CNS Stimulants

1. CNS Stimulants CNS stimulants can be divided into two distinct categories Psychomotor stimulants: these agents cause excitement & euphoria, relieve fatigue and increase motor activity. Psychomimetic drugs (hallucinogens) produce profound changes in thought patterns and mood. There are a few indications for the medical uses of these agents but they are popular as recreational drugs.

2. PSYCHOMOTOR STIMULANTS Methylxanthines Theophylline (dimethylxanthine) (~1mg/l tea), theobromine (an isomer of theophylline (dimethylxanthine)) Chocolate contains 0.5-2.7% theobromine) & caffeine (trimethylxanthine). Mechanism: There are several proposed mechanisms Translocation of extracellular calcium Increase in cAMP and cGMP due to phosphodiesterase inhibition Blockade of adenosine receptors* (most likely the main effect at common plasma levels).

3. Caffeine Adenosine

4. Actions CNS: 100-200 mg of caffeine (1-2 cups) results in a decrease in fatigue and increased alertness. 1.5gs (12-15 cups) produces anxiety & tremors. Tolerance rapidly develops to these effects and abstinence results in a withdrawal syndrome of fatigue & sedation CV system: + inotrope & chronotrope, this may cause symptoms of cardiac ischemia and arrhythmias. Renal: it is a mild diuretic Gastric mucosa: it stimulates the secretion of HCl. Theraputic uses: xanthines relax smooth muscle of the bronchioles, the development of safer alternatives (β-adrenergic agonists and corticosteroids) has ~eliminated their use for bronchospasm

5. Pharmacokinetics: These xanthines are well absorbed orally and rapidly distributed throughout the body including the brain. Adverse effects: Moderate doses can cause insomnia (!!!!), anxiety and agitation. Higher doses can cause emesis & convulsions. The lethal dose of caffeine is 10.0 grams (100 cups of coffee), death is due to arrhythmias

6. Nicotine Nicotine: the active ingredient in tobacco (most cigarettes contain 6-8 mg of nicotine), its therapeutic use is limited to smoking cessation. Nicotine has been identified as one of the most addictive drugs currently known.

7. Mechanism: In low doses nicotine causes ganglionic stimulation by depolarization, at high doses it causes ganglionic blockade. Centrally located receptors respond similarly. Actions: CNS: Nicotine rapidly crosses the BBB; low doses produce the paradoxical state of aroused relaxation, improving attention, learning, problem solving and reaction time. At high doses nicotine produces medullary paralysis causing respiratory & cardiovascular failure. Peripheral effects: Stimulation of the sympathetic system result in increased blood pressure (vasoconstriction) and heart rate. Stimulation of the parasympathetic system increases intestinal motility. At high doses sympathetic & parasympathetic blockade result in hypotension and GI paralysis. Nicotine

8. Pharmacokinetics: Nicotine is highly lipid soluble so absorption occurs across any mucosa, 90% of inhaled nicotine is absorbed across the alveolar membrane. Clearance involves metabolism in the lung & liver ending with urinary excretion. Tolerance to the toxic effects develops rapidly (~days). Adverse effects: The CNS effects include irritability & tremors. It can cause intestinal cramps, diarrhea, hypertension & tachycardia. In addition cigarette smoke contains ~3000 components some of which induce the metabolism of other drugs.

9. Withdrawal syndrome: Physical dependence develops rapidly and is profound. Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating, headaches & insomnia. Treatment of withdrawal involves replacement of nicotine blood levels, two common mechanisms are gum and transdermal patches.

10. Cocaine Mechanism of action: The primary central & peripheral action of cocaine is the blockade of reuptake of monoamines (NE, 5-HT & DA) into presynaptic terminals. This potentiates the action of these neurotransmitters by prolonging their T1/2 in the synaptic cleft. In particular the prolongation of DA effect in the limbic system elicits an intense sublime euphoria; chronic use results in DA depletion creating a craving for more cocaine to experience the DA excess.

