α-adrenoceptor Antagonists

Non-selective α-adrenoceptor Antagonists

Irreversible Non-Competitive
Phenoxybenzamine (Dibenzyline®)
- Phenoxybenzamine is a non-selective irreversible non-competitive α- adrenoceptor antagonist. - It is binds covalently to both α1 and α2 receptors and the only way the body can overcome the   block; is to synthesize new a-adrenoceptors, which requires a day or longer. - Covalent binding with the receptors due to presence of N-chloro-ethyl. - Half-life: about 24 hours. (long acting) - Duration of action: 3 to 4 days. - Routes of administration:  Orally.
Reversible Competitive
Tolazoline (Priscoline®)	Phentolamine (Rogitine®)
- Tolazoline and Phentolamine are non-selective reversible competitive a-adrenoceptor antagonist. - They are      a competitive block of α1 and α2 receptors. - Phentolamine more potent than Tolazoline. - Duration of action: approximately 4 hours after a single injection. (short acting) - Route of administration: Parenterally.

 

Pharmacological  action	-  α1 receptor blocker effect:   Prevents vasoconstriction of peripheral blood vessels by endogenous   catecholamines à decrease peripheral resistance à reflex tachycardia. - α2 receptor blocker effect:   Block presynaptic inhibitory α2 receptors in the heart à increase NE release   àstimulates β1 receptors on the heart à increase CO .
Therapeutic uses	A) Hypertension in patients with pheochromocytoma. B) Non-specific uses of non-selective a blockers:      1) Symptomatic benign (non-cancerous) prostatic hyperplasia (BPH):         - Urinary retention associated with BPH treated by a-blockers which cause             àrelaxation of smooth muscle in the bladder neck, prostate, and prostate            capsule à Improve urine outflow.      2) Raynaud's  phenomenon:        - Is a recurrent vasospasm of the fingers and toes and usually occurs in          response to stress or cold exposure.     3) Impotence (Erectile Dysfunction; ED):        - Side effects of intrapenile injections of non-selective a-blockers à priapism         (painful prolonged erection lasting 4 hours or more), fibrotic reaction in penis         tissues and failure of ejaculation. C) Phentolamine used in prevention or treatment of dermal necrosis (caused by      following IV extravasation of NE). D) Phentolamine used in diagnosis of pheochromocytoma (Phentolamine blocking      test). E) OraVerse (Phentolamine) injection; is the only local anesthetic reversal agent.      In 2008 FDA has approved OraVerse for the reversal of soft-tissue anesthesia      and the associated functional deficits resulting from a local dental anesthetic         (about 55 min. vs. 155 min.).
Side effects	- Postural hypotension. - Reflex tachycardia. - Failure (difficulty) of ejaculation or retrograde ejaculation à due to blocking a   receptor in smooth muscles of vas deferens and ejaculatory ducts à failure of   contraction.

