PHARM

Central and Peripheral Nervous SystemsMichael Haines, MPH, RRT-NPS, AE-C

The Nervous System

•Two major control systems▫ Nervous system (hormones used to transmit

signals)▫ Endocrine system (Chapter 11) (secretion of

hormones)

• Both systems can be manipulated by drug therapy which either mimics or blocks the usual action of the control system

• (That’s all pharmacology is! We either mimic or block a natural hormone response)

The Nervous System

• Central nervous system▫ Brain▫ Spinal cord

• Peripheral nervous system▫ Sensory neurons▫ Somatic neurons▫ Autonomic neurons * Do not control

Parasympathetic branch (Acetylcholine receptors/ rest and digest reactions)

Sympathetic branch (Epinephrine receptors/fight or flight reactions)

Central and Peripheral Nervous System

Figure 5-1 Functionaldiagramofcentralandperipheralnervoussystems,indicatingthesomaticbranches(sensory,motor)andtheautonomicbranches(sympathetic,parasympathetic),withtheirneurotransmitters.Ach,Acetylcholine;NE,norepinephrine.

afferent

somatic:heat, light, pressure, pain

:voluntary muscle control

Autonomic nervous system:involuntary control

Autonomic Nervous System

neuronsneurons

synapse

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Autonomic Nervous System

•Parasympathetic Stimulation▫Good specificity because postganglionic

fibers arise near the effector site.•Sympathetic Stimulation

▫Because fibers innervate the adrenal medulla when sympathetic activation occurs

there is a release of epinephrine into the bloodstream▫causing a widespread reaction in the body.

Parasympathetic and Sympathetic Regulation• Parasympathetic Nervous System

▫Essential to life▫Finely regulated (good specificity)▫Controls digestion, bladder, and rectal

function• Sympathetic Nervous System

▫General alarm system “Fight or flight” response

▫Not essential to life▫Increases HR and BP and causes blood flow

to shift from the periphery to the core

Neutotransmitters•Nerve impulses are transmitted by electrical

and chemical means (neurotransmitters)•Acetylcholine

▫Neuromuscular junction▫Ganglia▫Parasympathetic end sites▫Sweat glands▫Adrenal medulla

•Norepinephrine▫Sympathetic end sites

Everywhere, except

Neurotransmission

•Neuron: basic cell of the nervous system, provide instant method of cellular communication

•Don’t confuse nerve with neuron, nerve is a collection of neuron axon fibers

•The signals in nerves can run both ways▫Efferent (out)▫Afferent (in)

Neurotransmission•Hormones such as epinephrine and AcH are

stored in packets in the neuron; action potential causes these stored transmitters to release into organs, muscles…

•AcH: made by mitochondria as part of energy transfer (Kreb cycle) along with lecithin that contains choline.

• AcH is in the neuromuscular junction. Voluntary muscle movement, stimulated at nicotinic receptors to cause muscle contraction

Efferent and Afferent Nerve Fibers•Efferent: signals that are transmitted

from the brain and spinal cord▫Autonomic Nervous System

•Afferent: signals that are transmitted to the brain and spinal cord▫Chapter 7: drugs used to block

parasympathetic impulses

Example of Neurotransmission Error

•Myasthenia Gravis antibodies block the nicotinic receptors in the neuromuscular junction from getting AcH.

•AcH is also used by the autonomic nervous system in the control of

•Parasympathetic smooth muscle movement (lungs, heart). The receptor here is called muscarinic

Neurotransmission•AcH also found in the CNS, and

affect brain and spinal cord transmissions.

•Catecholamines (Dopamine, norepinephrine, epinephrine):

•Made from the amino acid tyrosine. Located in the autonomic nervous system signals sympathetic smooth muscle movement and organ is epinephrine and norepinephrine. The receptors are alpha and beta

Neurotransmission

•AcH esterase breaks down AcH in the synapse. (cholinesterase)

•So, if we block AcH esterase, we end up with more AcH in the synapse

•MG patients are on cholinesterase inhibitors

Terminology

•Sympathomimetic = Adrenergic•Sympatholytic = Antiadrenergic•Parasympathomimetic = Cholinergic•Parasympatholytic = Anticholinergic

Parasympathetic Branch•Cholinergic

Neurotransmitter Function

Ach is synthesized from

Catalyzed by

Ach is concentrate in the presynaptic neuron

Nerve Impulse

Calcium triggers the secretion of Ach

Ach attaches to receptors on the postsynaptic membrane and initiates an effect in the tissue or organ site

Inactivates Ach through hydrolysis

Parasympathetic Branch

•Parasympathetic effects on the cardiopulmonary system:▫Heart: slows rate (vagus)▫Bronchial smooth muscle: constriction▫Exocrine glands: increased secretion

•Drugs can be used to block or mimic action▫Parasympatholytics▫Parasympathomimetics

Parasympathetic Branch

•Muscarinic Effects▫Musacrine stimulates Ach receptors at the

parasympathetic terminal sites: Exocrine glands: lacrimal, salivary, bronchial

mucous glands Cardiac muscle Smooth muscle: gastrointestinal tract

▫Increase in airway secretions after the administration of Ach-like drugs

Parasympathetic Branch

•Subtypes of Muscarinic Receptors

Parasympathetic Branch

•Nicotinic Effects▫Nicotine stimulates Ach receptors at:

Autonomic ganglia Skeletal muscle sites

▫Effects: Increase in blood pressure Muscle tremor

Cholinergic Agents

•Cholinergic drugs mimic the action caused by Ach at the receptor sites in the parasympathetic system and neuromuscular junction

