Nervous System Pharmacology

Principles of Pharmacology of the Autonomic & Somatic Nervous Systems

• The study notes cover the principles of pharmacology related to the autonomic and somatic nervous systems

• Learning objectives include anatomical and cellular components of the Autonomic Nervous System (ANS) & Somatic Nervous System (SNS)

• The key biochemical and cellular events during stimulation of autonomic or somatic nerve fibers are discussed

• Points of pharmacological intervention in neurotransmitter synthesis, release, receptor binding, and termination for acetylcholine and noradrenaline are summarized

• Subtypes of adrenergic and cholinergic receptors are to be discussed

• Identification of prototype drugs that mimic, stimulate, or block the synthesis, release, receptor binding, and removal of acetylcholine and noradrenaline at nerve terminals is a goal

• Hypothesizing integrated physiological responses to autonomic nervous system changes in homeostasis, with an emphasis on baroreceptor reflex response, is covered

• Strategies for pharmacological treatment of pathological situations involving the autonomic or somatic nervous systems are recommended

• Prediction of probable adverse responses from ganglionic blockade, nicotinic/muscarinic agonists/antagonists, adrenergic agonists, or uptake I inhibitors, are included

The Nervous System: A Review

• The nervous system's overall functions are integration and homeostasis

• Main divisions of the nervous system are the Central Nervous System (CNS) & Peripheral Nervous System (PNS)

• The CNS consists of the brain, brain stem, and spinal cord, and contains motor and sensory neurons

• Efferent fibers exit the CNS, while afferent fibers enter it

• The PNS originates from the hypothalamus, brain stem, & spinal cord

• PNS nerve endings are located outside the CNS

• The PNS is divided into the Somatic Nervous System and the Autonomic Nervous System

• In the ANS, one neuron leaves spinal cord and connects with a collection of nerve cells called a ganglion

• The first neuron to innervate with the ganglion is preganglionic nerve

• The neuron that leaves the ganglion and innervates the effector site is the postganglionic nerve ending

• In the somatic motor nervous system, the axon leaves the CNS but does not connect with a ganglion before innervating an effector cell

• Somatic motor nerves innervate skeletal muscle cells

• The ANS innervates smooth muscle, cardiac muscle, and exocrine glands

• The Somatic Nervous System is mainly under voluntary control

• The Autonomic Nervous System is mainly under reflex control

The Autonomic & Sympathetic Nervous System

The Autonomic system has two neuron chains: the sympathetic and parasympathetic

• The sympathetic division has cell bodies of preganglionic neurons in the thoracic and lumbar regions of the spinal cord
• Nerve fibers leave the spinal cord and enter the sympathetic ganglia
• Acetylcholine neurotransmitter is released between the pre and postganglionic neurons
• Noradrenaline neurotransmitter is released by postganglionic fibers at the effector organ
• The sympathetic nervous system has it's own Neurohormones from adrenal medulla
• Noradrenaline and adrenaline are released into circulation in response to sympathetic stimulus to produce a fight or flight response
• Neurohormones enable the sympathoadrenal system to discharge as a unit

The Parasympathetic ANS

• The parasympathetic nervous system has a ganglion near effector organ
• It contains long preganglionic neurons and short postganglionic neurons
• Postganglionic neurons are cholinergic
• It involves cranial and sacral nerves
• Acetylcholine(ACh) is the neurotransmitter released from all pre- and postganglionic parasympathetic fibers.
• Drugs can affect the biosynthesis, storage, release, and inactivation (hydrolysis) of ACh

Physiological functions controlled by the ANS

• Both the sympathetic and parasympathetic divisions help maintain homeostasis

• The ANS controls adjustment to stress and temperature changes

• It regulates the protection of eyes against bright light

• Urination, defecation, and digestion are also controlled by the ANS

• Other functions it controls include salivation, accommodation for near vision, and the balance of blood pressure at optimal levels

• It further regulates respiration

• For Parasympathetic NS: lower heart rate, lower B.P., secretions increase, eyes adjust eyes for light (miosis - constrict), emptying of bowel and bladder, and airways constrict

• "Rest and digest" responses are controlled by the Parasympathetic NS

• For Sympathetic NS: higher heart rate, higher B.P., secretions decrease, eyes adjust for dark (mydriasis - dilate), slow digestion, and airways open

