Pharmacology-1Unit-3(Pharmacology of Drug acting on Peripheral nervous system)

a) Organization and function of ANS

ANS(Autonomic Nervous System):-

• It involves involuntary responses(movement) of our body.
•  It further divided into two parts:-

1.  Sympathetic nervous system                                                               
2.  Parasympathetic nervous system

 i)Sympathetic nervous system:

• Fight/flight situation(Abnormal)
•  Activate in condition of fear, flight, fight 
• Those system which active in abnormal situation of body and maintain the body 

example: Increase heart rate, decrease digestion rate etc.

ii)Parasympathetic nervous system:

• Rest and Digest condition 
• In this our body come back to normal condition after any abnormal situation.
•  Also help to maintain the homeostasis of body.

  example:- increase digestion rate and normal heart rate etc.

-Both system are motory function of body.

-Both system are important to maintain the homeostasis and work of our body.

Sl. No	Sympathetic Nervous System	Parasympathetic Nervous System
1	Involved in the fight or flight response	Involved in maintaining homeostasis and also, permits the test and digest response
2	prepare the body for any potential danger	To bring the body to a state of calm
3	Increase heartbeat muscles tense up	Reduces heartbeat, muscles relaxes
4	Pupil dilate	Pupil contract
5	Saliva secretion is inhibited	Saliva secretion increases, digestion increases
6	Neurotransmitter release: Adrenalin and Nor-Adrenalin	Neurotransmitter release: Acetylcholine

b) Neurohumoral Transmission, co-transmission and classification of neurotransmitters:

       Neurohumoral Transmission: 

                    Neuro-nerve/neuron, Humoral-chemical Messenger

•  It is the process of transfer of any message or signal from one neuron to another neuron with the help of any messenger(neurotransmitter, hormones)
•  For this purpose, firstly neurotransmitter synthesized and stored in vesicles in nerve terminals.
•  Now, Neurohumoral transmission involves following steps:- 

      i)Impulse conductance: In this step impulse is generated by the process of "Action potential"

• At resting state(when nerve impulse is not transmitted from neuron) resting transmembrane potential is -70mv
•  Na+ ion have high concentration at outside the cell and more (+) charge at outside the plasma membrane.
•    k+ ion have high concentration at inside the cell and more (-) ve charge at inside the plasma membrane.

        -Resting membrane potential-70m

•   Depolarization: When any kind of stimulus detected, then it changes the resting membrane potential to less potential to less potential.(increase)
• If stimulus change resting potential(-70mv) to (-55mv) then it is called threshold potential.
• Threshold potential open Na+ ion channel, so Na+ ion enters the cell and (+)ve charge produce inside the cell and (-) ve at outside cell and it is called depolarization.
• Repolarization: Stimulus continues increase the potential , now when potential reach at(+20mv to +30mv) it open k+ ion channel and k+ ion move outside the cells.

• The ionic distribution is normalized during the refractory period by the activation of Na+ k+ pump
•  the cycle of depolarization and repolarization is called Action potential.
•   These action potential works 1000 times in one second.

ii)Transmitter release: 

• Nerve impulse promotes fusion of Vascular and axonal membrane, through C++ entry which fluidized membranes.
• This promotes exocytosis(transmitter release from vesicles) in synaptic cleft.

iii) Transmitter action on postjuction membrane: The transmitter release and attached with specific receptor on postjunctional membrane and depending on nature it induce two type of action- EPSP &IPSP

iv) Post Junctional Action

          a)EPSP(Excitatory postsynaptic potential) :

• Increase in permeability to all cation-Na+ or Ca+ influx cause depolarization followed by k+ efflux
• Nerve impulse, contraction in muscle, secretion in glands

    b) IPSP(Inhibitory postsynaptic potential):

•  If inhibitory neurotransmitter act increase in permeability to smaller ion or anions k+ and Cl- moves in resulting  Hyperpolarization
• Resist depolarizing stimulation

iv)Termination of transmitter action: Neurotransmitter is degraded locally or any other mechanism

                >It can also be degraded by enzymatic action.

e.g.:- Acetylcholine degraded by Cholinester 

Co-Transmission:

Peripheral and central nervous system release more than one active substance when stimulated

Definition: Co-transmission is the release of several types of neurotransmitter from a single nerve terminal.

