
1. Parietal cells M1 + M3 → ↑ HCL
2. CNS
M2 cardiac
1. Heart especially supraventricular bradycardia
M3
1. Blood vessels not innervated by either but drugs and ingested act on them - vasodilation via EDRF
2. Smooth muscle - contraction of wall relaxation of sphincter
3. Glands - increases secretion
4. Eyes - miosis + accommodation for near vision
- Miosis contraction of constrictor pupillae opening of trabecular mesh ↑ drainage of aqueous humorous ↓ IOP Glaucoma
- Contraction of ciliary muscles accommodation for near vision ↑ convexity of lens

Nicotinic
1. Skeletal muscle Nm
2. Ganglion Nn
3. Suprarenal gland Nn

Question 3

Why is acetylcholine not used as a drug?

Answer 3

Non-selective
Short duration 20secs
Irregular absorption

Question 4

Parasympathomimetic

Answer 4

Direct acting
Muscarinic CBC P
1. Carbechol - muscarinic and nicotinic
2. Bethanechol
3. Cevimeline and pilocarpine

Nicotinic VN
1. Nicotine
2. Varenicline

Indirect acting

Choline esterase inhibitors
Reversible - carboxymethylation
1. Stigmine family - physostigmine, neostigmine, pyridostigmine and rivastigmine
physo,neo,pyrido and riva
2. Edrophonium
3. Donepezil

Irreversible - phosphorylation
Organophosphate compounds
1. Insecticides - malathion and parathion
2. Nerve gas - sarin and soman
3. Drugs - echothiopate eye drops (2wks)

Question 5

Muscarinic agonists

Answer 5

CBC P
1. Carbechol - muscarinic and nicotinic
2. Bethanechol
3. Cevimeline and pilocarpine

Question 6

Carbachol

Answer 6

• Stimulates both nicotinic and muscarinic; non-selective - not used systemically
• Long duration 2-3 hrs not broken down by choline esterase
• Uses:
  Glaucoma eye drops

Question 7

Bethanechol

Answer 7

• Muscarinic ONLY
• Mainly on M3 → GIT and bladder
• Uses:
  Post operative to reverse urine retention and paralytic ileus NOT organic obstruction (rupture)
• Oral or S.C why? should not be given IV → stimulates M2 severe bradycardia and cardiac arrest

Question 8

Cevimeline (synthetic) and pilocarpine (natural plant derivative)

Answer 8

• Muscarinic ONLY
• Glandular M3 increases secretions
• Uses:
  1. Sjogren syndrome - HSR IV autoimmune
• Xerostomia
• Keratoconjunctivitis sicca
  2. Glaucoma

Question 9

Adverse effects of muscarinic agonists

Answer 9

DUMBELS
Diarrhea
Urination
Miosis
Bradycardia + Bronchoconstriction
Emesis
Lacrimation
Salivation + Skeletal muscle twitches (carbechol)

Question 10

Contraindications of muscarinic agonists

Answer 10

1. Organic obstruction - rupture
2. Peptic ulcer - increases HCL
3. Heart block - bradycardia
4. Bronchial asthma - bronchconstriction

Question 11

Nicotinic agonists

Answer 11

1. Nicotine
2. Varenicline

Question 12

Nicotine and varenicline

Answer 12

• Cigarette smoke; toxin
• Stimulates ganglion + skeletal muscle → ↑ sympathetic and parasympathetic
• Dosage
  1. Small dose → Stimulates ganglion HYPERTENSION via vasoconstriction
• Blood vessels do not have parasympathetic nicotine stimulates ganglion
• Suprarenal gland Nn → adrenaline + noradrenaline release
• Pituitary gland → ADH release
• Damages endothelial wall
  2. Large dose - toxic → CNS depression + hypotension
• Use: nicotine patch start one week before stopping

BETTER OPTION → varenicline
- Partial agonist
- Start one week before stopping
- Contraindicated in pregnancy
- Side effects - vomiting and nausea

Question 13

Indirect acting cholinergic agonists

Answer 13

Choline esterase inhibitors
Reversible - carboxymethylation
1. Stigmine family - physostigmine, neostigmine, pyridostigmine and rivastigmine
physo,neo,pyrido and riva
2. Edrophonium
3. Donepezil

Irreversible - phosphorylation
Organophosphate compounds
1. Insecticides - malathion and parathion
2. Nerve gas - sarin and soman
3. Drugs - echothiopate eye drops (2wks)

