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University of Toronto St. George
Dwayne Pare

Chapter 1- Psychopharmacology in Perspective January-21-12 8:39 PM  Psychopharmacology is the discipline that attempts to systematically study the effects of drugs on behaviour, cognitive functioning, and emotions  Drugs that alter behaviour, cognitive functioning, or emotions arpsychoactive or psychotropic drugs- they are chemicals that induce psychological effects by altering the normal biochemical reactions that take place in the nervous system  Originallypsyche referred to the soul, but not referred to as the mind  Pharmakos originally meant scapegoat- or a person who was sacrificed for another persons maladies  A drugs chemical structure, how much of the drug is taken, how long it has been since the drug was taken, and how frequently it is takenre important factors in drug experience  3 other things important drug experience: o the set( the psychological makeup and the expectations of the individual taking the drug) o The setting(the social and physical environment in which the drug is taken) o The individuals unique biochemical makeup, some of which dependent on genetics o All these factors help to explain why there is many diffs in terms of ppls responsiveness to drugs  Drugs should not be viewed as simply bad or good, you need to take into considhow much of the drug is taken, what it is taken for, and in what context it is taken in  A historical Overview of Psychopharmacology o Humans have been using drugs to alter moods and behaviours for thousands of years--> there as thousands of plants available that contain psychoactive substances o Early vikings used the mushroom Amanita Muscaria to enhance their ferciousness, gaiety, exuberance, and berserk behaviour o Native Americans use the peyote cactus, which contains the hallucinogen mescaline for their religious ceremonies o Cannabis (marijhana) was first used more than 4000 years ago, mostly for its medical value o Opium poppies (which have the narcotics morphine and codeine, were used by the ancient sumerians in mesopotamia almost 7000 years ago) o South american indians chewed the cocoa leaf (cocaine) to reduce fatigue, elevate modd, and reduce hunger o Tea began in chine, coffee beans introduced to the Arabians in the 13 century o Witches could have used toad sweat glands which contain the hallucinogenic drug bufotenine, one of the few psychoactive drugs from animal origin o Most common psychoactive substance used around world today is alcohol or caffeine o Even nonhuman animals have been observed to seek out substances with mood-altering properties: Siegal  This has led Siegal to propose the hypothesis that intoxication is a universal "forth drive" as natural as the innate drives for hunger, thirst, and sex  Even research with C. elegans and fruit flies show that they have proteins that are the sites of action of many drugs of abuse  Predecessors to Modern Pharmacotherapies o During the 1800s a number of psychoactive drugs were isolated or distilled from plants or developed from nonplant sources  Morphine from opium for treatment of periodic insanity  Bromine and chloral as sedatives or sleep inducers Gases chloroform and nitrous oxide treatments for insanity   The first phenothiazine (a type of antipsychotic drug used for calming effects on manic and hallucinators o During the 1800s the investigations of the formal relationships between drug variables and psychological processes, especially those involved in mental illness began  It started with Jacques Moreau du Tours who published the book Hashish and Mental Illness  After taking a hasish (concentrated form of marijuana) concoction that he made, he compared the drug induced symptoms with the mental symptoms that occur spontaneouly in psychoses  He was one of the first to say that the person's particular or immediate context greatly influenced both the quality and intensity of the drug experience  He also studied the psychoactive effects of opiates, nitrious oxide, and a number of sedative hypnotic drugs, but his work was large unrecognized until his book was published  Some view Moreau as the first psychopharmacologist o The very first book in modern experimental psychopharmacology as the first book devoted to drugs and animal behaviour was published by A. P. Charvel, a young medical student who studied the effects of opium on many animals o Sigmund Freud spent 3 years investigating the effects of cocaine on fatigue, depression strength, morphine addications and he was the test subject o Pavlov , best known for conditioning the reflexes, attempted to treat Schizophrenics by using some of his conditional techniques and inducing long periods of sleep with bromides, but he was not successful because bromides tend to accumulate in the body and can be toxic o The Pavlovian process is important in drug dependence o William James established the first psychology lab in the U. S., he found that consciousness could be influenced by the laughing gas nitrous oxide, he would have mystic revelations o The first half of the 20th century was accompanied by the synthesis or clinical use of a wide variety of new psychoactive substances with potential therapeutic value  Albert Hoffman first synthesized lysergic acid diethylamide and he figured out that it was one of the most potent psychoactive substances known to mankind, it was used later as a psychedelic (mind-manifesting) to induce a model psychosis  The Psychopharmacological Revolution o Interest in studying drugs and their influence started around middle of the 20th century with the discovery ofchlorphromazine that could reduce the core symptoms of schizophrenia and improve their though processes  This discovery showed that certain forms of mental illness could be linked to