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UNIT 1: AUTONOMIC NERVOUS SYSTEM

Carey Francis Okinda 1

PHARMACOLOGY & THERAPEUTICS

Lecturer: B. Carey Francis Okinda Department of Clinical Medicine September 2012

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 of 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

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 their actions are antagonistic. The dual innervation is well controlled and allows participation of the innervated receptors 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 post-ganglionic 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



The parasympathetic division has relatively long pre-ganglionic and relatively short post-ganglionic 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

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 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 post-ganglionic 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 CLASSIFICATION OF DRUGS ACTING ON THE ANS

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



Lesson 2: Cholinergic Stimulants (Cholinomimetics) and Cholinergic Antagonists (Blockers)

Learning Outcomes

At the end of the lesson, the learner should be able to - 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

CHOLINOMIMETICS (CHOLINERGIC STIMULANTS)

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. Acetylcholine is the neurotransmitter for the parasympathetic system at the autonomic ganglia, skeletal muscles and anatomically the sympathetic. Acetylcholine can also act as an autacoid. The cholinergic receptors in the blood vessels have diffuse effect. Acetylcholine can also be found in the placenta.

2.0 CHOLINERGIC TRANSMISSION

Terminals of cholinergic neurones have large vesicles containing acetylcholine (Ach), a chemotransmitter at various sites in the body mediating many physiological functions. 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. Neurotransmitters – Acetylcholine (Ach)

Acetylcholine synthesized locally in cholinergic nerve ending from choline and acetate in energy dependent enzyme driven reactions is a major neurohormonal transmitter at the autonomic and somatic sites. 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. Toxins that interfere with cholinergic transmission by affecting its release include 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 2.1: Acetylcholine Transmission

Cholinoceptors

There are two types of cholinoceptors namely muscarinic (M1, M2 and M3) receptors and nicotinic (NN and NM) receptors.

Table 2.1: 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

3.0 CLASSIFICATION

Cholinomimetic agents can be classified as: -

1. Direct acting cholinomimetics which act on nicotinic and muscarinic receptors a. Muscarinic

i. Choline esters – Acetylcholine, Methacholine, Carbachol, Bethanechol ii. Alkaloids – Muscarine, Pilocarpus, Lobeline, Avecoline

b. Nicotinic 2. Indirect acting cholinomimetics that act by inhibiting acetylcholinesterase

a. Carbamates – Neostigmine, Physiostigmine b. Organophosphates - Echothiophate, insecticides, Echophomium c. Edrophonium



4.0 DIRECT ACTING CHOLINOMIMETICS

4.1. 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 Table 2.2: 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) and refractory period

AV node o Decrease conduction velocity (negative dromotropic effect)

Ventricles o Small decrease in contractile strength

Blood vessels

Arteries o Dilatation (low dose) but constriction (high dose)

Veins o Dilatation (low dose) but 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

4.2. Mode of Action

Directly bind to and activate muscarinic or nicotinic receptors. Cholinomimetics are divided into two main groups namely the choline esters (acetylcholine) and alkaloids (muscarine and nicotine) based on their chemical structures.

4.3. 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 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



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

7. Central nervous system 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)

4.4. 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

4.5. Contraindications

1. Asthma 2. Hyperthyroidism 3. Coronary insufficiency 4. P.U.D

4.6 Individual Cholinomimetics

1. Choline esters - Acetylcholine, methacoline, carbochol, bethanechol 2. Alkaloids - Nicotine, Muscarine, Pilocarpine and Arecloine

Explain the reasons for

the contra-indication



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

NICOTINIC DRUGS

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. Nicotinic receptors are found on post-synaptic membrane and are uniformly distributed. Modification may be at the synthesis, storage and release. 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

NICOTINE

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 tremors, 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

Iincreased motility and tone, nausea, vomiting and diarrhoea. Increased motility and diarrhoea – predominant form in parasympathetic

9) Exocrine glands

Causes bronchorrhoea initially and later inhibition

NICOTINE POISONING

It is usually acute

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

5.0 INDIRECT ACTING CHOLINOMIMETICS

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 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. 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. 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

5.1 ANTICHOLINESTERASES/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

NEOSTIGMINE (Prostigmin)

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

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.

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.

