CHAPTER 7

1. CHAPTER 7 Drugs Affecting the Parasympathetic Nervous System

2. Neurotransmitters • 50 different molecules • Most common: • 1. acetylcholine • 2. nor epinephrine (& epinephrine) • 3. dopamine • 4. serotonin • 5. histamine • 6. GABA (gamma amino butyric acid) • ACh & NE primary autonomic signals

3. Acetylcholine (ACh) • 1. all skeletal muscle nerve endings – NMJ • 2. adrenal medulla & all autonomic ganglia • 3. Post synaptic parasympathetic nerve endings • Cholinergic transmitters

4. Norepinephrine (NE) • 1. all sympathetic post ganglionic nerve endings except sweat glands • Adrenergic transmitters

5. Control of organ function • All internal organs are controlled by one or both of the autonomic nervous systems • Sympathetic – stimulates or increases function • Parasympathetic – decreases function • Drugs hijack this process to exert control of organ function • Cholinergic drugs  acetylcholine recept. • Adrenergic drugs  norepinephrine recept

6. Cholinergic Nerve Endings • Cholinergic nerve endings synthesize and release acetylcholine (ACH) • Released ACH stimulates cholinergic receptors located on smooth, cardiac, and skeletal muscle membranes to initiate a variety of effects • ACH is inactivated by the enzyme acetylcholinesterase

7. Classification of Cholinergic Receptors • There are three main types of cholinergic receptors • Cholinergic receptors, also referred to as muscarinic, are associated with the parasympathetic nervous system • Nicotinic-neural receptors are located on autonomic ganglia and discussed in chapter 8 • Nicotinic-muscle receptors are located on skeletal muscle and discussed in chapter 9

8. Cholinergic Receptor Actions • Cholinergic receptors are located on smooth and cardiac muscle membranes in association with parasympathetic nerve endings • Parasympathetic nervous activity is associated with body functions during rest and restoration of energy such as eating and digestion • Parasympathetic activity also controls the elimination of waste products from the urinary and intestinal tracts

9. How could we increase the action of acetylcholine (ACh) • 1. Give a drug that stimulates Ach receptors • 2. give a drug that slows the breakdown of ACh

10. Direct-Acting Cholinergic Drugs • Direct-acting cholinergic drugs are similar to ACH and stimulate receptors like ACH • Direct-acting drugs have longer durations of action than ACH and are clinically useful • These drugs are used in opthalmology as miotics and in the treatment of glaucoma • Bethanechol stimulates urinary bladder contraction and is taken orally to treat nonobstructive urinary retention & GI paralytic ileus • Pilocarpine- topically in eye – glaucoma

11. Ach destruction • Acetylcholine is either reabsorbed or taken up by the presynaptic nerve ending or broken down to choline and acetate by the enzyme acetyl cholinesterase in the neural cleft. When this enzyme is inactivated it prolongs the lifetime (effect) of ACh in the cleft.

12. Indirect-Acting Cholinergic Drugs • Indirect-acting drugs increase ACH levels at receptors by inhibiting the enzyme acetylcholinesterase • These drugs primarily increase ACH at cholinergic and nicotinic-muscle receptors • Drugs classified as reversible inhibitors of acetylcholinesterase are the most widely used • These drugs are also referred to as anticholinesterase drugs

13. Clinical Uses of Reversible Anticholinesterase Drugs • Reversible inhibitors increase ACH levels • Increased ACH at skeletal muscle is useful in myasthenia gravis and also to reverse the effects of skeletal muscle blocking drugs after surgery • These drugs are antidotes to overdosage with anticholinergic drugs such as atropine • Administered as drops these drugs are used to decrease intraocular pressure in glaucoma • Tacrine and donepezil are used in Alzheimer’s disease to increase memory

14. Clinical anticholinesterase drugs • Physostigmine – used in glaucoma and reversal of anticholinergics like atropine • Neostigmine – used in myesthenia gravis and to reverse NM blockade of tubocurarin after surgery

15. Irreversible anticholinergics • Permanently bind anticholinesterase • Hence: flood the system with Ach • Used as insecticides, nerve gas in war & chronic treatment of glaucoma • Isoflurophate - insecticide

