PHCL 762 PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM

Chapter 2 and 6.8 in Mosby

I. Introduction to Autonomic Pharmacology

A. Introduction

• Know the anatomical features that define the sympathetic and parasympathetic branches of the autonomic nervous system, with particular emphasis on neurotransmitters and end-organ specificity.
• Recognize that there is not dual innervation of all organs.

—Why is this important?

• Understand the concept of "fight-or-flight" and "rest-and-repair" with regard to sympathetic and parasympathetic activity.
• Understand the following suffixes:

-ergic
-mimetic
-lytic

B. Neurotransmitter Chemistry of the Autonomic Nervous System

• What are the primary neurotransmitters of the autonomic nervous system?
• Know the steps involved in storage, release and inactivation of the primary autonomic neurotransmitters.
• What additional substances are "putative" autonomic neurotransmitters?

—Where are they found?
—What are their major properties?

C. Autonomic Receptors

• What are the major neurotransmitter receptors associated with the autonomic nervous system?
• Where are they located typically?
• What signal transduction mechanisms (second messenger systems) are involved?

D. Functional Organization of Autonomic Activity

• What is the importance of the 4 functional levels of autonomic regulation?
• Understand the importance of the baroreceptor reflex in drug-induced cardiovascular responses.
• What is the predominant autonomic tone to various effector organs?

—Why is this important?

E. Pharmacological Modification of Autonomic Function

• Understand the general processes by which drugs can affect autonomic transmission.

II. Cholinoceptor-Activating and Cholinesterase-Inhibiting Drugs

A. Spectrum of Action of Cholinomimetics Drugs

• What are the major subtypes of cholinoceptors?
• Know the differences between muscarinic and nicotinic receptors.

—Where are they located?

—With which signal transduction systems are they associated?

B. Mode of Action of Cholinomimetic Drugs

• What are the major differences between "direct" and "indirect" cholinoceptor agonists?

C. Direct-Acting Cholinomimetics

1. Basic Pharmacology

• How do choline esters differ from each other?

—How are they similar?

• Which choline esters are potentiated by the presence of anticholinesterase agents?
• What cellular events occur when cholinoceptors are activated?
• What are the physiological responses produced by muscarinic and nicotinic agonists?
• What is EDRF?

2. Clinical Uses

• GI and GU
• Ophthalmology

3. Adverse Effects

• salivation, sweating, colic, defecation, headache, loss of accommodation

4. Contraindications

• peptic ulcer
• asthma
• coronary insufficiency
• hyperthyroidism

D. Indirect-acting Cholinomimetics

1. Basic Pharmacology

• What are the major differences among the 3 groups of cholinesterase inhibitors?

—How do these differences influence the pharmacokinetics of the drugs?

—What is unique about parathion and malathion?

• By what mechanisms can drugs inhibit acetylcholinesterase and/or butyrylcholinesterase?

—Understand the importance of the mechanisms.

• Understand differences between reversible and irreversible cholinesterase inhibitors.
• What is "aging" as it relates to acetylcholinesterase inhibition?
• Which organ systems are prominently affected by cholinesterase inhibitors?

—What are the actions of acetylcholinesterase inhibitors on these systems?

2. Clinical Uses

• GI and GU
• Ophthalmology
• Myasthenia gravis

3. Adverse Effects

• Predictable based on excess acetylcholine and overstimulation of muscarinic and nicotinic receptors: miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea, followed by peripheral nicotinic effects particularly manifest as neuromuscular blockade.

E. Important Drugs

1. Direct muscarinic agonists

2. Direct nicotinic agonist

3. Indirect cholinomimetics

III. Cholinoceptor-Blocking Drugs

A. Muscarinic Receptor Antagonists

1. Basic Pharmacology

• What is the original source of the prototypic antimuscarinic drugs?
• What is the importance of their structures (tertiary vs. quaternary amines) as related to absorption and distribution?
• What are the effects of antimuscarinic drugs on various organ systems?
• Do all drugs affect each system similarly or is there some degree of organ selectivity?

2. Clinical Pharmacology

• Gastric or intestinal hypersensitivity or secretion
• Excessive salivation
• To produce mydriasis and cycloplegia
• Adjunct prior to general anesthesia
• Asthma
• Understand how antimuscarinics can be used to treat insecticide poisoning and exposure to nerve gas.
• Understand the importance of "aging" as it relates to organophosphate poisoning and pralidoxime (2-PAM).