•A cholinergic drug can also activate muscarinic and nicotinic rceptors

▫Direct-Acting Cholinergic Agents▫Indirect-Acting Cholinergic Agents

Cholinergic Agents

•Direct acting▫ Mimic acetylcholine

Methacholine – diagnostic, asthma•Indirect acting

▫ Inhibit cholinesterase enzyme Neostigmine – reversal of nondepolarizing

muscle relaxants Tensilon – diagnostic, MG

Anticholinergic Agents• Block acetylcholine receptors

▫Parasympatholytic (antimuscarinic) effects Bronchodilation Preoperative drying of secretions Antidiarrheal agent Prevention of bed-wetting in children (increase

in urinary retention) Treatment of peptic ulcer Treatment of organophosphate poisoning Treatment of mushroom (Amanita muscaria)

ingestion Treatment of bradycardia

Sympathetic Branch

•Adrenergic neurotransmitter function

Is converted t0…

Is converted t0…

Is converted t0…

NE is stored in the presynaptic neuron

Nerve impulse

Calcium triggers the secretion of NE

NEattaches to receptors on the postsynaptic membrane and initiates an effect in the tissue or organ site

3 ways of inactivating NE

Sympathetic Branch

•Enzyme Inactivation▫Catecholamines: chemicals structurally

related to epinephrine▫Two enzymes inactivate catecholamines:

catechol O-methyltransferase (COMT) Monoamine oxidase (MAO)

▫Chapter 6

Sympathetic Branch

•Sympathetic effects on the cardiopulmonary system:▫Increased heart rate and contractile force▫Increased BP▫Bronchodilation

•Drugs can be used to block or mimic action▫Sympatholytics (antiadrenergic)▫Sympathomimetics (antiadrenergic)

Sympathetic Branch

•Sympathetic (Adrenergic) Receptor Types

Sympathetic Branch

•α and β Receptors

▫α receptors: Vasoconstriction

▫β1 receptors: Increase the rate and force of cardiac contraction

▫β2 receptors: Relax bronchial smooth muscle Chapter 6

Dopaminergic Receptors

•Because dopamine is chemically similar to epinephrine and stimulates α and β receptors, dopaminergic receptors are classified as a type of adrenergic receptor.

Receptors• Adrenergics:

▫ Beta 1 (heart, when stimulated cause contraction, increased HR)---Isoperternal, Epinephrine

▫ Beta 2 (lungs, when stimulated cause dilation)----Albuterol/Xopenex

▫ Alpha 1 (blood vessels/brain/kidney, when stimulated cause vessel constriction)—Racemic Epinephrine

▫ Alpha 2 (Sphincters, GI tract, inhibits insulin release; stimulation causes constriction)

Stimulated by neurotransmitter Epinephrine/ norepinephrine

*Stimulation of a receptor= agonist*Blocking of a receptor = antagonist

Receptors

•Cholinergic:▫ Nicotinic (found in the CNS and the peripheral nervous

system. The neuromuscular receptors are found in the neuromuscular junctions of somatic muscles; stimulation of these receptors causes muscular contraction)

• Blocked with Nicotinic acetylcholine receptors can be blocked by curare; used for anesthesia and mechainical ventilation▫ Muscarinic (found primarily in lung; G-protein-coupled

receptors that activate other ionic channels via a second messenger cascade. sub types; M1-M5)

▫ responds to the binding neurotransmitter acetylcholine

Airway Receptors• Adrenergic receptors

▫ Also known as sympathetic and

sympathomimetic receptors

▫ Sympatholytics = block response

▫ Stimulated by epinephrine or

norepinephrine

▫ Antiadrenergic drugs block receptors for

norepinephrine or epinephrine (usually to

slow the heart rate or decrease blood pressure)

Airway Receptors• Cholinergic receptors

▫ Also known as parasympathetic or

parasympathomimetic receptors

▫ Stimulated by acetylcholine

▫ Blocked by ant-cholingergics

▫ In airway anti-musacarinic (anti-cholinergic) =

bronchodilation

▫ Anti-nicotinics= neuromuscular paralysis

ACh • Airway smooth-muscle cells are innervated by postganglionic parasympathetic nerves. Acetylcholine (ACh) release from these nerves triggers the contraction of airway smooth muscles. This activity is predominantly mediated by smooth-muscle M3 receptors, but activation of postsynaptic M2 receptors is also likely to contribute to this response/ ACh also leads to the activation of pre-junctional M2 muscarinic Ach receptor (mAChR) autoreceptors, which mediate the inhibition of ACh release

• M2 receptive for cholinersterase (we block all M receptors, so also the “good” M2)

Adrenergic Receptors

•The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). 

Adrenergic Receptors• The mechanism of adrenergic receptors.

Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenergic receptors.

• Blood vessels: α1 couples to Gq, which results in increased intracellular Ca2+ which results in smooth muscle contraction. α2, on the other hand, couples to Gi, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle contraction.

• Heart/Lung: β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

Beta Receptors• Beta Receptors Beta receptors have been

further subdivided into beta1 and beta2

receptors.  • beta3 and beta4 receptors have recently been

isolated, cloned and characterized.  The beta3 receptor may be involved in regulating the metabolism of fatty acids.  This receptor could be the site of antiobesity drugs in the future.  The functions of the beta4 receptor remain to be discovered. 

• The classification of beta receptors is based on the interaction of a series of drugs with these receptors. 

Beta Receptors

•Beta Receptor Systems•Most tissues express multiple receptors. 

However, the receptor mainly utilized by the sympathetic nervous system to affect myocardial function in the normal heart is the beta1 receptor; while in vascular and nonvascular smooth muscle it is the beta2 receptor.