Psychoactive Drugs Dr. Kline Part I

I. How drugs are handled by the body? 1.     Absorption –into the body.  2.     Distribution – of the drug through the body, including the fetus, at time drug is taken.   3.     Metabolism – the detoxification of the drug by the body (liver). Most drugs are broken down into metabolites (by-products or waste) that no longer exert an effect. 4.     Elimination – of the drug, usually excreted through urine.

Six routes of drug entry into body: 1.     Orally (tablets, capsules, liquid) 2.     Rectally (suppositories) 3.     Intravenous (injected in liquid form through a needle into the skin) 4.     Inhaled through the lungs (as gases, vapors, or particles) 5.     Through skin (patches on skin) 6.     Through mucous membranes (snorting or sniffing; under tongue)  

How drugs act on the system The pharmacological, physiological, or behavioral effects induced by a drug follow their interaction with receptors. This is called pharmacodynamics & involves the mechanisms of drug action that occur at the molecular level.

Drugs produce effects by: binding to & interacting with specialized receptors, located on the synapses of neurons.

What are receptors? A receptor is a large molecule on the cell’s surface where endogenous compounds (neurotransmitters) induce their normal effects. Usually only 1-2 neurotransmitters is specific enough to fit or bind to a specific receptor.

Binding to receptors 1.    A drug that binds to a receptor normally occupied by a given transmitter can initiate a cellular response similar or identical to that exerted by the transmitter. The drug mimics the action of the transmitter. Here, the drug is an agonist for that transmitter.   2.  A drug that binds to a receptor & blocks the neurotransmitter from stimulating the cell is called an antagonist.

II. Dose-Response Relationships A dose-response curve may be plotted as: the dose of a drug given as a function of the % of people who show an effect at a given dosage.

Drug Effectiveness The dose of a drug that produces the desired effect in 50 % of subjects tested is called the ED50. The lethal dose for 50% of subjects (animals) is called the LD50. The ratio of the LD50 to the ED50 is used as an index of the relative safety of the drug & is called the therapeutic index

III. Drugs A. ALCOHOL (ethanol) Alcohol is found in different concentrations in liquid: -12% in wine -3.5-5% in beer -40-50% in liquors It is most often expressed as “proof” which is twice the percent concentration (i.e., 80 proof = 40 % ethanol).

Alcohol absorption: Alcohol readily diffuses across all biological membranes & is completely absorbed by the entire GI tract. Alcohol usually takes 30-90 minutes to reach peak levels in the blood. About 20% of a single dose of alcohol is absorbed directly via the stomach. The remaining 80% is absorbed rapidly by the large intestine.

Alcohol metabolism: 85% by liver 5%-by lungs (can be detected by breath) 15%- broken down by stomach enzymes. A full stomach reduces a person’s blood alcohol level, because the enzymes have longer time to metabolize the alcohol.

Who has the higher blood alcohol level, men or women? 1.  Women --50% less gastric metabolism of alcohol, because they have lower levels of gastric enzymes. 2.  Since men have greater ratio of muscle to fat than do women, alcohol is more diluted in their blood (fat has little blood supply in contrast to muscle).  

What are the effects of alcohol? 1. Physiological effects- Slows Respiration (CNS depressant) Sedative effects are additive when combined with other depressants (e.g., barbituates). Dilates blood vessels in skin (decreases body temp; blushing). Lowers cholesterol (low doses) by lowering LDL & increasing HDL. May cause heart damage (high doses-5 drinks per day). May cause liver damage (high doses over time)

2. Psychological effects Behavioral disinhibition (low doses) Euphoria (low to moderate doses) Violent or irascible mood (moderate to high doses) Memory, concentration, & insight are impaired Reaction time is impaired Motor system is impaired (cerebellum)  

How does alcohol produce its effects? 1. Alcohol is a GABA agonist, it facilitates expression of GABA (inhibitory transmitter). Contributes to behavioral disinhibition, motor slowing. 2. Alcohol inhibits glutamate (excitatory system). Receptors, which may cause cognitive effects of alcohol intoxication, such as slurred speech & memory loss. Alcohol increases levels of dopamine & serotonin, likely providing both euphoric & sedative effects.