Question 14

Physostigmine Vs Neostigmine

Answer 14

Physostigmine
- Natural plant alkaloid
- Tertiary amine ie crosses BBB
- Stable therefore well absorbed from GIT
- Effect - central AND peripheral
Muscarinic, nicotinic and central (insomnia, headache, excitation, convulsions)
Neostigmine
- Synthetic
- Quaternary amine does not cross BBB
- Ionized therefore not well absorbed from GIT
- Effect - peripheral ONLY
Nictonic and muscrainic
- Uses
1. Reverse postoperative urine retention and paralytic ileus not caused by mechanical obstruction
2. Reverse muscle relaxant effect of non-depolarizing skeletal muscle relaxants postoperative
3. Treatment of myathenia gravis + atrophine (muscrainic blocker)

Question 15

Drugs used to reverse the effect of postoperative urine retention and paralytic ileus

Answer 15

1. Bethanceol
2. Neostigmine

Question 16

Pyridostigmine

Answer 16

Advantages
1. More selective - works only on motor end plate + very low muscarinic side effects do need for atrophine
2. Longer duration of action 5-6 hrs

Question 17

Edrophonium

Answer 17

• VERY selective very short duration of action 5-15 mins
• Uses
  Tensilon test
  1. Diagnosis of myasthenia gravis - improvement yes
  2. Differentiate between myasthenic crisis and cholingeric crisis (overdose leading to maintained depolarization muscle fatigue)- improvement mysathenic crisis no improvement cholingeric crisis due to overdose

Question 18

Donepezil and rivastigmine

Answer 18

• Central ChE inhibitors ONLY
• Uses - treatment of alzheimer

Pysostigmine (both) + donepezil + rivastigmine - central
Neostigmine + pyridostigmine - peripheral only

Question 19

Irreversible choline esterase inhibitors

Answer 19

Organophosphates
1. Insecticide - malathion + parathion
2. Drugs - echothipate (eye drops 2weeks)
3. Nerve gas - sarin + soman

Pharmacokinetics
- VERY rapid absorption
- Bind irreversibly to cholinesterase after 12 hrs aging of enzyme

Management
Triad
1. Atropine - non-selective muscarinic blocker + can cross BBB
IV 2mg/5 mins until >80 systolic BP and pulse
2. Pralidoxime (PAM) + diacetylmonoxime (DAM) - choline esterase reactivators
dephosphorylate ChE but should be taken as early as possible <12 hrs before bonding is complete
IV 2mg/20-30 mins or auto-injector
3.Diazepam - control convulsions 10mg IV

Question 20

Muscarinic blockers

Answer 20

Natural
1. Atropine
2. Scopolamine/hyoscine

Synthetic

Question 21

Treatment for
1. Bronchial asthma
2. Abdominal colic
3. Diarrhea
4. Peptic ulcer
5. Acute cystitis
6. Urine incontinence
7. Fundoscopic examination
8. Iridocyclitis
9. Motion sickness
10. Parkinson’s disease
11. Organophosphate toxicity

Answer 21

1. Bronchial asthma - ipratropium
2. Abdominal colic - buscopan “ hyoscine butyl bromide”
3. Diarrhea - lomotil → atropine + diphenoxylate
4. Peptic ulcer - pirenzepine PP
5. Acute cystitis - oxybutynin AO
6. Urine incontinence - tolterodine UT tortilla
7. Fundoscopic examination - cyclopentolate (pen in cyclop eye), tropicamide and eucatropine
   - Phenylephrine alpha agonist (preferred)
8. Iridocyclitis - long acting atropine
9. Motion sickness - scopolamine (M1) + antihistamine (H1)
10. Parkinson’s disease - benztropine
11. Organophosphate toxicity - atropine

Question 22

Side effects of atropine

Answer 22

Blurred vision زغلوله
Dryness of all body secretions الناشفه
Urine incontinence حبست
Glucoma جوزها
Tachycardia ابو سرعه

CNS
SAD HC
Sedation
Amnesia
Delirium
Hallucinations
Coma

Question 23

Contraindications of atropine

Answer 23

1. Children
   - Atropine flush
   - Atropine fever - no sweat
2. Elderly
   - Urine incontinence especially BPH
   - Narrow angle glucoma
3. Obstructive disease of GIT → pyloric stenosis, paralytic ileus, intestinal atrophy

