Clinical Pharmacology notes:Drugs acting on the autonomic nervous syste mby drmonda edited by jennings argwings

UNIT 1: AUTONOMIC NERVOUS SYSTEM
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CMS 252 PHARMACOLOGY & THERAPEUTICS
Lecturer: Dr. Monda J.M.N.
Department of Clinical Medicine
April-May 2014
Pharmacology & Therapeutics II
Unit 1: Drugs Acting on the Autonomic Nervous System
UNIT 1 OUTLINE
1. Introduction to Pharmacology of the Autonomic Nervous System
2. Cholinergic/Cholinomimetics/Cholinergic stimulants/Parasympathomimetics and Anti- Cholinergic/Cholinergic antagonists/Parasympatholytics
3. Antimuscarinic (Parasympatholitics) and Antinicotinic agents
4. Sympathomimetics and Sympatholytics
5. Autacoids, Ergot Alkaloids and Eiconsanoids
Lesson 1: Review – Anatomy and Physiology
Leaning Outcomes
At the end of the lesson, the learner should be able to -
1. Outline the structure of the autonomic nervous system
2. Explain the process of neurohormonal transmission
3. Describe the neurotransmitters and receptors in ANS
4. Classify drugs acting on the autonomic nervous system
1.0 INTRODUCTION
Autonomic nervous system has autonomic afferents and efferents and central connections. The autonomic afferents mediate visceral pain as well as cardiovascular, respiratory and other visceral reflexes through afferent fibres of cranial nerves such as the vagus nerve. The central connections are found mainly in the hypothalamus (anterior and posterior) and the mid brain and medulla where a number of cranial nerves originate.
The autonomic efferents which form the motor limb of the ANS are anatomically divided into sympathetic and parasympathetic potions that are functionally antagonistic with most organs receiving both sympathetic and parasympathetic. Most blood vessels, spleen, sweat glands and hair follicles receive only sympathetic while ciliary muscle, gastric and pancreatic glands receive only parasympathetic innervation.
2.0 ANATOMY AND PHYSIOLOGY

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The autonomic nervous system (ANS) is a division of the efferent (motor) portion of the peripheral nervous system (PNS). The other division of the motor system is called the somatic. The ANS is largely autonomous (independent) in its activities as it is not under direct conscious control. It consists of afferent, centre and efferent connections. The ANS carries efferent neurones to the autonomic or visceral receptors in visceral organs.
Diagram 1.1: Autonomic Nervous System
Plan of ANS
The ANS regulates function of cardiac muscle, smooth muscles and glands. The ANS has two divisions – the sympathetic and parasympathetic divisions both which consist of separate neural pathways supplying the same autonomic effectors where there is dual innervation but

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their actions are antagonistic. This dual innervation is well controlled and allows innervated receptors to participate in events requiring rapid alteration of innervation such as sexual responses.
Diagram 1.2: Plan of Autonomic Nervous System
Neurotransmitters and Receptors
The ANS has chemical transmitters and receptors, which facilitate transmission and reception of impulses respectively.
3.0 STRUCTURE AND DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system has two divisions – the sympathetic (thoraco-lumbar) system and the parasympathetic (cranio-sacral) system. Each autonomic pathway is made up of autonomic nerves, ganglia and plexuses consisting of autonomic neurones. All autonomic neurones are efferent (motor) conducting impulses away from the brain and spinal cord to the autonomic effectors.
Autonomic nervous system operates as a relay of two neurones – pre-ganglionic and postganglionic neurones. The sympathetic system has relatively short pre-ganglionic and relatively long post-ganglionic neurones. The axon of one synaptic pre-ganglionic neurone synapses with many post-ganglionic neurones and that is why sympathetic responses are wide spread.
Diagram 1.3: Sympathetic Nervous System Neurone

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The parasympathetic division has relatively long pre-ganglionic and relatively short postganglionic neurones. The neurones arise from the cranial and sacral regions of the spinal cord. Axons of many pre-ganglionic neurones synapse with one post-ganglionic neurone and hence parasympathetic effects involve only one organ.
Diagram 1.4: Parasympathetic Nervous System Neurone

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4.0 NEUROHUMORAL TRANSMISSION
Neurohumoral transmission refers to the process of neural transmission of messages across synapses and neuroeffector junctions by the humoral (chemical) messengers.
Steps in neurohumoral transmission
1) Impulse conduction
2) Transmitter release
3) Transmitter action on post junctional membrane
4) Post junctional activity
5) Termination of transmitter action
5.0 AUTONOMIC NEUROTRANSMITTERS
Axon terminals of autonomic neurones synthesize and release either norepinephrine (noradrenaline) or acetylcholine neurotransmitters which act as chemical transmitters at their various synaptic junctions. Axons that release norepinephrine are called adrenergic fibres and those that release acetylcholine are called cholinergic fibres.
Almost all efferent fibres leaving the central nervous system, most parasympathetic postganglionic and few sympathetic post-ganglionic fibres are cholinergic while most sympathetic post-ganglionic fibres are adrenergic fibres.
Diagram 1.5: Neurotransmitters in the Autonomic Nervous System
6.0 CHOLINERGIC TRANSMISSION
Introduction

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Terminals of cholinergic neurones have large vesicles containing acetylcholine (Ach), a chemotransmitter at various sites in the body mediating many physiological functions. Acetylcholine is synthesized from choline and acetate and stored in the vesicles.
Its release depends on extracellular calcium and occurs when an action potential reaches the terminal and triggers sufficient influx of calcium ions. Calcium destabilizes the storage vesicles by interfering with special proteins on the vesicular membrane called vesicular associated membrane proteins (VAMPs) and synaptosome associated proteins (SNAPs)
Acetylcholine binds to active acetylcholine receptors – cholinoceptors where it will be spilt into choline and acetate by acetylcholinesterase (AchE) present in most cholinergic synapses. AchE is also present in other tissues such as red blood cells.
Acetylcholine is primarily a chemotransmitter at the ANS ganglia, somatic neuromuscular junction and parasympathetic postganglionic nerve endings. It is a primary excitatory transmitter to smooth muscle and secretory cells in the enteric nervous system.
Neurotransmitters – Acetylcholine (Ach)
Acetylcholine is a major neurohormonal transmitter at the autonomic and somatic sites. It is synthesized locally in cholinergic nerve ending from choline and acetate in energy dependent enzyme driven reactions.
Choline is actively taken up by the axonal membrane and acetylated with the help of ATP and coenzyme A under influence by enzyme cholineacetylase present in the axoplasm. Release of Ach from nerve terminals occurs in small amounts from vesicles where it is extracted by exocytosis.
Two toxins interfere with cholinergic transmission by affecting its release. Botulinus toxin inhibits release and black widow spider toxin induces massive release and depletion. Ach is hydrolysed by enzyme cholinesterase immediately after release producing choline and acetate. Choline is recycled.
Diagram 1.6: Acetylcholine Transmission

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Cholinoceptors
There are two types of cholinoceptors namely muscarinic (M1, M2 and M3) receptors and nicotinic (NN and NM) receptors.
Table 1.1: Cholinoceptors Cholinoceptor Sites Action M1 o NS neurones, Postganglionic neurones o Some presynaptic sites, Gastric glands Increase intracellular Ca M2 o Myocardium – SAN, AVN, atria and ventricles, Smooth muscles, Some presynaptic sites Increase intracellular Ca M3 o Exocrine glands, Visceral smooth muscle o Blood vessels (smooth muscle and endothelium Increase intracellular NN o Postganglionic neurones, Adrenal medulla o Some parasympathetic cholinergic terminals Open Na/K channels NM o Skeletal muscle neuromuscular end plates Open Na/K channels
Table 1.2: Characteristics of Some Important Cholinoceptors in the Peripheral Nervous System Recceptor Location Mechanism Major Functions M1 o Nerve endings, Gq coupled IP3, DAG cascade M2 o |Heart and some nerve endings Gi coupled camp, activates K+ channels M3 o Effector cells – smooth muscles, glands, endothelium Gq coupled IP3 DAG cascade NN o ANS ganglia Ion channel Depokinases, evokes action potential NM o Neuromuscular end Ion channel As for NN

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plate
IP3 – inositol 1,4,5 triphosphate
7.0 NORADRENERGIC TRANSMISSION
Terminals of adrenergic fibres have vesicles containing norepinephrine (noradrenaline) which acts as a chemotransmitter at the synaptic junctions. Release of norepinephrine is similar to that of acetylcholine.
Norepinephrine (noradrenaline) which is synthesised from dopamine is the chemotransmitter in most sympathetic postganglionic neurones. The adrenal medulla and brain, norepinephrine (noradrenaline) is converted to epinephrine (adrenaline). Norepinephrine binds to receptors called adrenoceptors found in various target organs.
Actions of norepinephrine are terminated by being broken down in 2 ways – most of the norepinephrine is taken up by the synaptic knobs of the postganglionic nerve and broken down by an enzyme monoamine oxidase (MAO) while the remaining is broken down by the enzyme catechol-O-methyl transferase (COMT). Norepinephrine is primarily a transmitter at most sympathetic postganglionic nerve fibre.
Neurotransmitters
Adrenergic transmission is restricted to the sympathetic division of the autonomic nervous system. It is mediated by three closely related endogenous catecholamines namely adrenaline, noradrenaline and dopamine. The catecholamines are synthesized from amino acid phenylalanine.
Phenylalanine Tyrosine DOPA Dopamine Noradrenaline Adrenaline
Adrenaline
Adrenaline is secreted by the adrenal medulla and may have transmitter role in the brain.
Noradrenaline
Noradrenaline acts as a transmitter at post-ganglionic sympathetic sites except sweat glands, hair follicles and some blood vessels and in certain brain areas.
Dopamine
Dopamine is a major transmitter in the basal ganglia, limbic system and anterior pituitary gland.
Diagram 1.7: Norepinephrine Transmission

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Adrenoceptors
There are two types of adrenoceptors alpha, 1 and 2) adrenoceptors and beta and 3) adrenoceptors.
Table 1.3: Adrenoceptors Receptor Site Action  Postsynaptic effector cells especially smooth muscle Increase intracellular Ca, causes contraction and secretion  Presynaptic adrenergic nerve terminals, Nerve terminals, Smooth muscle Reduce cAMP, causes contraction  Postsynaptic effector cells – Heart, Brain, Presynaptic adrenergic fibres, Cholinergic nerve terminals Stimulate cAMP and adenylyl cyclase, Heart rate, force and rennin release  Postsynaptic effector cells especially smooth and cardiac muscle Stimulate cAMP and adenylyl cyclase, relax smooth muscle, glycogenolysis, heart rate, force  Post synaptic effector cells, adipose cells lipolysis D1 Smooth muscle cAMP, relax renal vascular smooth muscle

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Table 1.4: Characteristics of Some Important Adrenoceptors in ANS Receptor Location G- Protein 2nd Messenger Major Function  Effector tissue, smooth muscle, glands Gq IP3, DAG Ca2+, causes contraction, secretion  Nerve endings, some smooth muscles Gi cAMP transmitter release, cause contraction  Cardiac muscle, juxtaglomerular apparatus Gs cAMP heart rate, force and rennin release  Smooth muscle, liver, heart Gs cAMP Relax smooth muscle, glycogenesis, heart rate, force  Adipose cells Gs cAMP lipolysis D1 Gs cAMP Relax renal vascular sooth muscle
8.0 CLASSIFICATION OF ANS DRUGS
1. Cholinergic stimulants (cholinomimetics)
a. Direct acting cholinomimetics - Choline esters and Alkaloids
b. Indirect acting cholinomimetics
i. Cholinesterase inhibitors (anticholinesterases) – physiostigmine & neostigmine
2. Anti-cholinergics (Cholinoceptor blockers)
a. Antimuscarinic agents - Atropine
b. Antinicotinic agents - Ganglion blockers and Neuromuscular blockers
3. Adrenoceptor stimulant or agonists (Sympathomimetics)
a. Alpha and beta agonists
b. Alpha agonists
c. Selective alpha agonists
d. Beta agonists
e. Selective beta agonists
4. Adrenoceptor antagonists (Adrenoceptor blockers)
a. Alpha and beta blockers
b. Alpha blockers
c. Beta blockers