Selective α1-adrenoceptor Antagonists

Prazosin (Minipress®)
About The DRUG	- Prazosin is a selective competitive α1 receptors blocker. - In contrast to non-selective α1-adrenoceptor blockers, produce less reflex   tachycardia. - It acts by blocking postsynaptic α1-adrenoceptors on vascular smooth muscle     àvasodilatation à decrease total peripheral resistance à decrease BP. - Routes of administration: Orally.
Therapeutic uses	- Treatment of hypertension. - Symptomatic benign prostatic hyperplasia (BPH). - Congestive heart failure (CHF): -        Used as an adjunct to digoxin and diuretics for the treatment of CHF.        Due to decrease systemic resistanceà decrease preload and        afterload à  increaseCO. - Pheochromocytoma:        Used alone or in combination with B-blockers. - Peripheral vasospasm caused by ergot alkaloid toxicity. - Raynaud's phenomenon.
Side Effects	- First-dose orthostatic hypotension (initial syncope attack or first-dose   phenomenon) to overcome; the first dose must be minimized and giving at bed   time. - Headache, dizziness, drowsiness and nausea. - Edema (sodium and water  retention). - Priapism and failure of ejaculation (rare).
Doxazosin (Cardura®)		Terazosin (Hytrin®)
- Doxazosin and Terazosin are selective competitive α1 receptors blockers used Orally for:    symptoms of BPH and treatment of hypertension. - Side effects: same as Prazosin.
Alfuzosin (Xatral®)
- Alfuzosin is a selective a1 blocker used for symptoms of benign prostatic hyperplasia (BPH).   Not used for the treatment of hypertension. - Alfuzosin have better cardiovascular tolerability than Prazosin, Terazosin or Doxazosin. - Most common side effects: dizziness, upper respiratory tract infection, headache and fatigue. - Contraindication: patients with renal insufficiency and patients with history of QT prolongation.
Tamsulosin (Omnic Ocas®)
Tamsulosin is a selective α1 blocker that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels. - Tamsulosin is the most drug prescribed (more selective) in symptoms of benign prostatic hyperplasia (BPH). - It has some benefit in allowing kidney stones to pass through the ureter. - Dosage form:         Tamsulosin MR (Modified Release) capsule.         Tamsulosin OCAS (Oral-Controlled Absorption System) capsule.   Tamsulosin OCAS appeared to have the most favourable efficacy/tolerability ratio. - Dose: Initial Dose: 0.4 mg orally once a day - Maximum Dose: 0.8 mg orally once a day. - Most common side effect: Failure of ejaculation or retrograde ejaculation.
Silodosin (Rapaflo®)
- Silodosin is a selective a1 blocker (selective a1A receptor) in the prostate. - It is used in symptoms of benign prostatic hyperplasia (BPH). - same uses of Tamsulosin but Silodosin acts more rapidly.
Other Drugs Used in BPH (Not Act on α1 Receptors)
Dutasteride (Avodart®)		Finasteride (Proscar®)
- Finasteride and Dutasteride are a 5α-reductase inhibitors. - They are inhibits 5α-reductase enzyme which convert testosterone into the more potent androgen   dihydrotestosterone this lead to reduction in prostate size with improve in urinary flow. - Used primarily in the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia. - Side effects: ↑ risk of impotence (5%), dercease sexual desire (3%) and failure of ejaculation (1%). - Duodart (Dutasteride 0.5 mg + Tamsulosin 0.4 mg) is a combination used once daily in BPH.
Tadalafil (Cialis®)
- Approved for treatment of erectile dysfunction, symptoms of benign prostatic hyperplasia (BPH)  or combined erectile dysfunction and symptoms of BPH. (discussed in next topic)

Selective α2-adrenoceptor Antagonists

Yohimbine (Yohimbex®)

- Yohimbine is a selective competitive α2-blocker. - It is a natural alkaloid derived from the bark of the yohimbe tree in Central Africa. - Uses: mydriatic and erectile dysfunction. - Mechanism of action: The exact mechanism for its use in impotence has not been fully                                            elucidated.                                            Yohimbine blocks central pre-synaptic a2-adrenergic receptors                                             leads to ↑ release of neurotransmitters in CNS and in corpora                                            cavernosum penis such as nitric oxide (NO), noradrenaline, and                                            dopamine. - Common side effects: Tachycardia, hypertension increased motor activity, tremor, and dizziness.

                                                        

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Indirect-acting adrenergic agonists →

- Increase release of epinephrine or norepinephrine.

- Inhibit the reuptake of epinephrine or norepinephrine.

- inhibit the degradation of epinephrine or norepinephrine.

➢ Not directly affect postsynaptic receptors.

Amphetamine (Adderall®)

About

The drug

- Amphetamine is a potent CNS stimulant.

- It is a racemic mixture of phenylisopropylamine.

- It is readily enters the CNS marked stimulant effects on mood and

alertness and a depressant effect on appetite.

- It is has a mood-elevating (euphoria) effect, this effect is the basis

for widespread abuse of this drug.

- It is D-isomer is more potent than L-isomer.