-It is a chemical substance that is released along with primary neurotransmitter

example:-In autonomic nervous system

• Primary neurotransmitter: Ach, NA
• Co-transmitter: Purines:-  ATP, Adenosine                    Peptides: vasoactive intestinal peptide 

 

#On release of acetylcholine(Ach), Glutamate, vasoactive intestinal peptide co-transmitter release

Classification of Neurotransmitter:-

C. Parasympathomimetics, Parasympatholytic, Sympathomimetics, Sympatholytics:

-These all are those drugs which act on Autonomic Nervous system and produce effect on it.

• Adrenergic drugs[ Sympathomimetics]
• Antiadrenergic drugs[Sympatholytics]
• Cholinergic drugs[Parasympathomimetics]
• Anti-cholinergic[Parasympatholytic]

1.Cholinergic drugs [Parasympathomimetics]

Parasympatho-parasympathetic nervous system, mimic -copy the action

• These are those chemical agents or drugs which copy the action of parasympathetic nervous system
• These drugs bind with cholinergic receptors and give their action.
• Acetylcholine is the neurotransmitter in the cholinergic system.
• The neurons that synthesize, store and release of acetylcholine are called as cholinergic neurons.

The sites of release acetylcholine:-

1. Ganglia-All the Preganglionic fibers of ANS
2. Adrenal Medulla
3. CNS-brain and spinal cord
4. Skeletal muscles-somatic nerve endings supplying skeletal muscles.

Classification:

#Cholinergic drugs are chemicals that act the same site as Ach and there by mimic its action. They are called as Parasympathomimetics.

Pharmacological Actions :

 

1.Cardiovascular system:-(M2 receptor)

• Depress auricular muscles
• Decrease contraction of bundle of his AV node
• BP decrease due to vasodilation

2.Eye:-

• Constrict the pupil and cause pupil.
• Intraocular pressure decrease.
• Used in Glaucoma

3. Skeletal Muscles:-

• Constriction of skeletal muscle.
• Useful in myasthenia gravis

4.Respiratory system:-

• Bronchoconstriction
• Induce Asthma

5.Gastrointestinal system:-

• Contract smooth muscle of GIT.
• Increase tone, motility and peristalsis movement.
• increase salivary, pancreatic, liver, gall bladder and intestinal secretions.

Therapeutic uses:

• Acetylcholine is rapidly destroyed in the gut.
• On IV route, Ach is metabolized by pseudo-cholinesterase.
• Acetylcholine is not used therapeutically except occasionally 1% eye drops to produce mitosis rapidly.
• Atropine poisoning 
• Alzheimer's disease.

Adverse effects:-

Parasympathomimetics may cause-

• Nausea
• vomiting
• Bradycardia/Hypotension
• Cause Asthma.

2.Anti-cholinergic[Parasympatholytic]

Parasympatho - parasympathetic nervous system, lytics- oppose the effect

• These are those drugs which inhibit the effect of acetylcholine or Parasympathomimetics by blocking the cholinergic receptors.

Pharmacological Actions:-

1.CNS:- 

• It can cross BBB(Blood Brain Barrier) so it can produce their effect CNS.
• It cause respiratory depression.
• Cause drowsiness and sedative effects.

2.Cardiovascular system:-

    

It block M receptors and cause:

• Increase the heart rate.
• Increase the conduction from SA node.

3.EYE:-

• Cause Mydriasis 

4.Exocrine gland:-

• Decrease secretion of salivary, bronchial, gastric, pancreatic, lacrimal and sweat gland,
• rise in body temperature.