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Table 1.5: Effects of Autonomic Nerve Activity Organ Sympathetic Parasympathetic Action Receptor Action Receptor Eye Iris radial muscle Contracts  …………. …………. Iris circular muscle …………….  Contracts M3 Ciliary muscle Relaxes  Contracts M3 Heart Sinoatrial node Accelerates  Decelerates M2 Ectopic pacemakers Accelerates  ……………… ……… Contractility Increases  Decreases (atria) ……… Blood vessels Skin, splanchic vessels Contracts  ………………. ……... Skeletal muscle vessels Relaxes  ……………….. ……… Relaxes  Endothelium ……………  Releases EDRF M3 Bronchial smooth muscle Relaxes  Contracts M3 GIT Smooth muscle walls Relaxes  Contracts M3 Sphincters Contracts  Relaxes M3 Secretion ……………  Increases M3 Mysenteric plexus Activates M1 GUT smooth muscle Bladder wall Relaxes  Contracts M3 Sphincter Contacts  Relaxes M3 Uterus, pregnant Relaxes  ……………… ……… Contracts  Contracts M3 Penis, seminal vesicles Ejaculation  Erection M Skin Pilomotor smooth muscle Contracts  …………….. ……….. Sweat glands - thermoregulatory Increases  Sweat glands – apocrine (stress) Increases  Metabolic functions Liver Gluconeogenesis  Liver Glycogenolysis  Fat cells Lipolysis  Kidney Renin release  Autonomic nerve endings Sympathetic ………………  Decreases NE release M Parasympathetic Decreases Ach release  ………………… …………

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Lesson 2: Cholinergic Stimulants (Cholinomimetics)
And Antagonists (Blockers)
Learning Outcomes
1) Classify cholinergic and anticholinergic agents
2) Describe the pharmacology of cholinergic and anticholinergic agents
3) Outline the indications of cholinergic and anticholinergic agents
4) Outline the side effects of cholinergic and anticholinergic agents
1.0 INTRODUCTION
Acetylcholine acts as a chemotransmitter at various sites mediating many physiological effects cholinomimetic drugs act on the muscarinic and nicotinic acetylcholine receptors (cholinoceptors) at all sites in the body where acetylcholine is the neurotransmitter chemical. Cholinomimetic drugs include acetylcholine receptor stimulants (agonists) and cholinesterase inhibitors.
Cholinomimetics are drugs whose action is similar to the action of acetylcholine (Ach) at the receptors (muscarinic and cholinergic). The difference is in the pharmacodynamics due to lipid solubility. The distribution of acetylcholine is that it is the neurotransmitter for the parasympathetic system at the autonomic ganglia, skeletal muscles and anatomically the sympathetic. Acetylcholine can also act as autacoids. The cholinergic receptors in the blood vessels have diffuse effect. Acetylcholine can also be found in the placenta.
1.0 CLASSIFICATION
Cholinomimetic agents can be classified as: -
1. Direct acting cholinomimetics which act on nicotinic and muscarinic receptors
a. Choline esters – Acetylcholine, Methacholine, Carbachol, Bethanechol
b. Alkaloids – Muscarine, Pilocarpus, Lobeline, Avecoline
2. Indirect acting cholinomimetics that act by inhibiting acetylcholinesterase
a. Carbamates – Neostigmine, Physiostigmine
b. Organophosphates - Echothiophate, insecticides, Echophomium
NOTE:
Acetylcholine cannot be used as a drug because its effects are short and diffuse (receptors are in many parts of the body) and most of it will be destroyed by cholinesterases including pseudocholinesterases in plasma. For the indirect acting cholinomimetcis, their effects are reversible or effects are surmountable especially for the carbamates (neostigmine and physiostigmine) and the effects can be irreversible especially for organophosphates, insecticides and echothiophate.

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Table 1: Comparison of Effects of Various Drugs Drug Cholinesterase susceptibility Muscarine Nicotine Acetylcholine ++++ +++ +++ Methacholine + +++ None Carbachol Negligible ++ +++ Bethanichol Negligible ++ None
Carbachol has both muscarinic and nicotinic activity but the difference is in the penetration. Muscarinic receptors are concentrated in the heart, smooth muscle, glandular tissue and eye. Parasympathetic system predominates in the eye and heart therefore, the effects are more pronounced in the heart and eyes.
Table 2: Effects of Drugs on Various Body Systems Drug CVS GIT GUT Eye Atropine Acetylcholine ++ ++ ++ + ++ Methacholine ++ ++ ++ + +++ Carbachol + +++ +++ ++ ++ Bethanichol +++ +++ ++ +++ Pilocarpine + +++ +++ ++ +++
2.0 SITES OF ACTION
The sites of action of cholinomimetics include -
1. Autonomic nervous system
a. Parasympathetic system - ganglia and all postganglionic endings
b. Sympathetic system – ganglia and few postganglionic endings e.g. sweat glands
2. Neuromuscular junctions
3. Central nervous system
4. Blood vessels – arterioles
5. Adrenal medulla
3.0 MODE OF ACTION
The direct acting cholinomimetic agents directly bind to and activate muscarinic or nicotinic receptors. The indirect acting agents inhibit acetylcholinesterase, which breaks down acetylcholine into choline and acetic acid through the process of hydrolysis. This prevents degeneration of acetylcholine and hence increases the concentration of endogenous acetylcholine in synaptic clefts and neuromuscular junctions. The excess acetylcholine stimulates the cholinoceptors to evoke increased responses resulting in amplified activities.
4.0 PHARMACOLOGY OF DIRECT ACTING CHOLINOMIMETICS
Cholinomimetics are divided into two main groups namely the choline esters (acetylcholine) and alkaloids (muscarine and nicotine) based on their chemical structures.

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5.0 CHOLINE ESTERS
Pharmacokinetics
Choline esters are poorly absorbed and poorly distributed in the CNS because they are hydrophilic hence their durations of action is usually prolonged. Choline esters are usually excreted through the kidney with excretion being accelerated by acidification of urine
Mechanism of Action
Choline esters are agonist at muscarinic receptors, which leads to initiation of physiological effect. The difference in effect is at the 2nd messenger transduction system. M2 leads to hyperpolarisation (in the heart), M1, M3, M4 and M5 leads to depolarization. Muscarinic receptors are grouped M1 - 12 . Muscarines are lipid-soluble agents well absorbed across the skin but poorly absorbed from the GIT.
Activation of the parasympathetic nervous system influences organ function by activating the muscarinic receptors or inhibiting neurotransmitter release by the muscarinic receptors. Muscarinic stimulants increase intracellular calcium, cellular cAMP concentration and potassium flux across cardiac cell membranes and reduce it in ganglion and smooth muscle cells.
Muscarinic effect on cAMP generation causes a reduction in physiologic response of organs to stimulatory hormones such as catecholamines. It can inhibit acetylyl cyclase in some tissues such as the heart and intestines. Nicotinic receptor stimulation causes depolarization of nerve cell or neuromuscular end plate membrane through opening of Na/K channels.
Effects on organ systems
Effects of muscarinic and nicotinic cholinoceptor stimulants are easily predictable in organs where the receptors are distributed.
1. The Eye
 Muscarinic agonists cause contraction of smooth muscle of the iris sphincter resulting in miosis and contraction of the ciliary muscle causing accommodation for near vision.
 Reduce intraocular pressure by causing dilatation of blood vessels within the eye and effect of contraction of iris and ciliary muscles. Contraction of iris pulls it away from the angle of the anterior chamber and contraction of ciliary muscle opens the trabecular meshwork facilitating outflow of aqueous humour into the canal of Schlemm and into the anterior chamber
2. Cardiovascular system
 Muscarinic agonists reduce peripheral vascular resistance and heart rate (bradycardia) and refractory period (negative inotropic) but these effects are

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modified by homeostatic reflexes. The effect is mainly on SAN and Atria with minimal effect on the ventricles
 Direct actions of muscarinic stimulants include: -
o Increase potassium flow in atrial muscle cell, SAN and AVN cells
o Decrease the slow inward flow of calcium
o Reduce hyperpolarization
3. Respiratory system
 Muscarinic stimulants contract bronchial smooth muscle and stimulate secretion by glands of the tracheobronchial mucosa.
4. Gastro-intestinal tract
 Muscarinic stimulation increases exocrine secretory and motor activity of the gut. Gastric and salivary glands are strongly activated whereas the pancreas and small intestine are stimulated mildly.
 Peristalsis is increased throughout the gut and most sphincters are relaxed. May be accompanied by colicky pain
5. Genito-urinary tract
 Muscarinic agonists stimulate detrussor muscle and relax the trigone and sphincter muscles of the bladder hence promote Micturation.
 Uterus is not sensitive to muscarinic agonists
6. Secretory glands
 Muscarinic agonists stimulate secretion of thermoregulatory sweat, lacrimal and nasopharyngeal glands
 The CNS has both muscarinic and nicotinic receptors. The brain is rich in muscarinic receptors and the spinal cord is rich in nicotinic receptors.
 Muscarinic – tremors, hypothermia, reduced appetite
 Nicotinic – emesis, tachypnoea, convulsions and alertness.
8. Peripheral nervous system
 Nicotinic stimulation initiates action potentials in postganglionic neurones of both sympathetic and parasympathetic neurones in various tissues.
o Has sympathetic effects on the heart
o Has parasympathetic effects on the GIT – nausea, vomiting, diarrhoea
o Increases micturation
 Nicotinic receptors are present on sensory nerve endings especially afferent nerves in coronary arteries, carotid bodies and aortic bodies
9. Neuromuscular junction
 Nicotinic stimulation causes muscle fasciculation flowed by neuromuscular block (in excess concentrations)

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Table 4: Effects of Direct Acting Cholinomimetics Organ Response Eye Sphincter muscle of iris o Contraction (miosis) Ciliary muscle o Contraction for near vision Heart Sinoatrial node o Decrease heart rate (negative chronotropic effect) Atria o Decrease contractile strength (-ve inotropic effect) o Decrease refractory period AV node o Decrease conduction velocity (negative dromotropic effect) Ventricles o Small decrease in contractile strength Blood vessels Arteries o Dilatation o Constriction (high dose) Veins o Dilatation o Constriction (high dose) Lung Bronchial muscle o Constriction (bronchoconstriction) Bronchial glands o Stimulation GIT Motility o Increase Sphincters o Relaxation Secretion o Stimulation Urinary bladder Detrusor o Contraction Trigone and sphincter o Relaxation Glands Sweat, salivary, lacrimal, nasopharyngeal o Secretion
6.0 CLINICAL PHARMACOLOGY OF CHOLINOMIMETICS
Cholinomimetics are useful in management of diseases of the: -
1. Eye – glaucoma and accommodative esotropia (strabismus)
2. GIT – post operative atony, gastroparesis, gastric atony, post operative abdominal distension
3. GUT – neurogenic bladder (urine retention especially in spinal injury or terminally ill patients)
4. Heart – rare
5. Neuromuscular – myasthenia gravis, curare induced neuromuscular paralysis
6. CNS – Alzheimer disease
7.0 CONTRAINDICATIONS
1. Asthma
2. Hyperthyroidism
3. Coronary insufficiency
4. P.U.D
8.0 INDIRECT ACTING CHOLINOMIMETICS
The action of acetylcholine is terminated by destruction of the molecule in a hydrolysis reaction driven by acetylcholinesterase. Activity of acetylcholine can be enhanced by inhibiting the action of acetylcholinesterase by cholinesterase inhibitors. There are three main types of cholinesterase inhibitors based on their chemical structure. These are

