CNS Stimulants

CNS Stimulants: Caffeine and Nicotine

Nicotine

Identity: naturally occurring liquid alkaloid that is colorless and volatile

it probably is the only pharmacologically active drug in tobacco except for carcinogenic tars

Pharmacokinetics: inhalation is a very effective route of drug delivery.

effects of one cigarette equals 1 mg of nicotine, i.v. 60 mg is lethal;

Tolerance: may be due to induction by tars of liver drug metabolizing enzymes.

Pharmacological Effects:

Acts on nicotinic type of acetylcholine receptor. Nicotine is not readily deactivated and leads, first to stimulation and then blockade of synaptic transmission.

Activates all levels of the CNS especially cortex

Increased dopamine release via nicotinic receptors (limbic regions, intimately involved in addictive affects)

Stimulates the release of adrenaline (norepinephrine and epinephrine) from adrenal glands resulting in sympathomimetic effects: Ý heart rate, Ý blood pressure.

Adverse reactions: Low Level Toxicity: nausea, dizziness, and general weakness, High Doses: tremors and convulsions

Carcinogenic effects: due to tar in cigarette

Tobacco Addiction

Behavioral Basis: production of a mild state of euphoria, facilitation of learning, ß weight gain and appetite (smokers weigh 5 lbs less on average)

Neurobiology: tobacco is addictive - Nicotine being the active component.

withdrawal symptoms - irritability, Ý appetite, dysphoria, weight gain (similar to cocaine and heroin)

Treatment for nicotine addiction: initial therapy includes:

cigarettes without nicotine

"nicorette" (nicotine laced gum)

nicotine patch - subcu admin constant administration (Ý prob of nicotine overdose)

welbutrin

buproprion (dopamine uptake blocker - supplying dopamine to edge craving, initially marketed as an antidepressant but bad therapeutic index since it can produce seizures outside treatment window)

Caffeine

Identity: Methylxanthines: caffeine, theophylline and theobromine (in tea)

Cellular Basis of Action of Caffeine:

Inhibition of phosphodiesterase - increased intracellular accumulation of cAMP

Blockade of adenosine receptors - responsible for stimulant effects

Mobilization of calcium from cells (ß skeletal contractility)

Pharmacological Properties: stimulation

CNS: alertness, less fatigue produced by 85-250 mg of caffeine (amount contained in 1-3 cups of coffee).

Methylxanthines also stimulate respiratory center (similar to amphetamines)
Tissue sensitivity: Cortex > brainstem > spinal cord
Potency: Caffeine > theophylline > theobromine
Peak effect: within 3 hrs of administration but reaches peak plasma level in 3 min

Cardiovascular: tachycardia, arrhythmias (only at high doses because of Ý catecholamine release)

Potency: Theophyline > Theobromine > Caffeine

Vascular: ß peripheral vascular resistance (vasodilation) and Ý cerebrovascular resistance (treatment for headaches)

Smooth Muscle Relaxation - e.g., those of the bronchi. (Theophylline used in the treatment of bronchial asthma)

Stimulation of Skeletal Muscle - tremors (receptor specific effect)

Diuretic: inhibition of the secretion of antidiuretic hormone (ADH)

GI: stimulates GI motility, erode intestinal lining Þ ulcers (stimulate acid secretion)

Medical Use: asthma (vasodilation of smooth muscle), apnea, relief of headache (Ý resistance in cerebrovascular)

Tolerance effect: primarily due to CV effects (contrast to amphetamines - no tolerance because of CV effects but rather CNS)

Clearance rate: Ý by smoking

Adverse Reactions: Caffeinism: nervousness, anxiety, irritability, muscle twitching, insomnia, elevated temperature, induction of panic attacks in susceptible individuals, Addiction: can become dependent with 1-3 cups/day in 1 week

withdrawal symptoms: mimic flu - ache in joints, headache, fatigue, dysphoric, irritable, nausea lasts 2 days

Prevalence: beverages (e.g., coffee-115mg, tea-40 mg, cola drinks-45), stimulants (No-Doz-100, Vivarin-200), old remedies (e.g., Coryban-D), analgesics (e.g., Anacin) and diuretics (Aqua-Ban-100)

Drug Regulations

Therapeutics

1906: Pure Food and Drug Act: prevented misbranding and adultering of drugs
1938: Food, Drug and Cosmetic Act: required application for New Drug Application (NDA)
1967: Kefauver-Harris amendments: required application of Investigational New Drug (IND) before human testing. Must establish efficacy of drug. Established four phases of drug development:

Phase I: normal volunteers tested for Pharmacokinetics

Phase II: small number of patients studied to establish dose, Pharmacokinetics

Phase III: large number of patients to establish safety and efficacy

Phase IV: post-marketing surveillance
Total - could take 2-10 yrs (typically 5 yrs) preclinical 3 yrs, drug trials - 2-3 yrs. Must all be performed before new drug application

Controlled Substances

1965: Drug Abuse Control Amendments: focused on LSD and amphetamines
1970: comprehensive Drug Abuse Prevention and Control Act (Controlled Substances Act):

enforcement moved from Treasury Dept. to DEA of the Justice Dept
creation of Schedule of Substances based on medical utility of agent and potential for abuse. Law specifically excludes distilled spirits, wine, malt beverages and tobacco.

SCHEDULE	CRITERIA	EXAMPLE
Schedule I	High abuse potential and no acceptable medical use	Heroin, LSD
Schedule II	High abuse potential and limited medical use	Cocaine, Morphine, Amphetamine
Schedule III	Less abuse potential than I or II and accepted use	Barbiturates
Schedule IV	Less abuse potential than others, accepted use	Benzodiazepines

Scheduling of substances determined by Dept. of Health and Human Services (FDA) and is based on:

Evidence of pharmacological effects, state of current knowledge, risk to human health, psychic or physiological dependence liability, substance is precursor of already controlled substance