5.GIT:-

• Reduce motility of GIT
• Gastric Juice secretion reduced.
• Used to treat peptic ulcer.

Therapeutic uses:-

• Mydriasis
• Anti-parkinsonism agent
• Pre-anesthetic medication
• Motion sickness
• peptic ulcer
• Bronchial Asthma
• Anti-cold tablets.

Adverse effects-

• Can cause glaucoma in some patients
• Tachycardia.

3.Adrenergic drugs[ Sympathomimetics]

• It involves Sympathomimetics drugs.
• Sympatho- sympathetic nervous system, mimetics- copy the action 
• These are those  chemical agents or drugs  which copy the action of sympathetic nervous system.
• These drugs bind with adrenergic receptors [Alpha&Beta] and give their action.
• e.g. Adrenaline

Pharmacological action

1.Cardiovasscular system:

• Increase force of contraction
• Increase in Heart rate
• Increase in Cardiac output

2.Respiratory system

• On  β2 receptor -Bronchodilation 
• α1 receptor present in the blood vessels of nasal mucosa- cause vasoconstriction of nasal mucosa

3.Eye(α1 receptor)

• Contraction of radial muscle of iris.

4.GIT

• Relaxation of GI smooth muscles.

5.Urinary tract

• Relaxation of Urinary bladder and closure of sphincter.
• Urinary relaxation.

Mechanism of Action 

• Both α and β adrenergic receptor are G-protein coupled receptor. Stimulation of  α receptor activates phospholipase c in the cell membrane which act through generation of second messengers inositol triphosphate(IP3) and diacylglycerol (DAG) and increase intracellular calcium.
• Stimulation of  β  receptor activates an enzyme adenylyl cyclase resulting in increased intracellular cyclic AMP. This second messenger acts through various intra cellular proteins to bring about the response.

Pharmacokinetics:-

•  As Catecholamines are rapidly inactivated in the gut and the liver, they are not given orally .
• Adrenaline and NA are metabolized by COMT and MOA

Uses:

• Bronchial asthma
• Nasal decongestant
• As a cardiac stimulant in case of sudden cardiac arrest

Adverse effect:

• Restlessness
• Anxiety
• insomnia 
• Blood pressure increase
• contra-indicated in - Hypertsion, Diabetes, Arteriosterosis

4.Antiadrenergic drugs[Sympatholytics]
 

Sympatho-Sympathetic Nervous system lytic- oppose

• These are those drugs which inhibit the effects of sympathomimetic drugs by blocking the receptor.
• Adrenergic antagonists are of two types:- 1) α blockers, 2) β blockers

 α adrenergic blocking agent

α receptor antagonist block the adrenergic response mediate through α adrenergic receptor.

     Pharmacological action:

 

The Pharmacological action of α blockades by α-antagonists are:-

i) α1-blockers inhibits vasoconstriction leading to vasodilation and thereby decrease BP.

ii) α2-blockers enhances the release of Nor-Adrenaline which stimulate β receptors.

iii) Selective α1-blockers enhance Hypotension, tachycardia, increased cardiac output.

iv) Selective α2 -blockers results in increased Nor-Adrenaline release resulting in Hypertension.

    Adverse effect:

• Palpitation
• Nasal stuffiness
• Miosis
• postural hypotension

β-Adrenergic blocking agents:-

β-blockers are drugs that block the action of catecholamines mediated through the β receptor.

  

    Pharmacological action:-

i) β1 blockers, decrease heart rate.

ii) β2 blockers, cause bronchoconstriction.

iii) β3 blockers, block lipolysis & Glycogenolysis

    Adverse effect

• Bardycardia
• CCF
• Rebound Hypertension
• Dizziness.