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namely: - simple alcohols, carbamates (esters of alcohol e.g. neostigmine) and phosphoric acid derivatives (organophosphates)
Pharmacokinetics
Carbamates are poorly absorbed from the conjunctiva, skin and lungs because they are insoluble in lipids. They have negligence CNS distribution. Carbamates are relatively stable in aqueous solution. Physiostimine is well absorbed from all sites.
Organophosphate cholinesterase inhibitors are well absorbed from the skin, lung, gut and conjunctiva. This is why organophosphate is dangerously poisonous in humans but an effective insecticide/pesticide. They are stable in aqueous solution and hence have a limited half life in the environment compared to DDT. Thiosulpahte (e.g. Malathion) are quite lipid soluble and are rapidly absorbed by all routes.
Mechanism of Action
Acetylcholinesterase is an extremely active enzyme, which binds to acetylcholine and splits it into choline and acetate in a process of hydrolysis. Acetylcholinesterase inhibition increases the concentration of endogenous acetylcholine at the cholinoceptors thereby enhancing its activities.
Effects on Organ systems
The pharmacologic effects of cholinesterase inhibitors are encountered in the CNS, GIT, eye, skeletal muscle neuromuscular junction.
1. CNS
 In low concentrations lipid soluble cholinesterase inhibitors cause diffuse activation of EEG and alert response while in high concentration cause generalized convulsions, coma and respiratory arrest
2. CVS
 Increase activation of both sympathetic & parasympathetic ganglia supplying the heart
 Stimulation of acetylcholine receptors on the neuroeffector cells on the cardiac and vascular smooth muscles causes the following effects: -
o Heart
 Parasympathetic activity, which dominates (mimics vagal tone activation) leading to reduced cardiac, output (negative chronotropic effect, ionotropic effect and dromotropic effects).
 Bradycardia, reduced atrial and ventricular contractility
o Vascular smooth muscle – vasodilatation and reduced blood pressure
3. Eye, respiratory tract, GIT, GUT – as direct acting cholinomimetics
4. Neuromuscular junction
 Low concentration – prolong and intensify actions of physiologically released acetylcholine which increase the strength of contractions e.g. in myasthenia gravis
 High concentrations – fibrillation of muscles
INDIVIDUAL CHOLINOMIMETICS

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CHOLINE ESTERS
1) Acetylcholine 2) Methacoline 3) Carbochol and 4) Bethanechol
ALKALOIDS
1) Nicotine 2) Muscarine 3) Pilocarpine and 4) Arecoline
ACETYLCHOLINE
Actions of acetylcholine are classified according to the type of receptor through which its peripheral actions are mediated. This can be muscarinic or nicotinic.
Muscarinic stimulation causes the following effects: -
1. Heart – reduce rate of depolarization and bradycardia, slow conduction and reduce force of atrial and ventricular contraction
2. Blood vessels - dilatation and fall in blood pressure
3. Smooth muscle – contracted, increased tone and peristalsis in GIT abdominal cramps, Relaxation of GIT sphincters bowel evacuation
o Bronchial muscle constriction dyspnoea, wheezing
4. Glands - Increased secretion sweating, salivation, lacrimation, gastric
5. Eye - contraction of circular muscle of iris miosis & contraction of ciliary muscle
Nicotinic stimulation has the following effects: -
1. Autonomic ganglia - Stimulates both sympathetic and parasympathetic
2. Skeletal muscles - Contraction of muscle fibre twitching, fasciculation
ANTIC
HOLINESTERASES
CHOLINESTERASE INHIBITORS
These fall in 3 chemical groups namely:-
a) Simple alcohols e.g. edrophonium
b) Carbamic acid esters of alcohol e.g. neostigmine
c) Organic derivatives of phosphoric acid e.g. organophosphates such as malathione
TASK: FIND OUT ABOUT NICOTINE AND MUSCARINE

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NEOSTIGMINE (Prostigmin)
Neostigmine (prostigmine) is a synthetic reversible anticholinesterase with marked effects on the neuromuscular junction & alimentary tract than on the CVS and eye.

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Mechanism of Action
Neostigmine inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at the sites of cholinergic transmission. Has some direct cholinergic activity.
Indications
1. Myasthenia gravis
2. Paroxysmal tachycardia
3. Migraine
4. Intestinal atony
5. Post-operative atony
6. Termination of effects of neuromuscular blocking agents (antidote)
Precautions
1. Bronchial asthma (extreme caution)
2. Bradycardia
3. Cardiac arrhythmias
4. Elderly
5. Myocardial infarction
6. Hypotension
7. Epilepsy
8. Peptic ulcers
9. Parkinsonism
10. Renal impairment
Drug interactions
Aminoglycosides accentuate neuromuscular blockade
Contraindications
1. Pregnancy and lactation
2. Concomitant use with depolarising muscle relaxants
3. During anaesthesia – halothane, cyclopane
4. Diabetes
5. Gangrene
6. Intestinal obstruction
7. Urinary obstruction
Preparation and Dose
o Preparations – 15 mg. 0.5 mg tablets, 2.5 mg/ml, 12.5 mg/5 ml, 500 micrograms/l injections
o Dose - Tabs Neostigmine 5 – 30 mg T.I.D or Q.I.D
o S/C or IM injection 0.5 2.0 mg, Higher doses may be required; It is often combined with atropine to reduce unwanted muscarinic effects.

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COMMON NAMES: Neostigmine and Prostagmin
PYRIDOSTIGMINE (Mestinon)
Mechanism of action, indications, precautions, contraindications and side effects – as for neostigmine
Preparations and Dose
o Preparations – 60 mg tablets
o Dose – Myasthenia gravis 30 – 120 mg in divided doses (up to 0.3 – 1.2 gm); Neonates - 5 – 10 mg 4 hourly; Under 6 years – 30 mg 4 hourly initially, 6 – 12 years – 60 mg 4 hourly initially then increase by 15 – 30 mg daily until control. Total dose – 30 – 360 mg.
PHYSIOSTIGMINE (Eserine)
Physiostigmine is an alkaloid obtained from seeds of the physiostigma (a West African plant). It is used synergistically with pilocarpine to reduce intraocular pressure. It improves cognitive function in Alzheimer type of dementia.
ANTICHOLINESTERASE POISONING
This can occur through overdose or poisoning from pesticides containing carbamates and organophosphate compounds, which inhibit the enzyme almost or completely irreversibly so that recovery depends on formation of new fresh enzyme. Organophosphate agents are well absorbed through the skin, conjuctiva, gastrointestinal tract and by inhalation (lungs).
Features
1. Gastrointestinal tract – salivation, vomiting, abdominal cramps/colic, diarrhoea and involuntary defecation
2. Respiratory system – bronchorrhoea, bronchoconstriction, cough, wheezing and dyspnoea
3. Eyes – miosis, contracted pupils (pin point pupils)
4. Cardiovascular system - Bradycardia
5. Genitourinary system - Involuntary micturation
6. Skin - Sweating
7. Skeletal system - muscle weakness and twitching
8. Nervous system – miosis, anxiety, headache, convulsions and respiratory failure
Causes of Death
1. Paralysis of respiratory muscles
Side Effects
GIT disturbances – nausea, vomiting, diarrhoea, Abdominal cramps, Increased salivation, Headache, Miosis, Increased bronchial secretions, Increased sweating, Involuntary defecation and micturation, Nystagmus, Hypotension, Bradycardia, Excessive dreaming and Muscle fasciculation then weakness and eventually paralysis

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2. Excessive bronchial secretions and constriction – respiratory obstruction
Management
1. Supportive
a. Remove contaminated clothing, wash the skin
b. Gastric lavage
c. IV fluids
d. Mechanical ventilation – clear airway, suction
2. Definite
a. Atropine – IM or IV Atropine 2 mg repeat every 15 – 60 minutes until dryness of mouth and heart rate of 70 beats per minute
b. Diazepam – if convulsions are present
c. Atropine eye drops – relieve headache caused by miosis
d. Enzyme reactivation - IM Pralidoxime 1.0 gm 4 hourly (best within the first 12 hours of poisoning)
ANTI-CHOLINERGIC (CHOLINOCEPTOR BLOCKING) AGENTS
Anticholinergic agents (cholinergic antagonist) are divided into two groups of muscarinic and nicotinic antagonists or antimuscarinic and antinicotinic drugs. The anti-nicotinic drugs comprise of ganglion blockers and neuromuscular junction blockers. Antimuscarinic drugs act principally at postganglionic cholinergic (parasympathetic) nerve endings at M1 receptors (brain), M2 receptors (heart) and M3 receptors (blood vessels)
ANTIMUSCARINIC DRUGS
Antimuscarinic drugs block the effects of the parasympathetic autonomic discharge by competitively blocking the binding of acetylcholine to the muscarinic receptors at the postganglionic cholinergic fibre endings, thus described as parasympatholytics. They block acetylcholine from accessing the muscarinic receptors principally at post-ganglionic cholinergic (parasympathetic) nerve endings. The effects are pronounced in organ or tissues with predominant parasympathetic control e.g. eye, heart, smooth muscle and exocrine glands.
Classification
1. Naturally occurring alkaloids
a. Atropine (Hyoscyanine)
b. Scopolamine (Hyoscine)
Atropine exists in d and L forms and is obtained from plants such as the night-shade (Atropa belladonna) or Datura stramonium.
2. Semi-synthetic and synthetic drugs

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a. Quaternary ammonium compounds (Amines) – protropium (atrovent), tropropium (spiriva), methscopolamine, gylcopyrolate (robinil) - These are charged therefore are more polar and do not penetrate the blood brain barrier
b. Tertiary amines – homatropine, cyclopentalate, tropicamide, trihexyphenidyl, dicylomine, flavoxale, oxybutynin. These are less hydrophilic and can easily penetrate the BBB)
3. Selective antimuscarinic drugs – most are M1 antagonists
Include – pipenzepine (pirenzepine), telenzepine, triptamine, darifenacin, tolterodine
Discus the pharmacokinetics of the antimuscarinic agents

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INDIVIDUAL ANTIMUSCARINIC AGENTS
1. Atropine,
2. Hyoscyamine
3. Hyoscine
4. Hyoscine butylbromide (Buscopan)
5. Ipatropium (Atrovent)
6. Homatropine
ATROPINE
Atropine a natural alkaloid from the plant Atropa belladonna (deadly nightshade) and Datura stramois is the most commonly used antimuscarinic drug. It is nium (Jamestown weed). Generally the effects of atropine are inhibitory but large doses cause stimulation in the central nervous system.
Mode of Action - Atropine is an antimuscarinic agent
Pharmacokinetics
Atropine is well absorbed from the gut and conjunctival membranes. It is well distributed in the body attaining sufficient concentrations in the CNS within 30 minutes to 1 hour and has a half life of 2 hours. It is partly destroyed in the liver and 60% is excreted unchanged in urine
Mechanism of action
Atropine causes reversible blockade of cholinomimetic actions at the muscarinic receptors. The effect of atropine various among tissues based on sensitivity of the tissues to atropine. Salivary, bronchial and sweat glands are tissues most sensitive to atropine while parietal cells are least sensitive. Antimuscarinic drugs are more effective in blocking exogenous cholinoceptor agonists than endogenous acetylcholine. Atropine is highly selective for muscarinic receptors but has low potency at the nicotinic receptors. It is none selective for the various muscarinic receptors. Synthetic agents are less potent.
 Minimal stimulatory effects on the CNS in normal doses

