Chapter two

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 Nervous System

Peripheral nervous Central nervous

system (PNS) system (CNS)

Afferent Efferent Brain Spinal

(sensory) (motor) cord

Somatic nervous Autonomic nervous

system (SNS) system (ANS)

Sympathetic Parasympathetic Enteric nervous system

(thoraco-lumbar) (Cranio-sacral)
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 Difference between Somatic NS and ANS

Somatic NS Autonomic NS
 concerned with  activities are not under conscious
consciously controlled control
functions *concerned primarily with visceral
e.g. Movement , Respiration functions: Regulation of the heart,
temp., secretary glands, digestion,
metabolism
 Innervate skeletal muscle  Innervate visceral organs
 consist of a single motor  consist of two motor neurons in
neuron series
 Has no peripheral ganglia  Has ganglia b/n pre-synaptic and
post synaptic

 Effect is both excitatory &
Effect is always excitation
inhibitory 3
 ANS Functions
Sympathetic nervous system functions
1. Regulating the cardiovascular system
 Increase cardiac output
 Causes vasoconstriction

2. Regulate body temperature

 By regulating blood flow to the skin
 By promoting secretion of sweat, thereby helping the body
to cool
 By inducing piloerection (erection of hair) can promote
heat conservation 4
 Sympathetic nervous system functions……..

3. Implementing the “ fight – or – flight” reaction which consists

 Increasing heart rate and blood pressure

 Shunting blood away from the skin and viscera into skeletal
muscles
 Dilating the bronchi to improve oxygenation
 Dilating the pupil to enhance visual acuity

 Mobilizing stored energy

 thereby providing glucose for the brain and fatty acids for
muscles
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 Parasympathetic nervous system functions

 maintains essential bodily functions

• such as digestive processes, elimination of wastes and is

required for life
 usually acts to oppose or balance the actions of the sympathetic
division
– Is dominant over the sympathetic in “rest and digest”
situations

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 Functions of parasympathetic nervous system

• Slowing the heart rate

• Increase gastric secretion
• Emptying of the bladder
• Emptying of the bowel

• Focusing the eye for near vision

• Constricting the pupil
• Contracting bronchial smooth muscle

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 Definition

 Cholinergic neurons

– are neurons which synthesis, store & release Ach

 Cholinomimetics

– are those agents which mimic the activity of Ach

– Are also called parasympathomimetics
 Chlinoreceptors

– are binding site for Ach & cholinomimetics

 Cholinoreceptor antagonists

– are agents which antagonize the actions of Ach

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 Adrenergic neurons
– are neurons which synthesis, store & release NE

 Adrenomimetics
– are agents which mimic the activities of NE
– Are also called sympathomimetics
 Adrenoceptors

– are binding sites for NE, EP & adrenomimetics

 Adrenoceptor antagonists

– are agents which antagonize the activities of NE

– are also called sympatholytics/sympathoplegics
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 Autonomic receptors

• Includes cholinergic and adrenergic receptors

Cholinergic receptors
• Two types: muscarinic & nicotinic cholinoceptors

Muscarinic receptors
• Are activated by muscarine (plant alkaloid)
• Found in many visceral organs such as smooth muscle cells,
cardiac cells, exocrine glands, CNS, Autonomic ganglia
• Further classified into M1, M2, M3, M4 & M5

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Muscarinic Receptor Activation

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Muscarinic Receptor Activation

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 Cholinergic receptors ………..