Mechanism

Of action

Amphetamines increase release and decrease reuptake of monoamines (NE and

Dopamine)

Amphetamines { Amphetamine and amphetamine-like drugs} are non-

catecholamine sympathomimetic amines with CNS stimulant activity.

- Amphetamines enters the nerve terminal via the norepinephrine transporter

(NET) and enters synaptic vesicles via the vesicular monoamine transporter

noradrenaline (displace (VMAT), in exchange for stored NE), which escapes into

the cytosol.

- Amphetamines also reduces NA reuptake via the transporter.

Pharmacological

Action

CVS

Indirect sympathomimetic effects of amphetamines → stimulate

both a and ß receptors.

- It causes VC, ↑ HR and ↑ CO → lead to modest ↑ in blood

pressure.

CNS

- Due to increases central dopamine and norepinephrine → causing

wakefulness and euphoria.

- Stimulate cerebrospinal axis, cortex, brain stem and medulla

increase alertness and decrease fatigue.

- Stimulate respiratory center (RC) → producing faster and deeper

breaths.

- Slight analgesic effect.

- Anorexigenic effect (loss of appetite).

GIT

- Contraction in the urinary bladder sphincter difficulty urination. The

effects of amphetamine on the GIT are unpredictable (diarrhea or

constipation)

Therapeutic

uses

- Attention Deficit Hyperactivity Disorder ADHD):

*ADHD; implies the presence of hyperactive- impulsive or inattentive symptoms

that caused impairment and were present before age 7 years.

*Children with ADHD may produce weak dopamine signals in the brain.

*Amphetamines may help to increase the ability to pay attention, concentrate,

stay focused, and stop fidgeting.

Indirect-Acting Adrenergic Agonists

Narcolepsy (chronic sleep disorder):

- Narcolepsy; is a chronic neurological disorder involving the loss of the brain

ability to regulate sleep-wake cycles normally.

- Amphetamines helps to stay awake during the day. It should not be used to treat

tiredness or to hold off sleep in people who do not have a sleep disorder.

Off-label uses:

- Performance-enhancing:

Improve overall work performance.

- Treatment of depression:

Usually in conjunction with a standard antidepressant drug.

- Obesity treatment:

Due to anorexigenic effect.

Side

Effects

Cardiovascular side effects:

- Palpitations (tachycardia) and increase blood pressure.

CNS side effects:

- Insomnia, anxiety, confusion, hallucination and tremor.

Other side effects:

Weight loss, bladder pain (painful urination), headache, nausea, vomiting,

abdominal cramps and diarrhea.

Contra-

indication

-Patients with; Cardiovascular diseases, advanced arteriosclerosis, hyperthyroidism,

severe agitation or severe anxiety and glaucoma.

- Patients with a history of drug abuse those taking MAO inhibitors.

FDA

Warning

Administration of amphetamines for prolonged periods of time may lead. to drug

dependence, and, therefore, this must be avoided.

{ AMPHETAMINES-RELATED DEATH }

Misuse of amphetamines may cause sudden death and serious cardiovascular

adverse events (heart attack and heat stroke).

Amphetamine Derivatives

Dextroamphetamine (Dexedrine®) Lisdexamfetamine (Vyvanse)

- Dextroamphetamine is the more active (dextrorotatory) enantiomer of the amphetamine molecule.

- Lisdexamfetamine is a prodrug that is converted to the active component dextroamphetamine after

GI absorption and metabolism.

- The pharmacological effects and therapeutic uses of dextroamphetamine like amphetamine.

Methamphetamine (Desoxyn®)

- Methamphetamine also known as "speed".

- The effects of methamphetamine like amphetamine but, much stronger, act quicker, and can be

considered more addicting.

- Therapeutic Uses: approved by the FDA for treating :

Attention Deficit Hyperactivity Disorder (ADHD).

Exogenous obesity (obesity originating from factors outside the patient's control)

in both adults and children.

Off label Uses narcolepsy, Increase sexual desire, lift the mood, increase energy and depression

Methylphenidate (Ritalin®)

- Methylphenidate is an amphetamine derivatives with less side effects.

