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Autonomic Nervous

System (ANS)

Chapter 2

Ali Jaber, Ph.D.

MS in Pharmacy

MS in Pharmaceutical Chemistry

Organization of The Nervous System

Central Nervous System Peripheral Nervous System

Somatic Nervous System Autonomic Nervous System

Sympathetic Parasympathetic

Organization of the Peripheral

Nervous System Three major divisions:

– Efferent

» Somatic (motor)

» Autonomic

Sympathetic and Parasympathetic

– Afferent

» Sensory

The Peripheral Nervous System

Sensory

Motor

Sympathetic

Parasympathetic

Parasympathetic

Autonomic Nervous System

2 divisions:

– Sympathetic

» “Fight or flight”

» “E” division

Exercise, excitement, emergency, and embarrassment

– Parasympathetic

» “Rest and digest”

» “D” division

Digestion, defecation, and diuresis

Sympathetic (adrenergic) with exceptions)

cardiac output increases

SA node: heart rate (chronotropic)β1, β2: increases

cardiac muscle: contractility (inotropic)β1, β2: increases

conduction at AV nodeβ1: increases

vascular smooth muscle M3: contracts; α = contracts; β2 = relaxes

smooth muscles of bronchiolesβ2: relaxes (major contribution); α1: contracts (minor contribution)

Sympathetic (adrenergic) with exceptions)

pupil of eyeα1: relaxes

ciliary muscleβ2: relaxes

salivary glands: secretionsβ: stimulates viscous, amylase secretions; α1 = stimulates potassium cation

smooth muscles of GI tractα, β2: relaxes sphincters of GI tractα1: contracts

glands of GI tractinhibits

Parasympathetic (muscarinic)

cardiac output M2: decreases

SA node: heart rate (chronotropic) M2: decreases

cardiac muscle: contractility (inotropic) M2: decreases (atria only)

conduction at AV node M2: decreases

smooth muscles of bronchioles M3: contracts

pupil of eye M3: contracts

ciliary muscle M3: contracts

salivary glands: secretions stimulates watery secretions

GI tract motility M1, M3: increases

smooth muscles of GI tract M3: contracts

sphincters of GI tract M3: relaxes

glands of GI tract M3: secretes

Function Sympathetic and parasympathetic divisions

typically function in opposition to each other. But this opposition is better termed complementary in nature rather than antagonistic.

For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake.

The sympathetic division typically functions in actions requiring quick responses.

The parasympathetic division functions with actions that do not require immediate reaction. Consider sympathetic as "fight or flight" and parasympathetic as "rest and digest".

The Synapse

Gap between the axon and the dendrite

Neurotransmitters are released across this gap

Sometimes, if all of the transmitter isn’t absorbed it is

taken back up, this is known as reuptake

There is lots of variation in synapses

Some are excitatory (Type I)

Some are inhibitory (Type II)

The Seven Steps in

Neurotransmission Synthesis

Storage

Release

Receptor interaction

Inactivation

Reuptake

Degradation

Mechanism: Acetylcholine Release and

Recycling 1. Acetylcholine synthesized

from choline and acetyl CoA by choline acetyltransferase (ChAT)

2. ACh loaded into synaptic vesicles by VAchT

3. Released ACh broken down by acetylcholinesterase (notable difference from other neuro-transmitters)

4. Choline taken up by presynaptic terminal as precursor to further ACh synthesis

Mechanism: Norepinephrine Release

and Recycling

Neurotransmitters and Receptors

The parasympathetic nervous system uses only

acetylcholine (ACh) as its neurotransmitter.

The ACh acts on two types of receptors, the

muscarinic and nicotinic cholinergic receptors.

Most transmissions occur in two stages: When

stimulated, the preganglionic nerve releases ACh at

the ganglion, which acts on nicotinic receptors of the

postganglionic nerve.

The postganglionic nerve then releases ACh to

stimulate the muscarinic receptors of the target organ.

Summary of parasympathetic neurons

and synapses

Preganglionic neurons Long

Synapse with postganglionic neurons at or near organ

Release acetylcholine (ACH) to activate nicotinic receptors on

postganglionic neurons

Postganglionic neurons Short

Synapse on the target organ

Release acetylcholine (ACH) to activate muscarinic receptors on

the target organ

Neurotransmitters and Receptors

At the effector organs, sympathetic ganglionic

neurons release noradrenaline (norepinephrine) to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla:

Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will act on adrenoceptors, producing a widespread increase in sympathetic activity.

In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter, to stimulate muscarinic receptors.

