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Transcript
PSYCHOPHARMACOLOGY • The scientific study of psychoactive drugs and their effects. General Principles of Psychopharmacology • 1. Drug use in of itself is neither good nor bad…it just is. – Let’s study the phenomena objectively, without preconceived moral judgment. • 2. All drugs have multiple effects – Therapeutic and side-effects may be context dependent..i.e. SSRIs may be used as a sleep aid, or drowsiness may be seen as a side effect. General Principles of Psychopharmacology 3. Drugs do not produce effects that are outside the organisms behavioral repertoire. – Instead they may magnify or diminish “normal behaviors, or alter the probability or context of responses, etc.. 4. Drug effects are influenced by “nonspecific” factors – In many cases the environmental context may alter a drugs’ effects. The physiological state and Psychological “set” of the individual may also have major influences. Non-specific Factors • “Set” The physiological and psychological state of the user. Setting The environment and social context in which the drug is taken Cigarettes to “get going” or to “chill out” Non-specific drug effects cont’ The “Placebo Effect” Effects NOT based on specific biological actions of the drug, but instead are produced in some way by the Expectations of the user. Placebo Effect• Placebo- Latin for "I shall please.” • A placebo is an inert substance,..sugar pill..sham medication • Typically about 35% + of subjects are responsive. • Has been effective in treating Pain, anxiety, depression, etc. • Some people may even experience placebo side effects/withdrawal General Principles of Psychopharmacology Drug Effects are influenced by “Pharmacokinetics Pharmacokinetics – the influences of route of drug administration, drug absorption, drug distribution, drug transformation, and drug elimination. – These factors influence how fast and how much of a drug gets to its’ sites of action, as well as the duration of a drugs’ effects. General Principles of Psychopharmacology cont’ • Psychokinetic studies clearly indicate that drug effects are: • 5. Dose-dependent – Consider the effects of mild coffee vs espresso! General Principles of Psychopharmacology • 6. Drug Effects are Time-Dependent – Consider early intoxication vs late Early Later Way Late Drug Effects are influenced by “Pharmacodynamics” • Drug effects on the target tissue • psychoactive drugs produce effects in the central nervous system (CNS) – Many psychoactive drugs bind to “Neurotransmitter receptors” • And alter the activity of brain cells ( neurons) and their functional relationships with other neurons • More on this later General Principles of Psychopharmacology cont’ • Pharmacodynamic studies clearly indicate that drug effects are: • 7. dependent on the type of drug and its’ site of action DRUG SITES OF ACTION (more when we cover the nervous system) • Different Psychoactive Drugs affect different Neurotransmitter Systems in the Brain that in turn have different consequences for behavior, thought and mood. Classical Neurotransmitters • Acetylcholine – In the brain, it appears to be involved in learning/memory, attention as well as sleeping and dreaming. Classical Neurotransmitters cont’ Dopamine •implicated in movement control – Parkinson’s Disease •Dopamine excess may be involved in Schizophrenia. •involved in the “reward system of the brain.” Classical Neurotransmitters cont’ • Norepinephrine – primarily involved in control of alertness/vigilance. – Possible involvement in mood state Classical Neurotransmitters cont’ • Serotonin –plays a role in the regulation of mood –It also has a role in the control of eating, sleep and arousal. Classical Neurotransmitters cont’ • Endorphin/ Enkephalin – Modulates the experience of pain – Controls breathing and heart rate, cough reflex, nausea and vomiting – Modulates feelings of euphoria and reward Classical Neurotransmitters cont’ GABA – Most prevalent inhibitory neurotransmitter in the brain – GABA secreted by “local” interneurons all over the brain. – Implicated in relaxation/anti-anxiety More on…. Pharmacokinetics • • • • • Administration