abnormalities in the biochem of the brain, rather than due to purely environment  It was this discovery that lead to the discipline known as psychopharmacology o The story began wit the development of one of the first antihistamines (promethazine) used to reduce surgical shock and to calm patients before and after surgery and it was used to treat schzio as a sedative The development of promethazine lead to the development of a compound with similar  structures and more specific action(4560 RP- or chlorpromazine) , which had little antihistamine function but it reduced both para and sympathetic activity, abolished conditioned reflexes and had other good properties, it could reduce surgical stress  It was then suggested that chloropromazine to be used to treat psychosis So it can be said that chloropromzine stated the pharamacological revolution in  psychiatry, it allowed new drugs to be developed and old ones to be clinically tested again  Meprobamate was first anxiolytics used for neuroses  Treatment of depression using MAmineOxidase inhibitor o John Cade discovered that lithium had mood stabilizing effects in manic patients, but it took almost 10 years for the medical community to realize the value of lithium bc it was believed that lithium would be too toxic o LSD also important during 1950s, with chloropromazine they made an interesting team: chloro wuld reduce psychotic symptoms whereas LSd would induce the psychotic symptoms  In 1950s, many articles published about therapeutic benefits of LSD, and LSD induced psychosis became the model with which other potential antipsychotic drugs could be tested, and it became a tool for exploringetiology (the science of causes or origins of disease) of schizophrenia  But by the 1960s, its role was reduced bc of the realization that the psychotic state it could induce did not resemble any endogenous psychosis and LSDs unreliable effects made it play a small role in the pharama over the next 4 decades o Since the 1950's psychopharmacologists have made great strides in understanding and treating every affliction in the human mind and most mental disorders are not view as having a biochemical basis and can be treated as much, but environmental factors can still play a role o With the development of MRI, CAT scans, PET etc., we are able to look at working of living brains o But psychotherapeutic drugs do not cure mental disorders or suppress their symptoms in all ppl, it can do harm in some: leads to ethics, and we need to continue to search for drugs with greater specificity although we've made progress  Recreational and Social Drug Use o Many ppl use psychoactive drugs (like caffeine, nicotine and alcohol)--> they are socially accepted drugs o The mass media reflect the national culture and have conditioned Americans to accept drug use as a part of daily life o Americans and heavy consumers of illicit drugs like cocaine, marijuana, heroin, methamphetamine, barbiturates o See Table 1.1 for the percentage of persons aged 12 or older using illicit drugs--> according to the national surveys, use of recreational and social drugs in the US rose a lot during the 1960's to around the 1980 and was followed by a cyclical pattern of use over the next 2 decades o For as long as humankind has been using drugs, there have been concerns over drug abuse and attempts to restrict it--> there have been laws/acts passed to restrict use of certain drugs: like in 1920-1933 US passed the prohibition of alcoholic beverages o Most of these restrictions have failed mostly because it is not clear to the users why they must stop using the drug s, because they feel that their drug consumption affects only themselves o and is dependent on The criteria for what constitutes drug abuse is not universal one's culture and the time period o The term drug abuse generally refers to the self-administration of any drug in manner that deviates from the approved medical or societal patterns within a given culture  A more operational definition of drug abuse would be: the use of any drugs that causes function or structural damage to the users or to others, or which results in the users inability to voluntarily control their social or drug-taken behaviour o Surveys estimate that the nationcost of drug abuse in the US is over 500 billion with alcohol first, then tobacco, and illicit drugs o The legislation passed by the US like t1914 Harrison Narcotic Act have done little to dampen the desire for drugs (it engaged in a war on drug abuse, with ppl wanting to sell it and ppl committing crimes to buy it, and the government having to invest more money at diff levels of government to control for this) o Drug control policies are responsible for the 4-fold increase in the prison population since 1980 and a higher incarceration rate, the highest in western democracies o Drug Gulag: At the present time, more ppl are sent to prison for nonviolent drug offenses than for crimes of violence  Black men are sent more to prison for drug use even though whites are 5 times more likely to use drugs than blacks  Despite these legislation prison efforts, illicit drug business continues to grow o Some argue that it is best to legalize drug use: you would not get in the way of drug users, it would use less tax money and you would reduce imprisonment of illegal drug users, and gangs and crimes should be reduced  But some belief that this idea will increase the number of new addicts, newer more potent drugs would be made, and even with legalization there would have to be age restrictions for legally obtaining drugs  Today ppl are moving forward with a number of drug policy reforms (like allowing ppl to use marijhana for med reasons, increasing access to sterile syringes), but in most of these cases the federal gov has tired to block or circumvent these measures  When