B. MARIJUANA Dried & crushed leaves & flowering tops of the hemp plant, Cannabis sativa. Major ingredient-- delta-9-tetrahydrocannabinol (THC) Marijuana has 2-5 % THC May be smoked, chewed, or eaten (in baked goods).

What are effects of marijuana? 1. Physiological effects Produces analgesia Has antiemetic properties (decreases nausea & vomiting) Increased HR & blood pressure Dilated blood vessels in eyes (bloodshot eyes) Sedative effects

2. Psychological effects Shifts in emotion Disrupted attention Impaired STM Altered sensory perception Time distortions (time moves more slowly) Motor activity impaired Hallucinations (with heavy doses) Panic (with heavy doses)

How does marijuana produce its effects? We have cannabis receptors in the brain. These receptors are found in the: 1. basal ganglia (fine motor system) 2. cerebellum 3. cortex (especially the frontal lobe) 4. hippocampus We don’t have any cannabis receptors in the brainstem. THC does not affect basal body functions.

Do we have a transmitter substance like THC in our brains? Yes!!! We have anandamide which binds to cannabinoid receptors & produces cannabinoid-like pharmacological effects.

C. HALLUCINOGENS 1. LSD First synthesized in 1938, as a compound of ergot (a fungus that grows on rye) by Hoffman. Hoffman accidentally ingested the drug & noticed its unusual effects. During 1950s, LSD was used as a model for examining & treating psychosis; was also used in therapy.

LSD administration: Is taken orally. ED50 is 25 micrograms to 300 micrograms. Usually is found on sugar cubes, stamps, candy dots Is absorbed within 1 hour; peaks in 3 hours. Duration: 6-8 hours.

What are the effects of LSD? 1. Physiological Effects Slight increase in body temperature pupil dilation slightly increased HR & blood pressure dizziness; nausea

2. Psychological Effects 1.     Altered perception, thinking, emotion, arousal 2.     time distortions (slowed) 3.     Intense visual & auditory hallucinations (trasers) 4.     Cross-sensing (hearing colors; seeing sounds) 5.     emotions shift rapidly (happiness to pit of despair) 6.     tension & anxiety make lead to panic 7.     psychotic experience

How does LSD produce its effects? LSD exerts its effects by interacting with serotonin receptors (5-HT receptors). Most researchers argue it’s a serotonin agonist.

2. MESCALINE Comes from the crown or “button” of the peyote cactus. The crown is dried into a hard brown disk that softens when ingested. Is absorbed in 1-2 hours. Effects occur between 3.5 & 4 hours after ingestion. Vivid hallucinations most salient. --trip is long (10 hours) Right frontal activity seems to be high in people on mescaline. Agonistic for norepinephine & serotonin.

3. PSILOCYBIN Found in mushrooms (genera Psilocybe). Mushrooms are eaten raw. mushrooms grow through out world, including northwestern US. It peaks in about 2 hours, & effects last 6-10 hours.

How does it produce its effects? It appears to exert its effects as a serotonin agonist that stimulates 5-HT receptors especially in the frontal areas.

4. MYRISTIN & ELEMICIN Are agents found in nutmeg & mace, two common household spices. ED50--1-2 teaspoons—usually brewed in tea Within 2-5 hours, you get symptoms similar to LSD (euphoria, visual hallucinations, psychosis, etc.) However, most people experience vomiting, nausea, & tremors prior to the “trip” making it a one time event for many.

D. STIMULANTS In general these drugs: increase behavioral activity elevate mood increase alertness allay sleep increase brain’s metabolic & neuronal activity.

1. COCAINE: Comes from the coca plant (Erythroxylon coca) found in South America. The active alkaloid in E. coca was isolated in 1855, purified in 1860, & named cocaine. In late 1800s, cocaine was used as an anesthetic (spinal, local), was added to medicines & Coca-Cola. It was banned from use in medicines & beverages in 1914 in the Harrison Narcotic Act.

COCAINE (history): By 1930s, amphetamines replaced the popularity of cocaine. 1960s- cocaine makes a comeback when amphetamines become pricey. 70s-80s – cocaine becomes “chic” with jetset. & cheap “crack” cocaine becomes hit in poor areas.  