Nicotinic receptors
• Activated by nicotine (tobacco alkaloid)
• Based on their location nicotinic Ach receptors are grouped
into two types
– Nn (at ganglia)

– Nm (at neuromuscular junction)

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Adrenoceptors
– Interact with NE, EP & other related drugs

– Two types

1. α-adrenoceptors (α-1, α-2)

2. β-adrenoceptors (β-1, β-2, β-3)

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 Adrenoceptors
Receptor Location Effect
Alpha1 (α1) Effector tissues: ↑ Ca2+, causes contraction,
smooth muscle, glands secretion

Alpha2 (α2) Nerve endings, some ↓ Transmitter release (nerves),

smooth muscle causes contraction (muscle)

Beta1 (β1) Cardiac muscle, ↑ Heart rate, ↑ force; ↑ renin

juxtaglomerular release
apparatus
Beta2 (β2) Smooth muscle, liver Relax smooth muscle; ↑
glycogenolysis

Beta3 (β3) Adipose cells ↑ Lipolysis

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 Neurotransmission

• Involves
– Synthesis
– Storage

– Release

– Interaction
– removal

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 Steps in cholinergic neurotransmission

1. Synthesis of acetyl choline (ACh)

 From choline and acetyl CoA which catalyzed by choline acetyl

transferase

2. Up take to storage vesicle

3. Release of acetyl choline by exocytosis

4. Binding to receptor

5. Degradation of acetyl choline by cholinesterase

 To acetate & choline

6. Recycling of choline
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Cholinergic neurotransmission

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Adrenergic neurotransmission

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 Cholinomimetic drugs

• Similar effects to acetylcholine (Ach)

• Elicit all or some of the effects of Ach

• Classified as

1. Direct acting

 Cholinergic receptor agonists

2. Indirect acting

 acetyl cholinesterase enzyme inhibitors (AchEIs) also

called anticholinesterase

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Cholinomimetic drugs

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 Direct Cholinergic Agonists
 Choline esters: Methacholine, Carbachol, Bethanechol

 Alkaloids: Muscarine, Pilocarpine, Arecholine

 Differ from Ach
Have longer duration of action

Effective orally & parenterally

Relatively more selective in their actions
But, still less potent than Ach

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 Cholinomimetic drugs: therapeutic use
a) Pilocarpine
• Use: Glaucoma, xerostomia, reverse mydriatic effects of
atropine
• Dose: 1–2 gtts TID in eye 1–6 times/d
• SE: Temporary reduction in visual acuity, headache
b) Bethanecol
• Use:
1) Urinary retention - because relax urinary sphincter
2) Gastric atony
3) Paralytic ileus
• CI: gastric ulcer, recent surgery of the bowel, asthma
• Dose: 10-15mg po tid or QID, 5mg SC QID
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 Anticholinesterases drugs

Irreversible
Reversible

• Carbamates • Organophosphates
• Physostigmine • Diisoproyl fluorophosphates
• Neostigmine • Echothiophate
• Pyridostigmine
• Parathion
• Malathion
• Demecarium • Diazinon (Tlk-20)
• Rivastigmine • Tabun Nerve gases for
• Phenol • Sarin chemical warfare
• Edrophoniuim • Soman

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 Anticholinesterases: therapeutic uses
1) Paralytic illeus or bladder atony - Neostigmine 0.5mg sc
2) Glaucoma: Physiostigmine
3) Alzheimer's disease: donepezil
4) Mayesthenia glavis
– Pyridostigmine: 30-60mg oral
– Neostigmine: 7.5-15mg oral
– Ambenonium: 2.5-5mg oral
5) Insecticide (irreversible ACEI)
– Result in bradycardia, hypotension, bronchospasm
– Parathion, malathion
 Note: poisoning with anti cholinesterase can be treated by
atropine.
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Properties of Indirect-Acting Cholinomimetics

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 Treatment

– Maintenance of respiration

– Atropine parenterally in large doses

– Pralidoxime chloride (2-PAM, or 2-

pyridine aldoxime methyl chloride)

effective as an antidote for poisoning by

phosphate ester AChEIs

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 Contraindication to cholinomimetics
– Bronchial asthma

– GIT hyper-motility
– Peptic ulcer disease
– Coronary artery disease

– Hypotension
– Bradycardia
– Hyperthyroidism: may cause atrial fibrillation

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 Adverse effects

• Choline esters can cause:

– Nausea
– Abdominal cramps

– Salivation
– Diarrhea
– Hypotension
– Reflex tachycardia

– Bronchoconstriction
– Sweating
– Flushing 31
 Cholinergic antagonists
 Cholinergic blockers or anti-cholinergic drugs
 Bind to cholinergic receptor but do not trigger the usual
receptor mediated intracellular effects
 These drugs are classified as:
– Anti-muscarinic agents
– Ganglionic blockers
– Neuromuscular blocking drugs

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 Antimuscarinics…
Target Effect Use Drug

Glands secretion PUD Pirenzepine, Telenzepine

Eye Mydriasis Ophthalmic Atropine, Tropicamide,

examination Cyclopentolate

Urinary  tone with Urinary frequency Tolferodine, Darifenacin,

bladder constriction Fesoterodine

GI smooth  motility with Hyper motility Hyoscine

muscle tone

CNS Block all -motion sickness -Hyoscine

muscarnic -parkinsonism -Benzotropine

Respiratory Relaxation Asthma Ipratropium, Tiotropium

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 Neuromuscular blocking drug
• Succinyl choline, Vecuronium, Mivacurium, Pancuronium,
Rapacurium, Gallamine
• These drugs generally block the action of acetylcholine and
produce different effect.

1) Adjuvant in general anesthesia: muscle relaxation

2) Control ventilation i.e. facilitation of endotracheal intubation

3) Prevention of trauma in electro shock therapy of psychiatric
disorder E.g. Succinyl choline

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Contraindications
– Glaucoma, Cardiac diseases

– Hyperthyroidism, Reflux esophagitis

– Prosthete hypertrophy

Side effects
 Dry mouth
 Urinary retention

 Constipation
 Confusion

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 Adrenomimetics
• Drugs which mimic the effects of adrenergic SN stimulation
• Also called sympathomimetics
• Have a wide range of effects

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 – Adrenomimetics can be classified into three groups

1. Direct acting adrenomimetics

– Directly interact & stimulate adrenoceptors
– Their effects are not reduced by prior treatment with
reserpine or guanethidine
– Prior treatment with reserpine or guanethidine can increase
their effects due to receptor up regulation
Examples: NE, EP, DA, IP, Dobutamine, phenylephrine,
albuterol, salmiterol, metaraminole, terbutalin, clonidine,
oxymethazoline

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2. Indirect acting adrenomimetics
• Don’t interact with the adrenoceptors
• Increase availability of NE/EP to stimulate the adrenoceptors
• Their action emanates from one of the following
– Displace stored neurotransmitters from the vesicles

E.g. amphetamine, tyramine, methamphetamine

– Inhibit reuptake of neurotransmitters into the neuron

E.g. cocaine, TCAs

– Inhibit the metabolizing enzymes (MAO & COMT)

E.g. pargyline, entacapone

• Their response is abolished by prior administration of reserpine or
guanethidine 39
3. Mixed acting adrenomimetics
– Work by both direct & indirect mechanisms

– Increase release of NE & also activate adrenoceptors

E.g. ephedrine
– Their responses are blunted but not abolished by prior
treatment with reserpine or guanethidine

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 Catecholamines
 Derivatives of β-phenyl ethylamine

Phenyl ring Ethyl amine

 When 3,4 OH is added to phenyl ring (3,4 OH)→ catechol ring

 Hence, catechol ethyl amine→catecholamines

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 Catecholamines…..
 These compounds share the following properties:
 High potency: by activating α or β receptors

 Rapid inactivation: metabolized (MAO&COMT)

- have a brief of action when given parentrally, and are

ineffective when administered orally because of inactivation
 Poor penetration into the CNS

- Catecholamines are polar & do not cross BBB

- Nevertheless have some clinical effects that are attributed to

the action of CNS.

