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Transcript
PHARMACOLOGY: THE SCIENCE OF DRUG ACTION Chapters 4 and 5 Pharmacology Pharmacokinetics Explains the processes involved in administration, absorption, distribution, transformation, and elimination a drug Pharmacodynamics Explains the nature of physiological and biochemical interactions between a drug and the target tissue responsible for the drug effect Pharmacokinetics Administration Absorption Distribution Biotransformation Excretion Routes of Administration Oral Intramuscular (IM) Intraperitoneal (IP) Intravenous (IV) Inhalation Intracranial (IC) Intracerebroventricular Topical Absorption Moving from the site of administration to the bloodstream Drugs exert effects by first traveling into the bloodstream 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 a drug’s ability to reach a wide range of tissues Solubility – Lipid solubility. Highly lipid soluble = greater distribution and effect. Blood Brain Barrier Depot binding: Drug binding to inactive sites Fat, Protein, Muscle THC testing Blood-brain barrier limits drug access to brain Biotransformation Drug Metabolization – Mainly in LIVER Many drugs are broken down into other compounds. Some are not transformed at all Enzymes break down drugs into metabolites Drugs that use the same enzyme interact Metabolites can be active or inactive Metabolization occurs in an ordered manner Half-life – The amount of time it takes for drug plasma level to be reduced by half THC – 20 hours – 9 days Cocaine – 45 minutes Zoloft 2-3 days Prozac 7-9 days Drug Elimination Drugs are excreted in a variety of ways Urine Breath Feces Sweat Can be excreted changed or unchanged (alcohol vs. psylocibin) Target - Receptor Depot – Bone & Fat Blood Plasma Absorption & Distribution Administration Oral, IV, IM, IP, SC, Inhalation, TC Plasma Protein Binding Metabolites Liver Excretion Intestines, Kidneys, Lungs, etc. Feces, Urine, Sweat, Saliva Pharmacodynamics Interaction between the drug and the target tissue For psychoactive drugs target tissues are receptors in CNS General Terms Receptor Site of initial interaction Ligand Any molecule that binds to a receptor Agonists Increases NT for a transmitter system Antagonists Decreases NT for a transmitter system Receptors IONOTROPIC Work rapidly. Involved in “fast” NT Ion channels open when NT occupies Sodium Calcium Chloride METABOTROPIC Slower, longer lasting Work through a “second messenger” Agonist/Antagonist Agonist Drug binds and induces full pharmacological effect Partial Agonist Drug binds and exerts only a partial effect Competitive Antagonist Binds to same receptor as agonist Reduces the effect Effect can be overcome by sufficient dose Noncompetitive Antagonist Binds in other ways, but disrupts agonist binding Reduces the effect Effect can not be overcome by sufficient dose Forms of Drug Action at the Synapse Ways to agonize Stimulate release Receptor binding Inhibition of reuptake Inhibition of deactivation Promote synthesis 8. Autoreceptors Ways antagonize Block release Receptor blocker Prevent synthesis Acetylcholine Agonists Nicotine Physostigmine Antagonists Muscarinic receptor Atropine Nicotinic receptor Curare GABA •Valium, Xanax, Ativan •Act as GABA agonists •GHB, Rohypnol •GABA agonist Dopamine Cocaine dopamine reuptake inhibitor Amphetamine increases DA release Antipsychotics block post-synaptic dopamine receptor Serotonin Selective-serotonin reuptake inhibitors (SSRIs) – used to treat depression Dose Issues General Drug Effects Main Effect – The reason why the drug is taken This may be therapeutic or recreational Side Effects – All effects other than the main effect One person’s side-effect is another person’s main effect. Ultimately drugs have an effect, we label it base on need or context. Dose Response Curve Dose-Response Curve Plots the relation between the dose of the drug and the size of the effect Specific to the behavior you are measuring Drugs have multiple effects and curves DRC Characteristics Slope gradual versus steep Potency amount required to produce effect Maximum efficacy upper end where response levels out 100 80 % of Maximal 60 Effect 40 20 0 0 200 400 600 Drug Dose 800 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 ISSUES OF REPEATED USE Tolerance Sensitization Dependence and Withdrawal Tolerance Decreased response to drug with repeated use Shifting DRC to the right 3 types Metabolic Liver enzymes Cellular Receptor down-regulation Learned Context/cues 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-induced, movement, cataplexy and seizures Cocaine is a good example of a drug induces tolerance (euphoria) and sensitization (movement) 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 Dependence/Withdrawal Physiological Dependence Body adapts to presence of drug. Needs drug on board to maintain homeostasis Indicated by the display of withdrawal symptoms upon cessation of drug use Withdrawal symptoms Behaviors displayed by a user when drug use ends Typically the opposite of the drug effect BEHAVIORAL PHARMACOLOGY Behavioral Pharmacology Study of the relationship between the physiological actions of drugs and their effects on behavior and psychological function Drugs do not create behaviors outside the normal species-typical repertoire They alter the probability or form of behaviors 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 Tail-flick test Food and shock Hot plate test w/lever press Administer a drug to test effects Xanax Light source