الحلقة 14 من كورس كلنيكال فارما من جزء (ANS)

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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