2. 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)
2
3. Difference between Somatic NS and ANS
Somatic NS
concerned with
consciously controlled
functions
e.g. Movement , Respiration
Innervate skeletal muscle
consist of a single motor
neuron
Has no peripheral ganglia
Effect is always excitation
Autonomic NS
activities are not under conscious
control
*concerned primarily with visceral
functions: Regulation of the heart,
temp., secretary glands, digestion,
metabolism
Innervate visceral organs
consist of two motor neurons in
series
Has ganglia b/n pre-synaptic and
post synaptic
Effect is both excitatory &
inhibitory 3
4. 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
5. 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
5
7. 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
7
8. 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
8
10. Important terminology
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 (anticholinergic or parasympatholytics)
– are agents which block/ oppose the actions of Ach
10
11. Adrenergic neurons
– are neurons which synthesis, store & release EP and 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, EP
– are also called sympatholytics/sympathoplegics
11
12. 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
12
15. 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)
15
16. 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)
16
19. 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 acetylcholinesterase /AChE
To acetate & choline
6. Recycling of choline
19
22. Cholinergic Drugs
1. 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
22
24. 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
24
25. 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
25
29. 29
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
30. Contraindication to cholinomimetics
– Bronchial asthma
– GIT hyper-motility
– Peptic ulcer disease
– Coronary artery disease
– Hypotension
– Bradycardia
– Hyperthyroidism: may cause atrial fibrillation
30
32. 2. 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 (Nn)
– Neuromuscular blocking drugs (Nm)
32
33. 33
Target Effect Use Drug
Glands secretion PUD Pirenzepine, Telenzepine
Eye Mydriasis Ophthalmic
examination
Atropine, Tropicamide,
Cyclopentolate
Urinary
bladder
tone with
constriction
Urinary
incontinency
Tolferodine, Darifenacin,
Fesoterodine
GI smooth
muscle
motility with
tone
Hyper motility Hyoscine
CNS Block all
muscarnic
-motion sickness
-parkinsonism
-Hyoscine/ scopolamine
-Benzotropine
Respiratory Relaxation Asthma Ipratropium, Tiotropium
Antimuscarinics…
34. 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
34
36. Adrenergic drugs
1. Adrenomimetics
• Drugs which activate the effects of adrenergic SN
stimulation
• Also called sympathomimetics
• Have a wide range of effects
36
38. – 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 upregulation
Examples: NE, EP, DA, IP, Dobutamine, phenylephrine,
albuterol, salmeterol, metaraminole, terbutalin, clonidine,
oxymethazoline
38
39. 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. selegiline, rasagiline, entacapone, tolcapone
• Their response is abolished by prior administration of reserpine or
guanethidine
39
40. 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
40
42. Catecholamines
Derivatives of β-phenyl ethylamine
When 3,4 OH is added to phenyl ring (3,4 OH)→ catechol ring
Hence, catechol ethyl amine→catecholamines
Phenyl ring
42
Ethyl amine
43. 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.
43
44. 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 superficial 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
45. α1 adrenergic agonists
• Phenylephrine
• Xylomethazoline
• Methoxamine
• Use:
1) Nasal decongestant
2) To raise BP in hypotensive state & shock
45
46. Alpha 2 - adrenergic agonist
Methyldopa (aldomet)
• MOA - sympathetic outflow,
• Use: moderate to severe hypertension in pregnant mom.
• Dose: initial 250mg 2-3X/day
– Usual dose range 250mg -1000mg po bid.
• AE:
– headache, fatigue, sleep disturbance
46
47. 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
47
48. 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)
48
49. 2. 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
49
52. 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), first dose syncope (fainting)
52
53. -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, 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
54. • Some of the β-blockers have some intrinsic activity &
membrane stabilizing activity
– May be considered as partial antagonists
– Examples
• Pindolol
• Acebutolol
• Bucindolol
54
55. β – Blocker: Therapeutic use
Hypertension- alone or with diuretic
For angina treatment: by decreasing cardiac work with
oxygen demand
For chronic heart failure… only metoprolol, bisoprolol & carvedilol
For cardiac arrhythmia
Glaucoma treatment: Timolol
Anti anxiety related to performance: Propranolol
Prophylaxis of migraine
55
60. Assignment
1. Management of Shock (types, pathophysiology of shock
and their management).
2. Pharmacology of anesthetics (local anesthetics and
general anesthetics)
3. Management of Neurodegenerative disorders
(Alzheimer’s disease, Huntington disease, multiple
sclerosis….)
4. New drug development process (preclinical trial and
clinical trials)
5. Management of selrected cardiovascular disorders
(myocardial infraction, ischemic stroke, haemorrhagic
stroke, valvular heart disease).
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