Download CHOLINERGIC AND NORADRENERGIC SYSTEM

AUTONOMIC PHARMACOLOGY
NERVOUS SYSTEM
The Nervous system has two divisions i.e :
Central Nervous System:
Brain and spinal cord
Peripheral Nervous System:
Somatic system
Autonomic system (ANS)
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM
THE NEURON
The nervous system is
made of nerve cells or
neurons and glial cells.
Glial cells are not
excitable and provide
metabolic and physical
support for the neurons.
90% of the cells are glial
cells. Neurons are
excitable and control
behavior
NERVE CELL
ACTION POTENTIAL GENERATION
SYNAPTIC JUNCTION
NEUROTRANSMITTER RELEASE
At rest Neurotransmitters are stored in vesicles in the nerve
terminals.
• Vesicles are held in place by Ca2+ sensitive VAMPS( vesicle
associated membrane proteins) which bind to actin filaments,
microtubules and various elements of the cytoskeleton
•When action potential reaches terminal of presynaptic neuron
there is influx of Ca2+ which leads to freeing of neurotransmitter
containing vesicles.
NEUROTRANSMITTER RELEASE
•The free vesicles migrate to the active zone where Docking takes
place.
•Fusion occurs, i.e, the vesicle membrane and presynaptic membrane
fuse/connect to form an opening/pore . The pore grows larger
until the vesicle membrane collapses into the presynaptic
membrane and releases its contents into the synapse via exocytosis.
PERIPHERAL NERVOUS SYSTEM:
Somatic NS
conscious senses and voluntary muscles
Autonomic NS
unconscious senses and involuntary muscles
AUTONOMIC NERVOUS SYSTEM (ANS)
Responsible for:
Glandular secretion
Smooth muscle control
Metabolic regulation
Via hormone secretion
Extrinsic cardiac regulation
AUTONOMIC NERVOUS SYSTEM
2 divisions:
 Sympathetic
 “fright, fight or flight”
 “E” division
 Exercise, excitement, emergency, and embarrassment
Parasympathetic
“Rest and digest”
“D” division
Digestion, defecation, and
diuresis
AUTONOMIC NERVOUS SYSTEM (ANS)
Two fibre system: pre and post ganglionic fibres
All preganglionic fibres make synapses with clusters of neurons
outside the CNS (ganglion)
PARASYMPATHETIC SYSTEM
Actions:
1. Decrease heart rate
2. Noisy breathing (bronchial constriction)
3. Small pupils (contraction of the circular muscle)(miosis)
4. Increased salivation
5. Increased gut motility
PARASYMPATHETIC SYSTEM
Preganglionic
fibre
Ganglion
Effector
tissue
Postganglionic
fibre
PARASYMPATHETIC SYSTEM
•Preganglionic fibres are Long
•Ganglia close to or within organs innervated
SYMPATHETIC SYSTEM
Actions:
 Increased heart rate and force of contraction
 Blood vessels constrict (especially in the skin and viscera)
Skeletal muscle blood vessels dilate so muscles can get more blood
 Pupils dilate (contraction of radial muscles)(mydriasis)
 Bronchioles dilate
This is not due to a direct innervations by sympathetic nerves. Instead, adrenaline
released from the adrenal glands cause the dilation
Blood sugar rises
Hair becomes erected on skin
SYMPATHETIC SYSTEM
Ganglion
Effector
tissue
Preganglionic
fiber
Postganglionic
fiber
NEUROTRANSMITTERS & TYPICAL PATHWAYS
All preganglionic neurons release Ach
Almost all sympathetic neurons release NA
Exceptions:
Sympathetic postganglionic neurons of sweat glands release Ach
Sympathetic neurons of the renal vascular beds release dopamine
Postganglionic parasympathetic neurons release Ach
TYPICAL PATHWAYS
CHOLINERGIC SYSTEM
Cholinergic neurons secrete acetyl choline (Ach) when activated
ACETYL CHOLINE SYNTHESIS:
Precursor – choline and acetyl CoA
Enzymes – ChAT ( Choline acetyltransferase)