3. Adverse effects

• Dry mouth (often seen at therapeutic doses with drugs used primarily for other properties)
• Blurred vision
• Others

4. Contraindications

• Relative, not absolute

B. Ganglion Blocking Drugs

• What is the selectivity of ganglion-blocking drugs for sympathetic vs. parasympathetic nervous systems?
• For nicotinic vs. muscarinic receptors?
• For autonomic ganglia vs. neuromuscular junction?
• Even though ganglion blockers are very effective in lowering blood pressure in patients with malignant hypertension, why are they used rarely today?

C. Important Drugs

1. Muscarinic antagonists

** PRALIDOXIME (2-PAM) is a reactivator of acetylcholinesterase in the periphery.

2. Ganglionic blocking drugs

IV. Adrenoceptor-Activating Drugs

A. Basic Pharmacology of Adrenoceptor Agonists

• Know the classification of adrenoceptors (alpha₁, alpha₂, beta₁, beta₂ and D₁), molecular consequences of their activation, and their important locations.
• What is meant by "desensitization" as it applies to adrenoceptor regulation?
• Understand in general how changes in structure can affect receptor selectivity and pharmacokinetics of adrenoceptor agonists.
• Review how norepinephrine and the other catecholamines are removed from the biophase:

—metabolism

—neuronal uptake (Uptake I, as distinguished from vesicular uptake)

—extraneuronal uptake (Uptake II)

—blood

• Know the pharmacologic effects of the sympathomimetics. Keep in mind that the net effect of any sympathomimetic depends not only on its direct receptor activity, but also on compensatory reflexes by the direct actions.

B. Clinical Pharmacology of Adrenoceptor Agonists

• Understand the rationale for the use of sympathomimetic drugs in general, with particular emphasis on the importance of receptor selectivity, preferred route of administration and the predictable nature of adverse effects.
• Therapeutic use of -adrenoceptor agonists:

1. alpha₁-selective

—nasal congestion, hypotension, paroxysmal atrial tachycardia and to cause mydriasis or to cause vasoconstriction with local anesthetics

2. alpha₂-selective

1. central antihypertensives — these are never injected intravenously to lower blood pressure due to vasoconstrictive effects via vascular, nonjunctional alpha₂-adrenoceptors

• Adverse effects of alpha-adrenoceptor agonists:

1. alpha₁-selective

—hypertension, headache, restlessness, excitability

2. alpha₂-selective

—xerostomia, drowsiness, sedation, constipation, dizziness, headache and profound hypotension

• Therapeutic use of beta-adrenoceptor agonists:

1. non-selective

a. epinephrine

• bronchodilator activity is limited by its cardiovascular effects
• improvement of cardiac function
• adjunct to local anesthetics

b. isoproterenol

• bronchodilator activity is limited by cardiac and vascular effects

2. beta₁-selective (relative)

a. dobutamine

• short term treatment of cardiac decompensation
• acts primarily to increase cardiac output with minor, if any, effect on heart rate (may be related to slight alpha₁-agonist activity)
• alpha₁-agonist activity tends to increase total peripheral resistance and blood pressure at high doses

3. beta₂-selective (various drugs)

• asthma, bronchospasm, emphysema, uterine relaxants in premature labor

• Therapeutic uses of indirect adrenoceptor agonists:

1. tyramine

• none, but tyramine is found in cheeses, beer and wine
• effects are markedly potentiated by older MAO inhibitors such as pargyline and tranylcypromine (lead to hypertensive crisis)

2. ephedrine and pseudoephedrine

• nasal decongestants with modest CNS effects (greater than many other indirect sympathomimetics)

3. amphetamine

• use (very limited) as appetite suppressant with high abuse potential

• Therapeutic uses of dopamine:

—at appropriate doses produces selective renal vasodilation

—at higher doses dopamine will activate vascular alpha₁-adrenoceptors leading to vasoconstriction and hypertension

C. Important Drugs

1. Catecholamines

2. Direct adrenoceptor agonists

3. Indirect sympathomimetics

V.Adrenoceptor-Blocking Drugs

A. Basic Pharmacology of alpha-Adrenoceptor Antagonists

• Know the receptor selectivity of alpha-adrenoceptor antagonists and how this affects their pharmacologic actions and uses.
• Understand the term "epinephrine reversal" and how it applies to alpha-adrenoceptor antagonists.

B. Clinical Pharmacology of the alpha-Adrenoceptor Antagonists

• What are the clinical applications of the alpha-adrenoceptor antagonists?

1. non-selective:

—pheochromocytoma

2. alpha₁-selective:

—hypertension

3. alpha₂-selective:

—impotence (?)

• Why is their use rather limited?

—excessive tachycardia (much more prevalent with non-selective antagonists)

—postural (orthostatic) hypotension

—headache, dizziness, etc.

