Reversal Action Of

Adrenaline on

Blood pressure

By Dr Sameh AM Abdelghany

Physiology Review

• The autonomic nervous system (ANS) is that division of the nervous system concerned with regulation of involuntary functions.

• It consists of 2 divisions, sympathetic and parasympathetic, controlled by higher CNS centers.

Sympathetic Parasympathetic

Autonomic nerve:

Origin

Pre-gang fiber

Post-gang fiber

Ganglia

Thoracic part: T 1-12

Lumbar part: L 1-3

Short

Long

Outside organs

Cranial part: III, VII, IX, X

Sacral part: S 2,3,4

Long

Short

Inside organs (é few

exceptions)

Chemical

transmitters:

1ry:

2ry:

Co-transmitters

NA, A

Dopamine

ATP, NPY, Substance-P, etc.

Ach

–

The same

Receptors:

Main:

Other:

Alpha: α1, α

2

Beta: β1, β

2, β

3

Dopaminergic: D1, D

2

Imidazoline: I1, I

2

Muscarinic: M1,

M2,

M3,

m4,

m5

Nicotinic: Nn, N

m

–

Autonomic tone

Predominates on:

- Heart (vent ms) → ↑ contraction

- Bl.V → VC

Predominates on:

- Heart (S-A node) → ↓ rate

- Iris (circular ms) →

Chemical transmitters in the ANS

Primary transmitters:

I. Adrenaline and noradrenaline(NA)

II. Acetylcholine

Adrenaline and noradrenaline(NA)

Synthesis and storage:

1. In nerve terminals, most of catecholaminesare in the form of NA because the enzyme N-methyl transferase is not present

2. In adrenal medulla, most of catecholaminesare in the form of adrenaline.

Sites of release:

all sympathetic system except:

I. Sympathetic ganglia

II. Postganglionic sympathatheticfibers to sweat glands.

Fate: all sympathetic system except:

I. Re-uptake (80%):

Neuronal uptake (uptake 1)

Tissue uptake (uptake 2)

Granular uptake (uptake 3)

II. Metabolism (20%):

Monoamine oxidase (MAO) enzyme

Catechol-O-methyl transferase(COMT)

Autonomic receptors

1. Adrenergic receptors.

2. Cholinergic receptors.

Adrenergic receptorsType Tissue Second

messenger

Actions

1 Most vascular smooth ms

Pupillary dilator muscle

Pilomotor smooth muscle

Liver (in some species)

IP3, DAG Contracts (vasoconst)

Contracts (mydriasis)

Contracts (erects hair)

Glycogenolysis

2 Adrenergic and cholinergic

nerve terminals

Platelets

Some vascular smooth ms

Fat cells

Pancreatic B cells

cAMP Inhibits transmitter

release

Stimulates aggregation

Contracts

Inhibits lipolysis

Inhibits insulin release

Type Tissue Second

messenger

Actions

1 Heart

Juxtaglomerular cells

cAMP Incease rate and force

Stimulates renin release

2 Respiratory, uterine, and

vascular smooth muscle

Liver (human)

Somatic motor nerve terminals

(voluntary muscle)

Pancreas

cAMP Relaxes

Stimulates glycogenolysis

Causes tremor

Increase insulin release

3 Fat cells cAMP Stimulates lipolysis

D1 Renal and other splanchnic

blood vessels

cAMP Relaxes (reduces

resistance)

D2 Nerve terminals cAMP Inhibits adenylyl cyclase

Organ Alpha(α) Beta(β)

Eye Mydriasis (α1) -

Heart - ++ all cardiac properties(β1)

Bronchi - Bronchodilatation (β2)

GIT Cont. Sphincters (α1) Relax wall (β2)

UT Cont. Sphincters (α1) Relax wall (β2)

Uterus Cont. (α1) Relax (β2)

Bl.vessel V.C esp skin-mm(α1) V.D esp skeletal- coronary(β2)

Insulin release decrease(α2) Increase (β2)

Others - ++ NM transmisssion - Glycogenlysis (β2)- Lipolysis(β3)- ++ Renin release(β1)- ++ K uptake(β2)

Alpha Adrenergic receptors agonists & antagonists

I. Alpha adrenoceptor agonists:

Alpha 1 and alpha 2: EP and NE.

Alpha 1: phenylephrine and methoxamine.

Alpha 2: clonidine.

II. Alpha adrenoceptor antagonists:

Alpha 1 and alpha 2: phentolmaine

Alpha 1: prazosin.

Alpha 2: yohmbine.

Beta Adrenergic receptors agonists & antagonists

I. Beta adrenoceptor agonists:

Beta1, beta2, beta3: isoproterenol and EP.

Beta 1: dobutamine

Beta 2: salbutamol, terbutaline

II. Beta adrenoceptor antagonists:

Beta1, beta2: propranolol

Beta 1: Atenolol

Beta 2: butoxamine

Sympathomimetics

Definition:

o These are drugs, which produce pharmacological actions and effects similar to sympathetic stimulation.

