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PSYC 3030
Taryn Grieder

Principles of Pharmacology and Techniques in Behavioural Neuropharmacology Pharmacology: The scientific study of actions of drugs and their effects on a living organism Neuropharmacology: Study of drug-induced changes in the functioning of neurons and CNS Psychopharmacology: Emphasizes drug-induced changes in mood, thinking, and behaviour, macroscopic level Neuropsychopharmacology: Identifies chemical substances that act upon the nervous system to alter behaviour, microscopic view  Uses chemical agents as probes to gain an understanding of the neurobiology of behavior Drug Action: Specific molecular changes produced by a drug when it binds to target site or receptor (neuropharmacology, micro) Drug Effect: Widespread alterations in physiological and psychological functions (psychopharmacology, macro) Therapeutic Effects vs. Side Effects  Drugs work at many different sites; have multiple effects o Therapeutic: drug-receptor interaction produces desired physical or behavioural changes, main effect o Side Effects: all other effects  Can be annoying to severe  Can take the drug for the desired ‘side effect’ (e.g. amphetamines for weight loss programs, birth control for acne) Specific vs. Nonspecific Effects  Specific Effects: those based on the physical and biochemical interactions of a drug with a target site  Nonspecific Effects: based not on chemical activity but on unique characteristics of the individual o Experience of the drug (did you like it last time?), mood, expectations, attitude (placebo - want to make sure drug has effect beyond placebo effect) o Explains why same individual self-administers the same about of ethyl alcohol may experience lightheartedness at one situation and depression at another administration of same dose o Double-blind experiments: neither patient nor observer knows what condition the participant is in Placebo  In group 1 - medication provided by doctor and told it would provide relief o 70% found relief  In group 2 - medication provided by nurse who said it was still experimental o 25% found relief Pharmacokinetics  “Pharmakon” - drug  “Kinetiko” - to do with motion o How drugs move through body - effect of body on drug o Different from pharmacodynamics (effect of drugs on body)  Factors that contribute to bioavailability (amount of drug in blood plasma that is free to act / bind to target site): o Routes of Administration  How and where drug gets into body o Absorption and Distribution  Movement of drug from site of administration to the blood and to the rest of the body o Binding  To target sites or plasma proteins / bone / fat (inactive storage depots [depot binding], when bound to proteins, drug cannot pass through membranes) o Metabolism/Inactivation - Biotransformation  Breakdown of drug (GABA, if active for too long will cause respiratory depression), largely happens with liver  Inactivation influences intensity and duration of drug effect o Elimination/excretion of drug’s metabolic waste products from the body o May also depend on how fast drug gets to target, dosage, frequency and history of drug use and nonspecific factors (see earlier) Pharmacokinetic Factors Determining Drug Action  Route of drug administration: how and where the drug is administered o Determines how quickly drug is absorbed and enters bloodstream  Enteral - “gut”, drugs that are absorbed through gastrointestinal tract, mainly through oral or rectal administration  Generally slow in onset and have variable flood levels of drug, most drugs not fully absorbed until reaching small intestine  Parenteral - “beyond / away” from gut adsorption 1. Oral Administration (PO, most common)  Safest, most convenient and economical. Drug is self-administered.  Drug must be soluble and stable in stomach fluid and pass through stomach wall to reach capillaries in order to get effect, otherwise you would just excrete it - comes in form of pill, capsule, tablet or liquid  Disadvantages: o Vomiting and stomach distress o Hard to know how much of drug will be absorbed and affect the person due to genetic differences, food in stomach (determines rate, lots of fat in stomach - slows rate of adsorption because many enzymes needed to break down fat), etc. o Stomach acid destroys some drugs - why insulin cannot be taken in oral form  Examples: LSD, alcohol, amphetamines (speed), MDMA (ecstasy), caffeine 2. Injection  Intravenous (IV, fastest and accurate) o Drug introduced directly into bloodstream o Dosage can be extremely precise o Fastest onset of pharmacological action (and the most dangerous route, cannot pump your blood stream like you can your stomach when you’ve had too much to drink) - because drug is going directly into the blood stream o Drugs usually suspended in a vehicle solution, often come in powders and must dissolve them o IV use of street drugs can be dangerous - reach brain very quickly, drugs can be impure, lack of sterile injection equipment, attempting to dissolve drugs that have insoluble filler materials which when injected can be trapped and lead to death  Intramuscular (IM) o Drugs injected into skeletal muscle o More rapid than absorption from stomach (oral) , but slower than intravenous (~10-30 min) - makes it safer, can counteract the effects o Rate of absorption depends on rate of blood flow to muscle o For slower, more sustained action the drug can be injected as suspension in veg. oil o Injection can be irritating and cause muscular discomfort  Intraperitoneal (IP) o Injection into abdominal