Summary of sympathetic neurons

and synapses

Preganglionic neurons Short

Synapse with postganglionic neurons near spinal cord

Release acetylcholine (ACH) to activate nicotinic receptors on

postganglionic neurons

Postganglionic neurons Long

Synapse on the target organ

Release norepinephrine to activate adrenergic receptors on target

organs

Sweat glands: » Postganglionic neurons

involved with stress-related

excretion release

norepinephrine (“sweaty

palms”)

» Postganglionic neurons

involved with

thermoregulation release

acetylcholine

Exceptions in the sympathetic nervous system:

Kidneys: » Postganglionic neurons to the

smooth muscle of the renal

vascular bed release dopamine

Adrenal gland: » Preganglionic neurons do not

synapse in the paraverterbral

sympathetic ganglion

» Preganglionic neurons synapse

directly on the adrenal gland,

release acetylcholine, and

activate nicotinic receptors on

the adrenal gland

» Adrenal glands release

epinephrine into systemic

circulation

Exceptions in the sympathetic nervous system:

How do drugs influence the ANS?

Mimic or block the effects of the two primary neurotransmitters,

Acetylcholine and Norepinephrine/Epinephrine

Drugs that mimic neurotransmitters are referred to as “receptor

agonists”

These drugs activate receptors

Drugs that block neurotransmitters are referred to as “receptor

antagonists”

These drugs block the endogenous neurotransmitters from

activating receptors

Classification of drugs affecting the ANS

Parasympathetic nervous system Mimic acetylcholine = cholinergic = muscarinic agonists =

parasympathomimetic Block acetylcholine = anticholinergic = muscarinic antagonist =

parasympatholytic

Sympathetic nervous system Mimic norepinephrine = adrenergic = adrenergic agonist =

sympathomimetic Block norepinephrine = antiadrenergic = adrenergic antagonist =

sympatholytic

Adrenergic Receptors

Adrenergic receptors are the sites where adrenergic drugs bind and produce their effects.

Adrenergic receptors are divided into alpha-adrenergic and beta-adrenergic receptors depending on whether they respond to norepinephrine or epinephrine.

Both alpha- and beta-adrenergic receptors have subtypes designated 1 and 2.

Alpha Receptors

Alpha1-adrenergic receptors are located on the

postsynaptic effector cells.

Alpha2-adrenergic receptors are located on the

presynaptic nerve terminals.

Beta Receptors

Both beta-adrenergic receptors are located on the

postsynaptic effector cells.

Beta1-adrenergic receptors are primarily located in

the heart.

Beta2-adrenergic receptors are primarily located in

the smooth muscle of bronchioles, arterioles, and

visceral organs.

Dopaminergic Receptors

Dopaminergic receptors are only stimulated by

dopamine which causes the vessels of renal,

mesenteric, coronary, and cerebral arteries to dilate

and the flow of blood to increase.

Adrenergic Receptor Specificity

Drug α1 α2 β1 β2 Dopaminergic

Epinephrine

Ephedrine

Norepinephrine

Phenylephrine

Isoproterenol

Dopamine

Dobutamine

terbutaline

• The adrenengic drugs supplement, mimic & reinforce the message transmitted by the natural neuro hormones norepinephrine & epinephrine.

• These hormones are responsible for transmitting nerve impulses of the sympathetic nervous system.

Sympathomimetic (Adrenergic) Drugs

ADRENERGIC AGONIST

Alfa agonist: 1. Norepinephrine 2. Epinephrin 3. Dopamine 4. Dobotamine(doubetrex) 5. Clonidina (catapress) 6. Metildopa (aldomet) 7. Phenilephrine (afrin)

Beta agonist: 1. Albuterol 2. Formoterol 3. Salmoterol

1) Albuterol or salbutoml (Ventolin)

Class.: sympathomimetic agent, bronchdialtor

Action: stimulate β 2 receptors of the bronchi leading to bronchodilation.

Uses:

- Bronchial asthma.

- Bronchospasm due to bronchitis or emphysema.

- Parenteral for treatment of status asthmaticus.

ADRENERGIC AGONIST

1) Albuterol or salbutoml (Ventolin)

Side effects:

Tachycardia, arrhythmias, anginal pain.

Nausea, vomiting.

Dizziness, sweating, flushing.

Headache, weakness, vertigo, and insomnia.

ADRENERGIC AGONIST

2) Dopamine Hydrochloride (Intropin)

Class: Direct & indirect acting adrenergic agent.

N.B. : Available for hospital use only on 5 ml ampules containing 200 mg dopamin hydrochloride.

Action:

- It is the immediate precursor of epinephrine in the body.