Therapeutic uses:-

1) α blockers:- 

• Hypertension
• Congestive heart failure
• peripheral vascular disease

2.β blockers 

• Angina pectoris
• Myocardial infarction
• Glaucoma

d. Neuromuscular Blocking agents and skeletal muscle relaxants

Neuromuscular Blocking agents

• These are those agents or drugs which are used to block the Neuromuscular junction and inhibit the contraction of muscle and cause relaxation of muscles.
• They are also known as skeletal muscle relaxants.

Neuromuscular Junction

• It is the junction between the neuron and muscles in which, neurotransmitter release from neuron and bind with receptor present on muscle and cause contraction & movement.

#Neuromuscular blocking agent blocks this Neuromuscular junction.

uses:

• generally used by doctor for relaxation of muscle during operation.
• used to improve symptoms such as muscle spasm, pain and hyperreflexia.
• used as a curare-for hunting animals.
• used as a alternate of anesthetic.

 General procedure of muscle contraction

Skeletal muscle relaxants

Classification:

Depolarizing(Succinylcholine)

• These are non-competitive antagonist.
• mostly used-succinylcholine as general clinical use.
• succinylcholine does not hydrolyzed by Acetyl cholinesterase

   Mechanism of Action

• The neuromuscular effects of Sch stimulates the NM nicotinic receptors and depolarizes the skeletal muscle membrane
• Continued presence of the drug causes persistent depolarization resulting in flaccid paralysis

  Pharmacological Action

• Muscle Twitching.
• muscle  soreness.
• Apnoea.

   Therapeutic uses: 

• Adjuvants to general anesthesia.
• Prevent trauma during electroconvulsive.
• To control ventilation.

  Adverse effect

• Muscle rigidity
• prolonged Apnoea
• nausea & vomiting
• Muscle soreness

Non-depolarizing blockers:

• The first neuromuscular blocking drugs was found-curare-used by south American hunter to paralyze the animals.
• most used -d-Tubocurarine.

   Mechanism of Action

• The non depolarizing blocker d-tubocurarine block the Neuromuscular nicotinic receptor on the motor end plate and block the action of acetylcholine
• The d-tubocurarine is reversible. This can be done by increasing the concentration of agonist acetylcholine

Pharmacological Action:

1.Skeletal muscles:

• Induced flaccid paralysis
• paralyze acc to this order-muscles of face-eye-finger-limb-neck
• recovery occurs in reverse order..

2.histamine release

• d-tubocurarine has a greater tendency to liberate histamine from mast cells.

3.cardiovascular

• d-tubocurarine produce hypotension due to histamine release.
• Gallamine cause tachycardia

4.Respiratory effect

• Bronchospasm

#It can overcome or reverse by use of Neostigmine and pyridostigmine which increase the availability of Ach by inhibiting Acetylcholinesterase.

  Adverse effect:

• Hypoxia 
• Respiratory paralysis
• Hypotension
• constipation
• Tachycardia 

E)Local Anaesthetic agents 

• These are those drugs which blocks the neuronal conduction at any particular area in body.
• They produce reversible loss of sensation 
• Also cause muscular paralysis

Classification 

Mechanism of Action

• The main site of action for Local Anesthetics is cell membrane.
• The Local Anesthetics is unionized form penetrate the nerve myenlinated sheath and membrane.

• The action of Local Anesthetics depend on the ph. the penetration of Local Anesthetics is increased in alkaline ph. when Local Anesthetics is in the unionized form.
• Sensory nerve fibers are block earlier than motor nerve fibers because of higher firing rate.

Pharmacological Action

1.Nervous System:-

    (i) Central nervous system : Local anesthetics can cross the blood brain barrier. Initially Local anesthetics cause the CNS stimulation and then depression in high dose

• Local anesthetics cause excitement, tremor, restlessness.
• Large doses of local anesthetic cause respiratory depression, Coma and death.

    (ii)Peripheral nerve : The order of nerve fiber affected are automatic fiber, pain, temperature, touch, pressure and motor nerve fibers.

2.Cardiovascular system

   (i)Heart: Local Anesthetics block the Na+ ion channels, decrease contractility, conductivity, heart rate and increase effective refractory period.