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 Slower, long lasting sedative effect on the brain
 High doses – excitement, agitation, hallucinations, coma
2. Eye
 Dilatation of the pupils (mydriasis)
 Increase intraocular pressure (in predisposed individuals) as the dilated iris blocks drainage of the intraocular fluids from the angle of the anterior chamber.
 Ciliary muscle weakness (cycloplegia)- eye is accommodated for distant vision
 Reduced lacrimal secretion - dry, “sandy” eyes
 Reduce vagal tone resulting in increased heart rate (SAN is very sensitive to antimuscarinic effects) – tachycardia
 Enhanced conduction in the bundle of His
 Minimal effects on blood vessels (do not receive direct innervation from parasympathetic nervous system)
 Parasympathetic nerve stimulation dilates coronary arteries and sympathetic cholinergic nerves cause vasodilatation in the skeletal muscle vascular bed. This dilatation can be blocked by atropine.
4. Respiratory system
 The smooth muscle and secretory glands of the respiratory system have vagal innervation and contain muscarinic receptors
 Atropine causes bronchodilatation and reduction of secretions
5. Gastrointestinal tract
 Reduced tone and motility (peristalsis)
 Reduced secretion of saliva – dry mouth and gastric secretions
 Relaxation of smooth muscle of the GIT from the stomach to the colon – delayed gastric emptying
6. Genitourinary tract
 Relaxes smooth muscle of the ureters and bladder wall and slows micturation (important in treatment of spasm induced by mild inflammation, surgery and neurological conditions but may precipitate urine retention in BPH).
7. Sweat glands - Suppress thermoregulatory sweating
Indications
1. Organophosphate poisoning
2. Preoperative medication
3. Central nervous system such as Parkinson’s disease, Motion sickness (anti-emetic) and sedation (in anaesthetic premedication)
4. Ophthalmologic uses - ophthalmologic examination of the retina which needs mydriasis and prevent synthesis(adhesion) formation in uveitis and iritis
5. Respiratory system - drying of bronchial and salivary secretions due to inhalations in anaesthetics and intubations

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6. Cardiovascular system - prevention of bradycardia, evaluation of coronary artery disease and diagnosis of sinus node dysfunction
7. Gastrointestinal tract - reduce hypermotility and spasm of the gut and treatment of traveller’s diarrhoea
8. Urinary tract - relieve muscle spasms and reduce urinary agency
9. Cholinergic poisoning
Precautions
Myasthenia gravis, renal impairment, hepatic impairment, cardiovascular disease, children, the elderly, diarrhoea, glaucoma, hypertension, ulcerative colitis and Down’s syndrome
Contraindications
Glaucoma (closed-angle), Prostate enlargement, Paralytic ileus, pyloric stenosis and High ambient temperatures
Preparations and Dose
1. 1 mg/ml Injection given IV or IM
2. Dose
o Pre-operative medication IV Atropine 300 – 600 micrograms (commonly 0.6 mg in adults)
o Organophosphate poisoning IV or IM Atropine 2 mg every 20 – 30 minutes until skin becomes dry, pupils dilate and tachycardia develops
o Child: 20 micrograms/kg
ATROPINE POISONING
Clinical Features
 Peripheral effects - Dry mouth, Dysphagia, Mydriasis, Blurred vision, Hot, flushed dry skin and hyperthermia
 CNS effects - Restlessness, excitement (later followed by depression and coma), hallucination, delirium and mania
Treatment
1. Activated charcoal to absorb the drug - Tabs activated charcoal 2 – 4 tablets TDS after meals
2. Diazepam for excitement
Side Effects
Dry mouth, Blurred vision, Cycloplegia, Mydriasis, Photophobia, Urinary hesitancy and retention, tachycardia, Increased ocular tension , Loss of taste sensation, Headache, Nervousness, Drowsiness, Weakness, Dizziness, Nausea and vomiting , Bloated feeling and Mental confusion and/or excitement (in geriatics)

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NICOTINIC DRUGS
1.0 INTRODUCTION
Nicotinic drugs work through having effects on the nicotinic receptors found in the autonomic ganglia, neuromuscular junctions and the brain. The receptors have ion channels and stimulation usually leads to hyperpolarization. They are ionotropic unlike muscarinic receptors.
Autonomic Nervous Activity
Nicotinic receptors are found on post-synaptic membrane and are uniformly distributed. Modification may be at the synthesis, storage and release. On binding to a receptor, the electrico-physiological changes are: -
a. EPSP
b. IPSP (Hyperpolarization)
c. Slow EPSP
d. Late slow EPSP
a. EPSP
 Nicotinic receptor
 Influx of Na+
 Threshold -55 leading to action potential
b. IPSP (Hyperpolarization)
 At -80 mV, Served by M2 receptors
 Decreased Na+ conduction, Efflux of K+
 M2 receptors can be acted upon by catecholamines especially acetylcholine
 Action is through an interneurone, thus neurotransmitter is not acetylcholine alone
c. Slow EPSP
 Through M1 receptors
 Delayed K+ conductance
d. Late slow EPSP
 Subserved by neuropeptide e.g. dopamine, cGRP, VIP, 5HT and neuropeptide Y.
The predominant neurotransmitter (NT) is Ach acting on nicotinic receptors. At the autonomic ganglia, there are two major receptors.
NICOTINIC AGONISTS
1) Nicotine
2) Tetramethane ammonium
3) Dimethane ammonium
2.0 NICOTINE

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Nicotine is an alkaloid commonly found in cigarettes. On stick of cigarette has about 10 mg and the dose in one cigarette smoke is 3mg. It is clear and volatile. Has pH of 8.5 (alkaline). It is stimulatory when it binds to receptors.
Organ Specific Pharmacological Activity
1) Peripheral nervous system
 binds on autonomic nervous ganglia to activate post synaptic neuronal response (sympathetic or parasympathetic) hence the effects are unpredictable
 Initially polarises the receptor and eventually desensitizes (small doses sensitize while higher doses desensitize)
2) At the medulla
 Smaller doses – release of catecholamines
 Higher doses – block catecholamine release
3) Neuromuscular junction
 Causes paralysis by causing muscle contraction, then paralysis and later desensitization
4) Sensory receptors for pain, pressure in the mesentery, lungs and skin
5) Chemoreceptors in aortic and carotid and stimulates them. Nicotine causes increased rate and force of respiration.
6) Central nervous system
 Nicotine is a stimulant at low doses and in high doses it becomes a depressant leading to tremorns, convulsions and excitotoxicity
 It usually occurs from depression of respiratory and cardiovascular centre
 It is an analgesic
 Acts at the medulla via the chemoreceptor trigger zone (CTZ) to cause vomiting
 It has a pleasant effect by acting on the reward centres through the release of dopamine and amino acids
 Chronic exposure leads to addiction and upregulation or receptors
7) Cardiovascular system
 Predominantly its effects is because of release of catecholamines from the adrenal medulla leading to increased output and tachycardia
8) G.I.T
 It causes autonomic nerve stimulation resulting in increased motility and tone, nausea, vomiting and diarrhoea. Increased motility and diarrhoea – predominant form in parasympathetic
9) Exocrine glands
 Causes bronchorrhoea initially and later inhibition
3.0 NICOTINE POISONING
 It is usually acute

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 Sources – insecticides or tobacco
 Can occur in children
 Effects are usually less pronounced if it is through the G.I.T (causes vomiting and diarrhoea)
Clinical Features
 Increased salivation, sweating, abdominal cramps (increase in motility and reduced thermoregulatory sweating)
 Dizziness, confusion, disorientation, skeletal muscle weakness that progress to skeletal paralysis
 Death results from respiratory failure. There is cardiovascular collapse because of reduced blood pressure
 It is dose dependent
Nicotine is only used as a research drug. The drug causes vomiting but as cats as an anti- emetic
Ganglion Blockers (Nicotinic Antagonists)
1.0 INTRODUCTION
Ganglion blockers are competitive antagonists with surmountable effects that block transmission at autonomic nerves. They bind to nicotinic receptors and block ion channels in both parasympathetic and sympathetic systems. They have limited use because they lack chemical selectivity. They are synthetic quaternary ammoniums and therefore volume of distribution is low. Oral bioavailability is poor hence is given intravenously. Most are research drugs and only one has limited clinical use. Ganglion blockers include – tetyraethylamine, hexamethonium, mecamylamine, decamethomine and trimetaphan (limited clinical use)
GANGLION BLOCKERS
Ganglion blockers block the action of acetylcholine and similar agonists at the ganglion nicotinic receptors of both sympathetic and parasympathetic autonomic nervous system. These agents block of ganglionic outflow.
Pharmacokinetics
All ganglion blockers are synthetic with variable degree of absorption from the GIT.
Mechanisms of Action
Ganglionic nicotinic blockers are sensitive to both depolarization and non-depolarizing blockade.
1. Central nervous system – sedation, tremor choreiform movements and mental aberrations

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2. Eye
 Cycloplegia with loss of accommodation
 Moderate dilatation of pupils (because the iris has both parasympathetic and sympathetic innervation)
 Vasodilatation, venodilatation , hypotension (marked othostatic or postural hypotension), decreased cardiac muscle contractility and tachycardia
4. Gastrointestinal tract - Reduced secretion, reduced motility, constipation
5. Genito-urinary tract - Urinary hesitancy, urine retention, impaired sexual dysfunction (erection and ejaculation )
6. Response to autonomic drugs – effector cell muscarinic, and  receptors are not blocked hence patients will respond to autonomic drugs with the effects being exaggerated or reversed because of the absence of homeostatic reflexes.
NEUROMUSCULAR JUNCTION – NICOTINIC BLOCKERS – READ ABOUT THESE DRUGS

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Lesson 3: Adrenoceptor Stimulants/Agonists (Sympathomimetics) & Antagonists (Blockers)
Learning Outcomes
1. Classify adrenoceptor stimulants
2. Describe the pharmacology of adrenoceptor stimulants
3. Outline the indications of adrenoceptor stimulants
4. Outline the side effects of adrenoceptor stimulants
Adrenoceptor Stimulants (Sympathomimetic Drugs)
1.0 INTRODUCTION
The sympathetic nervous system is important in regulation of activities of various organs in the body such as the heart and blood vessels especially in response to stressful states. The effects of the sympathetic nervous system are mediated through release of noradrenaline from nerve terminals. Norepinephrine activates adrenoceptors on postsynaptic sites thereby executing the effects. During stressful situations the adrenal medulla releases a lot of adrenaline, which is transported by blood to various organs. Drugs that mimic the actions of noradrenaline and adrenaline are called sympathomimetic drugs.
Adrenaline, noradrenaline and dopamine are synthesized in the body from tyrosine. The natural synthetic pathway is tyrosine dopa dopamine noradrenaline adrenaline
2.0 MODE OF ACTION
Noradrenaline is synthesized and stored in adrenergic nerve terminals in the body. It is usually released by stimulating nerve endings or drugs. Noradrenaline stores can be replenished and abolished using drugs such as ephedrine and reserpine respectively or by cutting the sympathetic neurone.
3.0 CLASSIFICATION
A. According to their mode of action into: -
1. Direct acting (adrenoceptor agonists) - directly interact and activate adrenoceptors such as adrenaline, noradrenaline, isoprenaline and dopamine. They bind to receptors and lead to physiological responses
2. Indirect acting – promotes release of endogenous neurotransmitters or prevents their reuptake. The effects are limited by denervation or depletion of the vesicles. They can act by entering post-ganglionic neurone an d displacing the neurotransmitter from the vesicle and subsequently release into the synaptic cleft (vesicles are released without depolarization)

