الحلقة 13 من كورس كلنيكال فارما من جزء (ANS)

Phenylephrine (prefrin®)

About

The drug

- Phenylephrine is a direct-acting adrenergic drug, binds primarily to α1

receptors.

- Because it is not a catechol derivative, it is not inactivated by COMT

and has a longer duration of action than the catecholamines.

- It is a vasoconstrictor → increase blood pressure.

- It has no effect on the heart itself ,but induces reflex bradycardia

when given parenterally.

Therapeutic

Uses

- Hypotension → act as Vasopressor, used parenterally mainly in hospitalized or

surgical or vasodilatory shock patients (especially those with a

rapid heart rate).

- Haemorrhoids → used topically to prevent symptoms of haemorrhoids.

- Nasal Decongestant→ oral or nasal spray.

- Mydriatic → eye drops.

Side effects - Hypertension, headache and nausea or vomiting.

- Reflex bradycardia (If given parenterally).

Methoxamine (Vasoxyl®)

Methoxamine injection used for the treatment and management of hypotension, but clinical

application are rare and limited.

Midodrine (Gutron®)

- Midodrine is a prodrug that is hydrolysed to Desglymidodrine.

- Midodrine given orally for the treatment of symptomatic orthostatic hypotension (OH).

Metaraminol (Aramine®)

- Metaraminol injection is indicated for prevention and treatment of the acute hypotensive state

occurring with spinal anesthesia.

- It acts through peripheral vasoconstriction by acting as a α1-adrenergic receptor agonist.

- It releases norepinephrine from its storage sites indirectly.

Naphazoline (Naphcon-A®) Tetrahydrozoline (Visine®)

Xylometazoline (Otrivin®) Oxymetazoline (Afrin®)

- Naphazoline , Tetrahydrozoline , Xylometazoline and Oxymetazoline are vasoconstrictor

decongestants derivatives of imidazoline, are founds in OTC eye drops and nasal drops or sprays. It

works by constricting swollen blood vessels in the eye or nose reduces eye redness (relieve

irritation) and nose congestion.

- Oxymetazoline is a drug of choice for epistaxis.

- Oxymetazoline over dose → Hypotension and CNS depression? (clonidine-like effect)

- It has significant affinity for a2-adrenergic and imidazoline receptors (partial agonist effects).

# Presynaptic α2-receptors agonist → decrease NE release → decrease blood pressure.

Central α2 and imidazoline receptors agonist→ decrease NE release in the brain→ CNS depression.

Selective α1-adrenoceptor Agonists

Clonidine (Catapres®)

About

The drug

- Clonidine is an α2 agonist (centrally and peripherally) that is used for the

treatment of hypertension.

- It is lipid soluble rapidly enters the brain activate central α2 receptors.

- Oral preparation (Catapres®) given twice a day.

- Transdermal preparation (Catapres-TTS®) - given once every 7 days.

Mechanism

Of action

1) Stimulate presynaptic α2 receptors:

- Decrease Presynaptic Ca2+ → Decrease NE release therefore

decrease blood pressure.

2) Stimulate central α2 receptors:

- Decrease Sympathetic vasomotor centers → Decrease

Sympathetic

outflow → Decrease NE release then decrease renin release

therefore blood pressure decrease.

3) Stimulate I1 (Imidazoline) receptor:

- Sympatho-inhibitory action→ Decrease blood pressure.

Therapeutic

Uses

- Hypertension. (used alone or with other antihypertensive agents)

- Attention deficit hyperactivity disorder (ADHD).

- Withdrawal symptoms (narcotics, alcohol, benzodiazepine and nicotine).

- Prophylaxis for migraine.

- Psychiatric disorders (stress & sleep disorders).

- Hot flashes that occur with menopause.

- Diagnosis of pheochromocytoma (Clonidine suppression test).

Side effects - Most adverse effects are mild and tend to diminish with continued therapy.

- The most frequent adverse effects (dose-related) are:

Dry mouth, drowsiness, dizziness, constipation and sedation.

- The less frequent (rare) adverse effects are:

Fatigue, headache, mental depression and Na+ and water retention.

- FDA pregnancy category C

Withdrawal - Clonidine therapy should be gradually tapered off.

- Clonidine suppresses sympathetic outflow resulting in lower blood pressure,

but sudden discontinuation can cause rebound hypertension due to a

rebound in sympathetic outflow.

- Clonidine withdrawal hypertension treated by α1, and β blockers.

Selective α2-adrenoceptor Agonists

α-Methyldopa (Aldomet®)

About

The drug

- Methyldopa is an α2 agonist that has both central and peripheral effects.

- Its primary clinical use is as an antihypertensive agent

Mechanism

Of action

Methyldopa has a dual mechanism of action:

1) Methyldopa is converted into the false transmitter (metabolite) called;

alpha-methylnorepinephrine, in the CNS by dopamine beta-hydroxylase (DBH)

enzyme → The false transmitter is central a2-agonist → decrease sympathetic

out flow → decrease NE release then decrease renin release → decrease

blood pressure.

2) It is a competitive inhibitor of dopa-decarboxylase enzyme which converts

L-dopa into dopamine

~Dopamine is a precursor for norepinephrine and subsequently epinephrine~

Therapeutic

Uses

- Hypertension.

- Gestational hypertension and pre-eclampsia (pregnancy-induced

hypertension).

- FDA pregnancy category B

- Used with caution in lactating women (appears in breast milk).

Side effects Sympathetic blocked:

- Postural hypotension, failure of ejaculation and nasal congestion.

CNS manifestation:

- Sedation, drowsiness, depression and Parkinsonian symptoms.

Increase prolactin hormone:

- Due to inhibition of dopaminergic mechanism → Increase prolactin hormone

Gynecomastia (breast enlargement) and impotence in male,

galactorrhea (Spontaneous flow of milk from the breast) and

amenorrhea (absence of menstrual cycles) in female.

Others → May cause bone marrow depression and hepatotoxicity. Effects

Clonidine Like Drugs

Guanfacine (Tenex®)

-Guanfacine used in the treatment of attention deficit hyperactivity disorder (ADHD) and

hypertension

Guanabenz (Wytensin®)

- Guanabenz an antihypertensive agent.

Apraclonidine (lopidine®)

- Apraclonidine is an α2 agonist with weak α1 agonist effects, used in glaucoma therapy (prevent

intraocular pressure elevation).

Brimonidine (Alphagan®)

- Brimonidine is an α2 agonist, used in open-angle glaucoma and ocular hypertension → α2 agonist

then decrease CAMP → Decrease aqueous humour production by the ciliary body.

- In 2013, the FDA approved topical application of Brimonidine 0.33% (Mirvaso) for facial erythema or

rosacea by narrowing blood vessels.

Lofexidine (Detoxydine®)

- Lofexidine is an a2 agonist. It can be used as a short acting anti-hypertensive, but is mostly used to

help relieve symptoms of heroin or opiate withdrawal in opiate dependency.

Selective Imidazoline Receptors Agonists

Rilmenidine (Hyperium®) Moxonidine (Cynt®)

- Used in treatment of hypertension.

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