CNS Stimulants 1. Analeptics stimulate autonomic system (respiratory and circulation) 2. Methylxanthines (caffeine, theobromate and theophylline) 3. Central sympathomimetics agents Analeptics Provigil (Modafinil) Atypical 1 norepinephrine receptor stimulant Nacrcolepsy, sleep apnea Adverse side effects: nervousness, anxiety and sleeplessness

Methylxanthines (Caffeine, theophylline and theobromine) CNS stimulation is believed to be linked to adenosine receptors Dopram (Doxapram HCl) Respiratory stimulant, Overdose with CNS depressant, chronic obstructive pulmonary diseases (COPD) and apneas.

Compound R R’ R” Caffeine CH3 CH3 CH3 Coffee, Tea Theophylline CH3 CH3 H Tea Theobromine H CH3 CH3 Cocoa Caffeine is widely used CNS stimulant. It found in brewed coffee, brewed tea and cola beverages. Dosage range for stimulation is 85 to 250 mg. Adverse side effects include restlessness, anxiety and nervousness. At high dose, convulsion may occur. Use to treat migraine and tension headaches (central vasoconstriction) Theophylline has been used as CNS stimulant, used as bronchodilator. Caffeine being more lipophilic than theophylline thus having higher brain concentrations. Caffeine’s half-life (5 to 8 hours) and theophylline’s half-life (3.5 hours). Mechanism of action: CNS stimulation (antagonize adenosine A1 and A2 receptors).

Methylxanthines Adenosine

Central Sympathomimetics Agents -phenylethylamine Structure Activity Relationship (SAR) Lower alkyl groups adjacent () increases CNS rather than peripheral activity Branching generates a chiral center. The dextro(S) of amphetamine is 10 times more potent than levo (R) isomer. Hydroxylation of ring or () carbon decrease activity. Phenylpropanolamine Halogenation (F, Cl, Br) of the aromatic ring decreases activity. Chloroamphetamine has strong central serotoninergic activity. Methoxy substitution cause dopaminergic activity (D2) N-methylation increases activity (methamphetamine) Mono substitution larger than methyl decrease activity Di-N-methylation decreases activity

p-Chloroamphetamine 5-HT releasing agent Fenfluramine 5-HT releasing agent. Appetite suppressant S (+)-Amphetamine p-hydroxyamphetamine P-methoxyamphetamine (PMA) Weak CNS stimulant (10% potency)

Cathines Ephedra used as dietary supplement contain ephedrine and caffeine.

Norephedrine Khat (leaves eaten in Middle East)

Benzedrine (Amphetamine Sulfate) racemic mixture more cardiovascular effect Dexedrine (Dextroamphetamine Sulfate and Dextroamphetamine Phosphate) (IV) mechanism of action involves the release of Norepi to a smaller extent inhibition of Norepi uptake at postsynaptic cleft (1) Adderall (combination of salts saccharate, sulfate, aspartate) Dextroamphetamine is strongly basic. (S) configuration has fewer cardiovascular effects and 10 times more potent than (R) as CNS stimulant. Systemic acidosis can cause 60 to 70% of the drug to excreted unchanged. -methyl group retards metabolism by MAO. What is the major route of metabolism of dextroamphetamine? Uses narcolepsy, Parkinson’s disease, attention deficient disorders (ADD), dieting.

Amphetamine Metabolism

Desoxyn (Methamphetamine HCl) Very highly abuse drug Street name “Meth, Ice, or glass” Uses same as amphetamine Didrex (Benzphetamine HCl) A decrease in activity. Maintain Anorexiant activity ( receptor agonist) Tenuate, Tepanil (Diethylpropion HCl) Anorexiant agent Pondimin (Fenfluramine hydrochloride) Sedation rather than excitation (serotoninergic) In combination with phentermine (phen-fen) Removed from market because heart valve Damage 1997 (5HT2B)

Ritalin (Methylphenidate hydrochloride) marketed as racemate Its p-hydroxy metabolite blocks Norepi reuptake and acts as postsynaptic agonist. In the stomach the protonate form is resistant hydrolysis. Uses Narcolepsy or attention deficit disorder (ADD). Pemoline Requires 3 to 4 weeks after administration to elicit an effect. Delay relayed to increase in dopamine synthesis. Trade name Cyclert discontinued Liver toxicity

Ionamin (Phentermine Ion-Exchange Resin) Diet supplement Didrex (Benzphetamine Hydrochloride) Diet supplement (b agonist)

Central Sympathomimetic agents (Continue) Plegine (Phendimetrazine) Anorexiant Merida (Sibutramine) Anorexiant and Antidepressant