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a. Displace stored noradrenaline from the adrenergic nerve endings causing its release e.g. Amphetamine, Ephedrine, Tryamine
b. Inhibit reuptake of catecholamines that have already been released – Cocaine and Tricyclic antidepressants (for example!)
3. Both direct and indirect acting - Some drugs have both effects but one mechanism is predominant
B. According to chemical nature
1. Catecholamines
a. Natural - Adrenaline, Noradrenaline, Dopamine
b. Synthetic – Dobutamine, Isoprenaline
2. Non-catecholamines - usually synthetic
a. Indirect acting e.g. Ephedrine, Metaraminol, Amphetamine
b. Direct acting – Phenylephedrine, Mathoxamine, Terbutaline, Albutenol, Purbutenol, Salmeterol, Isoethamine, Medodrine
C. According to receptor selectivity
a. -adrenergic agonists
i. 1-selective agonists (effector organs) – methoxamine, phenylephedrine, metaraminol, midodrine, mephantermine
ii. 2- selective agonist (usually presynaptic – clonidine, oxymetazoxine, apraclonidine, methyldopa. Most of them are lipid soluble and can cross the blood brain barrier. Their activities are predictable
b. -adrenergic agonists
i. 1 – selective agonists (found in the heart) – dobutamine, isoproterenol(isoprenaline)
ii. 2-adrenergic selective agonists (receptors found in the smooth muscles, glandular tissue, liver, pancreas, pulmonary) – terbutaline, critodrine, isoetharine, salmeterol, metaproleranol
c. Dopamine receptor agonists
i. D1 agonists – Fenoldopam in renal vasculature
ii. D2 agonists e.g. Bromocriptine

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D. Miscellaneous Agonists – amphetamine (Class I drug) , methylphenidate, pemocine, ephedrine, naphazoline, oxymetazoline, xylometazole, tetrahydrozocine
4.0 BASIC PHARMACOLOGY
The basic pharmacology of sympathomimetic drugs depends on the type of adrenoceptors (membrane protein receptors) present in an organ or tissue. The main adrenoceptors are the  and adrenoceptors. There are also D receptors. The location of the receptors is under the control of various genes on various chromosomes.
Alpha Adrenoceptors
Alpha adrenoceptors activation of 2 cells produces the opposite effect to 

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Beta Adrenoceptors
The adrenoceptors are divided into various subtypes and stimulation of adrenoceptors produces effects by stimulating production of cyclic AMP within the target cells.
Table 5: Distribution of Adrenoceptors Type Tissue Action 1 Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscle Contraction (dilates pupil – mydriasis) Prostate Contraction Pilomotor smooth muscle Erects hair Heart Increases force of contraction 2 Postsynaptic CNS adrenoceptors Multiple Platelets Aggregation Adrenergic and cholinergic nerve terminals Inhibit release of neurotransmitter Some vascular smooth muscle Contraction Fat cells Inhibition of lipolysis 1 Heart Increases force and rate of contraction  Respiratory Relaxation Uterine Vascular smooth muscle Liver Activates glycogenolysis  Fat cells Activates lipolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release
Dopamine Receptors
Endogenous catecholamine dopamine produces a variety of biological effects, which are mediated by specific dopamine receptors. These receptors are important in the brain, splanchic and renal vasculature.
Table 6: Types of Receptors Organ Alpha (1) Beta Receptor and Effect Receptor and Effect Eye Mydriasis Heart 1 and 2  Increased rate (SAN) – positive ionotropic  Increased automaticity (AVN & muscle)  Increased velocity in conducting tissue (positive dromotropic)  Increased contractility of myocardium (positive chronotropic)  Increased oxygen consumption

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 Decreased refractory period of all tissues Organ Alpha (1) Beta Receptor and Effect Receptor and Effect Arterioles Constriction (only slight in coronary and cerebral) - Dilatation Bronchi - Relaxation Uterus Contraction (pregnant)  Relaxation (pregnant) Inflammation Inhibit release of histamine and leukotreines from mast cells Skeletal muscle  Tremor Skin Sweat Pilomotor Male sexual Ejaculation Metabolic Hyperkalaemia Hypokalaemia and hepatic glycogenolysis, and Lipolysis Platelets Aggregation Bladder Contraction sphincters Relaxation of detrussor Intestinal smooth muscle Relaxation Relaxation
5.0 PHARMACOKINETICS
The pharmacokinetics of sympathomimetic drugs involves changes in the chemical structure, which involves substitutions on phenylethylamine from which the drugs are derived from. Phenylethylamine is made up of a benzene ring with an ethylamine side chain. Substitutions may be made on the terminal group, benzene ring and carbons. Substitution by –OH groups at the 3 and 4 positions results in formation of sympathomimetic drugs called catecholamines while the others will be called non-catecholamines
Phenylethylamine

CH2- CH2 -NH2 OH
Catechol
Substitution on the amino group increases b receptor activity e.g. methyl substitution on noradrenaline produces adrenaline, which has increased activity. Substitution on the benzene ring produces catecholamines having –OH groups at the 3 and 4 positions have maximal  and activity (e.g. adrenaline, noradrenaline, and dopamine).
OH

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Substitutions at carbon block oxidation by monoamine oxidase (MAO) and prolong action of such drugs (e.g. ephedrine, amphetamine). These are non-catecholamine sympathomimetics. Substitution at  carbon produces sympathomimetic agents, which activate adrenoceptors. The hydroxyl group present is important for storage of sympathomimetic amines in the neural vesicles (long acting drugs).
Metabolism
Catecholamines (adrenaline, noradrenaline, dopamine, dobutaline, isoprenaline) which have a plasma half life of 2 hours are metabolized by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) produced by the liver and kidney respectively. MAO is also present in the intestinal mucosa (nerve endings, peripheral and central).
Termination of action of noradrenaline released at the nerve endings is by reuptake into the nerve endings where it is stored, diffusion away from the area of the nerve ending and receptor (junctional cleft) and metabolism by MAO and COMT.
Synthetic non-catecholamines such as salbutamol (ventolin) have longer half-lives of 4 hours and are more resistant to enzymatic degradation and conjugation. They penetrate the CNS and may have prominent effects e.g. amphetamine.
6.0 PHARMACODYNAMICS
Cardiovascular system
1. Blood vessels
Catecholamines regulate the vascular smooth muscle tone and hence control peripheral vascular resistance and venous capacitance.
 Alpha receptors – contraction of arterioles (increase arterial resistance)
 Beta 2 receptors – promote smooth muscle relaxation
 Skin and splanchic vessels have predominantly  receptors hence constrict in the presence of adrenaline and noradrenaline
 Skeletal muscle vessels have both  and  hence they constrict or relax depending on what receptors are stimulated and – increase venous tone
2. Heart
The effects of sympathomimetics are mediated by mainly  receptors even though 2 and  have some effects. The effects include: -
 Increased calcium influx in cardiac cells modulating mechanical and electrical activities
 Increased pace maker activity in SAN and Purkinje fibres (positive chronotropic effect)
 Increased conduction velocity in AVN (positive dromotropic effect)
 Reduce refractory period
 Increased intrinsic contractility (positive ionotropic effect)
 Accelerated relaxation of cardiac muscle
3. Blood pressure

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The effects of sympathomimetics drugs on blood pressure emanate from their effects on the heart and blood vessels – peripheral resistance (arterioles) and venous return (veins)
 Pure agonist – increase peripheral resistance and decrease venous capacitance
 adrenoceptor agonist - increases heart rate and cardiac output
4. Respiratory
The bronchial smooth muscle contains 2 receptors whose activation results in bronchodilatation. The blood vessels and upper respiratory mucosa contain  receptors whose activation has decongestion effects
5. GIT
 The GIT has both and  receptors. Relaxation of the GIT smooth muscle can be mediated by both and  receptors
 Beta receptors located directly on the smooth muscle cells mediate relaxation directly by hyperpolarization
 Alpha agonists relax the muscles indirectly via reduction of presynaptic release of acetylcholine and effects of enteric nervous system stimulants. Decrease salt and water influx into the lumen of the intestines.
6. GUT
 The uterus has both and receptors. The  receptors mediate relaxation while receptors mediate contraction of the uterus
 receptors mediate contraction of the bladder, urethral sphincter and prostate (promote urinary continence)
 receptors mediate bladder wall relaxation
 Receptors mediate ejaculation
7. Eye
 Radial papillary dilator muscle has  receptors whose activation causes mydriasis
 receptors stimulation relaxes the ciliary muscle
8. Metabolic effects
Adrenaline produces glycogenolysis leading to hyperglycaemia (affects insulin), hyperlactacidaemia and lipolysis leads to increased free fatty acids and transient hyperkalaemia
7.0 CLINICAL PHARMACOLOGY (INDICATIONS)
a. Increase blood flow or blood pressure – shock and hypotension
b. Reduction of regional blood flow
c. Heart failure
2. Respiratory system - Bronchial asthma
3. Anaphylaxis – anaphylactic shock
4. Ophthalmic

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5. Genito-urinary
6. Central Nervous system
7. Others
8.0 TOXICITY
Toxicity of sympathomimetic drugs reflects primarily extension of their pharmacologic effects in the cardiovascular and central nervous system
9.0 THERAPEUTIC USES OF ADRENERGIC AGENTS
1. Pressor agents - Ephedrine, Noradrenaline, Dopamine
2. Cardiac stimulants – Adrenaline, Isoprenaline, Dobutamine
3. Bronchodilators – Adrenaline, Isoprenaline, Salbutamol, Salmoterol, Terbutaline, Formetterol
4. Nasal decongestants - Pseudoephedrine
5. CNS stimulants - Amphetamine , Dexamphetamine
6. Anorectics
7. Uterine relaxants and vasodilators – Salbutamol, Terbutaline
10.0 THERAPEUTIC USES OF SYMPATHOMIMETICS
The selection of an agent to use depends on; -
a. Desired receptor selectivity
b. The duration of action intended which dictates the route of administration and method; whether intermittent or continuous infusion (titrated dose)
1. Vascular uses
a. Enhance flow or increase pressure (To increase blood flow to tissues; preferential redistribution of blood to the brain and kidney. the brain does not have much of adrenergic receptors. The drugs used for: -
i. Vasoconstrictive effects (agonists) e.g. noradrenaline, adrenaline, phenylephedrine, methoxamine
ii. Orthostatic hypotension e.g. ephedrine which has long action (both direct and indirect). It stimulates and causes further release of noradrenaline
iii. Hypotensive states – shock, spinal anaesthesia, hypotensive drugs. Use adrenaline, dopamine and midodrine
iv. Cardiogenic shock – need for positive ionotropes e.g. dopamine, dobutamine
b. To restrict blood flow – usually to achieve surgical haemostasis, this may be regional or local. to achieve surgical haemostasis the drugs used include adrenaline (vasoconstrictor, promotes von-willibrand factor, local anaesthesia/analgesic), cocaine (vasoconstrictive and local anaesthetic)
c. Along with local anaesthetics – prolong duration of anaesthetics
d. Control of local bleeding – e.g. epistaxis
e. Nasal decongestant – colds, rhinitis, sinusitis, blocked Eustachian tubes e.g. ephedrine
f. Peripheral vascular disease – use vasodilators e.g. isosuprine

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2. Cardiac uses
a. Asystole – ephedrine because of its redistributive action, 1 effects, cardiac ionotropism, chromatropims, causes cardiac fibrillation
b. Heart block – isoprenaline
c. Cardiac arrest – drowning, electrocution
d. CCF – dopamine to reduce cardiac decompensation during myocardial infarction, cardiac surgery; dobutamine
e. Paroxysmal supraventricular tachycardia (PSVT) which presents with hypotension – ephedrine, phenylephedrine
f. Generalized hypotension especially of spinal anaesthesia. The drug of choice is ephedrine (whenever you give spinal anaesthesia you must have ephedrine)
g. Hypertension – centrally acting -agonists e.g. clonidine (analgesic effect, sedative effect)
3. Pulmonary indications - Bronchial asthma (bronchodilatation)
4. Allergic disorders such as physiological antagonist of histamine, urticaria, angioedema, laryngeal oedema and anaphylaxis
5. Ophthalmic uses – for diagnosis and treatment
a. Mydriatic agents – fundal examination e.g. phenylephedrine
b. Glaucoma – to reduce intra-ocular pressure e.g. apraclomidine, bromopidine (2- agonist)
6. Genito-urinary
a. Tocolitics (suppress labour) e.g. retodrime, ventolin or terbutaline
b. Stress incontinence e.g. ephedrine, pseudoephedrine
7. CNS indications
a. Mood elevation e.g. amphetamine
b. Antidepressants – TCA, MOAI
c. Narcolepsy (sleep occurring in fits/excessive sleep) – amphetamine, TCA, MOAI, mazidol
d. Attention deficit hyperactivity – clonidine, pemoline
e. Weight reduction – amphetamine, mazidol
f. Alcohol withdrawal – clonidine
g. Autonomic neuropathic/diarrhoea associated with autonomic nervous system – clonidine
h. Hyperkinetic children – amphetamine
i. Obesity – use anorectics
j. Nocturnal enuresis in children
8. Other Indications
a. Peripheral vasodilatation
b. Dysmenorrhoea and post menopausal flushes – isoxsuprine
c. Symptomatic hyperkalaemia - ventolin to promote K+ entry into cells
Individual Sympathomimetic Drugs