6.0 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

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



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 2. Excessive bronchial secretions and constriction – respiratory obstruction

Management 1. Supportive - remove contaminated clothing, wash the skin, gastric lavage, IV fluids, 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)

7.0 ANTI-CHOLINERGIC (CHOLINOCEPTOR BLOCKING) AGENTS (ANTAGONISTS)

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)

7.1 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. 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 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

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 in that the salivary, bronchial and sweat glands are tissues most sensitive to atropine while parietal cells are least

Discus the pharmacokinetics of the antimuscarinic agents



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. Effects on organ systems

1. Central nervous system Minimal stimulatory effects on the CNS in normal doses 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

3. Cardiovascular system Reduce vagal tone resulting in increased heart rate Enhanced conduction in the bundle of His Minimal effects on blood vessels 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

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

7.2 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)



7.3 GANGLION BLOCKERS (NICOTINIC ANTAGONISTS)

Ganglion blockers are competitive antagonists with manageable 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. Effects on organ systems 1. Central nervous system – sedation, tremor choreiform movements and mental aberrations 2. Eye

Cycloplegia with loss of accommodation Moderate dilatation of pupils (because the iris has both parasympathetic and sympathetic

innervation) 3. Cardiovascular system

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

patients will respond to autonomic drugs with the effects being exaggerated or reversed because of the absence of homeostatic reflexes.



Lesson 3: Adrenoceptor Stimulants/Agonists (Sympathomimetics) &

Adrenoceptor Antagonists (Blockers)

Learning Outcomes At the end of the lesson, the learner should be able to - 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.

2.0 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 3.1: Norepinephrine Transmission

Adrenoceptors

There are two types of adrenoceptors alpha, and 2) adrenoceptors and beta and ) adrenoceptors.

3.0 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.

4.0 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 re-uptake. Can act by entering post-ganglionic neurone and displacing the neurotransmitter from the vesicle and subsequently release into the synaptic cleft (releasers and reuptake inhibitors) 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. Non-selective

ii. 1-selective agonists (effector organs) – methoxamine, phenylephedrine, metaraminol, midodrine, mephantermine

iii. 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. Non-selective

ii. 1 – selective agonists (found in the heart) – dobutamine, isoproterenol(isoprenaline)

iii. 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

D. Miscellaneous Agonists – amphetamine (Class I drug) , methylphenidate, pemocine, ephedrine, naphazoline, oxymetazoline, xylometazole, tetrahydrozocine

5.0 BASIC PHARMACOLOGY

This 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. Alpha Adrenoceptors

2 Beta Adrenoceptors

The adrenoceptors effects by stimulating production of cyclic AMP within the target cells.



Table 3.1: Distribution of Adrenoceptors Type Tissue Action

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

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

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 3.2: Types of Receptors

Organ Alpha () Beta

Receptor and Effect Receptor and Effect

Eye Mydriasis

Heart 1 and 2

Increased rate (SAN) – positive ionotropic, automaticity (AVN & muscle), velocity in conducting tissue (positive dromotropic)

Increased contractility of myocardium (positive chronotropic)

Increased oxygen consumption

Decreased refractory period of all tissues

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 Lipolysis

Platelets Aggregation

Bladder Contraction sphincters Relaxation of detrussor

Intestinal smooth muscle

Relaxation Relaxation



6.0 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 andand 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).

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.



7.0 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 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 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

2 receptors whose activation results in bronchodilatation. The

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 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

8.0 CLINICAL USES (INDICATIONS)

1. Cardiovascular system 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 - produce mydriasis, reduce conjunctival itchiness 5. Genito-urinary – suppress premature labour 6. Central Nervous system – narcolepsy, attention deficit disorders 7. Others

9.0 TOXICITY

Toxicity of sympathomimetic drugs reflects primarily extension of their pharmacologic effects in the cardiovascular and central nervous system

10.0 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



11.0 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

2. Cardiac uses

a. Asystole – ephedrine because of its redistributive action 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- 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

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 bothand2 receptors.

Mechanism of Action

Adrenaline affects bothand 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 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 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

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



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 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)

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 e.g. Ergot alkaloids – ergotamine, ergotaxine; Hydrogenated ergot alkaloids; Inidiolines e.g. phentoline, tozaline; Prazosin; Terazosin; Dexazosin

b. Alpha-2 selective e.g. yohimbine

Side Effects

Nausea and vomiting, hypotension, hypertension, tachycardia and peripheral vasoconstriction



1.0 GENERAL EFFECTS OF ALPHA BLOCKERS

1. Block ache of vasoconstrictionand2)

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

2.0 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

Voiding symptoms (hesitancy, narrowing of stream, dribbling, increased residual urine) are relieved

