AUTONOMIC SYSTEMS AND DRUGS-2

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

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

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)

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

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.

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.

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

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).

Postsynaptic Receptors (Cholinergic) Muscarinic Nicotinic

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

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.

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.?

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.

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.

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

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).

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.

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

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.

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

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.

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

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).

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.

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)

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.

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.

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