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CATECHOLAMINES
ADRENALINE (EPINEPHRINE)
Adrenaline is an adrenergic agonist, which acts as a bronchodilator, vasopressor, cardiac stimulant and adjuvant local anaesthetic, topical anaesthetic, topical anti-haemorrhagic and anti-glaucoma agent. Epinephrine (adrenaline) is an effective rapidly acting bronchodilator, which is given as S/C injection (0.5 mls of 1:1000 solutions) or inhaled as a microaerosal from a pressurized canister (320 μg per puff). It stimulates both and 2 receptors.
Mechanism of Action
Adrenaline affects both and  receptors on effector cells and thus causes vasoconstriction, bronchodilatation and increased heart rate. It is likely to cause cardiac arrhythmias.
Pharmacokinetics
Adrenaline is a neurotransmitter with a very short duration of action (shortest acting of the sympathomimetics). After passage of transmission, it is re-taken up to the storage site i.e. sympathetic nerve endings and adrenergic tissues. The other part is metabolised by catechol- o-methyl transferase and deamminated by monoamine oxidase (MAO). Sympathetic nerve endings and adrenergic tissues such as the bronchi, blood vessels and heart take it up. Maximal dilatation is achieved 15 minutes after injection/inhalation and lasts 60 – 90 minutes.
Absorption
Adrenaline is well absorbed after S/C, IM injection. It has a rapid onset, short duration of action. Bronchodilatation occurs within 5 – 10 minutes and peak action occurs after 20 minutes after subcutaneous injection. Oral inhalation acts within 1 minute.
Uses
1. Provide rapid relieve in hypersensitivity reaction & congestion in the bronchial tree
2. Relive of moderate to severe bronchial asthma
3. In treatment of cardiac arrest

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4. Relief of respiratory distress and restoration of blood pressure in anaphylactic shock
5. To control superficial haemorrhage in the skin and mucous membranes
6. To prolong the action of infiltration anaesthesia (local anaesthesia)
Precautions
1. Elderly patients aged over 50 years
2. Patients with heart disease
3. Hyperthyroidism
4. Hypertension
5. Diabetes mellitus
6. Parkinsonism

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Contra-Indications
1. Shock – except anaphylactic shock
2. Organic heart disease
3. Cardiac dilatation
4. Cardiac arrhythmias
5. Extremities in local anaesthesia – tissue necrosis
NOTE: for Noradrenaline, Isoprenaline (Isoproterenol), Dobutamine and Dopexamine see Asthma management
DOPAMINE
Dopamine is a dopamine (D1) receptor agonist in the CNS and the renal and other vascular beds. It also activates presynaptic autoreceptors (D2) which suppress release of noradrenaline. It is also a 1-agonist in the heart. High doses of dopamine activate D1- adrenoceptors in the blood vessels causing vasoconstriction and release of noradrenaline from the nerve endings.
Mechanism of action
Dopamine is an inotropic sympathomimetic that acts on b1 receptors in the cardiac muscle
Indications
1. Shock – cardiogenic, septic
2. Cardimyopathies
3. Cardiac surgery
Precautions
Hypovolaemic shock due to acute myocardial infraction (use low dose)
Contraindications
1. Phaeochromocytoma
2. Tachyarrhythmia
Preparations - 40mg/ml injection
Dose
Adverse Reactions
Sudden death if given IV due to ventricular fibrillation, tissue necrosis due to vasoconstriction, anxiety, tremors, arrhythmias, tachycardia, palpitations, worsening of angina, mild hypertension, headache, sweating and G.I.T symptoms

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 IV infusion 2 – 5 mcg/kg/minute and increase by 5 – 10 mcg/kg/min at intervals of 15 – 30 minutes until desired effect is attained (monitor pulse rate, blood pressure, urine output closely)
 Can be in solution with sodium chloride and dextrose
NON-CATECHOLAMINES
1. Salbutamol (ventolin)
2. Salmeterol(Severent)
See asthma management
3. Clenbuterol)
4. Ephedrine
5. Xamoterol
Adrenoceptor Antagonists
These are drugs which antagonize the receptor action of adrenaline and related drugs which competitively antagonize and  adrenergic receptors at various sites.
Alpha-Receptor Antagonists (Blockers)
1.0 INTRODUCTION
Alpha-receptor antagonists (blockers) inhibit adrenergic responses mediated through the alpha-adrenergic receptors without affecting those mediated by beta-adrenergic receptors.
Classification
1. Nonequilibrium
a. Beta-Haloalkylamines e.g. Phenoxybenzamine
2. Equilibrium (competitive )
a. Non-selective
i. Ergot alkaloids – ergotamine, ergotaxine
ii. Hydrogenated ergot alkaloids
iii. Inidiolines e.g. phentoline, tozaline
iv. MiscellaneousAlpha-selective
i. Prazosin
ii. Terazosin
iii. Dexazosin
b. Alpha-2 selective e.g. yohimbine
Side Effects
Nausea and vomiting, hypotension, hypertension, tachycardia and peripheral vasoconstriction

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2.0 GENERAL EFFECTS OF ALPHA BLOCKERS
1. Block ache of vasoconstriction (and2)
 Reduced peripheral resistance resulting in pooling of blood in competence vessels which causes reduced venous return, cardiac output and blood pressure
 Interfere with postural reflex → dishes + syncope on standing
 Hypovolaemia
2. Reflex tachycardia - reduced arterial pressure which causes release of noradrenalin due to block ache of polysynaptic 2 receptors
3. Nasal stuffiness – nasal blood vessels
4. Meosis – vessels in radial muscles of iris
5. Increased intestinal motility - ↓inhibition of relaxant sympathetic influences → D
6. Hypotension - blockers ↓ RBF→↓ GFR → fluid and sodium retention
7. Reduced smooth muscle tone in the bladder trigone, sphincter, prostate → increased urine flow in BPH
8. Inhibit ejaculation due to reduced contraction of the vas deferens and related organs resulting in impotence
3.0 USES OF ALPHA-BLOCKERS
1. Phaechromocytoma – tumour of adrenal medulla cells
2. Hypertension – Prozasin
3. Secondary shock
 Counteract vasoconstriction resulting in improved tissue perfusion and allows fluid replacement without increasing the central venous pressure
 Shifting of blood from pulmonary to systemic circulation hence pulmonary oedema does not develop with rapid fluid infusion
 Fluid returns to the vascular compartment and cardiac output improves
4. Peripheral vascular diseases
 Increases blood flow
 Burger’s disease
 Ischemia is the most potent vasodilator in the skeletal muscles
 Raynaud’s disease/phenomenon
5. Congestive cardiac failure - Vasodilatation results in symptomatic relieve
6. BPH
 Improves urine flow
 Blockade of alpha-1 adrenoceptors in the bladder trigone, prostate and prostatic urethra reduce the muscle tone resulting in reduction of obstruction increasing urine flow rate and complete emptying of bladder
Side Effects
Palpitations, Postural hypotension, Nasal blockage, loose motions, Fluid retention, Inhibit ejaculation and impotence

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 Voiding symptoms (hesitancy, narrowing of stream, dribbling, increased residual urine) are relieved
 May alleviate irritative symptoms (urgency, frequency, nocturia)
 Drugs – terazosin, doxazosin, tamsulosin
7. Migraine e.g. ergotamine

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Beta-Receptor Antagonists (Blockers)
1.0 INTRODUCTION
Beta-adrenergic blockers are competitive antagonists
2.0 CLASSIFICATION
1. First Generation -1 and 2 Non-selective
 Propranolol, Sotalol, Timolol
2. Second Generation - 1 selective
 Atenolol, Acetabulol, Metaprolol, Bisoprolol, Esmolol, Betaxolol
3. Third Generation – (Non selective  and 2 Blockers)
a. Direct vasodilators (via nitric oxide) – cardedilol, nebivolol
b. -blockers – carvedilol, labetolol
c. -blockers – acebutolol, pindolol
3.0 PHARMACOLOGICAL ACTIONS
a. Heart - reduce heart rate, force of contraction, cardiac output, conduction and automaticity
b. Blood vessels - increases total peripheral resistance, blocks vasodilatation and reduce blood pressure – reduce noradrenaline release , rennin release and central sympathetic flow
2. Respiratory system - Bronchoconstriction
3. Central nervous system - behaviour changes , increase forgetfulness, dreaming and nightmares
4. Local anaesthesia - Potent local anaesthetic – lidocaine
5. Metabolic - Blocks lipolyisis reducing the amount of free fatty acids
6. Skeletal muscle - reduce tremors and increase blood flow to exercising muscles
7. Uterus – contraction
8. Eye – reduce secretion of aqueous humour
Pharmacokinetics
 Well absorbed after oral administrations
 Low bioavailability
 Metabolized in the liver
Interactions
1. Increase effects of digitalis/verapamil
2. NSAIDS increase its antihistamine effects
3. Cimetidine inhibits its metabolism
Adverse Effects
Accentuates myocardial infarction, bradycardia, worsens chronic obstructive lung disease, exacerbates variant (prazmetal’s) angina, impaired carbohydrate tolerance in pre-diabetics, increase lipids (hyperlipidaemia), rapid withdrawal results in rebound hypertension

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4. Reduce lignocaine metabolism

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Lesson 4: Autacoids 1 – Histamine and Antihistamine
Learning Outcomes
At the end of the lesson, the learner should be able to: -
1. Outline the structure of autacoids
2. Describe functions of autacoids
3. Describe the process of histamine synthesis, storage and release
4. Outline the pharmacological effects of autacoids
5. Explain the side effects of autacoids
1.0 INTRODUCTION
Autacoids are endogenous substances with complex physiologic and pathologic functions. They commonly include histamine, serotonin, prostaglandins(eicosanoids), kinins and kininogens, platelet activating factor (PAF) and vasoactive peptides/rennin angiotensin system. These endogenous molecules have powerful pharmacological effects that do not fall into traditional autonomic groups. They have important actions on smooth muscles. Most are agents of inflammation and the drugs acting through them arte mostly anti-inflammatory agents. These chemicals can act as local hormones, neurotransmitters and neuromodulators.
Histamine
1.0 INTRODUCTION
In the body, histamine is present in various biological fluids and in the platelets, leucocytes, basophils and mast cells. Histamine is an imidazole compound that is widely distributed in plant and animal tissues. It is also present in the venom of bees and wasps. Histamine is a naturally occurring biologically active amine found in many tissues in an inactive form. Histamine is released locally and has complex physiological and pathological effects through multiple receptor subtypes (H1, H2, H3, H4 and H5). Histamine is an important chemical mediator in allergic reactions.
Diagram 4.1: Structure of Histamine

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Histamine together with endogenous peptides, prostaglandins, leukotrienes and cytokines make up autacoid (Greek for self-remedy) or local hormones because of their properties. Serotonin has similar properties. Active free histamine is released from the cells in response to stimuli e.g. trauma or antigen-antibody reactions. Various chemicals can also release histamine e.g. snake venom.
Histamine is an important mediator of immediate allergic and inflammatory reactions. The major effect of histamine in respiratory tract is bronchospasms in asthmatics
2.0 STORAGE AND RELEASE
Stores of histamine in mast cells can be released through immunologic, chemical and mechanical processes. A major portion of histamine is stored in mast cells and basophils.
Immunologic Release
This is an important mechanism of histamine release from mast cells and basophils. These cells are sensitized by IgE antibodies attached to their surface membranes and degranulate releasing histamine in a process that requires energy and calcium.
Histamine has a modulating role in inflammatory and immune responses. Following tissue injury, released histamine causes local vasodilatation and leakage of plasma containing mediators of acute inflammation and antibodies. Histamine has an active chemostatic attraction for inflammatory cells. It also inhibits the release of lysosomal contents and several T and B lymphocytes function.
Chemical and Mechanical Release
Some drugs e.g. morphine displace histamine from the heparin-protein complex within cells without use of energy and degranulation or injury to mast cells. Chemical and mechanical cell injury will cause degranulation and histamine release.
3.0 FUNCTIONS OF HISTAMINE
1. Mediation of immediate allergic reactions
2. Mediator of immediate inflammatory reactions
3. Plays role in gastric acid secretion, intestinal, lacrimal and salivary gland secretions.