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 Adrenaline/Epinephrine
• Stimulate both α with β receptor
Use:
1) Asthma (β2 - selective are better)
2) Anaphylactic shock
3) Potentiation with prolongation of action of local anesthetic
(by  absorption)
4) Restore normal cardiac rhythm in case of cardiac arrest
5) Topical hemostatic agent (control super facial bleeding)
• Dose:
 SC, IM 0.1mg - 0.5mg
 IV - 0.25mg (in emergency an IV can be used but should be
diluted and given by IV infusion because of cardiac
arrhythmia. 44
 α1 adrenergic agonists

• Phenylephrine

• Xylomethazoline

• Methoxamine

• Use:

1) Nasal decongestant

2) To raise BP in hypotensive state & shock

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 Alpha 2 - adrenergic agonist

Methyldopa (aldomet)
• MOA -  sympathetic outflow,  renin secretion

• Use: moderate to severe hypertension

• Dose: initial 250mg 2-3X/day

– Usual dose range 250mg -1000mg po bid.

• AE:

– headache, fatigue, sleep disturbance

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 β2 Agonist
Include
• Salbutamol/albuterol – rapid acting

• Terbutaline

• Formetrol & Salmetrol – long acting (nocturnal asthma)

• Ritodrine-for Preterm Labour

Use

1) Asthma, albuterol 2 puffs every 4-6 hours as needed (90

mcg/inhalation)
2) Premature labour, terbutaline 2.5-5 mcg/minute over 12hrs
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 Ephedrine

• Both α with β agonist (mixed acting)

Use:

1) Asthma - 25-50mg PO 3-4 PRN

2) To treat hypotension

3) Used to relieve broncho-constriction with mucosal

congestion (incorporated in cough syrup)

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 Adrenoceptor antagonists
 Works by competing with adrenomimetics for access to
adrenoceptors
– Reduce effects produced by both sympathetic nerve
stimulation & exogenous adrenomimetics
• Adrenoceptor antagonists
– Don’t prevent release of NE/EP from adrenergic neurons

– Are not catecholamine depleting agents

– Are also called, sympathoplegics, sympatholytics

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 α1 - Blockers

• Use:

– Hypertensive crisis
– Short term control of BP in pheochromocytoma

– Drug choice for HTN with benign prostate hyperplasia

(BPH)
• SE:
 orthostatic hypotension, headache, water retention
(relaxation)
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 -Blockers

A. Non selective -Blockers

– Are also called 1st generation -blockers
– Propranolol, Timolol, Nadolol, Pindolol

B. Cardio selectives [1Blockers ]

– Are called 2nd generation -blockers
– Atenolol, Acebutolol, Bisoprolol, Esmolol, Metoprolol

C. Non-selective adrenergic blockers( &  Blockers)

– Are also called 3rd generation -blockers
– Carvedilol, Labetalol, Bucindolol, Nebivolol
Longest half life: Nadolol, Cartelol (24 hrs)
Shortest half life: Esmolol (10 min) 53
• Some of the β-blockers have some intrinsic activity &
membrane stabilizing activity
– May be considered as partial antagonists
– Examples
• Pindolol

• Acebutolol
• Bucindolol

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 β – Blocker: Therapeutic use
 Hypertension- alone or with diuretic

 For angina treatment: by decreasing cardiac work with

oxygen demand
 For chronic heart failure

 For cardiac arrhythmia

 Glaucoma treatment: Timolol

 Anti anxiety related to performance: Propranolol

 Prophylaxis of migraine

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 Adverse effects of β-blockers
 CVS

– Bradycardia
More pronounced with 1 selectives
– hypotension
– AV block
 Bronchoconstriction

 Hypoglycemic effect

 Affect lipid profile

 Muscle pain & fatigue Produced by non-

selective blockers
 Sleep disturbances, nightmares

 Impaired sexual activity

 Reduce peripheral blood flow  cold extremities

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 Contraindications to β-blockers

 Acute Heart failure

 Bradycardia

 Slow AV-node conduction

 Asthma & COPD

 Diabetes mellitus

 Hypothyroidism

 Combination with Ca++-channel blockers

 Some general anesthetics- cardiac depression

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