how drugs affect the autonomic nervous system

7/31/2019 How Drugs Affect the Autonomic Nervous System

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Pharmacology

How Drugs affect the Autonomic

Nervous system

&Sympathetic Nervous system

Lecture 6

Done By:Maher.Khatib

Corrected .


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2) PAM: which won't act at the Receptor, It's Working Mechanism is re-generate or re-activate the

inhibited Enzyme,"cholinesterase"

The figure below, shows How PAM works on the deactivated Enzyme and reactivate it, Dyflos is a

kind of Organophosphate which bind to the active enzyme, and phosphorolate the enzyme and the

enzyme becomes Inactive, If we add (PAM), (PAM) will re-generate the enzyme by removing the

phosphate group, the enzyme is reactivated again, and it begins metabolizing the excess Ach.

Cholinergic AntagonistsCholinergic antagonists are Drugs that block Ach effect either on the level of * Muscarinic

receptor. * Nicotinic receptor.

A- Muscarinic antagonist

If we block a Muscarinic receptor at the effector Organ of parasympathetic nerve system

which secrets Ach

-"Tachycardia", this will cause an increase in the Heart rate.

- Bronchial Dilatation, Relaxation of the bronchial muscles which will decrease the

bronchial secretion.

- Mydriasis in the eyes accompanied with Cycloplegia.

Cycloplegia is paralysis of the ciliary muscles of the eye, and these Muscles control the lens of theeye, resulting in the ability to see far objects, and inability to see near object clearly, Cycloplegia

with accompanying mydriasis (loss of adaptation) can be induced pharmacologically by

Muscarinic antagonists.

- Urinary Retention in the Urinary Bladder.

- GIT Constipation. Decrease GIT Motility and Secretion.

The ophthalmologists use Atropine like drugs not Atropine itself, because the effect of

atropine lasts for days, but Atropine like drugs have less effect when used for eye

examination, so Atropine induce cycloplegia and Mydriasis more than other drugs and will

not seen for days after an eye drop, so cycloplegia is a problem, and that's why they use

drugs with less effect.


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The Prototype at the Muscarinic Receptor Blocking is Atropine.

Atropine Therapeutic Uses:1-Treatment and Management of colic. (Renal, Intestinal, Biliary Colic).

Due to the relaxation and paralysis of Muscles, especially smooth muscles and This causereduction in the motility such as Intestinal Colic.

2- Pre-operative Medication: Mediaction Before Major Surgeries, When we do a Surgery we have

two types of Drugs that induce Anesthesia.*Drugs induce Anesthesia *Drugs for maintenance of Anesthesia.

So in Pre-operative Anesthesia we use either Atropine, or Anti-Muscarinic Drugs.

They will reduce the Bronchial and GIT secretions. (This is an aim of use also).

3- Relief Bronchial spasm (Bronchodilators).The drug used for relieving bronchial spasm and Treating Bronchial Asthma is Ipratropium.

Ipratropium: is ananticholinergicdrug used for the treatment ofchronic obstructive pulmonary

diseaseand acuteasthma. It blocks themuscarinic acetylcholine receptorsin the smooth muscles

of thebronchiin the lungs, leading to bronchodilation (Taken By Inhalation).

Why Ipratropium is preffered more than Atropine to Relief Bronchial spasm ?!Both of these drugs has the Same effect on releiving Bronchial spasm, But Ipratropium has less

Adverse effects. Why? Because it is an ionized Drug, carrying a charge, Water soluble, so it is polar,

it fully penetrates the membranes, so it has low systemic adversed effect.

So Ipratropium and Atropine has the same effect, But adversed effect is less in ipratropium.

Minimal chance to produce Tachycardia, Constipation, Mydriasis; Because poor solubility to

Lipids.

4- Atropine is used as Antidote for cholinergic agonists.

Because cholinergic agonists overdose in the case of Organophosphatepoisoning.

5- Treatment of Parkinson Disease.

Prototype: The

first Used for

any Group.