• The Sympathetic NS controls "fight or flight" responses

Cholinergic Pharmacology

• Goals/objectives include understanding synthesis, storage, release, and hydrolysis of acetylcholine, and the effect of cholinergic agonists on tissues

• Understanding the drug structure, function and therapeutic properties of different acetylcholine receptors

• In biosynthesis of acetylcholine, the enzyme choline-O-acetyltransferase (ChAT) catalyses the reaction and exists in cytosol, surface of synaptic vesicles, and inner face of plasma membrane

• In storage, vesicles accumulate at nerve endings, and the greater part of neuronal ACh is stored in vesicles

• The vesicles also combine with membranes of nerve endings to discharge their content of ACh into the synaptic cleft

• In release, Ca2+ is essential to ACh release remains to be determined

• Drugs can chelate extracellular Ca2+ and prevent its influx can depress ACh release

• ACh is probably released from synaptic vesicles that are "docked" at plasma membrane

• After release from the nerve terminal, ACh diffuses across synaptic junction, and acts on a postjunctional receptor

• Activation of the post junctional receptor leads to physiological response

• In hydrolysis, ACh is degraded by the enzyme Acetylcholinesterase (AChE) to choline and acetate

• The choline from ACh hydrolysis is returned to prejunctional nerve terminal transport

• The acetate generated in the synaptic breakdown returns to nerve terminal, and forms the portion of the acetyl CoA used into the formation of ACh

• Factors increasing ACh synthesis & release include: hemicholinium, a- ketoacids, naphthoquinones, vesamicol, latrotoxin, botulinum toxin, calcium, physostigmine, atropine, d-Tubocurarine

• Hemicholinium blocks choline uptake, blocking ACH synthesis

• a-ketoacids, naphthoquinones directly inhibit ChAT

• Vesamicol blocks the transport of ACh into vesicles, so release of ACh is inhibited

• Latrotoxin causes an explosive release of ACh, causing muscular spasm

• Botulinum toxin binds to the neuron and interferes with trafficking proteins

Agents affecting Cholinergic Transmission

• Calcium is involved in the vesicular release as important components of vesicle fusion

• Physostigmine inhibits acetylcholinesterase and increasing ACh concentrations at the synaptic junction, increasing the effect on muscarinic and nicotinic receptors

• Atropine blocks muscarinic actions of ACh

• D-Tubocurarine blocks the nicotinic actions found primarily the endplate at the neuromuscular junction

• Cholinesterases are enzymes that interact with ACh

• There are two major types of autonomic receptors. Cholinoceptors respond to ACh, and adrenoceptors respond to Noradrenaline/norepinephrine (Adrenaline) and Dopamine

• Cholinergic receptors at organ cells are either nicotinic or muscarinic

• Two basic cholinergic receptor types are Nicotinic (N) and Muscarinic (M)

• ACh has both muscarinic and nicotinic activity

Nicotinic and Muscarinic Receptors

• Nicotinic Receptors have two subtypes: NN and NM

• NN subtype is found on the cell body of postganglionic autonomic neurons

• NM subtype is present at the endplate of the neuromuscular junction

• Hexamethonium blocks ACh action at the ganglia but not at the NMJ

• D-tubocurarine is more selective in blocking them at the NMJ

• Nicotinic receptors are ionotropic, and ligand gated, increasing permeability to Na+ and Ca2+ when activated

• They are located at neuromuscular junctions, the adrenal medulla, and autonomic ganglia

• Excess ACh or Nicotine at nicotinic receptors causes receptor desensitization

• Muscarinic receptors are activated by Acetylcholine endogenously and Muscarine exogenously, and blocked by atropine

• Smooth muscles, glands, and the heart are locations of Muscarinic receptors

• Subtypes include M1, M2, M3, M4, M5

• M1 receptor type - autonomic ganglia, CNS

• M2 receptor type - cardiac

• M3 receptor type - peripheral glandular tissue, e.g. pancreas and smooth muscles

• G-protein induced changes in membrane bound effector Activation of muscarinic receptors activates G-protein to stimulation of phospholipase C or adenylyl cyclase with activation of K+ channels