Sympathomimetics

Catecholamines

Natural e.g NE, EP

Synthetic e.g Isoprenaline

Non-Catecholamines

Classification

According to mechanism of action:

i. Direct acting: e.g. E, NE, and dopamine

ii. Indirect acting: e.g. amphetamine

iii. Both direct and indirect: e.g. ephedrine

According to selectivity:

i. Drugs acting mainly on α1 receptors: e.g. NE, phenylepherine

ii. Drugs acting mainly on β receptors:

a. On β1 mainly: e.g. dobutamine

b. On β2 mainly: e.g. salbutamol and turbutaline

c. On both β1 and β2: e.g. isoprenaline

iii. Drugs acting on α and β receptors: e.g. adrenaline, ephedrine

iv. Drugs acting on α, β, and dopamine receptors: dopamine

Adrenaline (Epinephrine)

Chemistry:

• Natural alkaloid synthesized by adrenal medulla.

Pharmacokinetics

Absorption:

• Slow (due to its local VC) and poor (because it is polar) from all sites.

• Slowly absorbed if given SC and rapidly after IM,IV

Distribution:

• all tissues except CNS (catecholamine).

Fate:

• Re-uptake: (80%)...(neuronal, tissue, and granular).

• Metabolism: (15%) by MAO and COMT.

• 5% Excreted in urine in the form of VMA (4-8 mg/ day).

Pharmacodynamics

Mechanism of action:

stimulates all α1, α2, β1, β2, β3 receptors.

Pharmacological effects:

CVS:

a) Heart: ↑ all cardiac properties (β1).

b) BV:

• VC of skin, visceral and brain BV (α1)

• VD of sk ms BV (β2)

c) BP:

• Small dose → ↓ BP (β2 is more sensitive than α1).

• Large dose → biphasic response:

i. Initial ↑: due to predominant α1 action.

ii. Delayed ↓: due to predominant β2 action (β2 is more sensitive to small doses of adrenaline).

• Hypertensive effect reversed by α-blocker

Respiratory system:

• Airway:

i. Bronchodilatation (β2).

ii. Bronchial decongestion due to VC of bronchial BV (α1).

GIT and urinary system:

• Wall: relaxation (β2).

• Sphincters: contraction (α1).

Metabolic effects:

Liver → ↑ glycogenolysis (β2).

Kidney → ↑ renin secretion (β1)

Fat cells → ↑ lipolysis ( β3)

Exocrine glands:

Sweat glands: sympathetic sweating (forehead and palms) (α1).

Atiallergic action:

It is the physiological antidote of histamine on BP and bronchi

Eye:

• Local adrenaline: no effects (destroyed by alkalinity of the tears).

• Local dibivalyl adrenaline:

↓ IOP (due to VC of ciliary BV → ↓ aqueous humor secretion)

Local actions:

• Decongestant -hemostatic

• Delay absorption of drugs given SC

Therapeutic uses

Acute bronchial asthma

Acute anaphylactic shock

a)Stimulation of bronchial β2 receptors → ↑ cAMP→ bronchodilatation.

b)Stimulation of bronchial α1 receptors → VC of bronchial BV →↓ br secretions.

c)↑ BP (due to ↑ COP “β1” + ↑ PR “α1”).

d)↓ histamine release from mast cells (β2).

Local uses:

1. In acute epistaxis (nasal bleeding) to produce VC of nasal BV.

2. Dibivalyl adrenaline is used as eye drops for treatment of glaucoma.

3. Injected locally with local anesthetics:

i. To prolong the duration of local anesthetics due to local VC.

ii. To minimize bleeding due to local VC.

Side effects

1. Severe hypertension and cerebral hemorrhage.

2. Tachycardia, palpitations, and ventricular fibrillation.

3. Acute heart failure.

4. Gangrene of fingers when used with local anesthetics in high conc (due to VC).

Contraindications

1. Heart diseases.

2. Hypertension.

3. Hyperthyroidism

4. During general anesthesia with halothane or cyclopropane because they increase the sensitivity of the sympathetic receptors.

5. With local anesthesia in fingers and toes

NOREPINEPHRINE (NORADRENALINE)► Source and Chemistry as adrenaline

► Pharmacokinetics as adrenaline

►Pharmacodynamics

Mechanism of Action:

• directly stimulates both and 1 receptors.

Pharmacological Effects

C.V.S.

Heart:

i. Increased cardiac properties (1)

ii. Reflex vagal effect due to its hypertensive effect leads to bradycardia (this bradycardia could be blocked by atropine)

Blood vessels: generalized V.C. (1)

Blood pressure: rise of both systolic and diastolic blood pressure.

Therapeutic Uses

1. Acute hypotensive states e.g. spinal anesthesia and after ganglion blockers.

2. Shock states when tissue perfusion is good

Adverse Effects

1. Bradycardia and palpitation

2. Headache and anxiety.

3. Severe hypertension leads to cerebral hemorrhage

4. Cardiac arrhythmias.

5. When used with local anesthesia in fingers, its extravasation may lead to necrosis and sloughing.

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