Forms of cocaine Cocaine can be snorted, smoked, taken orally, or injected intravenously. Powdered cocaine (cocaine hydrochloride) 25 mg per “line.” Crack cocaine- (250 mg-1 gm) per smoke.

Physical Effects: Vasoconstrictor Increases norepinephrine & dopamine Tachycardia Stroke, seizure, heart attack Increased blood pressure Local anesthetic

Psychological Effects Euphoria Elevated mood Agitation Flight-of-ideas Grandiose thoughts

How does it produce its effects? Cocaine blocks reuptake of dopamine, norepinephrine, & serotonin, thereby increasing them in the CNS. Increasing dopamine levels in dopaminergic reward system results in euphoric/addictive effects of drug.

2. AMPHETAMINES- Effects Vasoconstriction Hypertension Tachycardia Increased motor activity Loss of appetite Restlessness/tremors  hallucinations (amphetamine psychosis) Paranoid delusions

Amphetamines-today 1.  Therapeutic use in the treatment of narcolepsy & ADHD. 2.  To treat compulsive misuse of methamphetamine (amphetamine derivative).

How do amphetamines cause their effects? They cause release of norepinephrine & dopamine from presynaptic storage sites in nerve terminals. Peripheral NS activity --increased norepinephrine  

ICE- form of methamphetamine Was originally used to treat ADHD, not mostly a an illegal street drug. Street names of drug– Speed, crystal, crank, go, & ICE. Methamphetamine--orally, by IV injection, & snorted. The base form (ICE) can be smoked. ICE-methamphetamine, crack-cocaine. It’s the free-base, smokable form of the parent compound.

NONAMPHETAMINE BEHAVIORAL STIMULANTS Does not have the same nucleus structure of amphetamines, but shares same action of increasing SNS activation. One of the most common of these is: Methylphenidate (Ritalin)

Methylphenidate (Ritalin) Has a short half life (2-4 hours). Concerta--A new sustained-release formulation of methylphenidate--taken in the early AM, it is good through the day. Is much more expensive than regular Ritalin.

How does Ritalin exert its effects? Thought to increase norepinephrine & dopamine, by blocking reuptake in the presynaptic neuron. Also stimulates the release dopamine. Once thought to exert its behavioral effects (calming) via increased dopamine, it is now thought that effects may be result of increased serotonin activity (or balance of both).

3. CAFFEINE The most common psychoactive drug in world. Consumed -80% of adult population. 1 cup of coffee---50-150 mg of caffeine. Caffeine content of chocolate--25 milligrams per ounce. Average intake – 3-5 cups of coffee every day.

Absorption Significant blood levels of caffeine are reached in 30 to 45 min; with complete absorption in 90 min. Peaks in about 2 hrs & decreases thereafter. The half-life is about 3.5 to 5 hours in most adults.

Effects tachycardia Increased Blood pressure Vasoconstriction   tachycardia Increased Blood pressure Vasoconstriction Diurectic Increased mental activity; alertness Increased wakefulness Agitation Tremors Anxiety Insomnia

HOW DOES CAFFEINE EXERT ITS EFFECTS?   HOW DOES CAFFEINE EXERT ITS EFFECTS? Caffeine exerts its effects by blocking adenosine receptors. Adenosine is a neuromodulator that influences the release of several neurotransmitters in the CNS. It appears to exert sedative, depressant, & anticonsulsant actions. Thus, blocking adenosine causes anxiogenic effects.

E. OPIATES A group of addictive sedatives that in moderate doses relieve pain & induce sleep. The original principle opiate was opium, which is extracted from poppy seeds of the poppy plant (papaver somniferum). The psychoactive ingredient in opium is morphine, named for Morpheus—the Greek God of dreams. Two drugs are found in the exudate of the poppy: morphine & codeine.

OPIATES-History Opium--has been used for thousands of years to produce euphoria, analgesia, sleep, & relief from diarrhea & cough. Ancient Greece & Rome-- through the 16th- & 17th-centuries, opium’s medicinal & recreational uses were well established. A mixture of opium and alcohol, called laudanum, was used to treat practically every disease known during the 1800s.