Cholinergic Drugs

• Drugs mimic the effect of ACh, and so are known as cholinergic agonists or muscarinic stimulants for initiating a cholinergic response
• Cholinomimetics and Parasympathomimetics mimic the sympathetic nervous system as a cholinergic response
• Many cholinergic drugs are nonselective
• Cholinergic drugs: mimic effects of stimulation the parasympathetic system, act on receptors activated by ACh, and/or inhibit of acetylcholine breakdown
• Cholinergic drugs can be Direct-Acting or Indirectacting
• Direct-Acting cholinergic drugs include: ACh, synthetic esters of choline, and naturally occurring alkaloids
• Synthetic esters of choline: bethanechol carbachol, and methacholine
• Naturally occurring alkaloids: pilocarpine
• Cholinergic agonists biosynthesized and released by neurons
• Cholinergic agonists bind to postjunctional receptors, producing their effects and are broken down by cholinesterase

Acetylcholine Analogs

• Positively charged quaternary nitrogen N+ is centered on the cationic head.
• It fits into a depression in receptor surface that stimulates
• Ester group in ACh is substrate for cholinesterase, so ACh breaks down quickly in vivo
• Methacholine is synthetic parasympathomimetic, more stable to hydrolysis, is virtually immune to AChE, has a longer duration of action, and is specific to muscarinic receptors.
•  Carbachol is synthetic, immune to hydrolysis by both AChE and pseudocholinesterase, more potent than acetylcholine, has a longer duration of action, administered orally, and most active nicotinic drug among the commonly used parasympathomimetics.
• Bethanechol has reduced nicotinic potency, is immune to hydrolysis by AChE, and is long-acting muscarinic stimulant that is almost devoid of nicotinic activity
• Pilocarpine is a naturally occurring alkaloids, which accounts for the muscarinic activity, stimulates gland tissue e.g. sweat and salivary glands
• Muscarine, found in mushrooms, mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands

Physiological Responses to Cholinergic Drugs

• On the heart, they cause bradycardia with M₂-receptor-mediated increase in potassium currents
• On the GI tract, they increase acid secretion, tone, contraction amplitude, and peristalsis
• On the urinary tract, they can cause coordinated bladder evacuation by contraction of the detrusor muscle and relaxation of the sphincter
• On glands, muscarinic stimulation increases lachrymal glands in the eye, bronchial secretory glands, salivary glands (parotid etc.), pancreas, and sweat glands
• Muscarinic stimulation constricts the pupil & and thickens the ocular lens
• Muscarinic drugs cause smooth muscle contraction of the the bronchial smooth muscle
• They lead to relaxation in blood vessels from endothelial cells releasing NO and diffusing it to activate the smooth muscle
• Muscuranic agonists cause cortical arousal in CNS

Pharmacokinetics of Cholinergic Drugs

• Quaternary choline esters are poorly absorbed & administered parenterally, preferrably subcutaneously

• Pilocarpine is much better absorbed and administered topically

• As predicted, pilocarpine will reach the CNS while the quaternary choline esters have no CNS penetration

• Acetylcholine is cleared within minutes while carbamylcholine & bethanechol clear slower, and Pilocarpine has similar kinetics.

• Muscarinic agonist ophthalmic uses are the most significant

• Actions are important for understanding antagonists & over activity of parasympathetic processes

• Muscarinic agents are useful in cases of: Glaucoma, Gastric atony/Paralytic ileus, Bladder dysfunction and Xerostomia

• ACh is used intravenously for paroxysmal tachycardia at 20-200mg

• ACh is used topically for treatment of acute glaucoma as a miotic treatment

• Acetylcholine and 5% mannitol can be used constrict pupil in cornea grafting operations

• Amechol (provocholineTM drug) is used for its cardio vascular use, with restricted applications

• The use of constricted blood vessels, vasospastic conditions and xerostomia are the main uses cases of amechel

• To be effective it must use through a process known as iontophoresis or use very strong doses

• Bethanechol can be used for Functional gastric retention, Abdominal distension, and Post operative urinary retention, and Xerostomia

• Carbachol is used for effects in stimulating the intestine and bladder orally.