wall, don’t usually inject here in humans but highly used in animals o Produces rapid effects but not as fast as IV  Subcutaneous (SC) o Injected under the skin o Absorption slow and steady - dependent on blood flow to the site (rubbing skin increases rate of adsorption) o Injection of drug with non-aqueous solution decreases rate o Most often used to administer hormones  Epidural Injection o Spinal anesthetics are administered directly into the CSF  Intracranial o Injection into discrete areas of brain tissue  Intracerebroventricular o Injection into CSF chambers in ventricles o Infusion pump - implanted under skin of scalp and can be programmed to deliver dose into ventricles, good to treat brain injection when antibiotic cannot pass blood brain barrier, risk of infection and clogging 3. Inhalation  Popular for recreational drugs (e.g. tobacco, marijuana, cocaine, heroin)  Lung tissues’ large surface area allows for rapid absorption into blood o Blood from capillaries of the lungs goes straight to the brain without returning to the heart first - easy to get into the blood and easy to get into the brain  For some drugs, even faster onset than intravenous injection (e.g. psychoactive drugs)  Can cause irritation of nasal passage and damage to lungs 4. Intranasal (through nose) or Sublingual (under tongue - pill, foam or spray forms)  Absorbed through membranes in mouth or nose  Causes local effects but can also have systemic effects  Intranasal administration allows the blood-brain barrier to be bypassed and can get significant concentrations into the brain  Examples: heart patient’s nitroglycerine, snorting cocaine powder (insufflation), nasal decongestants, nicotine gum  Snorting cocaine can lead to holes in nasal septum because it is a vasoconstrictor - reducing blood flow and leading to necrosis of cartilage  Autism and intranasal oxytocin o In healthy humans - increases trust in others, enhances positive social memories, modulates memory for facial identity and increases time looking at someone’s eyes o Individuals with autism have lower levels of plasma oxytocin and have more of the polymorphism of oxytocin receptor o Oxytocin treated autistic individuals showed more visual scanning around eye area than untreated autistic o Also increased autistic individual’s skill in processing socially relevant cues - tossed ball back more to person who would toss ball back than in other conditions (untreated did not discriminate) 5. Transdermal  Adsorption through skin into blood, mainly done through patches  Provide continuous, controlled release, convenient, avoids first pass effect  Substance must be lipid-soluble  Allow for slow, continuous absorption over hours or days, minimizing side effects o Examples: nicotine, fentanyl (for chronic pain), nitroglycerine (for angina pectoris), estrogen (hormone replacement therapy)  Disadvantage - limited number of drugs can penetrate the skin o Can use inotophoresis that applys small electrical current through patch which repels drug molecules and forces them through skin, or an ultrasound device that temporarily increases size of pores in skin, or mechanical disruption of skin (penetrate superficial layers of skin and drug is administered without registering pain centers) 6. Rectal Administration  Coating of drug gradually melts and thus releasing the drug to be absorbed  Drug may avoid some first pass metabolism (e.g. if from lower rectum into hemorrhoidal vein), deeper placement means drugs get absorbed by veins which go to liver first  Effective for infants, individuals who are vomiting, unconscious or unable to take pills orally 7. Gene Therapy  Application of DNA encoding a specific protein to a particular target site to increase or block expression  Vector - what carries gene to nuclei of target cells  Viral vectors - used because of ability of viruses to bind and enter cells to alter DNA  Possible problems: immune response to foreign material, vector might cause disease, injection into wrong place can cause tumour growth First pass effect / first pass metabolism: drugs taken orally go to the liver first, where they may be broken down before reaching target tissue  Concentration of drug is greatly reduced before reaching circulation (reduces bioavailability, evolutionarily beneficial)  Some therapeutic drugs undergo extensive metabolism and thus must be administered at higher dosages or an alternative way (e.g. injection) Time-Course of Drug Blood Level  Influenced by route of administration  Peak levels reflect absorption rate  IV - instantaneous peak, placed directly into blood, IM is quite similar although you can see that when in oil, adsorption slows down  SC and PO - no sharp peak because some drugs metabolism before adsorption (first pass effect)  Peaks differ depending on person - nonspecific effects Factors Influencing Drug Absorption  Transport across membranes o Phosopholipid bilayer - have negatively charged head and uncharged tails o Prevent most molecules from entering unless they are lipid soluble  Lipid solubility o How readily a drug will pass through the lipid barriers to enter the brain (passive diffusion via the concentration gradient) o Larger concentration gradient - faster the diffusion o Partition coefficient - ratio of amount of drug dissolved in oil divided by concentration in water  Larger the number, more lipid soluble drug is  Ionized drugs o Lipophobic/Hydrophilic = Ionized molecules (charged) – water liking  Molecules dissolve in water o Hydrophobic/ Lipophilic = Non-ionized molecules (non charged) – fat