Parkinson disease is an immune-degenerated disorder caused by the imbalance between Ach and dopamine in the CNS,

High levels of Ach and Low levels of dopamine, commonly seen in elder patients such as Mohammad Ali clay, Yassir Arafat

This disorder characterized by Muscle rigidity and Bradykinesia, Tremor in lips, hands and legs.
http://en.wikipedia.org/wiki/Anticholinergichttp://en.wikipedia.org/wiki/Anticholinergichttp://en.wikipedia.org/wiki/Anticholinergichttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Asthmahttp://en.wikipedia.org/wiki/Asthmahttp://en.wikipedia.org/wiki/Asthmahttp://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptorhttp://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptorhttp://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptorhttp://en.wikipedia.org/wiki/Bronchihttp://en.wikipedia.org/wiki/Bronchihttp://en.wikipedia.org/wiki/Bronchihttp://en.wikipedia.org/wiki/Bronchihttp://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptorhttp://en.wikipedia.org/wiki/Asthmahttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_diseasehttp://en.wikipedia.org/wiki/Anticholinergic


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To overcome this problem, we must Increase Dopamine and decrease Ach, and we can decrease

Ach By Muscarinic Blocker by Benzatropine, Benzatropine antagonizes the effect ofacetylcholine,

decreasing the imbalance between the neurotransmitters acetylcholine anddopamine, which may

improve the symptoms of early Parkinson disease.

We could use dopamine to increase the Dopamine in CNS, But patients with P.D and schizophrenia

has high Dopamine levels, though we can't give them dopamine, so we use Benzatropine (Anti-cholinergic Drug).

Tremor and rigidity is eliminated more using Anti cholinergic drug, and not all symptoms relieved

by dopamine like drugs, But Bradykinesia is controlled by dopamine like drugs, so sometimes we

make a combination between drugs according to the patient's condition.

So in CNS, Atropine produces CNS excitation followed by CNS depression which leads to death.Atropine Adverse side effects are Constipation , Dry mouth, Urinary retention, Confusion,

Mydriasis and Blurred vision.

Hyoscine (Scopolamine): These are the Generic name, and it is a drug that is used as Anti-spasm

drug especially for intestinal colic. Differs from Atropine that low doses from it will cause CNS

depression,But High doses of Atropine only case CNS depression.

Hyoscine causes loss of short memory (Amnesia), due to that Medical students reject to take

Hyoscine.

Therapeutic Uses :-

*Commonly used as Pre-operative Medication because it induces Amnesia (loss of short memory).

*Controlling and preventing vomiting during motion sickness.

Atropine and similar drugs should not be given to patients with .?

+ Hypertension, because Atropine induce Tachycardia.

+ Conditions when Cholinergic agonists are indicated and Muscarinic Antagonists are

contraindicated.+ Hypoplasia, especially in Males. + Palitic Elias. Loosing Intestinal Motility and it will be worse and paralyzed.

----------------------------------------------------------------------------------------------

Atropine is used for the treatment of flat line ECG , means there is no Heart rate, and by atropine

we can initiate cardiovascular contraction with C.P.R, because atropine is responsible of

increasing heart rate and reach 60 beats/min so

C.P.R + Atropine For Cardiopulmonary Resuscitation ..
http://en.wikipedia.org/wiki/Acetylcholinehttp://en.wikipedia.org/wiki/Acetylcholinehttp://en.wikipedia.org/wiki/Acetylcholinehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Acetylcholine


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Cardiopulmonary

resuscitation (CPR) is an

emergency procedure which is

performed in an effort to manually

preserve intact brain function untilfurther measures are taken to

restore spontaneous blood

circulation and breathing in a

person incardiac arrest.

A revision to remind you that Cholinergic Antagonists are either

Muscarinic or Nicotinic, presented either at the level of

-Neuromuscular Junction or Ganglia.

B- Neuromuscular Blocker: is a Nicotinic Blocker, Blocking

neuromuscular transmission at the Neuromuscular Junctionand prevent Ach effect from Nicotinic Receptor, and Block the

Nicotinic Receptor inducing Muscle relaxation. These Blockers

are presented in two main Types.Depolarizing Blockers. Non-DepolarizingBlockers.

Depolarizing means There is an Action potential and activation.

Depolarizing Blocker. Ex, Succinylcholine (Suxamethonium), a drug that has a rapid onset andshort duration of action, It's mechanism of action is binding to Nicotinic receptor at

Neuromuscular Junction and they cause muscularfasciculations (a sudden twitch just before

paralysis occurs) while they are depolarizing the muscle fibers then binding to Ach and activating

it causes Muscle Paralysis.The drug attaches to the nicotinic receptor & act like Ach to depolarize the junction, but it is not

destroyed by cholinesterase, so the continued binding of depolarizing agent renders the receptor

incapable of transmitting further impulses. With time, membrane is repolarized but receptor is

desensitized to affect of Ach.Depolarizing Blocker is Mainly used in * Endotrachial intubation during surgeries.

* Elecrtoconvulsive Therapy. (ECT)

We will produce electricity to treat a condition .Electrode gives electricity to Brain and make

seizures, there is a mild controlled electricity to CNS, this is used to treat Mental disorders such as

severe depression associated with suicide attempts. Electrode is used with Muscle relaxant

(succinylcholine) to prevent Muscle Complication such as Muscle pain, Bone Dislocation, Bone

fracture.Adverse Side Effects: Apnea in patients who has genetic defect in the plasma cholinesterase.