- It is presently one of the most prescribed medications in ADHD.

- Addiction and psychological dependence are rare with methylphenidate.

- It is also effective in the treatment of narcolepsy.

- Off-label uses: Depression and performance-enhancing.

Modafinil (Provigil®)

- Modafinil is a wakefulness-promoting agent.

- Uses: sleep disorders; narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD).

- the exact mechanism which modafinil promotes wakefulness is unknown.

- In the US military, modafinil has been used on certain Air Force missions as a "go pill".

Fenethylline (Captagon®)

- Fenethylline is a prodrug, it is metabolized to form two drugs amphetamine and theophylline.

- Most of the amphetamines abused in Saudi Arabia and other Arab countries come in the form of

Captagon tablets.

Other Indirect-Acting Adrenergic Agonists

Tyramine

- Tyramine is a normal by-product of tyrosine metabolism and not a clinically used.

- It is important because it is found in fermented foods, such as aged cheese (ripe cheese).

- Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine.

- It is metabolised by MAO in the GIT and liver, but, if the patient is taking MAO inhibitors, tyramine is

not metabolized, as well as NE is not metabolized powerful ↑ in NE release from nerve ending→

serious vasopressor effects → Hypertensive crisis (treated by α1 and ß blockers).

Cocaine

- Cocaine is a powerful CNS stimulant.

- It is acts as a serotonin-norepinephrine-dopamine reuptake inhibitor, also known as a triple reuptake

inhibitors (TRI).

- It is a local anesthetic sodium channel blocker produce anaesthesia.

- Like amphetamines, it can increase blood pressure by indirect mechanism.

- Cocaine as a drug of abuse is discussed in CNS chapter.

Ephedrine (Ephedrine sulfate)

About

The drug

- Ephedrine is a natural alkaloid found in various plants in the genus Ephedra.

- It has been used in China for over 2000 years and it was introduced into

medicine in 1924 as the first orally active sympathomimetic drug.

- It is similar in structure to the derivatives amphetamine.

- It is not a catechol → resist MAO and COMT → long duration.

- Excellent absorption orally and penetrate into the CNS.

Mechanism

Of action

Direct and indirect actions (mixed-action) on the adrenergic receptors.

- Direct. Ephedrine increases post-synaptic noradrenergic receptor activity by

activate post-synaptic a-receptors and B-receptors. (weakly).

- Indirect: Amphetamine like action; Ephedrine increase release of stored

norepinephrine from synaptic vesicles.

Pharmacological

Action

CVS - Increase Systolic and diastolic blood pressures by

vasoconstriction (α1) and cardiac stimulation (β1).

CNS - Mild CNS stimulation → increase alertness, fatigue and

prevents sleep (improves athletic performance).

Lung - Bronchodilation, but it is less potent and slower acting than

epinephrine.

Nose - Decongestant effect (due to vasoconstriction).

Therapeutic

uses

-- Treat hypotension associated with anaesthesia.

-- Nasal decongestant.

Off-label uses:

1- As a stimulant or concentration aid (Performance-enhancing).

2- Relieve acute bronchospasm, but it is less effective than epinephrine.

3- Appetite suppressant.

Side

effects

- Palpitation (Arrhythmias).

- Insomnia and hyperactivity.

- Headache

- Nausea or vomiting.

Pseudoephedrine (Sudafed®)

- Pseudoephedrine is a diastereomer of ephedrine.

- It has fewer CNS and CVS effects than ephedrine.

- It used widely as a combination to relieve common cold symptoms. (Actifed)

- Uses: - Sinus congestion.

- Nasal congestion.

- Eustachian tube congestion.

Eustachian tube: is a tube that links the nasopharynx to the middle ear.

- Function:

- Equalizing pressure between the middle ear and the atmosphere

- Drains mucus from the middle ear.

* Otitis media, or inflammation of the middle ear, commonly affects the

Eustachian tube (congestion).

- It has been illegally used to produce methamphetamine (illicit manufacture), Therefore, products

containing pseudoephedrine have certain restrictions in some countries.