• Carbochol post-operative intestinal atony, urine retention, simple glaucoma, and tachycardia

• Pilocarpine for glaucoma and Xerostomia in order to achieve eye and muscle movement

Contraindications, Side Effects and Drug Interactions of Colhergic Drugs

• Contraindications are: Asthma, Coronary Insufficiency, Peptic Ulcer, Organic Obstruction, Hyperthyroidism
• Side effects are hypotension and bradycardia are common from systemic administration
• Flush, sweat, and abdominal cramps are regular side-effects
• Drug interactions will occur with cholinesterase inhibitors

AntiCholinergic Drugs

• Cholinoceptor antagonists are grouped by their blocking spectrum
• The antagonists are sorted into muscarinic or nicotinic binding
• Anticholinergic drugs are sorted into Antimuscarinic and Antinicotinic types
• Antimuscarinic are either M-selective or Nonselective types
• Antinicotinic are either Ganglion Blockers or Neuromuscular Blockers

Antimuscarinic Drugs

• Antimuscarinic drugs selectively antagonise (block) by either ACh or any other drug that stimulates ACh receptors of the muscarinic type
• The nicotinic actions of acetylcholine are blockable by antimuscarinic drugs
• Muscarinic receptor blockade does not interfere with transmission at autonomic, ganglionic, adrenal sites
• Sympathetic adrenergic functions are not affected
• Muscarinic receptors can act in in dual innervated organs and allow for the sympathetic receptors to dominate
• Antimuscarinics are selective for muscarinic receptors and do donít affect nicotinic or adrenergic receptors
• Antimuscarinics exhibit competitive blockage, and can be overcome by higher agonist(ACh) doses

Pharmacological Actions of Anti-Muscarinics

• Effects: Antagonistic to physiology of the PNS, and to the muscarinic agonists

• They inhibit acetylcholine by binding to muscarinic receptors

• Since they block Parasympathetic nerves, they allow the sympathetic nervous system to dominate.

• Since they both increase sympathetic actions, anticholinergic drugs can have similar responses to adrenergic drugs

• Salivary Glands: Anti-muscarinics inhibit salivation

• Cardiovascular System: Anti-muscarinics reverse vagal tone and accelerates heart rate

• Gastro Intestinal Tract: motility, acid secretion

• Urinary Tract: Anti-muscarinics effect micturition, cause urinary retention at high doses

• Ocular: Antimuscarinics cause pupil dilation and paralysis of accommodation

• Sweat Glands: Anti-muscarinics inhibit sweating.

• CNS: Agitation and Hallucinations

• Antimuscarinic drugs found in Atropa Belladonna, Datura Stamonium, and Hyocyamus Niger

Pharmacokinetics of Atropine & Other Tertiary Amines

• Readily absorbed orally and through mucosa and they can penetrate the blood-brain barrier easily.
• Half life approximately 4 hours
• Local effect lasts up to 7 days.
• Shorter agents (Tropicamide, Mydriacyl) are used in diagnostic.
• Charged molecules are more polar and less to penetrate lipid barriers such as BBB, and cornea
• Approximately 10-30% absorption rate.
• Their antisecratory and antispastic qualities are used for Ipratropium (ATROVENT), and Propantheline

Clinical indications (Antimuscarinics)

• Antimuscarics are implemented in for premedication, and for slowing heart rate and heart attack chances.
• Antimuscarics are utilized in cases of:
• Ophthalmologic diagnostic dilation
• GI hypermotility syndromes, Peptic Ulcers
• Parkinson's Disease. In treating maniac states such as alcohol use disorder, scopolamine is preferred. Motion Sickness

Side effects and adverse reactions

• Dry mouth, skin, decrease in perspirations is the hallmark of anticholinergic usage
• Blurred vision, Tachycardia, Constipation, Urinary retention and Seizures can also result
• Seizures and delirium may come as a result
• One might think opposite of the mneumonic DUMBBELS, for a way to remember adverse effects
• Peripheral Symptoms of Cholinergic Toxicity are dry skin, and no secretions
• 'Blind As a Hat'- cycloplegia, pupillary dilation, blindness ·
  -Central Symptoms are hallucinations, and a high fever -Treatment include symptomatic care and physostigmine, but no antipyretic
• Glacoma and prostrate hypertrophy are key contradictions

Indirect-Acting Cholinesterase Inhibitors

• Drug type prevent that hydrolysis ACh by cholinesterase, and forms competing compounds

• Inhibit acetylcholinesterase, transmission for cholinergic synapses increases and modifies at sites, resulting a higher load of acetylcholine that binds

• They influence autonomic ganglia, nerve endings and CNS synapses.

• Anticholinesterases delay destruction of ACh within synaptic cleft, stimulating neurotransmission more

• Cholinesterase inhibitors(reversible) consist of Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, Ambenonium, and Distigmine.