OPIATES-History During the civil war, opium addiction was a widespread problem. By 1914, the Harrison Narcotic Act was passed and the use of most opioid products was controlled.

Opiates vs. Opioids Opiate-- is a drug that is extracted from the exudates of the poppy. E.g., morphine and codeine. An opioid is any exogenous drug (natural or synthetic) that binds to an opiate receptor & produces agonist or morphine-like effects. E.g., heroin

Endorpins (“morphine-within”)  Endorphins --any endogenous substance (naturally occurring in the body) that exhibits pharmacological properties of morphine. We have 3 families of endorphins—enkephalins, dynorphins, & beta-endorphins.

MORPHINE Is still the most potent pain reliever available (no other drug has its clinical effectiveness). Is administered orally, rectally, or by injection. Absorption is slow & only 20% of the drug reaches the CNS. Is broken down by liver & produces metabolites (morphine t-glucoronide) that are 10 to 20-fold more potent that morphine itself. These continue exerting analgesic effects. Morphine’s half-life: 3 to 5 hours.

MORPHINE-DRUG TESTING For 2 to 4 days following opiate use, urine screening tests can be used to detect codeine & morphine as well as their metabolites. Heroin use can be tested for indirectly. Heroin is metabolized to morphine & also often contains acetylcodeine (metabolized form of codeine). Although the tests cannot accurately determine which drug (heroin, codeine, morphine) was present.

WHAT ARE EFFECTS OF MORPHINE? Analgesia Relaxation Euphoria Sedation Sense of transquility Reduced anxiety Respiratory depression Cough suppression

HOW DOES MORPHINE EXERT ITS EFFECTS? Morphine, like other opiates & opioids, exert its effects by stimulating opiate receptors widely distributed through the CNS (brain, brain stem, spinal cord).

  CODEINE Is usually combined with aspirin or acetaminophen for the relief of mild to moderate pain. Half-life--3 to 4 hours. Codeine is metabolized by hepatic cytochrome CYP2D6 enzymes to morphine, & many of its effects may be the result of morphine actions. Using serotonin-specific antidepressants can block the pain relief of codeine, because they block the conversion of codeine to morphine.

HEROIN (diacetylmorphine) Is produced by a slight modification of the chemical structure of morphine. It cross the blood-brain barrier very rapidly, leading to an intense rush when it is either smoked or injected intravenously. It is metabolized to monoacetylmorphine &morphine. Clinical use of heroin is legal in Great Britain & Canada.

F. ANTIDEPRESSANTS A broad class of drugs used to treat depression. What is depression??? A state of great sadness characterized by feelings of despair, worthlessness, hopelessness, & withdrawal from other. It’s the “common cold” of psychopathology—we’ve all had symptoms at some point.

Major depression: DSM diagnosis made if: Person has 5 of the following symptoms (next slide) for at least 2 weeks. Depressed mood or loss of interest & pleasure in enjoyable activities (anhedonia) must be included in symptoms.

Symptoms of major depression: 1. Depressed mood. 2. Loss of interest and pleasure. 3. Significant weight loss or weight gain. 4. Difficulty in sleeping-Insomnia or hypersomnia. 5. Shift in activity level, psychomotor retardation, or agitated. 6. Fatigue or loss of energy. 7. Negative self-concept. 8. Difficulty concentrating. 9. Recurrent thoughts of death or suicide.

1. Tricyclics E.g., imipramine (Tofranil) and amitriptyline (Elavil). These prevent reuptake of both norepinephrine & serotonin by the presynaptic neuron. 2. Monoamine oxidase (MAO) inhibitors - tranylcypromine (Parnate) Keeps enzyme monoamine oxidase from deactivating neurotransmitters, thereby increasing the levels of both serotonin and norepinephrine.

3. Selective serotonin reuptake inhibitors (SSRIs): fluoxetine (Prozac) & sertraline (Zoloft).   Selectively blocks reuptake of serotonin. Efficacy of all three classes of drugs about the same (50-70% effective). Side effects fewer in SSRI’s. Tricyclics can be dangerous.