1. AUTONOMIC SYSTEMS AND DRUGS-2

2. Neurotransmitters Epinephrine Norepinephrine Adrenergic Acetyl choline
Cholinergic
This is the starting point.
Important to remember that they also work in the CNS.

3. Innervation Sympathetic Parasympathetic HR Contractility
Transmitter(s)
Sympathetic
Norepinephrine
Epinephrine
Parasympathetic
Heart muscle as an example; other important organs are blood vessels, bronchial smooth muscle, urinary bladder, eye, uterus, and kidney. He made the point that sympathetic and parasympathetic influences are usually opposite to each other.
Acetyl Choline

4. Important Exception Vascular smooth muscle
Exception to the dual innervation generality.
Important because the primary determinant of blood pressure is peripheral vascular resistance.
Sympathetic only (or nearly so)

5. Catecholamine Biosynthesis
Synthesized from:
Tyrosine
Rate limiting reaction:
Tyrosine hydroxylase
Why is this important? (Parkinson’s disease)

6. Catecholamine Degradation
COMT - catechol-O-methyltransferase
MAO - monoamine oxidase
Actually, of minor importance with regard to regulation of catecholamine activity. Nevertheless, MAO inhibitors will be important later on.

7. Norepinephrine Inactivation
Reuptake into the nerve ending by an active transport system
The major mechanism for inactivation of norepinephrine activity in the synapse. We will revisit this system later. Cocaine is a NE reuptake inhibitor, any some of the antidepressants are reuptake inhibitors.

8. Drugs Acting Presynaptically
Reserpine
-Methyldopa
Guanethidine
Amphetamine
Imipramine
Fluoxetine
Inhibits storage in vesicles
False transmitter
Inhibits NE release
These drugs are not important at this point, though all will come up again later. This is mainly to illustrate some of the mechanisms that various drugs employ to interact with the sympathetic nervous system.
Stimulates NE release
Inhibits NE reuptake
Inhibits serotonin reuptake

9. Postsynaptic Receptors (Adrenergic)
Alpha Beta
Generally excitatory
Exception: intestinal smooth muscle
Generally inhibitory
Exception: beta1 in the heart
In the gut, both alpha and beta receptors cause relaxation. In the heart, beta 1 is excitatory (heart rate, conduction velocity, force of contraction).

10. Postsynaptic Receptors (Cholinergic)
Muscarinic Nicotinic

11. Acetyl Choline Inactivation
Acetylcholinesterase
Different from NE inactivation. In this case enzymatic degradation is important. Anticholinesterase drugs are important.

12. Cholinergics Cholinergic agonists Bethanechol Pilocarpine Carbachol
Antimuscarinics
Atropine
Scopolamine
Anticholinesterases
Neostigmine
Organophosphates (e.g. DFP)
Neuromuscular blockers
Tubocurarine
Pancuronium
Succinyl Choline
Preview of the next 8 slides. These are all drugs to know.

13. Cholinergic Agonists Parasympathomimetics: limited uses Glaucoma
Pupillary constriction (meiosis)
Not used for:
Bronchial Asthma
Coronary Insufficiency
Peptic Ulcer
Hyperthyroidism
Also used for the treatment of xerostomia (dry mouth). Stimulates salivation. Why are they not used for bronchial asthma, et al.?

14. Antimuscarinics Atropine; Scopalamine Therapeutic uses: Side effects:
Motion sickness
Pupillary dilation
Parkinson’s Disease
Side effects:
Dry mouth
Blurred vision
Tachycardia
Urinary retention
Constipation
These are muscarinic receptor antagonists. Side effects are important; antimuscarinic effects come up with other drugs. The five subtypes of muscarinic receptors probably explain the differences in susceptibility of various functions to these drugs.

15. Anticholinesterases Reversible Irreversible Predict effects on: Eye
Neostigmine
Physostigmine
Organophosphates
(e.g. DFP)
Predict effects on:
Eye
GI tract
Urinary tract
Skeletal muscle
Which one depends upon how long the agent remains bound to the cholinesterase, thereby inactivating it.
eye - miosis, decrease in intraocular pressure
GI - stimulates secretions and augments motor activity; used to treat paralytic ileus.
Urinary tract - contract detrusor muscle, relax sphincters, i.e., promotes urination.
Skeletal muscle - stimulates contraction.

