Sympathomimetic drugs are stimulant compounds which mimic the effects of agonists of the sympathetic nervous system such as the catecholamines. (epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine, etc.) Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

These drugs can act through several mechanisms, such as directly activating postsynaptic receptors, blocking breakdown and reuptake of certain neurotransmitters, or stimulating production and release of catecholamines.

Mechanisms of action

The mechanisms of sympathomimetic drugs can be direct-acting, such as α-adrenergic agonists, β-adrenergic agonists, and dopaminergic agonists; or indirect-acting, such as MAOIs, COMT inhibitors, release stimulants, and reuptake inhibitors that increase the levels of endogenous catecholamines.

Structure-activity relationship

For maximum sympathomimetic activity, a drug must have:

1. Amine group two carbons away from an aromatic group
2. A hydroxyl group at the chiral beta position in the R-configuration
3. Hydroxyl groups in the meta and para position of the aromatic ring to form a catechol which is essential for receptor binding

The structure can be modified to alter binding. If the amine is primary or secondary, it will have direct action, but if the amine is tertiary, it will have poor direct action. Also, if the amine has bulky substituents, then it will have greater beta adrenergic receptor activity, but if the substituent is not bulky, then it will favor the alpha adrenergic receptors.

Direct-acting

Adrenergic receptor agonists

Direct stimulation of the α- and β-adrenergic receptors can produce sympathomimetic effects. Salbutamol is a very commonly used direct-acting β₂-agonist. Other examples include phenylephrine, isoproterenol, and dobutamine.

Dopaminergic agonists

Stimulation of the D1 receptor by dopaminergic agonists such as fenoldopam is used intravenously to treat hypertensive crisis.

Indirect-acting

Norepinephrine and dopamine transporter blockade

Classic examples of indirect sympathomimetic drugs are amphetamines (including MDMA), ephedrine, and cocaine, which act by blocking and reversing norepinephrine transporter (NET) activity. NET is a transport protein expressed on the surface of some cells that clears noradrenaline and adrenaline from the extracellular space and into cells, terminating the signaling

Structure-activity relationship

A primary or secondary aliphatic amine separated by 2 carbons from a substituted benzene ring is minimally required for high agonist activity. The pKa of the amine is approximately 8.5-10.^[1] 1- Substitution on aromatic ring-

The presence of hydroxy group in the benzene ring at 3rd and 4th position shows maximum alpha and beta activity

Cross-reactivity

Substances such as cocaine also affect dopamine, and some substances such as MDMA affect serotonin.

Norepinephrine is synthesized by the body from the amino acid tyrosine,^[2] and is used in the synthesis of epinephrine, which is a stimulating neurotransmitter of the central nervous system.^[3] Thus, all sympathomimetic amines fall into the larger group of stimulants (see psychoactive drug chart). In addition to intended therapeutic use, many of these stimulants have abuse potential, can induce tolerance, and possibly physical dependence, although not by the same mechanism(s) as opioids or sedatives. The symptoms of physical withdrawal from stimulants can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving, as is apparent in the rebound withdrawal from certain substituted amphetamines. Physical withdrawal from some sedatives can be potentially lethal, for instance benzodiazepine withdrawal syndrome. Opioid withdrawal is very uncomfortable, often described as a bad case of the flu, with possibly severe abdominal cramps and diarrhoea as central symptoms,^[4] but it is rarely lethal unless the user has a comorbid condition.^[5]

Comparison

"Parasympatholytic" and "sympathomimetic" are similar, but not identical. For example, both cause mydriasis, but parasympatholytics reduce accommodation (cycloplegia) while sympathomimetics do not.

Examples

• amphetamine (Benzedrine)
• benzylpiperazine (BZP)
• cathine (found in Catha edulis)
• cathinone (found in Catha edulis, khat)
• cocaine (found in Erythroxylum coca, coca)
• ephedrine (found in Ephedra)
• lisdexamfetamine (Vyvanse)
• maprotiline (Ludiomil)
• MDMA (Ecstasy, Molly)
• methamphetamine (Meth, Crank, Desoxyn)
• methcathinone
• methylenedioxypyrovalerone (MDPV)
• methylphenidate (Ritalin)
• 4-methylaminorex
• oxymetazoline (Afrin, Vicks Sinex)
• pemoline (Cylert)
• phenmetrazine (Preludin)
• propylhexedrine (Benzedrex)
• pseudoephedrine (Sudafed, SudoGest, also found in Ephedra species)

See also

• Sympathetic nervous system

References

External links

• Amines, Sympathomimetic at the US National Library of Medicine Medical Subject Headings (MeSH)

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