ADRENERGIC AGONIST

2) Dopamine Hydrochloride

Action:

- It produces direct stimulation of β1 receptors resulting in increasing myocardial contraction, cardiac output as well as increase renal blood flow & sodium excretion.

- It exerts little effect on diastolic B.P. & induce fewer arrhythmias that seen on other adrenergics drug.

ADRENERGIC AGONIST

Indications:

- Cardiogenic shock specially in Myocardial Infarction associated with sever Congestive Heart Failure

- Hypotension due to poor cardiac output.

- Shock associated with septicemia, trauma, heart surgery, renal failure & C.H.F.

- Cardiomyopathy.

- In lower doses (1-5 Mcg/kg/min) used in renal failure.

ADRENERGIC AGONIST

Contraindications:

- Pheochromocytoma, uncorrected tachycardia, arrhythmias.

- Hypovolemia.

- Safety and efficacy is not established in children.

Side effects:

- GI: Nausea and vomiting.

- CV: tachycardia or bradycardia, anginal pain, palpitation, hypotension or hypertension, dyspnea.

ADRENERGIC AGONIST

3) Epinephrine:

Trade name: Adrenaline

Class : Direct acting-adrenergic agent.

Action:

A natural hormone produced from adrenal medulla, induce

marked stimulation of alpha, β1 + β2 receptors causing

cardiac stimulation, bronchodilation & decongestion..

ADRENERGIC AGONIST

3) Epinephrine:

Uses:

1- Relief of respiratory distress due to

bronchospasm.

2- Rapid relief of hypersensitivity reactions.

3- Cardiac arrest.

4- Open- angle glaucoma.

5- To prolong the action of local anesthesia.

6- Topically to stop bleeding.

ADRENERGIC AGONIST

3) Epinephrine:

Contraindications:

- Narrow angle glaucoma.

- Shock

- Lactation.

- Tachycardia

Side effects:

Fatal ventricular fibrillation.

Cerebral hemorrhage urinary retention, headache, necrosis

at injection side, blurring of vision, photophobia.

ADRENERGIC AGONIST

3) Epinephrine:

Dose:

Available in ampules of 1ml containing 1 mg adrenaline

Can be given by I.M injection., I.V. & S.C.

0.2 – 0.5 mg, IM or S.C. + Q 20 min – 4 hr as needed.

ADRENERGIC AGONIST

4) Dobutamine (Dobutrex)

Indications: In adults who require short-term treatment of cardiac failure secondary to acute myocardial infarction, or cardiac surgery.

Contraindication: DOBUTREX is contraindicated in patients with idiopathic hypertrophic subaortic stenosis

ADRENERGIC AGONIST

4) Dobutamine (Dobutrex)

Adverse effects:

GI: Nausea and vomiting.

CV:

a) tachycardia or

b) bradycardia,

c) anginal pain

d) palpitation

e) hypotension or hypertension

f) dyspnea

ADRENERGIC AGONIST

ADRENERGIC ANTAGONIST

Alfa antagonist: Alfazusin (Xatral) Prazosin (Cardura) yohimbin

Beta antagonist 1. Propanolol (Inderal) 2. Bisoprolol (concor) 3. Atenelol (tenormin) 4. Carvidolol (dilatrand) 5. Timolol (cospot)

ADRENERGIC ANTAGONIST

1) Propranolol hydrochloride(Inderal)

Classification: beta-adrenergic blocking agent, antiarryhthmic.

Action: manifests both beta1 and beta 2 adrenergic blocking activity.

Indication:

1. Angina pectoris. 2. Hypertension.

3. Cardiac arrhythmias. 4. Prophylaxis of migraine.

5. Prophylaxis of MI. 6. Pheochromocytoma

Dosage: Tablets: initial dose of 40 mg bid

ADRENERGIC ANTAGONIST

Propranolol hydrochloride(Inderal)

Contraindications:

• Bradycardia,

• C.H.F.

• diabetes,

• chronic bronchitis

• asthma

• emphysema

ADRENERGIC ANTAGONIST

Propranolol hydrochloride(Inderal) Side effects:

• psoriasis-like eruptions.

• Bradycardia,

• C.H.F.

• hypotension,

• dyspnia, shortness of breath

• Nausea and vomiting

• bronchospasm

ADRENERGIC ANTAGONIST

2) Bisoprolol fumarate.(Concor)

Indications: Hypertension and angina pectoris.

Contraindications:

• Acute heart failure

• Bradycardia

• Hypotension

• Severe bronchial asthma or severe chronic obstructive pulmonary disease.