At the high concentration of local Anesthesia may precipitate the cardiac arrhythmia.

(ii)Blood vessels : It cause the hypotension by the vasodilation and myocardial depression.

Uses :

• Loss of sensation(reduce pain)
• Nerve block (block voltage gated Na+ channel)
• Used as ointment, injection.

Adverse effects

• Tounge numbness 
• muscle twitching
• Hypotension'
• Redness of skin 
• Asthma

f. Drugs Used in Myasthenia Gravis and Glaucoma

Drugs Used in Myasthenia Gravis 

• A weakness and rapid fatigue of muscle
• It is an auto-immune disorder, in which our immune system produce antibodies that block or destroy muscle's receptor
• Breakdown in communication between nerves and muscles.

Symptoms:-  

• Weakness in the arms and legs muscles .
• Double vision.
• Difficulties with speech and chewing.
• fatigue, shortness of breath.

Mechanism:-

Normal:- When myasthenia gravis not occurred and our body behave normal and contraction and relaxation happened normally normally in muscles.

Treatment of Myasthenia gravis:-

• Anticholinesterase: use these drug to treat myasthenia gravis.

-cholinesterase inhibit the acetylcholine by hydrolysis

-So, when these drugs inhibit this enzymes concentration

 of Acetylcholine increase.

E.g. Pyridostigmine, Neostigmine

• Immunosuppressant:  use these drugs to suppress the immune system to decrease the formation of antibodies.

e.g. - Cyclosparine- A, methotrexate

• Corticosteroids: Decrease antibodies.

-Increase synthesis of nicotinic receptor                                 

• Plasmapheresis: It is a technique used to treat myasthenia gravis.

-The plasma of the blood is exchange with substitute plasma, so antibodies remove from body and immune system does not attack the body's own tisssue.

Drugs Used in  Glaucoma

• A Group of eye condition that can cause blindness(Loss of Vision).
• In this, the nerve connecting the eye to the brain (Optical nerves) is damaged due to high eye pressure(intra ocular pressure).
• Intra ocular pressure is more than 21 mmHg 

     Mechanism:

     

    Symptoms: 

• Eye Pain.
• Mid-Dilated pupil.
• Redness of the eye.
• Vision loss, blurred vision

    Risk Factor

• Increased pressure in the eye.
• Due to genetic factor.
• High blood pressure.
• Excessive use of liquid diets(such as alcohols

    Diagnosis:

• Dilated eye examination.
• two types :- 1) Open angle glaucoma. 2) Closed angle glaucoma

        1)Open angle glaucoma:

                - Also known as chronic and wide angle glaucoma.

  Symptoms:- 

• gradual vision loss, 
• optic nerve Damage.

2) Angle Closer Glaucoma:

        -Also known as acute and narrow angle glaucoma.

        -Flow of aqueous humor blocked.

Symptoms:

• Severe pain
• Nausea
• Blurred vision

Treatment:

    -By decrease I.O.P(Intra Ocular pressure) {Decrease the production of aqueous humor and Increase the drainage of aqueous humor}

1. α-agonist:- Decrease I.O.P by increasing the Uveoscleral (drainage of aqueous humor)outflow. Eg-Aprocloridine, Brominidine
   
2. β-agonist:- Decrease I.O.P by decreasing the formation of aqueous humor. e.g.- Timolol, Betaxolol.
3. Prostaglandin analogues:- Same as α-agonist decrease  I.O.P by decreasing Uveoscleral outflow. e.g. Latanoprost, Travoprast.
4. Carbonic anhydrase inhibitors: Used orally decrease aqueous formation by decreasing bicarbonate ion in cilliary epithelium.Eg- Acetazolamide, dorzolamide
   
5. Miotic agent: Decrease I.O.P by increasing ciliary muscle tone. (used rarely for glaucoma). e.g. pilocarpin

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