Choline + Acetyl coenzyme A→ Acetylcholine + Coenzyme A
CHOLINERGIC RECEPTORS
Muscarinic:
M1 CNS
M2 Smooth muscle, heart, presynaptic
M3 Exocrine glands, blood vessels
Nicotinic:
NM skeletal muscle
NN ganglia (post-), presynaptic
CHOLINOMIMETIC AGENTS/ CHOLINERGIC
AGONISTS
Classes:
Direct Agonists:
Choline Esters
Alkaloids
Indirect Agonists:
All are AchE ( Acetylcholinesterase) inhibitors
Quaternary ammonium cpds (Carbamates/endrophonium)
Organophosphates
CHOLINE ESTERS
Acetyl choline
Bethanechol
Carbachol
Methacholine
 Characteristics:
• Poorly absorbed and poorly
distributed
• Hydrolyzed by cholinesterase
CHOLINOMIMETIC ALKALOIDS
Pilocarpine
Muscarine
Nicotine
Lobeline
Characteristics:
 Well absorbed (skin absorption in case of nicotine)
 Excreted by urine ( enhanced by urine acidification)
INDIRECT AGONISTS: QUATERNARY AMMONIUM
COMPOUNDS
Physostigmine
Pyridostigmine
Neostigmine
Edrophonium
Characteristics:
• Charged molecules
• Poor absorption from most sites
• Poor CNS distribution
• Stable in aqueous solutions
• Physostigmine is lipid soluble, well absorbed, and distributed into the CNS
INDIRECT AGONISTS: ORGANOPHOSPHATES
Echothiophate
Parathion
Malathion
Soman
• Organophosphates are well absorbed from most sites and well distributed
including CNS (except ecothiophate)
• Unstable in aqueous media
• Parathion and malathion are prodrugs that require metabolic activation
ACETYLCHOLINESTERASE MECHANISM OF ACTION
Hydrolyses Acetylcholine to Acetic acid and Choline
The active site of AChEs is made up of two subsites; anionic and
esteratic
The anionic site serves to bind a molecule of Acetylcholine to the
enzyme, once the Ach is bound, the hydrolytic reaction occurs at the
second region of the active site i.e the esteratic subsite
Edrophonium and tacrine react only at the anionic site while
organophosphates react only at the esteratic site
CLINICAL APPLICATIONS OF CHOLINOMIMETIC
AGENTS
Pilocarpine ( Alkaloid from the leaves of Pilocarpus
microphyllus):
• Glaucoma
Neostigmine:
• Myasthenia gravis: Skeletal muscle contraction
• Postoperative abdominal distension; Urinary retention
• intoxication with atropine
CLINICAL APPLICATIONS
• Pilocarpine
used to increase salivary secretion e.g radiation
damage of the salivary glands.
MUSHROOM POISONING
Muscarine is an Alkaloid from the mushroom e.g Amanita Muscaria
No Clinical use
Symptoms are characteristic of Muscarinic actions; Salaivation, Lacrimination,
Bronchospasm, Diarrhoea, convulsions, coma
Antidote is Atropine Sulphate
Hallucinogenic type: due to ibotenic acid present in some mushroom. Blocks
muscarinic receptors in the brain and activate amino acid receptors. No
specific treatment, Benzodiazepines can be used to sedate patients.
ANTICHOLINERGIC AGENTS
•Antimuscarinic drugs
•Ganglion Blockers
ANTIMUSCARINIC DRUGS
Bind to Muscarinic Receptors to inhibit agonistic actions
Examples include;
ATROPINE (prototype)
SCOPOLAMINE
GLYCOPYRROLATE (Peptic disease
DICYCLOMINE ( hypermotility)
TROPICAMIDE (mydriatic,)
IPRATROPIUM (ASTHMA)
ATROPINE
Mechanisms of Action:
•Muscarinic antagonists
•is a competitive antagonist of Muscarinic receptors
•Well absorbed and widely distributed including CNS
ATROPINE: PHARMACOLOGICAL ACTIONS
AND CLINICAL USES
Reversible blockade of cholinomimetic actions: most sensitive are salivary,
sweat, bronchial glands.
glands: secretion↓preanaesthesia medication agent
Eye: 1) mydriasis : exam of retina
 smooth muscle: relax spasmodic smooth muscle
gastrointestinal spasm; bladder disorders; biliary and renal colic (with
analgesics), asthma.