Dose: 5 mg/10 mg once daily

ADRENERGIC ANTAGONIST

2) Bisoprolol fumarate.(Concor) • Adverse effects:

• Bradycardia,

• C.H.F.

• hypotension,

• cold extremities (due to peripheral vasoconstriction)

edema

• dyspnia, shortness of breath

• Nausea and vomiting

• bronchospasm

ADRENERGIC ANTAGONIST

3) Atenolol: (Tenormin)

Classification: beta 1 –adrenoreceptr blocking drug which

is a cardioselective.

Uses: Hypertension angina pectoris.

Dosage: Tablets: 50 mg or 100 mg daily

IV in case of acute MI: give 5 mg over 5 minutes, and if

there is no response, give another 5 mg after 10 minutes.

Specific nursing considerations:

3. For IV use, the drug may be diluted in sodium chloride,

dextrose, on dextrose saline.

ADRENERGIC ANTAGONIST

General considerations:

1. Instruct patient/family to take blood pressure and pulse.

2. Provide written instructions as when to call physician (e.g. HR below 50 beat/min).

3. Instruct patient to dress warmly during cold weather.

4. Diabetic patient should be very careful about symptoms of hypoglycemia.

5. Report any asthma-like symptoms.

ADRENERGIC ANTAGONIST

Alfazusin (Xatral)

Indication: Treatment of the functional symptoms of benign prostatic hypertrophy (BPH)

Contraindications:

• history of orthostatic hypotension;

• combination with other alpha-1 receptor blockers;

• hepatic insufficiency.

Dosage: 10 mg once daily

Side effects: tachycardia, palpitations, hypotension (postural)

Parasympathomimetic (cholinergic) Drugs

Parasympathomimetic (cholinergic) Drugs

Cholinergic drugs have the following

pharmacological effects on various structures:

1- GIT: - Enhance secretion by gastric & other

glands & this may cause:

nausea & vomiting.

Increase smooth muscle tone & stimulate bowel

movement.

3. GU system: Stimulation of ureter & relaxation of

urinary bladder resulting in micturation .

Action of cholinergic agonist

4. Cardiac muscle:

- Slowing heart rate (Bradycardia).

- Decrease atrial contractility, impulse formation &

conductivity.

5. Blood vessels: Vasodilation skin temperature &

local flushing.

Action of cholinergic agonist

6. Respiration: Mucus secretion & bronchial

constriction wheezing. coughing, shocking (specially

in asthmatic patients).

7. Eyes: Pupillary constriction (miosis), in intraocular

pressure.

8. Skin: activation of sweat & salivary glands

Action of cholinergic agonist

Classes of cholinergic agonist

Direct-acting

Receptor agonists

Choline esters ACETYLCHOLINE

BETHANECOL

Alkaloids PILOCARPINE

Cholinesterase inhibitors

Carbamates PHYSOSTIGMINE

NEOSTIGMINE

PYRIDOSTIGMINE

EDROPHONIUM

Phosphates ISOFLUROPHATE

Antidote

PRALIDOXIMINE

Indirect-acting

Direct Acting Agonist

1) Betanechol (Urecholine) p.o or sc

Action: Stimulant of the smooth muscle of the GI

tract and the urinary bladder.

Uses:Urinary retention and inadequate emptying of

the bladder;

- postoperative

- postpartum urinary retention

Adverse effects: sweating, salivation, diarrhea

bradicardia, nausea and bronchospasmo

Direct Acting Agonist

2) Carbachol (moistat) eye drops

Uses: Only to treat glucoma

Adverse effects: no systemic absorbtion at the doses

used

3) Pilocarpine nitrate(Salagen)

Chief alkaloid in pilocarpus

Uses: in emergency to treat glucoma

Dose: 1 gtt of 1-4 % solution

Indirect Acting (reversible inhibitors of Achestrase)

1. Pyridostigmine Bromide (Mestinon)

Class. : Indirectly acting, cholinergic-

acetylcholinestrase inhibitor.

M of Action: inhibiting REVERSIBILY the enzyme

cholinestrase, that lead to increase the concentration

of acetylcholine at the myoneural junction which

facilitate the transmission of nerve impulse across the

myoneural junction, that lead to increase muscle

strength in myasthenia gravis.

1. Pyridostigmine Bromide (MESTINON)

N.B. :

- It has a slower onset, longer duration of action &

fewer side effects than neostigmine.

- Atropine may be given to control side effects.

Uses: Myasthenia Gravis.