May alleviate irritative symptoms (urgency, frequency, nocturia)

Side Effects

Palpitations, Postural hypotension, Nasal blockage, loose motions, Fluid retention, Inhibit ejaculation

and impotence



Drugs – terazosin, doxazosin, tamsulosin

7. Migraine e.g. ergotamine

Beta-Receptor Antagonists (Blockers)

Beta-adrenergic blockers are competitive antagonists

1.0 CLASSIFICATION

1. First Generation -1 and 2 Non-selective e.g. propranolol, sotalol, timolol

2. Second Generation - 1 selective e.g. 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 – pindolol

2.0 PHARMACOLOGICAL ACTIONS

1. Cardiovascular system 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 4. Reduce lignocaine 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



Lesson 4: Autacoids 1 – Histamine and Antihistamines

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

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. 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) They are found on smooth muscle of the GIT, respiratory tract, endothelium and the brain and generally produce and mediate most of the peripheral actions.. 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 inotropism resulting in vasodilatation and bronchodilatation. It is a potent stimulator of gastric secretion.

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

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).



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 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.

1. Cardiovascular system 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 ↓plasma volume

Coronary vasoconstriction (H1) and coronary vasodilatation(H2) b. Blood pressure – reduced due to vasodilatation of blood vessels c. Heart



Increases sinus rate (positive chronotropic effect), amplitude of ventricular contraction (positive inotropic) and coronary blood flow

Impairs A-V conduction and 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 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

1. Hypotension 2. Flusing 3. Tachycardia 4. Headache 5. Bronchoconstriction 6. G.I.T upsets 7. Weals 8. Visual disturbances 9. Dyspnoea

Histamine Antagonists (Antihistamines)

The effects of histamine can be reduced or opposed in three ways namely: Physiological antagonists, Release inhibitors and Histamine receptor antagonists

TALKING POINT

1. What is the role of histamine in the body?

2. How does histamine contribute to disease process?

3. How can we utilize histamine in the process of

management of patients?



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- 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.

1.0 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 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

2.0 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, atopic dermatitis 4. Vascular disorders - Angioedema 5. Hypersensitivity reactions – Urticaria, pruritis, angioedema, conjunctivitis 6. Sedation 7. Miscellaneous – migraine, sedation, nausea and vomiting (emesis) in pregnancy and motion

sickness (Traveller’s sickness) vestibular disturbances e.g. phenargn

3.0 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

4.0 CLASSIFICATION OF H1 RECEPTOR ANTAGONISTS

A. First Generation (Sedating)

a) Ethylenediamines

Tripelennamine, Mepyramine (pyrilamaine) b) Ethanolamines

Diphendyramine (Benadryl) 25 – 50 mg T ½ ( 32 Hours)

Cinarrizine (stugeron)

Doxylamie, Dimenhydrate, Clemastine

c) Alkylamines

Brompheniramine (Dimetane) 4 – 8 mg

Chlormpheniramine (Piriton) 4 – 8 mg T ½ ( 20 Hrs)

Dexchlorpheniramien, Triprolidine, Acrivastine

d) Piperadines

Chlorcyclizine, Hydroxyzine

e) Piperazines

Hydroxyzine 15 – 100 mg

Meclizine, Cyclizine f) Tricyclics

Phenothiazine derivatives - Promethazine (Phenargan) 10 – 25 mg T ½ ( 32 Hrs)

Cyproheptadine (Periactin) 4mg

Ketotifen

Ebastine, Azatadine



B. Second Generation (Non- Sedating)

These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1-receptors in the CNS

Therefore, these drugs provide the same relief with many fewer adverse side effects

The structure of these drugs varies and there are no common structural features associated with them

They are however bulkier and less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily

a) Piperidines

Terfenadine (Triludan) 60 mg

Cetirizine (Zycet, cetrizect, atrizin) T ½ ( 7 Hours)

Fexofenadine (Telfast) 60 mg

Loratadine, Astomizole 10 mg

b) Others

Loratidine (Claritine) T ½ ( 15 Hours)

Azelastine, Acrivastine, Astemizole

Levocabastine, Olopatadine

C. Third Generation (Non- Sedating) Examples

Levocetirizine, Deslortadine, Fexofenadine

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.



