الحلقة 10 من كورس كلنيكال فارما (ANS) 

Epinephrine or Adrenaline (EpiPen®)

- Epinephrine is a natural catecholamine.

- Norepinephrine (NE) is methylated to yield epinephrine in the adrenal

About medulla which is stored in chromaffin cells.

- On stimulation, the adrenal medulla releases about 80% epinephrine and

20% norepinephrine directly into the circulation.

- L-isomer is about 20 times more potent than D-isomer.

SEE Adrenaline Synthesis in YOUTUBE ( 8 ل 5 الدقيقة من)

https://www.youtube.com/watch?v=lp176gZaK2M&t=664s

-Norepinephrine transporter (NET) is a transporter protein integrated into

the membrane of presynaptic neurons and it is responsible for reuptake of

extracellular monoamine neurotransmitters (NTs) such as norepinephrine,

dopamine and serotonin described as "Uptake 1".

-Extra-neuronal monoamine transporter (EMT) is a transporter protein

integrated into the membrane of postsynaptic neurons, it is responsible

for transport monoamine NTs into postsynaptic neurons described as

"Uptake 2".

- Vesicular monoamine transporter (VMAT) is a transporter protein

integrated into the membrane of synaptic vesicles of presynaptic neurons

and it is responsible for transport monoamine NTs into synaptic vesicles

described as "Uptake 3".

1)Uptake 1 (Neuronal):

- Inhibited by: Cocaine, Amphetamine, Tricyclic Antidepressants (TCAS)

2) Uptake 2 (Extra-Neuronal):

- Inhibited by: Cortisone.

3) Uptake 3 (Vesicle Uptake):

- Inhibited by: Reserpine.

Adrenaline or Epinephrine

Pharmacokinetics

-Epinephrine is ineffective orally due to rapid degradation by gut and rapid

metabolism by liver.

- Routes of administration:

- SC → VC → Slow absorption →Long duration and less toxicity.

- IM →VD → Rapid absorption → Short duration and high toxicity.

- IV →in emergency → rapid onset of action.

- Inhalation → in bronchial asthma.

- Intracardiac (IC) → in resuscitation.

- Eye drops in glaucoma. N.B: IV and IC routes are very dangerous (must be

diluted to 1:10,000).

- Duraton of action: - SC (4-6 hours) - IM (1-4 hours) Inhalation (1-3 hours).

-Metabolism :

Epinephrine ----------------------------------> Metabolites .

Epinephrine-----------------------------------> Metabolites

-Norepinephrine and epinephrine metabolites are metanephrine and

vanillylmandelic acid which are excreted in urine.

Vanillylmandelic acid (VMA) excreted in urine (normal adult value =4- 8mg

in a day)

- increase VMA in urine in patients with pheochromocytoma (tumour in

adrenal medulla).

Pharmacological

action

Local

effects

Nose → α1 → VC →used in epistaxis and congestion.

Skin Used with local anaesthesia .

e.g. Lidocaine→ VC → decrease absorption → prolonged the

action → decrease toxicity.

Cardio-

Vascular

System

Heart (β1)

→+ve Inotropic, chronotropic and dromotropic →

Increase Cardiac output → increase systolic pressure.

Blood Vessels (BV)

1) Skin, mucous membranes and viscera (α1):

→VC → increase peripheral resistance (PR)→

↑ diastolic pressure.

2) Skeletal muscles (β2):

VD→ decrease PR→ decrease diastolic pressure.

* At low doses, β2 effects (vasodilation) on the vascular

system predominate, whereas at high doses, a1 effects

(vasoconstriction) are the strongest.

* The cumulative effect is an ↑ in systolic blood pressure

(β1) and slight decrease in diastolic pressure (β2).

Monoamine oxidase(MAO)

Catechol-O-methyl transferase

N.B: Epinephrine activates β1 receptors on the kidney →

increase renin release. Renin is an enzyme involved in the

production of angiotensin II → potent VC.

LUNG

-Powerful bronchodilatation (β2).

- It also inhibits the release histamines from mast cells (B2).

- So it is used in bronchospasm and anaphylactic shock.

GIT

-Relax gastro-intestinal (GI) and genito-urinary (GU) smooth

muscles.

→ α1 Contraction of sphincter.

→ β2 Relaxation of wall.