• Cholinesterase inhibitors ( irreversible-organophophates), consist of Echothiophate and Di-isopropylfluorophosphate (DFP)

Pharmacological Actions of Anit-Cholinesterases

• anticholinesterases act like the combination of nicotinic and muscarinic stimulation
• Muscarinic results is massive parasympathetic activation, described as DUMBBELSS syndrome
• Nicotonic Effects from Nicotonic effects complex that may initially show stimulation activation with tremors, that turn to paralysis death is primarily through respiratory paralysis.

Therapeutics from Anit-Cholinesterases

• Paralytic ileus, Glacoma, and Alzehimers, are used to in some capacity

• Physostigmine and pyridostigmine preferred for Myasthenia gravis,

• Autoimmune disorder that affects ACh , More commen in women and the results in double vision

• Drug called steroids reduce the antibodies that bind to ACh receptor

• Irreversible anticholinesterase are mainly sourced from organic compounds and pentavalent phosphorus.

• The organic compound of R1R2, and chlorine-fluorine or iodine organohosphorus anti-ChEs or phosphostigmines can also come an irreversible compounds too

• However, they interact stronger with the ester sites for enzymes, due a reason it cannot react with cationic areas

• Molecule will then split an inhibitor from organophosphorus, which removes the phosphoryl group in month

• High toxicity by potency, they easily penetrate CNS and are absorbed by the skin.

USES

• They create an accumulated Ach, which is useful to treat glaucoma and increase toxicity

• These cause hyper reaction within in nictonic for paralyzing function and death and Muscarinic in nervous system, also causing death

• Pralidoxime has been used as as an inhibitor and optimally reactivate within the ring by adding a oxime to the complex.

• treatment essential so inhibit the complex effectively.

• antidode can only take care symptoms of organophsphourus

Nicotonic Phamcology

• Ganglion stimulants & blockers, describe transmission
• Roles of receptors in ganglia.
• Toxicity.
• Domination of the other division.
• Affect autonomic activities.

Gangilionic & Other Stimulants

• Have to useful treatment purposes but are pharmacological stimulant

• Akeyloid is obtain in a nicotinic agonist and partial

• Nicotine found in adrenal medulla and CNS stimulate junction-cause Emesis and effect blood pressure release ADH

• Respiratory and Muscular interaction by releasing the chemical

• Affect nicotinic receptors ,the blockade

• Vary interaction is antagonistic and analyzed

• A TMA stimulant and DMPP

Gangilionic Blockers, and Cardiac Output of Hexomethium

• These are used for hypertension uses where placed and pharmacology These create blockade in ganglions to prevent heart complications with sympathic nerve These are a main factor for the net effect .

• Hypotentions and a decreased BPM -Variable for a Cardiac output are there but venous return is cut

• The is blockage because the blood presser is high

• If an initial rates is high, The higher ,so be reduce -There some secretion blocked

• Sexual stimulation or urination may be effected

• The ganglionic activity • Aversion too • Are some of effect too to slow down the muscuric • Trimethophan some blockers are that stop the cycle as well .

Neuro junction.

• Blocking a new muscular.

• The new blocker can't touch general functions because of the general nature . of a patient like cardiac and ventilator • These cause many muscle problems within in the diaphragm due to high • The treatment with of this will need ventilation system due

• The depolarizing cause contraction to the muscle

• Quickly are the stimulation with Ach due to depolarization persistent

  Effects are not able to restore Muscle is the function from blood cell and

• There can damage of blood level in cell

• After that if and Atropine.

  They can lead over code of the code with or high use if a diaphragm.

• The cause of this of the body.

• It's recommend to take over to test or code the use but the side effect of the usage need to take to the full care or control

• The inj will take 4min before active and a gangoline blocking.

• the hypotenion take longer to release the histamine for peripheral effects.

DRUG

D-tubocaranine (d-rc)

• These use effect and only to those
• To is also break from that, and if use must used in combination to block

Drug interaction

• Anesthetic interaction
• Aminoglycoside interaction

Contradictions

• asthma succinylochloride
• Narrow angle with succinylochloride to Hyperthyroidism

distinctions

• Day old Chicken are with results some of and
• Code is by blocking functions

Final caution

• Code for any who do not have use if someone
• average nurses is also a code

Explore the distinctions between the somatic and autonomic nervous systems, delve into the effects of drugs on neurotransmitters like acetylcholine. Also study adrenergic receptors and the baroreceptor reflex. Discover appropriate drug strategies for treating conditions like asthma and myasthenia gravis.