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)

Indications 1. Peripheral vascular disease 2. Motion sickness 3. Vestibular disorders – vertigo, tinnitus 4. Nausea and vomiting

Precautions Severe heart failure

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)

Side Effects

Drowsiness, dry mouth, blurred vision, allergic

reactions, skin rashes and fatigue



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

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

Side Effects

Anorexia, increased appetite, taste perversion,

dyspepsia, gastritis, stomatitis, enlarged abdomen,

eructation, flatulence, constipation, malena, rectal

haemorrhage and pregnancy (risk category B2)



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)

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 Prophylaxis and treatment of: - 1. Allergic asthma 2. Rhinitis 3. Skin reactions Precautions 1. ral 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 1. Terfenadine (histadin, zenad) 2. H2 Receptor Antagonists

Side Effects

Drowsiness, headache, nausea, dry mouth, weight gain,

impaired reactions and CNS stimulation.

Read about H2 and H3 antagonists



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 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

Serotonin Agonists

Serotonin agonists are used clinically because of their selective effect. They include -

1. 5HT1 agonists e.g. sumatriptan. 5HT1 agonists are used for prophylaxis and treatment of migraine, vascular (cluster) headache, post-dural puncture headache because of their vascular effect (serotonin is a vasocontrictor except in skeletal muscles)



2. 5HT4 agonists in G.I.T – are useful in motility disorders like reflux oesophagitis; e.g. cisapride and tegaserod.

3. Selective Serotonin Re-uptake Inhibitors (SSRIs) used as anti-depressants. They allow serotonin to accumulate in the serotonin receptors leading to mood elevation.

4. Ergot alkaloids e.g. ergotamine and ergometrine have serotonin selective activity

Serotonin Antagonists

They are grouped as: -

a. Non-selective blockers – -adrenergic and histamine receptors e.g. chlorpromazine (largactil) and phenoxybenzamine.

b. Selective serotonin receptor blockers

i. 5HT2 blockers – e.g. cyproheptadine that also blocks histamine and muscarinic receptors. They

are also useful in carcinoid tumours and post-gastrectomy dumping syndrome. The side effects include stimulating appetite, sedation and secretion of insulin and growth hormone.

ii. 5HT2c blockers e.g. ketanserin, used in hypertension and peripheral vasospastic disorders iii. 5HT3 blockers, which are, concentrated in areas postrema and myecentric plexus. Examples –

ondansetron, tropisetron, grainsetron, dolasetron and alosetron. They are useful in the treatment and prophylaxis of vomiting of post-anaesthesia, vomiting following chemotherapy. They are not useful in morning sickness because receptors for motion sickness are histaminergic and muscarinic.

Ergot Alkaloids

Ergot alkaloids are usually produced by a fungus (Claviceps purpurea) found in wet or spoiled grain. Some are semi synthetic derivatives used ad therapeutic agents. The ergot alkaloids are partial agonist at the a-adrenoceptors and 5HT receptors while some are agonist at dopamine receptors. Classification They are classified based on the organ or tissue in which they have their primary effects.

1. Vessels

Marked and prolonged a-receptor mediated vasoconstriction e.g. ergotamine (overdose results in ischaemia and gangrene of the limbs)

2. Uterus

Powerful contraction in the tissue especially near term e.g. ergonovione. The uterine contraction is sufficient to cause and abortion or miscarriage but higher doses are required to produce this effect in early pregnancy. It is useful (ergovonine) or ergotamine in producing contraction of the uterus and reduced blood loss after delivery of the placenta.

3. Brain

Hallucinations may be prominent especially with lysergic acid diethylamine (LSD) a semi synthetic agent.

In the pituitary, bromocriptine and pergolide act via dopamine D2 receptors to inhibit prolactin secretion.



Clinical Uses 1. Migraine – ergotamine for acute attacks; ergonovine and methysergide for prophylaxis 2. Obstetric bleeding – ergonovine and ergotamine for reducing post-partum bleeding 3. Hyperprolactaemia and Parkisonism – bromocriptine and pergolide 4. Others – carcinoid tumours Side Effects 1. Ischaemia and gangrene 2. Hyperplasia of connective tissue 3. G.I.T upsets – nausea, vomiting and diarrhoea 4. Marked uterine contraction 5. Halluscinations resembling psychosis especially with LSD

Eicosanoids

Eicosanoids are a group of endogenous fatty acid derivatives produced from arachidonic acid. They include – prostaglandins (PG), thromboxane A (TXA), prostacyclin (PGI2), leukotrienes (LT) and platelet activating factors (PAF).