13. Cocaine Actions: CNS: Through effects in the cortex and brainstem cocaine produces an acute increase in awareness and euphoria, at higher doses it causes hallucinations, delusions and paranoia. Cocaine increases motor activity leading to tremors and convulsions followed by respiratory and vasomotor depression. Sympathetic nervous system: Cocaine potentiates the action of NE producing a “fight or flight” syndrome associated with sympathetic hyperstimulation. Hyperthermia: through hypothalamic mechanisms even a small dose of cocaine impairs thermoregulation, the mortality rate of cocaine overdoses increase during warm weather. Counter regulatory response is impaired along with the perception of thermal discomfort.

14. Therapeutic uses: Cocaine is one of the most effective local anesthetics when applied topically, it is used in ophthalmologic and otolaryngologic surgery due to its anesthetic effect in addition to the intense local vasoconstriction that reduces operative bleeding ( this is the mechanism for necrosis and perforation of the nasal septum associated with cocaine insuffilations). Pharmacokinetics: Nasal insuffilation results in peak levels after 15-20 minutes, the “high” lasts ~1-11/2 hours. IV or inhalation (smoking the freebase form (crack)) peak effect occurs within seconds but rapidly abates leading to repeated doses. Cocaine is rapidly de-esterfied and de-methylated to be excreted in the urine.

15. Adverse effects Anxiety: Cocaine overdose can result in an intense anxiety reaction including hypertension, tachycardia, sweating & paranoia. When consumed with ethanol metabolism of both results in the formation of cocaethylene which has psychoactive properties. Depression: Severe depression frequently follows cocaine induced euphoria, profound depression is a major component of the withdrawal syndrome. Cerebrovascular disease: Cocaine can induce fatal arrhythmias and overt myocardial ischemia even in those with a normal cardiovascular system. Frequently these sequels are independent of dose, particularly for chronic users. Seizures, stroke and intracranial hemorrhage are also seen.

16. Amphetamine: a non-catecholamine sympathetic amine Mechanism of action: Like cocaine, amphetamine effects on the central & peripheral nervous system involve elevated levels of neurotransmitters in the synaptic space. Amphetamine achieves this effect by promoting the release of intracellular stores of these catecholamines and the inhibition of monoamine oxidase. Actions: The major behavioral effects of amphetamine are due to the release of dopamine ( vs. NE). Amphetamine stimulates the entire neuraxis resulting in increased alertness, insomnia, decreased appetite and decreased fatigue. In the sympathetic nervous system amphetamine prolongs the action of NE in the adrenergic system.

18. Therapeutic uses: uses are limited due to the physical and psychological dependence which can develop and the tolerance to the euphoric and anorectic effects; there is less tolerance to the convulsive effects. Attention deficit hyperactivity disorder (ADHD): Dextroamphetamine and methylphenenidate (Ritalin) paradoxically alleviate the hyperkinesis and short attention span in these individuals. Atomoxetine (strattera) is a non-stimulant used for ADHD in children & adults, this drug blocks the reuptake of NE. Narcolepsy: This rare sleep disorder involves overwhelming, irresistible urges to sleep during the day despite adequate night time sleep there may be associated episodes of cataplexy or even paralysis.

19. Pharmacokinetics: Amphetamine is completely absorbed from the GI tract, metabolized in the liver and excreted in the urine. Acidification of the urine promotes excretion. The duration of action is 4-6 hours (much longer than cocaine).

20. Adverse effects: Amphetamine causes addiction and drug seeking behavior Central effects: These include insomnia, irritability, weakness, tremor, confusion, delirium, panic states and suicidal tendencies. Chronic use produces symptoms similar to an acute schizophrenic episode (amphetamine psychosis). Treatment with anti-psychotic agents can greatly reduce these symptoms. The anorectic effect of amphetamine is somewhat resistant to tolerance and is due to direct action in the feeding center located In the lateral hypothalamus. Cardiovascular effects: palpitations, tachyarrthymias, hypertension acute coronary ischemia and cardiovascular collapse can occur. GI effects: Nausea, vomiting, abdominal cramps and diarrhea.