C. Basic Pharmacology of the beta-Adrenoceptor Antagonists

• Know the difference between "selective" and "nonselective" beta-adrenoceptor antagonists.
• Why is it important that "beta₁-selectivity" is understood to be a relative term? Hint: What beta-adrenoceptors are found in the bronchi?
• Know the major differences in pharmacokinetics of the beta-antagonists.

—How do these differences affect their use?

D. Clinical Pharmacology of the beta-Adrenoceptor Antagonists

• In what diverse disorders are beta-adrenoceptor antagonists used?

1. non-selective:

—hypertension, anginal, arrhythmias, glaucoma, migraine

2. beta₁-selective:

—hypertension

E. Adverse Effects of beta-Adrenoceptor Antagonists

• What adverse effects are associated with beta-adrenoceptor antagonists?
• Are these adverse effects considered to be very serious?

1.non-selective:

—bronchoconstriction, due to beta₂-antagonism (use should be limited to non-asthmatics)

2. beta₁-selective:

—careful use in asthmatics because selectivity for beta₁- vs. beta₂- is limited

3. beta-antagonists, general:

—rebound hypertension and tachycardia upon abrupt discontinuation due to receptor "up-regulation" with chronic use

—may produce hypoglycemic episodes in insulin-dependent diabetics

—may increase plasma triglycerides (VLDL) and decrease plasma high-density lipoproteins (HDL)

F. Clinical Pharmacology of Reserpine

• Extremely effective antihypertensive but severe adverse effects and other safer agents make its use extremely rare today.
• Depletes peripheral and central stores of norepinephrine, dopamine, epinephrine and serotonin; leads to "denervation supersensitivity."
• Adverse effects include sedation, Parkinson-like syndrome, psychic depression, nightmares and increased gastric secretion, along with other predictable symptoms that would be associated with norepinephrine depletion.

G. Important Drugs

1. alpha-Adrenoceptor antagonists

2. beta-Adrenoceptor antagonists

3. Adrenergic neuron blocking drug

VI. Skeletal Muscle Relaxants

A. Introduction

• What are the two major drugs classes used as skeletal muscle relaxants?

B. Basic Pharmacology of Neuromuscular Blocking Drugs

• Be able to describe the underlying structural similarities between neuromuscular blocking drugs.
• Be able to describe the differing routes of elimination of the non-depolarizing neuromuscular blockers.
• Which non-depolarizing blockers are relatively longer vs. shorter in duration?
• What is the major depolarizing skeletal muscle blocker?
• Describe the basis of prolonged duration of succinylcholine blockade in a subset of patients. Indicate a test which may identify patients who may experience this effect.

C. Mechanism of Action

• What are mechanisms of actions for nondepolarizing blockers?
• Describe under what conditions acetylcholinesterase inhibitors may reverse the neuromuscular blockade of nondepolarizing blockers. What might be the clinical importance of this effect?
• What are the two phases of block that may accompany the use of depolarizing drugs?
• Why does the action of succinylcholine last longer than the naturally occurring transmitter acetylcholine?
• What type of paralysis is associated with depolarizing blockade?
• Be able to describe the conditions that may result in a phase II depolarizing blockade. What are the characteristics of a phase II blockade?

D. Clinical Pharmacology of Neuromuscular Blocking Agents

• What is the role of neuromuscular blockade as a part of surgical anesthetic protocols?
• Be able to describe the cardiovascular effects of the neuromuscular blockers.
• The use of depolarizing blockers may be associated with hyperkalemia, increases in intraocular pressure, increase in intragastric pressure, and muscle pain. Be able to describe these effects in more detail.
• Be able to discuss the interactions of neuromuscular blockers with anesthetics, antibiotics, local anesthetic and antiarrhythmic agents.
• Be able to describe the influence of myasthenia gravis, advanced age, severe burns on the pharmacological effectiveness of the neuromuscular blockers.

E. Other Uses of Neuromuscular Blockers

• Be able to describe the utility of neuromuscular blockers in control of ventilation in certain patients.
• Be able to describe the utility of neuromuscular blockers in treatment of convulsions.

F. Spasmolytic Drugs

• What is clinical spasticity?
• Be able to describe how drug therapy may improve some of the symptoms of spasticity.
• By what mechanism may diazepam (Valium) diminish spasticity? What neurotransmitter receptor is involved?
• By what mechanism may baclofen, a GABA-mimetic drug, diminish spasticity? How does the efficacy of baclofen compare to diazepam or dantrolene?
• How does dantrolene reduce spasticity? What is the role of dantrolene in the treatment of malignant hyperthermia?

G. Some Important Drugs

1. Neuromuscular blocking drugs

2. Spasmolytics