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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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Dobutamine (Dobutrex®)

- Dobutamine is a synthetie catecholamine.

- It is a predominantly β1 receptor agonist→ ↑ HR & CO with few vascular effects.

- Major advantage of dobutamine over other sympathomimetic drugs → it increases

cardiac output and does not significantly elevate oxygen demands of the

myocardium.

- Uses: Acute heart failure such as which occurs during cardiac surgery or in cases of

septic or cardiogenic shock (+ve inotropic effect).

- Adverse effects: hypertension, tachycardia, phlebitis (reactions at sites of IV

infusion), nausea, headache and anginal pain

- N.B: used with caution in atrial fibrillation, because it increases AV conduction

Xamoterol Prenalterol Denopamine

- All of these drugs cardiac stimulant.

Mechanism of

Action

In general activation of B2-adrenergic receptors :-

- Smooth muscles; Bronchodilatation and uterine muscle relaxation.

-Skeletal Muscles: Vasodilatation effect.

- Mast cells; decrease release of mediators (such as histamine) of

immediate hypersensitivity from mast cells (histamine).

- Liver; glycogenolysis (particularly if used in high doses).

Therapeutic

Uses

They are primarily used to treat bronchial asthma and other Disease

(COPD). pulmonary disorders such as Chronic Obstructive Pulmonary

Other specified uses:

- Ritodrine used in control of premature labor.

- Salbutamol may be used in treatment emergency hyperkalemia.

Routes of

Administration

- The choice of route of administration and drug to use depends on the

desired clinical effect.

- Inhaled route produces at least as much bronchodilation as oral or

parenteral therapy and does so with substantially fewer side effects.

Side

effects

- Tachycardia (palpitations); especially in parenteral administration.

- Tremor, especially in oral and parenteral administration.

-Insomnia, anxiety, dizziness, headache and nervousness.

Selective Adrenoceptor Agonist

Selective β1-adrenoceptor Agonist

Selective β2-adrenoceptor Agonists (BAA)

Short-acting Beta2-adrenoceptor Agonists (SABA)

- SABA used mainly 3-4 times daily.

Metaproterenol or Orciprenaline (Alupent®)

- Metaproterenol is a short acting B2 agonist.

- It is structurally and pharmacologically similar to isoproterenol.

- It is not metabolized by catechol-O-methyltransferase (COMT).

-Adult dose :-

Oral: 20 mg 3 to 4 times a day.

Inhalation aerosol: 2 to 3 inhalations every 3 to 4 hours, up to 12 inhalations/day.

Salbutamol or Albuterol (Ventolin®)

Adult dose:

- Oral: 2 to 4 mg orally 3 to 4 times a day.

- Metered-dose inhaler: 2 puffs every 4 to 6 hours.

- Inhalation capsules: 200 mcg inhaled every 4 to 6 hours.

Therapeutic Uses:

- Bronchospasm.

- Chronic obstructive pulmonary disease (COPD).

- Other Uses:

- Acute hyperkalemia (1 K+ to flow in cells thus level in the blood).

- Off-Label Uses: (Not approved by the FDA),But: Clenbuterol more preferred for this purposes

1.Bodybuilding and animal feeding:

2.Fat burning (lipolysis) and muscle gain (protein synthesis).

3.Doping: ↑ performance in healthy athletes.

Terbutaline (Bricanyl®(

Dose:

- Oral: 2.5 to 5 mg 3 times daily.

- SC: 0.25 mg as a single dose, May repeat in 15 to 30 min. (max. 0.5 as a total dose in 4 h).

Therapeutic Uses: Bronchospasm

- Off-Label Uses: (Not approved by the FDA)

- Preterm Labor: Brethine (Terbutaline) is one of the most frequently used drugs in the treatment of

preterm labor.

Subcutaneous dose is 0.25 mg every 20 to 60 minutes until a woman's contractions have subsided.