liking  Molecules penetrate membranes o For example: morphine vs. heroin (more soluble in lipid than morphine therefore more effective) o Degree of ionization depends on pH and pK (pHawhen 50% of drug would be ionized and 50% non-ionized)  Large surface area of the small intestine and the slower the movement allow for more absorption here than in stomach  Larger the individual the more diluted the drug will be and less drug will reach target sites within unit of time  Females have more adipose tissue weight than water weight and therefore producing a larger concentration at target site in women than men  Standard dosage is for person 18-65 and 150 lbs Distribution  How a drug gets to its site of action, or dispersed throughout the body  Factors that influence: o Blood Flow: Blood transports the drug  Regions of the body that get the most blood, get the most drug (brain - gets 20% of blood from heart) o Solubility of drug in fat  How hydrophilic / hydrophobic it is o Binding to proteins or fats in blood  slows distribution o Diffusibility (once drug is in blood, will have 2 mins for action to occur on brain) of membranes and tissues  Cell Membranes  Capillary Walls  Blood-Brain Barrier  Placental Barrier Capillaries  Made of endothelial cells that have small gaps (intercellular clefts) and big openings (fenestrations)  Tiny cylindrical blood vessels  Have small pores that are larger than most drugs so drugs can just pass through quite easily  Pinocytoic vesicles - envelope and transport larger molecules  Allow transport of drugs regardless of lipid-solubility  Blood and protein are too big for pores; drugs that bind to plasma proteins cannot pass through Blood Brain Barrier  The brain must protect neurons from toxins  Brain has a great need for nutrients and oxygen (it has a high blood flow), which increases the risk of toxic danger o Solution = the blood-brain barrier (BBB)  Capillaries in brain do not allow drugs to pass as easily as capillaries in rest of body o Caused by tight junctions between cells in the blood vessels of the brain - fenestrations are absent and pinocytoic vesicles are rare o Surrounded by astrocytes to make junctions even tighter  Selectively permeable not impermeable  Area postrema (chemical trigger zone - causes vomiting if toxic substance is detected here), median eminence of hypothalamus (fenestrations here allow hormones to move to pituitary), posterior pituitary (release of hormones), pineal gland (releases melatonin - associated with circadian rhythms), subfornical organ (regulation of body fluids) and OVLT (chemosensory area, detects osmotic pressure of the blood) are barrier-free o These areas are called circumventricular organs - lack a blood brain barrier  Cerebrospinal Fluid (CSF) - clear, surrounds bulk of brain and fills some ventricles and connecting channels o Made in choroid plexus o Contents remain stable Placental Barrier  Drugs cross primarily by passive diffusion o Important to know what drugs will have effect on fetus but can’t do experiments - unethical  Not a good barrier to drugs: The fetus is at least partly exposed to essentially all drugs taken by the mother  Acute toxicity - fetus might experience this after disproportionately high drug level of its mother and any remaining drug is likely to have slow and incomplete metabolism if in system when birthed  Teratogens induce developmental abnormalities o X-rays, smoking o Effects are dependent on timing of exposure - most susceptible during first trimester and when the individual organs are going through cell differentiation Drug Depots  Reservoirs where drug binding occurs at inactive sites and no measurable effect is initiated, cannot each active sites or be metabolized by liver  Reversible, has effect on magnitude and duration of drug action o Only free drug can pass through membrane - less reaches target o Many drugs with similar physiochemical characteristics compete with each other for the sites and can lead to higher free blood concentration of a different drug o Bound drugs cannot be altered by liver therefore depot binding increases amount of time drug is in body o Might be responsible for terminating action of drug  E.g. bone, fat, plasma proteins Metabolism (Biotransformation) / Inactivation and Elimination of Drugs  Definition of metabolism: chemical changes that usually reduce the effect of drugs and increase their excretion o Typically, change substances from hydrophobic to hydrophilic to aid elimination  Metabolism is done by enzymes in the liver*, the gastrointestinal (GI) tract, and the kidneys o May produce another lipid-soluble molecule, an “active metabolite” to be excreted  Frist Order Kinetics (exponential elimination, constant fraction of free drug in blood is removed during each time interval, rate is concentration dependent) vs. Zero Order Kinetics (drug molecules are cleared at constant rate, independent of concentration, happens when drug levels are high and mechanisms of metabolism and excretion are saturated) o Half life (first order,1/2)- time required to remove 50% of drug that is in blood  Determines time interval between doses - since 88% of drug is eliminated in 3 half lives, a drug given once a day should have half life of 8 hours (24 hours / 3 half lives = 8)  Determines steady state plasma level - blood concentration of drug achieved when absorption / distribution phase is equal to the metabolic / excretion phase - often approached after 5 half lives Phase I vs. Phase II Metabolism  Phase I o Involves non synthetic changes o Less reactive