Absorption Distribution Biotransformation Excretion DRUG ADMINISTERED DRUG ABSORBED DRUG DISTRIBUTED DRUG METABOLIZED DRUG ELIMINATED • • • • • • • • Routes of Administration Oral Intramuscular (IM) Intraperitoneal (IP) Intravenous (IV) Inhalation Intracranial (IC) Intracerebroventricular Topical Inhalation- a fast route From lungs a direct shot to brain through carotid artery Absorption • Moving from the site of administration to the bloodstream – Drugs first travel in the bloodstream to get to sites of action – How fast do drugs leave the site of administration? • Route • Acidity/Alkalinity • Absorption relates to bioavailability – The amount of the drug that reaches the bloodstream and/or site of action Distribution • Refers to factors influencing a drug’s ability to get to its site of action after absorption – First Pass effect • Depends on route of administration – Protein Complexing Role of the Liver in the “First Pass Effect.” BRAIN LUNGS INTRAVENOUS INJECTION RIGHT SIDE OF HEART INHALATION LEFT SIDE OF HEART ORAL LIVER INTESTINE INTRAMUSCULAR INJECTION Protein complexing Proteins in the bloodstream may bind to the drug and slow or prevent its distribution Distribution-Depot binding Bone, Fat, Muscle, nonspecific binding of drug ..affects distribution Distribution-Blood-brain barrier limits drug access to brain Biotransformation/Metabolism Drug Metabolization – Enzymes break down the drug molecules to prepare them for ELIMINATION Biotranformation occurs mainly in LIVER, but can occur in the nervous system, or in the blood stream as well Enzymes break down drugs into metabolites Metabolites can be active or inactive Some drugs are not transformed at all.. Metabolism usually occurs at a characteristic rate for a given drug Drug Half-Lifes The amount of time necessary for one half of the active compound to be metabolized ** Note most drugs obey the law of first order Kinetics Drug Elimination • Drugs are excreted in a variety of ways – – – – Urine Breath Feces Sweat • Can be excreted changed or unchanged (alcohol vs. psylocibin) Trace Amounts may be detectable for long periods of time Hence: Drug testing Methods used by Psychopharmacologist Dose-Response Curve • Plots the relation between the dose of the drug and the size of the effect 100 75 EFFECT 50 25 0 DOSE (DRUG AMOUNT PER UNIT OF BODY WEIGHT) REACTION TIME 100 Seconds 75 50 25 0 DOSE ALCOHOL (g/kg) DRC Characteristics • Slope – gradual versus steep 100 80 60 % of Maximal Effect 40 20 0 0 200 400 600 800 Drug Dose -Slope reflects sensitivity of effect to drug dose POTENCY THE DOSE OF A DRUG REQUIRED TO PRODUCE A GIVEN EFFECT (LOWER VALUE = MORE POTENT) Maximum efficacy upper dose where response levels out Drug A is more Potent than Drug B REMEMBER THAT ALL DRUGS HAVE MULTIPLE EFFECTS…… • SO DRCs can be developed for each effect.. NUMBER OF WORDS REMEMBERED 20 15 10 5 0 DOSE ALCOHOL (g/kg) Aggressive Behavior 20 15 10 5 0 DOSE ALCOHOL (g/kg) LOSS OF CONSCIOUSNESS % OF INDIVIDUALS SHOWING EFFECT 100 REACTION TIME 75 50 25 0 DOSE ALCOHOL (g/kg) COMA DEATH ED50 •NOT-THE DOSE OF A DRUG REQUIRED TO PRODUCE A 1/2 MAXIMAL EFFECT •ED50 IS- THE DOSE OF A DRUG REQUIRED TO PRODUCE A GIVEN EFFECT IN 50% OF THE INDIVIDUALS TESTED LD50 • THE DOSE OF A DRUG THAT WILL PRODUCE LETHALITY IN 50% OF THE INDIVIDUALS TESTED LD50 20 15 NUMBER OF DEATHS 10 5 0 10.0 30.0 DOSE MORPHINE (mg/kg) 100.0 THERAPEUTIC INDEX • THE RATIO OF THE LD50 OF A DRUG AND THE ED50 OF A PARTICULAR EFFECT LD50/ED50 Calculating the “Therapeutic Index.” MORPHINE ANALGESIA LETHALITY 20 15 10 5 ED50 0 DOSE (mg/kg) LD50 Effective vs. Lethal Dose • Effective Dose (ED) – Dose level for chosen effect in % of population – ED50, dose in which drug is effective for 50% of population • Lethal Dose (LD) – Dose level for death in % of population – LD50 = lethal dose for 50% of the population • Therapeutic Index – LD50/ED50 - Serves as margin of drug’s safety – Higher ratio more safe/less toxic – 20 or more = relatively safe, 100 preferred Drug Interactions • Using multiple drugs increases the complexity of the experience – Antagonism – One drug inhibits the effect of another drug • Cocaine and alcohol (Pharmacodynamic) • St. John’s Wort and Birth Control Pills (Pharmacokinetic) – Potentiation – The two drugs together produced and enhanced effect • Alcohol and nicotine Street “dynamics” • Reality is that with illicit drugs, pharmacodynamics is ignored • Most drugs are diluted – Changes ED • Most are “cut” with dangerous compounds – Changes LD • Sometimes dose is too high, leading to acute toxicity – Potentiation and Antagonism work here OTHER FACTORS THAT INFLUENCE DRUG EFFECTU Repeated useTolerance, Sensitization ,Dependence and Withdrawal Tolerance-Decreased response to drug /Shifting DRC to the right – Metabolic • Liver enzymes – Cellular • Receptor down-regulation – Learned/behavioral • Context/cues Tolerance cont’ • Acute vs. Protracted – Acute is within a single administration • Cross-tolerance – Tolerance to one drug leads to tolerance of other drugs in the same class. Sensitization- Increased response to a drug with repeated use/Shifting DRC to the left • Cocaine is a good example of a drug that induces tolerance (euphoria) and sensitization (movement) Cocaine-induced sensitization can lead to, exaggerated stereotypical behaviors and seizures Repeated Self-Administration • • • Mesolimbic dopamine system Abused drugs all tend to activate this system 3 stages – Pleasure – Associative learning through classical conditioning – Incentive salience • • Craving (wanting) Get DA release by cues/context alone Animal Research Methods • Self-administration Behavioral Pharmacology • Study of the relationship between the physiological actions of drugs and their effects on behavior and psychological function • Uses the principles of operant and classical conditioning to examine the effects of drugs as well as the differences and similarities between drugs – – – – Self-administration studies Discrimination studies Conditioned place preference studies Conflict paradigm studies Self-administration • Train animal to press lever for drug administration – All drugs shown to be SA by animals are SA by humans • Alcohol • Cocaine • THC Drug Discrimination Drugs can serve as discriminative stimuli – Animals learn to respond in certain ways in the presence of a drug – Discrimination is related to interoceptive cue – Using these techniques, it appears that animals classify drugs just like humans – Amphetamine and cocaine alike, but different from morphine, while morphine is like heroin and other opiates Method to ask animals about the interoceptive cues associated with different drugs Press left lever if on morphine > get food Right lever if given saline > get food Give new drug - is it like morphine? – Left lever - Yes – Right lever - No Conditioned Place Preference • Pair drug administration with a place in the environment • Give animal a choice of where to hang out. • Measure where animal spends time Conflict Paradigm • Train animal to associate both reinforcement and punishment with a certain behavior – Food and shock w/lever press • Administer a drug to test effects – Xanax Tail-flick test Light source Hot plate test Drug Self Administration Drug Development • Discovery of compound-in vitro tests • Animal studies--toxicity, efficacy, abuse potential , at least 2 species • Laboratory studies in humans • Clinical trials Institutional Review Board • Must include physician and lawyer • Must review all protocols involving human participants • Evaluate Risks/Benefits • Voluntary, informed consent Double-Blind- to control for placebo effects and experimenter bias Neither the subject nor the experimenter knows which condition (drug or placebo) the subject is in. Drug Interactions • Antagonism • Additive Effects/Synergy Drug Development • Discovery of compound-in vitro tests • Animal studies--toxicity, efficacy, abuse potential , at least 2 species Institutional Animal Care & Use Committee • Includes Veterinarian and Ethics expert • Evaluates all proposals • Weigh medical/scientific benefits against risk to animals • May refuse protocol or require changes • Unannounced site inspections (2/yr) Drug Development • Discovery of compound-in vitro tests • Animal studies--toxicity, efficacy, abuse potential , at least 2 species