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4. Functions as a neurotransmitter and neuromodulator
5. Chemotaxis of white blood cells (basophils, eosinophils, neutrophils, lymphocytes and monocytes).
6. In most cells near blood vessels it plays a role in regulating the microcirculation.
4.0 HISTAMINE RECEPTORS AND EFFECTS
H1 Receptors (Vascular Receptors)
Generally produce and mediate most of the peripheral actions. They are found on smooth muscle of the GIT, respiratory tract, endothelium and the brain. The actions are IgE mediated. The second messenger is increase in PI3 and DAG. It leads to the release of prostacyclin and is related to muscarinic receptors (analogue of muscarinic receptors). The effects vary depending on the site of action such as -
1) Coronary artery – vasoconstriction
2) Respiratory tract – bronchoconstriction
3) It is a stimulant to smooth muscle
4) Sensory neurones - mediates pruritus and sensation of itch and sneezing
5) Capillary – leads to capillary permeability due to its stimulant effect which contract, opening gaps in the permeability barrier which further exposes the membrane with resultant exudation of water and protein outside the vasculature leading to oedema formation, hypotension and tachycardia
H2 Receptors
H2 receptors are related to serotonin receptors (share homology i.e. what binds to H2 Also binds to serotonin receptors). They are commonly found in gastric mucosa of the G.I.T (stomach), heart and brain. The second messenger is cAMP via AC. stimulation involves the brain leading to CNS stimulation. In the heart, H2 leads to dysarrhythmias and positive

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inotropism resulting in vasodilatation and bronchodilatation. It is a potent stimulator of gastric secretion.
Note:
H1 and H2 occur together in the vascular beds. Both act via H1 (initial onset and transient response) and H2 (delayed onset and sustained response).
H3 Receptors
H3 receptors are presynaptic and are involved in presynaptic modulation of the histaminergic neurotransmission in the CNS. In the periphery, it is presynaptic heteroreceptor with modulatory effects on the release of other transmitters. Generally found in the brain and the mysenteric plexus. They are mainly autoinhibitory and inhibit the release of histamine and norepinephrine.
H4 Receptors
H4 receptors are found in the formed elements of blood; oesinophils, neutrophils, CD4 cell and bone marrow. They modulate the production of cells.
5.0 MECHANISM OF ACTION
Stimulation of H1 receptors produces smooth muscle contraction including bronchospasm, vasodilatation, increased vascular permeability and mucous secretion. In tissues, histamine serves as a chemostatic agent for neutrophils and oesinophils. Activation of H2 receptors increases gastric acid secretion due to increased cAMP in the cells.
6.0 PHARMACOKINETICS
Once histamine is formed it is either stored or rapidly inactivated by being converted into other substances e.g. methylhistamine. Most tissue histamine is sequestrated and bound in granules (vesicles) in mast cells or basophils. Non-mast cells histamine is found in the brain where it acts as a neurotransmitter. It plays a role in brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation and arousal. Histamine also activates the acid-producing parietal cells of the gastric mucosa.
Metabolism of Histamine
Histamine is formed from an amino acid L-histadine by a decarboxylation process catalyzed by enzyme histadine decarboxylase. It is inactivated by the metabolic process of deamination and methylation (rapid process) to form methylhistamine.
7.0 PHARMACODYNAMICS
Mechanism of Action

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Histamine exerts its biologic actions by combining with specific cellular receptors H1, H2, H3 and H4 on the surface of the membrane.
Receptor Site and Distribution
H1 Smooth muscle, endothelium, brain (postsynaptic)
H2 Gastric mucosa, cardiac muscle, mast cells, brain
H3 Postsynaptic, brain, mysenteric plexus and other neurons
H4 Eosinophils, Neutrophils, CD4 T cells
H5
8.0 EFFECTS OF HISTAMINE
Histamine majorly acts on the smooth muscle, endothelium, neural tissues and the btain.
a. Blood vessels
 Dilatation of pulmonary vessels resulting in a fall in pulmonary artery pressure
 Constriction of large veins
 Vasodilatation and stretching effects of pain sensitive structures in dura matter by fluctuations in pressure in blood vessels and cerebrospinal fluid.
 Increased capillary permeability (large doses) leading to oedema and reduced plasma volume
 Coronary vasoconstriction (H1)
 Coronary vasodilatation(H2)
b. Blood pressure – reduced due to vasodilatation of blood vessels
c. Heart
 Increases sinus rate (positive chronotropic effect)
 Increase amplitude of ventricular contraction (positive inotropic)
 Impairs A-V conduction
 Increases coronary blood flow
 Induce ventricular arrhythmias (ventricular fibrillation) at high doses
2. Smooth muscle
 Contraction of bronchial smooth muscle (bronchoconstriction)
 Uterine smooth muscle contraction
 GIT smooth muscle contraction
3. Endocrine: Secretory organs – powerful stimulant for gastric acid secretion and a less extent on pepsin and intrinsic factor (IF) secretion (H2). These effects are felt in the small and large intestines. Causes catecholamine release.
4. Nervous system

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a. Powerful stimulant of sensory nerve endings especially those mediating pain(nociception) and itchiness (H1)
b. Modulate neurotransmitter release (H3) – acetylcholine, norepinephrine and peptides
c. Histamine does not cross the BBB but it is formed locally in the brain from histadine. H1 receptors
d. Brain stem – stimulates respiratory neurones and facilitates breathing
5. Skin
 Causes the triple response (wheal, flare and redness)
6. G.I.T
 It acts on the smooth muscle to cause contraction and therefore peristalsis through H1 receptors(controls GIT motility)
7. Miscellaneous
a. Other smooth muscle organ – has a significant effect on the eye, G.U.T and uterus
b. Evokes pain and itchiness on the skin
c. Large doses lead to release of adrenaline form adrenal medulla
9.0 CLINICAL USE
1. Pulmonary Function tests - used for provocation of bronchial hyper-reactivity in asthmatics.
2. Testing gastric acid secretion
3. Diagnosis of pheochromocytoma – histamine can cause release of catecholamines from adrenal medullary cells.
10.0 SIDE EFFECTS OF HISTAMINE
Hypotension
1. Flusing
2. Tachycardia
3. Headache
4. Bronchoconstriction
5. G.I.T upsets
6. Weals
7. Visual disturbances
8. Dyspnoea
Histamine Antagonists (Antihistamines)
1. Outline mechanisms of action of antihistamines
2. Classify antihistamines
3. Describe the indications of antihistamines
4. Describe pharmacologic effects of individual antihistamines
5. Explain the side effects of antihistamines
1.0 INTRODUCTION
TALKING POINT
What is the role of histamine in the body?
How does histamine contribute to disease process?
How can we utilize histamine in the process of management of patients?

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The effects of histamine can be reduced or opposed in three ways namely: Physiological antagonists, Release inhibitors and Histamine receptor antagonists
Physiological Antagonists
These are drugs, which oppose the effects of histamine. Histamine causes bronchoconstriction, vasodilatation and increased capillary permeability so drugs such as adrenaline (epinephrine) oppose effects of bronchoconstriction, vasodilatation and reduce capillary permeability.
Release Inhibitors
Release inhibitors prevent histamine release by reducing the degranulation of mast cells that results from immunologic responses by antigen-IgE interaction. These include adrenal steroids, sodium chromoglycate and nedocromil, which suppress effects of antigen-antibody reaction on cells. 2 adrenoceptor agonists have a potential to reduce histamine release.
Histamine Receptor Antagonists
These are compounds, which prevent histamine from reaching its site of action at the receptors by competitively blocking the receptor sites. These drugs include H1 , H2 and H3 receptor antagonists.
2.0 H1 RECEPTOR ANTAGONISTS
Chemistry and Pharmacokinetics
H1 receptors antagonists competitively block histamine at H1 receptors, which mediate histamine effects on smooth muscles, endothelium and brain. H1 receptor antagonists are divided into 1st generation (sedating) and 2nd generation (non-sedating) based on the sedating properties. The 1st generation drugs are also likely to block autonomic receptors.
H1 receptor antagonists are rapidly absorbed following oral administration and peak blood concentration occurs in 1 – 2 hours. They are widely distributed in the body. The 1st generation drugs readily enter the central nervous system. The liver extensively metabolizes some of the 1st generation drugs.
They have active metabolites e.g. hydroxyzine is metabolized to citirizine, terfenadine has fexofenadine and loratadine has desloratadine.
Pharmacodynamics
Histamine receptor blockade – H1 receptor antagonists block actions of histamine by reverse competitive antagonism e.g. relives bronchoconstriction and effects on G.I.T smooth muscles. The non-blockade effects include: -
1. Sedation
2. Anti-nausea and anti-emetic action

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3. Anti-Parkinsonism effects
4. Anticholinergic actions (can cause urine retention, blurred vision)
5. Adrenoceptor blocking actions (a-blockade) – cause orthostatic hypotension
6. Serotonin blocking action
7. Local anaesthesia – block sodium channels in excitable membranes
3.0 CLINICAL USES/INDICATIONS
1. Prevent allergic reactions/symptoms produced by release of histamine such as increased capillary permeability, oedema, pruritis, smooth muscle contraction, urticaria in drug allergies and blood transfusion allergic reactions
2. Respiratory tract infections - allergic rhinitis, asthma, Hay fever
3. Dermatological conditions – urticaria, pruritis
4. Vascular disorders - Angioedema
5. Hypersensitivity reactions – Urticaria, pruritis
6. Miscellaneous – migraine, sedation, nausea and vomiting (emesis) in pregnancy and motion sickness (Traveller’s sickness) vestibular disturbances e.g. phenargn
4.0 ADVERSE EFFECTS
1. CNS - sedation, hypnosis, fatigue, lassitude, diplopia, insomnia, dizziness, nervousness, tremors
2. Antuimuscarinic effects – dry mouth, blurred vision, G.I.T disturbances
3. Cardiac – hypotension, chest tightness
4. GIT – nausea, vomiting, epigastric pain
5. Chest tightness
6. Dermatitis
7. Agranulocytosis
8. Postural hypotension
Convulsions ± coma
5.0 CLASSIFICATION OF H1 RECEPTOR ANTAGONISTS
A. First Generation (Sedating)
a) Ethanolamines
 Diphendyramine (Benadryl) 25 – 50 mg T ½ ( 32 Hours)
 Cinarrizine (stugeron)
 Doxylamie
 Dimenhydrate
 Clemastine
b) Alkylamines
 Brompheniramine (Dimetane) 4 – 8 mg
 Chlormpheniramine (Piriton) 4 – 8 mg T ½ ( 20 Hrs)
 Dexchlorpheniramien
 triprolidine
 Acrivastine

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c) Piperadines
 Cyproheptadine (Periactin) 4mg
d) Piperazines
 Hydroxyzine 15 – 100 mg
 Meclizine
e) Ethylenediamines
 Tripelennamine
f) Phenothiazine derivatives
 Promethazine (Phenargan) 10 – 25 mg T ½ ( 32 Hrs)
B. Second Generation (Non- Sedating)
a) Piperidines
 Terfenadine (Triludan) 60 mg
 Fexofenadine (Telfast) 60 mg
 Loratadine
 Astomizole 10 mg
b) Miscellaneous
 Loratidine (Claritine) T ½ ( 15 Hours)
 Cetirizine (Zycet, cetrizect, atrizin) T ½ ( 7 Hours)
c) Ethanolamines
 Ketotifen
 Ebastine
INDIVIDUAL ANTIHISTAMINES
1. Chlorpheniramine (pirition)
2. Cinarrizine (stugeron)
3. Cetirizine (zycet, atrizin, cetrizet)
4. Cyproheptadine (periactin, uniactin, ciplactin)
5. Promethazine (histargan, phenargan)
6. Ketotifen (zaditen, tofen, ketotif)
7. Terfenadine (zenad, histadin)
CHLORPHENIRAMINE
Mechanism of Action
Chlorpheniramine acts by competing with histamine for the H1 receptor sites on the effector cells. It has anticholinergic action that gives a drying effect on the nasal mucosa.