1.0 SYNTHESIS OF EICOSANOIDS

Arachidonic acid is an integral part of the lipid membrane of the cell. It is broken down by enzyme phospholipase A. active eicosanoids are synthesized in response to a wide variety of stimuli (physical, injury, immune reactions) which activates phospholipases in the cell membrane or cytoplasm ands arachidonic acid is released from the membrane phospholipids.

Arachidonic acid is then metabolized via one of the following mechanisms: -

1. Metabolism to straight chain products under the influence of enzyme lipoxygenase to produce leukotrienes.

2. Cyclization by the enzyme cyclo-oxygenase (COX) producing prostacyclin, prostaglandins and thromboxane. COX exists in two forms of COX-1 (found in many tissues and the prostaglandin produced in these tissues is important for several normal physiological processes such as GIT mucosal integrity, platelet aggregation and renal function) and COX-2 (found primarily in inflammatory cells and is responsible for mitogenesis, female reproduction, bone formation, mediates fever and renal function)

2.0 PROSTAGLANDINS

Introduction

Prostaglandins are lipid soluble substances with a variety of physiological actions and effects.

Nomenclature

Prostaglandin is designated PG and a third letter is added to denote the cyclopentane ring attached to

the molecule e.g. PGAG. Most of the PG drugs used fall under PGE, PGF and PGD. A subscript is



added to denote the number of double bonds on the cyclopentane ring e.g. PGE1, PGE2 and PGE3.

Alpha () or beta () are added to denote hydroxyl group e.g. PGF Diagram 5.1: Synthesis of Prostaglandins

Mechanism of Action

Once released PG acts on the cell surface receptors, which are linked to adenyl cyclase activity leading to either increased or reduced cAMP levels in the cell. Some of the receptors act via IP3. Specifity depends on the receptor and type of cell. PG predominantly increase or decrease cAMP activity. Prostacyclin acts through the nitric oxide cascade system leading to relaxation of smooth muscles.

Metabolism

Many tissues metabolize PG and other eicosanoids

Major sites – lungs, liver

Excretion – bile or urine

95% metabolized in the lungs

Effect on Organ System

1) Kidney

Pg modulates RAAS

Diuresis

PGE and PGI2 – renal vasodilatation



2) Haematological/blood

Intense platelet aggregation (TXA2, as serotonin)

Decreased platelet aggregation (prostacyclin PGI2– most potent inhibitor through reduction of cAMP)

There is usually a balance between the two

Leukotriens – potent chemotactic agent 3) Cardiovascular system – effects via ANS, adrenaline and noradrenaline

PGE2 - heart rate, positive ionotropic effect and contractility which is direct and they cause sympathetic reflex discharge; Leads to reduced BP because it decreases systematic vascular reactivity

PGI2 – Causes vasodilatation, peripheral vascular resistance and a shock-like state

TXA2 – Vasoconstriction

PGE – vasodilatation, inhibition of platelet, relaxation of smooth muscle in the G.I.T and uterus

PGD2 – vasodilatation 4) Pulmonary circulation

PGF and PGD2 – constriction in pulmonary circulation

PGE series – relaxation of pulmonary vascular bed

PGI2 – potent pulmonary vasodilator and decreases pulmonary vascular bed resistance

5) Lungs

PGE2a and TXA – bronchoconstriction 6) G.I.T

PGE – inhibit gastric acid secretion from parietal cells, increases gastric blood flow, promote healing and cytoprotection

7) Immune system

PG – signs and symptoms of inflammation 8) Central nervous system

PGE2 , PGF and PGI2 mediate pyrogen induced fever; GD2 – mediates sleep (sleep-wake up cycle); PGE – mediates nociception; PGE and PGI – sensitise neurones to pain; LTB4 – inflammation and hyperalgesia

9) Endocrine

PGE2 – increases secretion of the following hormones – ACTH, GH, prolactin, gonadotropin, steroids, insulin, thyroid and progesterone

10) G.U.T 11) Eyes - PGE and F series lower intra-ocular pressure by increasing the flow of aqueous humour

Therapeutic Uses of Prostaglandins

1) Gynaecological – PGE2 and PGF2are involved in contraction of the uterus – used as abortifacient

( effect of uterine muscle tone, cause luteolysis and secretion of progesterone ) 2) Obstetrics – for ripening the cervix at term (PGE2 – dimoprostone; common preparations –

carboprost, dimoprost, 3) Gastrology 4) Cardiology 5) Ophthalmology 6) Organ transplant 7) Kidney/urology

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