Uterus

- Effect of epinephrine on uterine smooth muscles are

variable.

-Usually it relaxes pregnant uterus, especially during last

month of pregnancy (β2).

-Selective B2 agonist e.g. Ritodrine can used to delay

premature labour.

EYE

-Active Mydriasis  Radial muscle contraction (α1)

-Due to high polarity of epinephrine, so no longer used for

glaucoma treatment.

- Dipivefrin is an epinephrine pro-drug that is converted to

epinephrine by esterase enzyme in the cornea.

Used to treat open-angle glaucoma by decrease intraocular

pressure (decrease aqueous humour formation and ↑

outflow).

- It is better than epinephrine due to ↑ lipophilicity→ easily

passes from cornea and penetrate into the anterior

chamber).

- Brimonidine (a2 agonist) also used in glaucoma (see later).

pancreas

[Hyperglycaemic effect]

- ↑glycogenolysis in the liver (B2).

- Decrease insulin release (a2).

- ↑ glucagon release (B2).

Other

Actions

Lipolysis:

- Initiates lipolysis → by stimulate B3 receptors in adipose

tissue

Skeletal Muscle:

- Muscle tremor B2 agonists

(The exact mechanism for tremor induction by B2 agonists is

still unknown).

Therapeutic

uses

1) Bronchospasm (acute asthma):

- Epinephrine is the primary drug used in the emergency treatment of

bronchoconstriction in acute asthma.

-Selective B2 agonists are favored in the chronic treatment of asthma

because of a longer duration of action and minimal cardiac stimulatory

-Within a few minutes after SC administration, respiratory function effects

greatly improves .

2) Anaphylactic shock:

- Epinephrine is the drug of choice for the treatment of type I

hypersensitivity reactions (including anaphylaxis) in response to allergens

(cause excess release of chemical mediators such as histamine.

- Epinephrine is a physiological antagonism of histamine:

Histamine : Bronchoconstriction & Vasodilatation → H1.

Epinephrine: Bronchodilatation & Vasoconstriction B2 & a1.

3) Cardiac arrest: Intracardiac injection of epinephrine can restore cardiac

rhythm in patients with cardiac arrest.

4) Local infiltration anesthetics:

- Local anesthetic may combined with low concentrations of epinephrine

(for example; 1:100,000 parts) → local infiltration anesthetics.

- Benefits of the combination : greatly increases the duration of local

anesthesia by producing VC at the site of application and decrease local

anesthetics toxicity.

5) Epistaxis (Nosebleed):

- Very weak solutions of epinephrine can also be applied topically to

vasoconstrict mucous membranes and control oozing of capillary blood.

DOSE

- One ampoule of epinephrine = 1:1000 (1mg in 1 ml)

- If one ampoule is diluted to 10ml = 1:10,000 (0.1 mg/1ml)

* Adult dose for cardiac arrest:

- IV: 0.5 to 1 mg (5 to 10 mL of 1:10,000) once.

- May be repeated every 3 to 5 minutes as necessary.

* Adult dose for allergic reaction:

- IM: 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution).

- May be repeated every 10 to 15 minutes.

* Adult dose for acute asthma:

-SC: 0.1 to 0.5 mg (0.1 to 0.5 mL of 1:1000 solution)

-May be repeated An every 20 minutes to once every 4 hours as neéded.

- Inhalation: Inhalation aerosol: 160 to 220 mcg (1 inhalation) once.

additional inhalation may be used after at least one min.

Side effects

1) Cardiac arrhythmias (tachycardia).

2) Pulmonary oedema.

Clarification: Tachycardia and increased systemic resistance causes excess load on

left ventricle, causing pulmonary congestion.

This is accompanied with mismatch in increased pulmonary artery pressure

compared with pulmonary alveolar pressure, causing hydrostatic flux of fluid.

3) CNS effects: anxiety, fear, tension, headache, and tremor.

4) Gangrene:

- Gangrene of fingers or toes may occur in patient used local infiltration

anesthetics, due to VC effects.

Contra-

Indications

- Hypertension, Coronary heart disease (Angina) and Arrhythmias.

- Hyperthyroidism (increase sensitivity to adrenaline).

-Pulmonary Oedema.

- With local anaesthetic special around fingers May cause gangrene.

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