16. Reversal of organophosphate poisoning:
Atropine
Pralodoxime
Reversal of atropine poisoning:
Atropine blocks muscarinic receptors, but has no effect on nicotinic receptors, so mechanical support of respiration may still be necessary.
Physostigmine

17. Therapeutic Uses of Anticholinesterases
Glaucoma
Paralytic ileus
Mysathenia gravis
Paralytic ileus is spasm in the GI tract, often postoperatively. Severe constitpation. Myasthenia gravis is an autoimmune disease directed against nicotinic receptors. Must control muscarinic side effects (atropine).

18. Pancuronium Succinylcholine Mechanism Competitive Depolarizing Onset
1-2 min
20-40 sec
Duration
30-60 min
2-5 min
Side Effects
BP tendency
Cardiac arrhythmia
Prolonged apnea
Malignant hyperthermia
Remember that pancuronium is a competitive nicotinic receptor antagonist. Tubocurarine also in the competitive group, and one that he said to remember. Remember (1) mechanism of action, (2) duration of action, and (3) side effects.

19. Adrenergics Autonomic reflexes modulate drug responses BP SNS PSNS BP
Reflexes must be considered in addition to the drug effects.

20. What is the treatment of choice for anaphylactic shock?
Epinephrine
Why?
It is the only drug that addresses the most serious manifestations:
b1 increases cardiac output
b2 relaxes constricted bronchioles
1 constricts capillaries
Massive release of histamine leads to vasodilation and a fall in blood pressure, and release of leukotrienes leads to bronchiolar contriction.

21. 2-Selective Adrenergic Agonists
Albuterol
Terbutaline
Bronchial dilators
Uterine relaxant (ritodrine)
“Selective” doesn’t mean “specific.” Beta 1 effects are still possible.

22. 1 Adrenergic Agonists Therapeutic uses: Phenylephrine Ephedrine
Nasal decongestants
Used with local anesthetics
Local hemostasis
Mydriatic
Glaucoma
Vasopressor
Appetite suppressant
Most effects mediated through contraction of smooth muscle. Hypertension is a contraindication.

23. Adrenergic Antagonists
Alpha blockers
Prazosin (1)
Phenoxybenzamine (12)
Phentolamine (12)
Phenoxybenzamine and phentolamine only used with pheochromocytoma until the tumor is removed. Prazosin more commonly used for other hypertension. Remember the first dose effect with prazosin.
Hypertension

24. Adrenergic Antagonists
Beta blockers:
Propranolol (1 2)
Metoprolol (1 )
Atenolol (1 )
Timolol (1 2)
Therapeutic uses:
Arrhythmia
Angina pectoris
Hypertension
What is the problem with beta blockers in bronchial asthma? (life-threatening breathing problems).
So would you give a beta-1 selective drug to an asthmatic? (No; selective does not mean absolutely specific).

25. Adverse Effects Alpha blockers Beta blockers Postural hypotension
Tachycardia
First dose (prazosin)
Beta blockers
Cardiac depression
Asthma attack
Nightmares, lassitude, depression
Angina pectoris (abrupt withdrawal)
Abrupt withdrawal from beta blockers is dangerous due to the aquired supersensitivity to norepihephrine.

26. Anti-Parkinson’s Drugs
Grossly oversimplified as to regulation of muscle tone and movement, but it demonstrates the rationale for Parkinson’s therapy.
Though successful, what was done to make it better? (decarboxylase inhibitors)

27. Carbidopa Tolcapone Selegiline
Inhibit the metabolism (decarboxylation) in the periphery to get more L-dopa into the brain. Further inhibit subsequent metabolism with tolcapone and selegiline.

28. Reduced with carbidopa
Adverse Effects
GI - nausea and vomiting
Hypotension
Dyskinesias
Psychiatric reactions
Reduced with carbidopa
GI and hypotesive effects dramatically reduced by combining L-dopa with carbidopa. Dyskinesias and psychiatric reactions not affected.

29. Drugs to Know Levodopa Carbidopa Amantidine Bromocryptine Selegiline
Tolcapone
used in combination
DA reuptake inhibitor (?)
DA receptor agonist
MAO-B inhibitor
COMT inhibitor