- Priapism (persistent penile erection):

Oral Terbutaline used in patients with prolonged erections of less than 4-hours duration, by relaxation

of the stretched corporeal smooth muscles

FDA warning Terbutaline should not be used to treat prolonged (more than 48 to 72 hours)

premature labor FDA pregnancy category C.

Long-acting Beta2-adrenoceptor Agonists (LABA)

- LABA used mainly 2 times daily (should not be used to treat acute symptoms).

Formoterol (Foradil®) Salmeterol (Serevent®)

- Formoterol , Salmeterol are long acting B2 agonist.

- Duration of action: extended up to 12 hours.

Treatment of Asthma:

- LABA must be used in asthma in combination with another long- term asthma-control medicine

(e.g. inhaled corticosteroids such as fluticasone and budesonide).

- Symbicort® → (Budesonide + Formoterol)

- Advair® → (Fluticasone + Salmeterol)

- Chronic obstructive pulmonary disease (COPD), may be used as mono-therapy or in combination

with corticosteroids.

- Before exercise: - LABA may be used before exercise to prevent exercise-induced bronchospasm

(EIB).

FDA Warning

- LABA have been shown to increase the risk of asthma-related death in pediatric and teenager

patients.

- LABA should not be used as a mono-therapy in the treatment of asthma to minimize serious

reactions such as asthma related deaths.

Contraindication

- Treatment of asthma without use of a long-term asthma control medication such as an inhaled

corticosteroid.

Clenbuterol (Spiropent®)

-Clenbuterol is a long acting B2 agonist.

- Effect of B-adrenoceptor agonists in body metabolism (Clenbuterol more potent) → Increase Fat

burning (lipolysis) and increase muscle gain (protein synthesis).

-Human Use:

Therapeutic Use (rare): Asthma and COPD. performance in athletes.

Off-Labd Uses: Bodybuilding, weight-loss and enhance

- Veterinary Use:

Therapeutic Use as bronchodilator in horses.

Animal Production: Clenbuterol (Ventipulmin®), Zilpaterol (Zilmax®) and Ractopamine (Optaflexx®)

are B2-adrenergic agonists widely used for increase the size of animals and the efficiency of feeding

them.

Levosalbutamol or Levalbuterol (Xopenex)

- Levosalbutamol is the R-enantiomer of salbutamol.

- Comparison to salbutamol;

- It has similar therapeutic effects.

- No benefit of levosalbutamol compared to salbutamol (systematic review in 2013).

Pirbuterol (Maxair®)

- Pirbuterol is a short acting B2 agonist used in asthma and COPD.

Ritodrine (Yutopar®)

- Ritodrine [RIT-oh-dreen] is a tocolytic drug, used to stop premature

Ultra-long-acting Beta2-adrenoceptor Agonists (Ultra-LABA)

- Ultra-LABA used mainly 1 times daily.

Indacaterol (Onbrez®)

- Indacaterol is an ultra-long acting B2 agonist.

- Indicated for long-term control of chronic obstructive pulmonary disease (COPD) symptoms.

- Used once daily at the same time of day.

- FDA warning Asthma-related death (Contraindicated in patients with acute asthma without use

inhaled corticosteroids).

Mirabegron (Myrbetriq®)

- Mirabegron is a B3 agonist.

- It is activate the B3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle

relaxation and an increase in bladder capacity.

- It is used for patients with overactive bladder (OAB).

- Adverse effect :- increase blood pressure and should not be used in patients with uncontrolled

hypertension.

Fenoldopam (Corlopam®)

- Fenoldopam is an agonist of peripheral dopamine D1 receptors.

- It is a racemic mixture and the R-isomer is the active component.

Routes of administration: For continuous IV infusion only due to extensive first-pass metabolism and

short half-life elimination (10 minutes).

- Period of administration: up to 48 hours in adults

up to 4 hours in pediatric.

- Mechanism of action: Rapid-acting vasodilator→ agonist of peripheral dopamine D1 receptors→

VD of renal blood vessels → diuresis.

- Uses: Treat severe hypertension in hospitalized patients.

- Adverse effects: Headache, flushing, dizziness, nausea and tachycardia (due to vasodilation).

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