Apnea is a term for suspension of externalbreathing. During apnea there is no movement of

themusclesof respiration and the volume of thelungsinitially remains unchanged when

prolonged Respiratory Muscles paralysis, and that may cause death.

Non-Depolarizing Blockers: Responsible to induce Muscle Relaxation, Bind nicotinic Receptorand presented as Neuromuscular Junction, prevent Ach from binding and prevent its Action.

Ex.Tubocurarine.Tubocurarine: is Mainly used in anesthesia to induce Skeletal Muscle relaxation During major

surgeries.
http://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Fasciculationhttp://en.wikipedia.org/wiki/Fasciculationhttp://en.wikipedia.org/wiki/Fasciculationhttp://en.wikipedia.org/wiki/Respiration_(physiology)http://en.wikipedia.org/wiki/Respiration_(physiology)http://en.wikipedia.org/wiki/Respiration_(physiology)http://en.wikipedia.org/wiki/Musclehttp://en.wikipedia.org/wiki/Musclehttp://en.wikipedia.org/wiki/Musclehttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Musclehttp://en.wikipedia.org/wiki/Respiration_(physiology)http://en.wikipedia.org/wiki/Fasciculationhttp://en.wikipedia.org/wiki/Cardiac_arrest


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Now We will begin with the new Subject Sympathetic Nervous system

Sympathetic Nervous system: Released on stressful situations, its general action is to mobilize the

body's nervous systemfight-or-flight response. It is, however, constantly active at a basic level to

maintainhomeostasis.

We have two types on Neurotransmitters released

Norepinephrine which is mainly released from Sympathetic Nerve Endings.

Epinephrine which is mainly released from adrenal medulla*Sympathomimetic Amines such As Epinephrine and Norepinephrine, Dopamine and Isoproternol

are all called Catecholamines, and They share the same properties:

Structure (Benzene ring ).

Rapid Inactivation by MOA and COMT enzymes.

But the primary process to terminate NE effect is the Re-uptake process.

NE is released from Sympathetic nerve fibers which after a while NE effect is terminated by

different Mechanisms.

Re-uptake to its stored vesicles in the pre-synaptic neurons.

Metabolize by Two enzymes either by *MOA enzyme in the pre-synaptic neurons. Or by*COMT enzyme in the synapse.

--------------------------------------------------------poor Penetrate to CNS, because they are polar and poor lipid solubility

Orally inactive, destroyed by walls of the mouth.

Brief duration of action, (They act on adrenergic Receptors so there is a difference in their toaffinity to type of Receptor).

---------------------------------------------------------------

Types of adrenergic receptorsAlpha Receptors1 and 2 receptors, and they are stimulated by NE and E. The image belowshows the synaptic cleft, presynaptic and postsynaptic membranes. Alpha 1 receptors are located on

the postsynaptic membrane of effector organs.

Alpha 1 is postsynaptic but Alpha 2 is pre-synaptic.

Alpha 1 activation by NE and E. Activation of 1 receptor causes*Mydriasis (Dilatation of the pupil) *Urinary retention *increase

vascular smooth muscle contraction, producing increases in blood

pressure(Vasoconstriction).* increase the closure of internal sphincter of bladder.

EEpinephrine

NE Norepinephrine
http://en.wikipedia.org/wiki/Fight-or-flight_responsehttp://en.wikipedia.org/wiki/Fight-or-flight_responsehttp://en.wikipedia.org/wiki/Fight-or-flight_responsehttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Homeostasishttp://en.wikipedia.org/wiki/Fight-or-flight_response


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Alpha 2 receptors Activation will inhibit further release of Neurotransmitters from the Pre-

synanptic neurons. (Auto-inhibitory Mechanism), E and NE bind to the receptor and this will

inhibit the release of Neurotransmitters, this is good for relieving Hypertnsion.

Beta Receptors1 and 2and 3,

1 and 2 are stimulated by E and isoprenaline.

NE stimulates 1 only.

So 2stimulated by E and Isoprenaline, and this will cause Bronchodilations, Vasodilation andincrease in blood Glucose levels ( by increasing the production of Glucose in liver), and Finally

Relaxation of the Uterine Smooth muscle.

In which case we can use a 2 receptor agonists?! "Drug that stimulate 2"

Ans: for Treatment Bronchial spasm, Some drugs under this category include: salbutamol

*NE can't be used as a treatment for local asthma, because it doesn't Stimulate 2and 2 is thereceptor that cause bronchodilator.