compound is converted to a more reactive molecule  Oxidation (most common), reduction, or hydrolysis o Oxidation makes the compound more water soluble, less lipid soluble and facilitates further reactions o Commonly done by microsomoal enzymes like Cytochrome P450 family  Oxidizes psychoactive drugs  People with higher cytochrome P450 activity - drugs effect them less  Phase II o Synthetic reactions o Active or toxic molecule is converted to a less active metabolite o Oxidized compound is conjugated with (coupled to) an endogenous molecule (e.g., glucuronide, sulfate, methyl groups)  Important for inactivating psychoactive drugs o Increases the water solubility for excretion  Produce one or more inactive metabolites that are water soluble Factors Influencing Drug Metabolism  Enzyme induction o After repeated use of the drug there is an increase in enzyme that breaks it down, increases rate of metabolism for that drug and for all other drugs in system o Oral contraceptives are an example of this  Enzyme inhibition o Drugs directly inhibit the actions of the enzyme o Reduces metabolism of other drugs that are broken down by the same enzyme o Experience prolonged effect and increased potential for toxicity  Drug competition o Occurs when drugs share metabolic system therefore concentration of drug increases and metabolic rate of other drugs decrease  Individual differences in age, gender and genetics (genetic polymorphisms) o E.g. stomach enzymes that break down alcohol are less effective in women Elimination / Excretion  Primarily accomplished by kidneys o Keep the right balance of water and salt in the body o Kidneys filter waste from blood, collect it in bladder, and then selectively reabsorb what is required / useful o Ionization of drugs reduces reabsorption because they are less lipid soluble Routes of Excretion  Kidneys excrete water-soluble drugs and metabolites in urine  Liver bile excretes some drug molecules in feces  Mother’s milk excretes small amounts of drugs  Some drugs, like alcohol, may be exhaled through the lungs Drug Categories 1. CNS Stimulants - increase electrical activity in the brain a. Amphetamine, cocaine, nicotine 2. CNS Depressants - depress CNS function and behaviour a. Barbiturates, alcohol, benzodiazepines 3. Analgesics - frequently have CNS-depressant qualities but their principle effect is to reduce the perception of pain a. Narcotics (heroin), opiates (morphine, codeine), aspirin, Motrin 4. Hallucinogens - “psychedelics”, alters one’s perceptions leading to vivid visual illusions or distortions of objects and body image a. LSD, MDMA, PCP 5. Psychotherapeutics - intended to treat clinical disorders of mood / behaviour a. Antipsychotics, antidepressants (do not produce effects of CNS- stimulants), mood stabilizers Pharmacodynamics: Drug-Receptor Interactions Pharmacodynamics: study of the physiological and biochemical interaction of drug molecules with cell receptors in target tissue  What the drug does to the body Receptors: proteins on cell surfaces or within cells and have binding sites Ligand: molecule that binds to a receptor with some selectivity  All drugs are ligands  Endogenous - from within the body  Exogenous - from outside the body Agonist: best chemical fit, highest affinity, produces chemical effect Antagonist: also fits receptor well but produces no cellular effect, blocks action of agonist at receptor, low efficacy Partial Agonists: intermediate efficacy, in between agonist and antagonist Inverse Agonists: initiate effect opposite of agonist, full efficacy, not the same as antagonist Competitive Antagonist: compete with agonist to bind receptor but have no intracellular effect, reduce effect of agonist, not all antagonists reduce effect of antagonists Noncompetitive antagonist: agonists at different binding site that reduce effect of agonist Physiological antagonism: involves 2 drugs that act in two distinct ways but interact in a way that they reduce each other’s effectiveness  Additive effects: sum of 2 effects  Potentiation: effect is greater than the sum of the two effects Binding  Temporary  Ligands binding produce physical change in 3D shape of receptor and thus initiate a series of intracellular events leading to biobehavioural effect  Number of receptors can be modified - up regulation (long term regulation, number of receptors increase) and down regulation (receptors are reduced, reflects compensatory changes after prolonged absence of agonist or chronic activation of receptor)  Receptor proteins of a given drug may have different characteristics in different target tissues (receptor subtypes - want to increase affinity for drug without designing drug that acts on related receptors to produce side effects) Dose-Response Curve  Concentration vs. effect of drug  Threshold dose: smallest dose required to produce measureable effect  ED 5050% effective dose, dose that produces half of maximal effect  ED 100- assume all receptors occupied, dose that produces maximal effect  Can change depending on route of administration, frequency of drug being taken and potency of drug (comparing ED of different drugs will show you 50 differences in potency) o If all reach same max on y axis they use the same receptor (same efficacy) - the differences in50 on x axis tell you they differ in affinity  Potency: the absolute amount of drug needed to produce specific effect Definitions Tolerance: reduction in response to the drug after repeating exposure to same dose  To produce same behavioural
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