16. Adverse Cholinergic Drug Reactions • Mild effects include nausea, diarrhea, blurred vision, and muscular tremors • Serious reactions involve hypotension, bradycardia, and bronchoconstriction; toxic reactions can cause muscle paralysis, respiratory depression, and death • The antidote to toxicity is administration of atropine, an anticholinergic drug

17. Anticholinergic Drugs • Anticholinergic drugs bind to cholinergic receptors and prevent binding by ACH • These drugs produce effects that are opposite to those of ACH and the cholinergic drugs • Anticholinergic drugs are competetive antagonists of ACH and their effects can be reversed by administration of cholinergic drugs

18. 3 Types of anticholinergic drugs • 1. Block muscarinic synapses (parasympathetic postganglionic) • Hence – leave sympathetic nerve actions unopposed Egg-cramps Rx belladonna • 2. Ganglion blockers – block Syn & Parasym ganglia – not useful • 3. Neuromuscular blocking agents – interfere with NMJ – efferent impulses to skeletal muscle

19. Antimuscarinic drugs • Block all functions of the parasympathetic NS & salivary and sweat glands which are sympathetic but use Ach • No effect on NMJ or autonomic ganglia • Atropine – a belladonna type drug – “deadly night shade” – binds competitively to all parasympathetic postganglionic neuroeffector junctions –vagus nerve (IX)

20. Antimuscarinic drugs • Scopalamine – another belladonna drug – the most effective anti-motion sickness drug but it readily enters the CNS and produces blocking of short term memory • Transderm scope

21. Actions of anticholinergics • Eye –strong Mydriatic effect –dilate pupil –may precipitate glaucoma • GI – strong antispasmotic – inhibitor of cramps & nausea • GU – slows urination – enuresis – danger in prostatism • Pre op – stops sweating & salavation

22. Anticholinergic drugs • 2. Ganglionic blockers - block Sym & Parasym ganglia - hard to control – not clinically • Nicotine – binds to all autonomic ganglia, adrenal medulla & all NMJ This is why smoking is so addicting!

23. Anticholinergic drugs • 3. Neuromuscular blocking drugs • Peripheral • Nondepolorizing – competative • Depolorizing – long acting • central

24. Peripheral neuromuscular blockers • Block motor end plates of skeletal muscle NMJ • A. Nondepolarizing – competitive – • Curare – native hunters in Amazon – arrow poison now used in surgery to relax patient so less anesthetic can be used • B. Depolarizing –binds tightly to receptors and fires ittwitch – then remains bound so muscle cell cannot repolorize • Succinylcholine – short acting given IV

25. Succinylcholine • Note – destroyed by hydrolysis by Pseudocholinesterase – a circulating plasma enzyme. There is a rare genetic defect in this enzyme so patient remains parolized for many hours post op. This produces apnea due to paralysis of diaphragm • Malignant hyperthermia – rare – muscular rigidity & hyperpyrexia can be fatel

26. succinylcholine • Drug responsible for “surgical locked in “ syndrome - patient awakens during surgery – awake but paralyzed

27. Clinical Uses of Anticholinergic Drugs • To increase heart rate • To dry respiratory secretions and promote bronchodilation • To decrease gastrointestinal secretions and motility • To inhibit excessive urination • To treat and prevent motion sickness • In eye examinations to dilate the pupil and paralyze the lens

28. Anticholinergic Adverse Effects • Primarily due to excessive blockade of the parasympathetic nervous system • Mild reactions include dry mouth, constipation, urinary retention, sedation, and blurred vision • Serious reactions include tachycardia, hyperpyrexia, CNS depression, respiratory depression, coma and death • The antidote in toxicity is administration of physostigmine and the support of vital functions

29. Contraindications to Use of Anticholinergic Drugs • These drugs should not be administered to patients with narrow-angle glaucoma, patients with urinary or intestinal obstruction, and males with prostatic hyperplasia • Elderly individuals are more susceptible to the central actions of anticholinergic drugs and may become confused and disoriented