Uterine contraction

Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of premature

labor, this clinical application illustrates how Beta 2 receptors mediate tocolysis on the uterine

muscle. Ritodrine is an example of a tocolytic drug.---------------------------------------------

1 stimulated by E and NE and Isoprenaline, and this will affect the heart compulsive byincreasing Heart Rate, and also increasing Cardiac Output.In the Renal system , 1 stimulating will cause release of Renin, this enzyme will activate therenin-angiotensin system by cleaving angiotensinogen, produced by theliver, to yield angiotensin

I, which is further converted into angiotensin II by ACE,
http://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Liver


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Beta 1 receptors are mainly located in the heart and kidneys.

Stimulation of beta1-adrenergic receptors on themyocardium, AV node, and SA node results in CARDIAC

STIMULATION:

Increased force of contraction

(positive inotropic effect) Increased heart rate

(positive chronotropic effect)

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Classification of Sympathomimetics/Adrenomimetics

Sympathomimetic drugs mimic the effects of transmitter substances of thesympathetic

nervous systemsuch

ascatecholamines,epinephrine(adrenaline),norepinephrine(noradrenaline),dopamine, etc.

Such drugs are used to treatcardiac arrestand lowblood pressure, or even delaypremature

labor.

Direct Acting Sympathomimetics. Drugs directly stimulate the adrenergic receptor (e.g.epinephrine, norepinephrine) ,Selective and Non-Selective.

Indirect Acting Sympathomimetics. Drugs that stimulate the release of NE or from

presynaptic adrenergic neuron or inhibit the re uptake of it. Ex amphetamine.

Mixed-Acting sympathomimetics (both direct and indirect acting)

Sympathomemtic Drugs

Angiotensin II then constrictsblood vessels, increases the secretion

ofADHandaldosterone, and stimulates thehypothalamusto activate

the thirst reflex, each leading to an increase inblood pressure.
http://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Catecholamineshttp://en.wikipedia.org/wiki/Catecholamineshttp://en.wikipedia.org/wiki/Catecholamineshttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Aldosteronehttp://en.wikipedia.org/wiki/Aldosteronehttp://en.wikipedia.org/wiki/Aldosteronehttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Aldosteronehttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Blood_vesselhttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Premature_laborhttp://en.wikipedia.org/wiki/Blood_pressurehttp://en.wikipedia.org/wiki/Cardiac_arresthttp://en.wikipedia.org/wiki/Dopaminehttp://en.wikipedia.org/wiki/Norepinephrinehttp://en.wikipedia.org/wiki/Epinephrinehttp://en.wikipedia.org/wiki/Catecholamineshttp://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttp://en.wikipedia.org/wiki/Sympathetic_nervous_system


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Epinephrine (E).

- Can be prepared synthetically .

- Orally Inactive.

- Secreted from adrenal Medulla.

Actions

1. Increase the heart rate and force of contraction.(destroyed by mouth Enzymes), caused by

1.2. Bronchodilation caused by 2.3. Increase Glucose level caused by 24. Eye Mydriasis caused by 15. Increase the Systolic Blood pressure and minimal change in Diastolic Blood pressure.

Why E affects the systolic Bp more than Diastolic Bp ?

Systolic Bp is increased due to increased Heart rate and force of contraction by 1, butminimal change is Diastolic, because 1in blood will lead to Vasoconstriction but inopposite there is 2 cause Vasodilation.

Therapeutic uses

Anaphylactic shock

When histamine is released (released from mast cells) this causes vasodilation, this will

lead to some symptoms like hypotension and flushing. In this Case Epinephrine should be

administrated I.M not I.V.( I.V is avoided because it is dangerous more than the shock).

Anaphylactic shock is type 1 hypersensitivity where bronchoconstriction , edema , vasodilationand histamine release occure . and all that may cause death so E act on B2 receptors causing

bronchodilation relieve dyspnea and increase the tidal volume

Stimulates the heart in cardiac arrest Can be used to prolong local anesthetic action

---------------------------------------------------------

Nor-Epinephrine (NE)

1 receptor causes increase in the systolic & 1 causes increase Diastolic blood pressure.

Uses:

Treatment of shock ( BP) given by I.V. infusion, but because of its effect (vasoconstriction) it blood flow in essential organs tissue damage Necrosis.

Good luck

Done by Maher.khatib


11/11

Excuse me for the delay in this script !! The delay was to make sure that the information in this script is Accurate.

Hope you will enjoy reading it as I enjoyed writing it .

how drugs affect the autonomic nervous system

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