Question 24

Classification of sympathomimetics

Answer 24

1. Mechanism of action
   - Direct acting - alpha and beta receptors
   - Indirect acting - increasing NE released or inhibiting MAO
2. Chemistry
   - Catechol ring (OH) - water soluble therefore are not well absorbed and do not cross BBB; broken down by MAO/COMT in 2-3 mins
   - Non-catechol ring (no OH)

Question 25

Adrenaline

Answer 25

**Uses** 1. Acute anaphylactic shock - bronchodilation + vasoconstriction - IM lateral thigh 2. Acute bronchospasm (children larynx RDS) - bronchodilation B2 agonist + vasoconstriction - IM, SC or inhaltion 3. Cardiac arrest IV - vasoconstriction then CPR 4. Dental clinic to prolong effect of anesthetic + vasoconstriction to reduce bleeding 5. Shock - increase BP 6. Insulin hypoglycemia - glycolysis and gluconeogenesis 7. Glucoma + red eye - decrease IOP 8. Local hemostatic in epistaxis **Adverse effects** 1. Tremor 2. Tachycardia ventricular fibrillation cardiac arrest if given IV 3. Acute heart failure/ Broken heart syndrome/ Stress induced cardiomyopathy 4. Pulmonary edema leading to pulmonary hypertension - Increased CO and vasoconstriction of vessels 5. Cerebral hemorrhage due to increased BP 6. Gangrene of fingers - severe vasoconstriction during anesthesia **Contraindications** 1. CVS problems 2. Hypertension 3. Large dose with local anesthetic 4. Cardiac outflow obstruction - Aortic stenosis - Dilated hypertrophic cardiomyopathy (>17mm) tachycardia - Embolus in pulmonary vein 5. Hyperthyroidism - thyroxine increases B2 receptors and their sensitivity over-reactivity AND decreases COMT overactivity of sympathetic system 6. Patients recieving digitalis therapy **Drug interactions** - exaggerated CVS action 1. Cocaine 2. Hyperthyroidism **Chemistry** - Natural catechol ring - Water soluble does not cross BBB - Not well absorbed 1. Not absorbed orally 2. Skin vasoconstriction 3. Minimal absorption in eye *dipivefrin* more readily absorbed 4. Can be inhaled, SC IM DO NOT GIVE IV cardiac arrest - Broken down by MAO and COMT to VMA + metanephrine in 2-3 minutes - Unstable can be oxidized by air or light **Effect** 1. Heart - increases heart rate and contractility - Can cause arrhythmia and ventricular fibrillation 2. Blood vessels - Vasoconstriction of skin and mucus blood vessels via alpha 1 - Vasodilation of skeletal and coronary via B2 3. BP - Therapeutic dose increases systolic and decreases diastolic - High increases systolic AND diastolic 4. Bronchi - bronchodilation and decreases mucus production via alpha 1 “bronchial decongestant” 5. CNS - no effect does not cross BBB 6. Eye - Vasoconstriction of cillary blood vessels via alpha 1 decreases aqueous humor production decreases IOP treats GLUCOMA and RED eye - Ciliary epithelium B2 receptors increase aqueous humor if too much is produced increase IOP glaucoma 7. Uterus relaxation 8. Hand tremor 9. Liver hypokalemia 10. Urinary bladder - B2 detrusor muscle relaxation - alpha 1 sphincter and trigone contraction 11. Inhibits tone and motility of GIT and smooth muscle

Question 26

Noradrenaline

Answer 26

**Uses** 1. Acute hypotensive shock - severe vasoconstriction via alpha 1 - IV infusion - Stimulates baroreceptor reflex - sudden increase in BP >170 - can lead to acute heart failure and aortic dissection *NE has minimal effect on HR and contractility since it is counteracted by the baroreceptor reflex that causes reflex bradycardia* *Dopamine is better since it does not reduce renal blood flow* **Adverse effects** 1. Headache, anxiety and bradycardia 2. Hypertension in patients with hyperthyroidism - Increased beta 1 receptors and sensitivity - Decreases COMT 3. Necrosis and sloughing - severe vasoconstriction **Mechanism of action** Work on 1. Alpha 1 90% and 2 (if given selective alpha 2 agonist) 2. Beta 1 10% **Chemistry** - Natural catcehol ring - Water soluble does not cross BBB - Not well absorbed 1. Not absorbed orally 2. Not absorbed from eyes DO NOT give as SC OR IM since it causes severe vasoconstriction leading to skin sloughing and necrosis