21. Methylphenidate Methylphenidate appears to be a frequent drug of choice among collage students (~25% in one survey of over 10,000). Its ability to promote wakefulness, increase attentiveness and focus, appetite suppression and induce euphoria are sited as reasons for use. Crushed and insufflilated or dissolved and administered parenterally produce effects similar to other sympathomimetics. Tolerance develops to its effects.

22. Methylphenidate (Ritalin) Mechanism of action: ADHD individuals appear to produce less dopamine when engaged in “interesting” activities ( DA is the “reward” neurotransmitter). Methylphenidate appears to be a more potent DA elevator than even cocaine but because it enters the brain much more slowly than cocaine (and methamphetamine) it produces less of a “high”. Therapeutic uses: ADHD and narcolepsy Pharmacokinetics: methylphenidate is rapidly absorbed after oral administration and is concentrated in the brain. It is excreted in the urine. Adverse reactions: Abdominal pain, nausea and anorexia are the most common. Insomnia and irritability occurs and it may increase the seizure frequency in patients with a seizure disorder. Drug interactions: methylphenidate interferes with the metabolism of warfarin, phenytoin, Phenobarbital, primidone and tricyclic antidepressants.

23. Hallucinogens These drugs have the ability to induce altered states of perception similar to dreams but in the awake state, users note plasticity to the physical world. These drugs have no therapeutic indications*.

24. LSD Lysergic acid diethylamide (LSD): this drug acts as a serotonin (5-HT) agonist at presynaptic receptors in the midbrain. Activation of the sympathetic nervous system occurs causing pupillary dilation,hypertension, piloerection and hyperthermia. Hallucinations and mood alteration occur, tolerance and physical dependence can occur. High doses may produce long-lasting psychotic changes in susceptible individuals. Hallucinations may be rapidly aborted by the use of haldoperidol (haldol) a major anti-psychotic agent particularly effective in the treatment of schizophrenia. 5-HT LSD

25. Tetrahydrocannaibinol (THC) This agent may produce euphoria, relaxation drowsiness, impair short-term memory and slow mental activity. It decreases muscle strength and impairs skilled motor activity. It produces xerostomia, delusions, enhanced sensory activity and is an appetite stimulant. THC receptors are found on inhibitory presynaptic nerve terminals that synapse with pyramidal neurons. Endocannabinoids have been identified and may act as local neuromodulators. Dronabinol (oral THC) has its peak effect 2-4 hours after oral administration (vs. ~immediately after inhalation) and lasts ~6 hours (vs. 3 hours) the appetite stimulation may last for up to 24 hours.

26. THC is highly lipid soluble and it is metabolized and excreted through the biliary system. At high doses a toxic psychosis can develop, recent data suggests that chronic use beginning during adolescence may promote the development of schizophrenia. Tolerance and physical dependence can develop with chronic use. THC (marinol) is prescribed for the anorexia associated with HIV/AIDS and as an anti-emetic for chemotherapy patients. Cannabinal receptor antagonists are in trial as appetite suppressants

27. Endocannabinoids have been identified and may act as local neuromodulators. Dronabinol (oral THC) has its peak effect 2-4 hours after oral administration (vs. ~immediately after inhalation) and lasts ~6 hours (vs. 3 hours) the appetite stimulation may last for up to 24 hours. Rimonabant: antagonist for THC-receptors used for treatment of obesity as it decrease the appetite

28. Phencyclidine (PCP): This impressive agent inhibits the re-uptake of dopamine, serotonin and norepinephrine. The major action of PCP is to block the ion channels regulated by the NMDA subtype of glutamate receptor, this blocks the influx of Ca+2 through the channel. PCP is an analog of ketamine and causes a dissociative anesthesia and analgesia (awake but feeling no pain). Other effects include slurred speech, hypersalivation, ataxia and muscular rigidity. Hostile, bizarre and violent behavior can occur, as one would expect these individuals are quite difficult to manage.