ATROPINE: PHARMACOLOGICAL ACTIONS
AND CLINICAL USES
. Used to counter intoxication by organophosphorus compounds
ADRENERGIC PHARMACOLOGY
WHAT THESE RECEPTORS DO
Alpha 1
Vasoconstriction, ↑ BP, ↑ tonus sphincter muscles
Alpha 2
Auto-receptors inhibit norepinephrine, in the pancreas
inhibit insulin release
Beta 1
Tachycardia, ↑ lipolysis, ↑ myocardial contractility
Beta 2
Vasodilation, bronchodilation, ↑insulin release
ADRENERGIC AGONISTS
Direct
 Epinephrine
 Salbutamol
 Dobutamine
 Dopamine
 Isoproteranol
Indirect
 Amphetamine
Mixed
 Ephedrine
ADRENERGIC AGONISTS
Direct Acting:
Epinephrine: Interacts with both alpha and beta
Low dose: mainly beta effects (vasodilation)
High dose: alpha effects (vasoconstriction)
Therapeutic uses: emerg. Tmt. of asthma, glaucoma, anaphylaxis
ADRENERGIC AGONISTS
Direct Acting:
 Ephedrine: pure alpha1 agonist
 Therapeutic uses: mydriatic and decongestant; may be used in hypotensive
states
 Midodrine: prodrug of desglymidodrine, alpha1 selective
 Therapeutic uses: orthostatic hypotension
ADRENERGIC AGONISTS
Direct Acting:
Clonidine, methyldopa, guanfacine: Interacts alpha2 receptors
Used for hypertension; S/E sedation
Dobutamine: beta 1 selective; used in CCF
Albuterol: beta2 selective; used for asthma
ADRENERGIC AGONISTS
Indirect Acting:
Cause NE release only
Amphetamine
CNS stimulant
Increases BP by alpha 1 effect on vasculature, & beta effect on
heart
ADRENERGIC AGONISTS
Indirect Acting:
 Tyramine
 Produced by decarboxylation of tyrosine in food
 Metabolized by MAO, can cause tyramine reaction with some MAO
inhibitors
 Increases BP
MIXED-ACTION
Causes NE release AND stimulates adrenoceptors
Ephedrine, pseudoephedrine, phenylpropanolamine:
Alpha and beta stimulants
Use: asthma, nasal sprays (decongestants)
ADRENERGIC ANTAGONISTS
Includes alpha blockers and Beta blockers
Alpha blockers
Reversible: terazosin (selective), phentolamine (non-selective)
Irreversible: phenozybenzamine
Beta blockers
Selective: metoprolol
Nonselective: propranolol
ADRENERGIC ANTAGONISTS
Alpha blockers
Prazosin
Selective alpha 1 blocker
Tmt: hypertension
Relaxes arterial and venous smooth muscle
Causes “first dose” response (what is this?)
ADRENERGIC ANTAGONISTS
Alpha blockers
 Phentolamine
 Nonselective reversible alpha blocker
 Tmt: phaeochromocytoma
ADRENERGIC ANTAGONISTS
Alpha blockers
Phenoxybenzamine
Irreversible blocker of alpha 1 receptors
Tmt: phaeochromocytoma,
Active orally
A/E: orthostatic hypotension, tachycardia
ADRENERGIC ANTAGONISTS
Beta Blockers
Example: Propranolol
Non-selective (blocks beta 1 and beta 2)
Effects:
↓ cardiac output, vasoconstriction, bronchoconstriction
ADRENERGIC ANTAGONISTS
Eg: Atenolol, Metoprolol
Preferentially block beta 1; no beta 2 effects
Partial Agonists:
Pindolol, acebutolol
Weakly stimulate beta 1 and beta 2
Causes less bradycardia
ADRENERGIC ANTAGONISTS
Eg: Nadolol
Nonselective beta blocker
Used for glaucoma
Eg: Labetolol
Alpha AND beta blocker
Used in treating Pregnancy induced hypertension