Contraindication:

- Hypersensitivity - Bradycardia

- Hypotension - Asthma

Indirect Acting (reversible inhibitors of Achestrase)

1. Pyridostigmine Bromide (MESTINON)

Side effects:

Skin rash, thrombophlebitis after I.V. use

Nausea, vomiting, diarrhea.

Bradycarda, Hypotension, headache, dizziness.

Urinary frequency (Incontinence) , bronchosporn.

Dose: Tab. 600 mg daily.

Indirect Acting (reversible inhibitors of Achestrase)

2) Neostigmine Bromide (Prostigmin).

Uses: Maestenia Gravis and atonic bladder

Dose: Tab. 150 mg daily.

All information as pyridostigmine.

Indirect Acting (reversible inhibitors of Achestrase)

3)Physostigmine salicylate(Eserine salicylate.)

Uses: For the treatment of glaucoma, and in the

treatment of severe anticholinergic

toxicity(atropina)

General considerations:

1- In case of systemic absorption Have adrenaline &

atropine available for emergency treatment.

2- Stress the importance of taking eye drops exactly

as prescribed

3- Minimize side effects by taking medication at bed-

time.

General considerations:

4- Advice client not to drive a car for 1-2 hrs after

administering eye drops.

5- Notify the physician, if side effects occurred.

6- Cold compresses for painful eye spasms.

7- Frequent eye examinations.

Cholinergic Antagonists

Cholinergic Antagonists(Parasympatholytic)

M. Of Action:

These agents prevent the neurotransmitter acetylcholine from

combining with receptors on the muscarinic site & nicotonic site.

The main effects:

1- Reduce spasm of smooth muscle such as spasm of the urinary

bladder or intestines.

2- To block vagal impulses to the heart which will increase heart rate

& conductivity.

3- To suppress or decrease gastric secretions, perspiration, salivation

and secretion of bronchial mucus.

Cholinergic Antagonists(Parasympatholytic)

The main effects:

4- To relax the sphincter muscles of the iris & cause pupillary dilation

(mydriasis) & loss of accommodation for near vision.

5- Act on CNS producing such reactions as depression (scoplamine) or

stimulation (toxic dose of atropine) to produce antiparkinsonism

effect.

Contraindications:

Glaucoma, myocardial ischemia, Prostate hypertrophy,

Myasthenia gravis, paralytic ileus,

Cholinergic Antagonists(Parasympatholytic)

Side effects:

Nausea,

vomiting, dry mouth,

constipation, dizziness,

headache,

insomnia, blurring of vision,

photophobia, flashing, euphoria.

Cholinergic Antagonists (Parasympatholytic)

1) Atropine sulfate:

Class.: Cholinergic blocking agent.

Action:

It is a parasympatholytic agent which cause relaxation of smooth

muscles & inhibition of secretary glands.

Uses:

- Treatment of spastic disorders of biliary tract .

- During anesthesia to control salivation & bronchial secretions.

- Ophtalmolgy as cycloplegic

- Prophylaxis and treatment of toxicity due to cholinestrase inhibitor

including organophosphate pesticides.

Cholinergic Antagonists (Parasympatholytic)

1) Atropine sulfate:

Contraindications: See parasympatholytics

Side effects: See parasympatholytics

Dose:

Tablets: 0.3 – 1.2 mg Q 4-6 hr

Available in 1ml-ampoule containing 1 mg atropine.”

IM, I.V. & S.C. 0.4 – 0.6 mg Q 4-6 hour for anticholinergic action

Cholinergic Antagonists (Parasympatholytic)

2) Scopalamine Hydrobromide (Hyoscine).

M.O.Action : depress the cerebral cortex, especially the

motor area, act as a powerful hypnotic.

Uses:

1- Motion sickness ( prevention and control of nausea and vomiting).

2- With other narcotics to treat biliary and renal colic.

N.B. N-Butil scopalamine (Buscopan) used as spasmolytic with

success in intestinal cramps as in severe cramps during menstrual

cycle

Cholinergic Antagonists (Parasympatholytic)

2) Scopalamine Hydrobromide (scopinal).

Contraindications:

- Hypersensitivity. - Glaucoma

- Bronchial asthma - Cardiac arrhythmias

- Pregnancy - Lactation.

Side effects:

Pupil dilation, photophobia, headache,

Dry mouth, constipation, nausea, vomiting. tachycardia, Suppression

of lactation.

.

Cholinergic Antagonists (Parasympatholytic)

3) Ipratropium bromuro (Atrovent) only by inhalation

Indications: asthma as substitute of beta agonist

and chronic obstructive pulmonary diseases (COPD)

- Side effects: no systemic absorption duo to positive

charge