книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

SOMATIC

Bridge to Physiology

For a more detailed discussion, see Section II, Chapter 2, in Physiology.

Neurotransmitters

λAcetylcholine (ACh) is the neurotransmitter at both nicotinic and muscarinic receptors in tissues that are innervated. Note that all direct transmission from the CNS (preganglionic and motor) uses ACh, but postganglionic transmission in the SANS system may use one of the organ-specific transmitters described below.

λNorepinephrine (NE) is the neurotransmitter at most adrenoceptors in organs, as well as in cardiac and smooth muscle.

λDopamine (DA) activates D1 receptors, causing vasodilation in renal and mesenteric vascular beds.

λEpinephrine (E, from adrenal medulla) activates most adrenoceptors and is transported in the blood.

BLOOD PRESSURE CONTROL MECHANISMS

Autonomic Feedback Loop

λBlood pressure is the product of total peripheral resistance (TPR) and cardiac output (CO).

λBoth branches of the ANS are involved in the autonomic (or neural) control of blood pressure via feedback mechanisms.

λChanges in mean blood pressure are detected by baroreceptors, which relay information to the cardiovascular centers in the brainstem controlling PANS and SANS outflow. For example, an increase in mean blood

Chapter 1 λ

pressure elicits baroreceptor discharge, resulting in increased PANS activity, leading to bradycardia and decreased SANS activity, which leads, in turn, to decreased heart rate, force of contraction, and vasoconstriction. The resulting decreases in cardiac output and total peripheral resistance

vasoconstriction

B P = T P R ×C O

C O = H R ×S V

Figure II-1-2. Autonomic Feedback Loop

Hormonal Feedback Loop

λBlood pressure is also regulated via the hormonal feedback loop shown in Figure II-1-3.

λThe system is affected only by decreases in mean blood pressure (hypotension), which result in decreased renal blood flow.

λDecreased renal pressure causes the release of renin, which promotes formation of the angiotensins.

λAngiotensin II increases aldosterone release from the adrenal cortex, which, via its mineralocorticoid actions to retain sodium and water, increases blood volume.

λIncreased venous return results in an increase in cardiac output.

λAngiotensin II also causes vasoconstriction, resulting in an increase in TPR.

The Autonomic Nervous System (ANS)

Note

Baroreceptor reflexes can be blocked at the ganglionic synapse with NN receptor antagonists. Alternatively, a reflex bradycardia can be blocked with muscarinic antagonists; a reflex tachycardia can be blocked with β1 antagonists.

Note

Antihypertensive Drugs

Both the ANS (neural) and endocrine feedback loops are invoked when patients are treated with antihypertensive drugs. Such

compensatory mechanisms may result in tachycardia and both salt and water retention.

Muscarinic stimulation

1.Miosis

2.Accommodation (near vision)

Muscarinic antagonism

1.Mydriasis

2.Accommodation to far vision, leading to cycloplegia (paralysis of accommodation)

α1-agonists

1.Mydriasis

2.No cycloplegia

Learning Objectives

Answer questions about cholinergic neuroeffector junctions

Differentiate between muscarinic receptor activators, receptor antagonists, and nicotinic receptor antagonists

CHOLINERGIC NEUROEFFECTOR JUNCTIONS

Release

Choline

ACh +

AcetylcholineEsterase Acetate

Muscarinic Nicotinic

Receptors

Effector cells

Figure II-2-1. Cholinergic Neuroeffector Junction

λCholine is accumulated in cholinergic presynaptic nerve endings via an active transport mechanism linked to a Na+ pump and similar to the sodium-dependent glucose transporter.

1Hemicholinium

2Botulinum toxin

3Acetylcholinesterase (AChE) inhibitors

4Receptor agonists and antagonists

45

In A Nutshell

λM receptor activation →↓ CV function

λ↑ secretions and ↑ smooth muscle contraction

λAll M receptor activators and blockers are nonspecific.

λCholine uptake is inhibited by hemicholinium ( in Figure II-2-1). ACh is synthesized from choline and acetyl-CoA via choline acetyltransferase (ChAT) and accumulate https://www.annualcreditreport.com s in synaptic vesicles.

λPresynaptic membrane depolarization opens voltage-dependent Ca2+ channels, and the influx of this ion causes fusion of the synaptic vesicle membranes with the presynaptic membrane, leading to exocytosis of ACh. Botulinum toxin ( in Figure II-2-1) interacts with synaptobrevin and other proteins to prevent ACh release and is used in blepharospasm, strabismus/hyperhydrosis, dystonia, and cosmetics.

λSome cholinergic nerve endings have presynaptic autoreceptors for ACh that on activation may elicit a negative feedback of transmitter release.

λInactivation via acetylcholinesterase (AChE) is the major mechanism of termination of postjunctional actions of ACh.

λAChE is a target for inhibitory drugs (indirect-acting cholinomimetics). Note that such drugs can influence cholinergic function only at innervated sites where ACh is released.

λReversible AChE inhibitors ( in Figure II-2-1) include edrophonium, physostigmine, and neostigmine. Irreversible AChE inhibitors include malathion, and parathion.

λPostjunctional receptors (N and M) ( in Figure II-2-1) activated by ACh are major targets for both activating drugs (direct-acting cholinomimetics) and blocking agents.

Table II-2-2. Nicotinic Receptor Activation

Note: N receptors desensitize very quickly upon exessive stimulation.

Table II-2-3. Cholinergic Receptor Mechanisms

MUSCARINICRECEPTOR ACTIVATORS

Muscarinic Agonists

Table II-2-4. Properties of Direct-Acting Cholinomimetics

Chapter 2 λ Cholinergic Pharmacology

Bridge to Physiology and Anatomy

λBlood vessels are solely innervated by the SANS, so the stimulation

of autonomic ganglia results in vasoconstriction.

λConversely, the gastrointestinal tract is dominated by the PANS, so ganglionic stimulation causes increased gastrointestinal motility and secretions.

Clinical Correlate

Alzheimer Disease

Late-onset dementia with progressive memory loss and cognitive decline. Neuropathology includes neurofibrillary tangles, amyloid plaques, and loss of ACh neurons in Meynert’s nucleus— rationale for clinical use of AChE inhibitors.

Acetylcholinesterase Inhibitors

Table II-2-5. Properties of Indirect-Acting Cholinomimetics

Classic Clue

AChE inhibitor poisoning: “Dumbbeelss”

Diarrhea

Urination

Miosis

Bradycardia

Bronchoconstriction

Emesis

Excitation (CNS/muscle)

Lacrimation

Salivation

Sweating

As insecticides

λLong-acting irreversible inhibitors (both carbamates and organophosphates)

λWide use in agriculture as insecticides

λExamples: malathion and parathion

Figure II-2-2. Activation of Organophosphate Insecticides

Acute toxicity

λExcessive muscarinic and nicotinic stimulations

λMuscarinic effects:

–Diarrhea

–Urination

–Miosis

–Bradycardia