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
cran
iosa
cralth
ora
colu
mb
ar
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.
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