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Indications
1. Symptomatic relief of allergic reactions
2. Emergency treatment of anaphylactic shock
Drug Interactions
 MAOI enhance the cholinergic effects
 Enhances CNS effects of CNS depressants and tricyclic anti-depressants (e.g.
amitriptyline)
Precautions
1. Prostate hypertrophy
2. Urinary retention
3. Narrow angle glaucoma
Contraindications
1. Premature infants
2. Acute asthmatic attack
3. Epilepsy
Preparations
1. Tablets (4 mg)
2. Syrups (2 mg/5 mls)
3. Injection (10 mg/1 ml)
Dose
 Adults – 4 mg every 4 – 6 hours (maximum 24 mg daily)
 Children
o 1 – 2 years – 1 mg BD
o 2 – 5 years – 1 mg every 4 – 6 hours (maximum 6 mg daily)
o 6 – 12 years – 2 mg every 4 – 6 hours maximum 12 mg daily)
Common Names - Chlorpheniramine, piriton, fenamine
CINARRIZINE (Stugeron)
Side Effects
Drowsiness, Psychomotor impairment, antimuscarinic effects – urinary retention, dry mouth, GI disturbances, blurred vision; Allergic reactions, Epileptic form seizures, Muscle weakness, tachycardia, tight chest, paradoxical CNS stimulation (in children), pregnancy (Risk category A)

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Indications
1. Peripheral vascular disease
2. Motion sickness
3. Vestibular disorders – vertigo, tinnitus
4. Nausea and vomiting
Precautions
 Severe heart failure
Preparations
 Tablets 25 mg
 Caps 75 mg
Dose
 Peripheral vascular disease, Raynaud’s syndrome
o 75 mg TID initially, maintenance 75 mg BD or TID
 Vestibular disorders- 25 mg TID
 Motion sickness – 25 mg 2 hours before travel, then 15 mg TID during the journey
 Children – half dose
CETIRIZINE (Zycet, Atrizin, Cetrizet)
Mechanism of Action
Cetirizine acts by competing with histamine for H1 receptor sites on effector cells. It has marked polarity hence it has reduced potential to cause CNS effects.
Indications
 Symptomatic relief of allergic reactions
Preparations
 Syrup (5 gm/5mls)
 Tablets 10 mg
Dose
 Children 2 – 6 years – 5 mg OD or 2.5 mg BD
 Adults and children – 10 mg OD or 5 mg BD
Side Effects
Anorexia, increased appetite, taste perversion, dyspepsia, gastritis, stomatitis, enlarged abdomen, eructation, flatulence, constipation, malena, rectal haemorrhage and pregnancy (risk category B2)
Side Effects
Drowsiness, dry mouth, blurred vision, allergic reactions, skin rashes and fatigue

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CYPROHEPTADINE (Periactin, Uniactin, Ciplactin)
Mechanism of Action
Cypreoheptadine is an H1 and serotonin antagonist
Indications
1. Allergies
2. Pruritis
3. Appetite stimulant
4. Promotion of weight
5. Suppression of vascular headache
Contraindications
1. Newborn or premature infants
2. Nursing mothers
3. Allergy
4. Angle-closure glaucoma
5. Stenosing peptic ulcer
6. Prostatic hypertrophy
7. Bladder neck hypertrophy
8. Elderly
9. Debilitated patients
Side Effects
Blood disorders after prolonged use, anaphylactic reactions, neurological and psychiatric disturbances, dry mouth, difficult in micturation, urine retention, weight gain, appetite increase, GI disturbances and pregnancy (risk category A)
Preparations
 Tablets 4 mg
 Syrup 2 mg/5 ml
Dose
 Allergies/pruritis
o Adult 4 mg TID (maximum 32 mg daily)
o 7 – 14 years – 4 mg BD or TID (maximum 8 mg in 4 – 6 hours period)
 Appetite stimulation – 4 mg TID with meals
 Promotion of weight gain – exceed treatment for 6 months
 Vascular headache suppressant – 4 mg at start of headache, repeat after 30 minutes if necessary
PROMETHAZINE (histargan, phenargan)

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Dr. Monda J.M.N.
Indications
1. Allergic or anaphylactic reactions
2. Occulogyric crises
3. Crisis of Parkinson’s syndrome
4. Premedication in anaesthesia
5. Motion sickness
6. Vomiting in pregnancy
7. Vertigo and labyrinth disorders
8. Night sedation
9. Insomnia
Preparations
 Tablets 25 mg
 Syrup, elixir 5 mg/5 ml
 Injection 25 mg/ml
Dose
1. Allergic or anaphylactic reactions – 50 mg deep IM or IV
2. Occulogyric crises – as above
3. Crisis of Parkinson’s syndrome – as above
4. Premedication in anaesthesia – 25 – 50 mg 1 – 2 hours before surgery
5. Motion sickness – 25 mg at bed time night before travelling or, repeat before travelling
6. Vomiting in pregnancy – 25 mg at bed time
7. Vertigo and labyrinth disorders
8. Night sedation – 25 mg at bed time
9. Insomnia – 25 mg at bed time
KETOTIFEN (zaditen, tofen, ketotif)
Mechanism of action
Stabilizes mast cells thus inhibits the release of chemical mediators involved in hypersensitivity reactions.
Indications
Side Effects
Drowsiness, headache, nausea, dry mouth, weight gain, impaired reactions and CNS stimulation.

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Dr. Monda J.M.N.
Prophylaxis and treatment of: -
1. Allergic asthma
2. Rhinitis
3. Skin reactions
Precautions
1. Oral diabetic therapy
2. Pregnancy
3. Breast feeding mothers
Contraindications
1. Pregnancy
2. Lactation
3. Hepatic impairment
Preparations
1) Tablets 1 mg
2) Syrup 0.2 mg/ml
Dose
 1 – 2 mg BD
 Children > 2 years 1 mg BD
TALKING OUT
In your various groups discus
Terfenadine (histadin, zenad)
H2 Receptor Antagonists
Read about H2 and H3 antagonists

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Dr. Monda J.M.N.
Lesson 5: Autacoids 2– Serotonin, Ergot Alkaloids
& Eiconsanoids
Serotonin (5HT)
1.0 INTRODUCTION
Serotonin is one of the autacoids. it is synthesized from amino acid tryptophan and stored in vesicles in the enterochromaffin cells of the gut and neurones of the central nervous system. Serotonin is widely distributed in plants, insects, snake venoms and bananas. Synthesis is via decarboxylation by MAO and 90% comes from enterochromaffin cells concentrated in the duodenum. Serotonin is also found in the brain, platelets and in the carcinoid tumours. Platelets do not synthesize serotonin. Serotonin is a precursor of melatonin in the pineal gland. Serotonin is depleted by reserpine and its metabolites are excreted in urine as 5- Hydroxyindole acetic acid (5-HIAA).
Serotonin is a vasoconstrictor agent, plays a physiologic role as a neurotransmitter (NT) in both CNS and the enteric nervous system together with VIP or somatostatin and substance P, and perhaps has a role in a local hormone that modulates G.I.T activity. In carcinoid tumours, the tumour cells can take a lot of trytophan from the circulation and lead to deficiency with resultant pellagra.
2.0 SYNTHESIS, DISTRIBUTION AND DEGRADATION
5HT occurs in high concentrations in the wall of the intestine, blood (platelets) and the central nervous system. It is found in diet but the endogenous 5HT is synthesized from tryptophan an amino acid in a pathway similar to that of adrenaline synthesis. 5HT is stored mainly in neurons and chromaffin cells (enterochromaffin cells).
3.0 SEROTONIN RECEPTORS
The effects of serotonin are usually via serotonin receptors (about 14 types have been identified) namely 5HT1A, B, D, , 5HT2A, B,C, 5HT3 and 5HT4., 5HT5., 5HT6. and 5HT7.
5HT1 Receptors
5HT1 receptors are most important in the brain (raphe nucleus, substancia nigra, putamen, and hypothalamus) and mediate synaptic inhibition via increased K+ conductance. They

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Dr. Monda J.M.N.
function mainly as inhibitory presynaptic receptors. Peripheral 5HT1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues. Subclasses of 5HT1 are 5HT1a, 5HT1b, 5HT1c, 5HT1d, 5HT1e, 5HT1f and 5HT1p. Most drugs used and acting via 5HT receptors are serotonin agonists e.g. sumatriptan and naratriptan (5HT1d agonists).
5HT2 Receptors
5HT2 receptors are important in both brain and peripheral tissues. They mediate synaptic excitation in the CNS and smooth muscle excitation leading to contraction in the gut, bronchi, uterus, vessels or vessel dilatation. The mechanism involves increased IP3, reduced K+ conductance and reduced cAMP. The subclasses are 5HT2a, b and c. 5HT2a (smooth muscle and skeletal muscle), 5HT2b (fundus and stomach) and 5HT2c (brain).
5HT3 Receptors
Most are concentrated in area postrema and in the enteric neurones (brain stem and G.I.T). They are especially numerous in chemoreceptive area and vomiting centre and peripheral sensory neurones.
Other Serotonin Receptors
5HT4, 5HT5, and 5HT6, 7 are commonly in the brain
4.0 ORGAN SYSTEMIC EFFECTS
1) Nervous system
 Neurotransmitter in the brain (excitation – autonomic reflexes in heart and lungs and inhibition of neurotransmitter release from adrenergic fibres)
 Stimulates nociceptive sensory nerve endings (pain)
2) Cardiovascular system
 Direct vascular smooth muscle contraction – causes vasoconstriction (5HT2)
 Heart – positive ionotropic and chronotropic effect
 Causes reflex bradycardia
 Vasoconstriction
 Platelet aggregation
3) Respiratory system
 Facilitates acetylcholine release from vagal nerve endings
 Hyperventilation
4) G.I.T
 Powerful stimulant of G.I.T smooth muscle
 Increases peristalsis leading to vomiting and diarrhoea
5) Skeletal muscles
 Associated with skeletal muscle contraction

Clinical Pharmacology notes:Drugs acting on the autonomic nervous syste mby drmonda edited by jennings argwings

Clinical Pharmacology notes:Drugs acting on the autonomic nervous syste mby drmonda edited by jennings argwings

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