you compare a country (the Netherlands) that has decriminalized the use of marijuana to the US, surveys show that marijuana use between the two countries was similar between age groups and lower for young adolescents in the Netherlands  A number of countries have been using, or are beginning to experiment with drug decriminalization approaches  Germany with cannabis marijuana  Swiss with the use of heroin--> opened needle park but got closed down  There was a Swiss experimentation with the idea of prescribing heroin to addicts in hopes of reducing both criminal activity and the risk of spreading AIDS , these experiments are designed to answer a qtns about how to deal with heroin abuse  Results of this experiments have shown that prescriptions of heroin:  Increases health of addicts in the program  Heroin prescription is feasible and has produced no black market in diverted heroin  Heroin used in a controlled administration causes little probs  Heroin addicts are not insatiable  The way that many countries are pursuing the drug approach is tough police measure against drug deals and a "harm reduction (through making accesses to needles or injection rooms)" approach toward the users  These procedures have been shown to be effective in reducing the spread of AIDS and drug-risk behaviours without increasing illicit drug injection rates  For many years, drug legislation in the Netherlands has been directed mostly towards reducing the risks of drug use for the individual users as wells as society in general , there are great efforts to prevent criminal prosecution from being more damaging to the individual drug user than the relevant drug itself; these approaches are made to reduce human and economic costs of drug use o One approach to deal with illicit drug use that has been fruitful is to tell exaggerated stories about the potentially harmful effects of particular drugs o Since alcohol use and tobacco use by teens can lead to illicit drug use later and since these two drugs can produce more adverse consequences than illegal drugs, approaches focussing on the demand for (price and accessibility) and acceptability of these substances may be the most fruitful approach to decreasing all forms of drug use o Unfortunately, drug prevention programs targeted at youth, which have tried to talk about consequences of drug use , skills used in resisting drugs have provided minimal benefits in altering drug taking patterns of behaviour o The FDA determined in 1996 that tobacco was a nicotine delivery systemand that tobacco companies intended to provide nicotine to satisfy users addictions: and this intention allows the FDA to regulate cigs by considering it a drug if the vendor intends it to be one, so then the FDA issued a number of rules to curb the use of tobacco by youths  In 1997 the tobacco industry conceded the FDAs authority over tobacco products and agreed to a settlement that went well beyond the FDAs rules at attempting to reduce youth access to tobacco produces and tobacco marketing But in march 2000, the US supreme court ruled that the FDA did not have the power to  regulate the manufacture and sale of tobacco products o Despite media depictions of increased drug use in the US, surveys indicate that illicit drug use is much lower now than it was in the late 1970s, the peak year of American's illicit drug use, the cycling of drug use from being lower to being higher in certain years has appears to have leveled off or been reverse o The incidence of use of specific illicit drugs other than marijuana is generally to low to register clear trends in surveys, but the use of hallucinogens appears to have peaked between 1975- 1980- the biggest change in hallucinogen change has been with the use of mildly hallucinogenic ecstacy (MDMA) o Alcohol is the most commonly used illegal drug for individuals under the age of 21d its use by highschoolers have declined o The general trend toward increased use of illicit drugs by youths from the early to late 1990s appears to be coupled with their decreased perception of the negative consequences of drug use  Summary o Use of drugs important to understand because:  Recreational use and abuse of drugs are persistent and it needs to be understood  It is common to use drugs for psychiatric disorders, so we need to understand psychopharmacology  Drugs are tools for unlocking the mysteries of the brain , so research with drugs has led to benefits in terms of understanding the neural basis or normal and pathological behaviour --> so the psychopharmacology revolution is intertwined with the neuroscience revolution Chapter 2- Drug Classification and Behavioural Assessment January-22-12 5:27 PM  In many cases there are no sharp distinctions can be made between drugs, diff textbooks may classify drugs in a number of diff ways  Drug Classifications Based Upon Behavioural or Therapeutic Actions  It is common to describe a drug in a class or type based on the psychological effect produced or the desired therapeutic action  There is no universal agreement on classifying drugs  In tabl2.1, there are advantages to using such a classification system because it a drug is said to be an anxiolytic (antianxiety agent) or a minor stimulant, this does convey some meaning about the effects of the new drug, or it aleast says that the new drug shares a profile of effects with other drugs that already belong to that class  Drugs classed as: o Major psychomotor stimulants : they share properties such as enhancing attention and increasing various types of motor activities o Anti-psychotic : blunt symptoms ofschizo (hallucinations and delusions) and can trmania o But there are limitations to this system:  Many drugs classed as sedative-hypnotics induce stimulant like effects or behavioural disinhibition at low does (ethyl alcohol)  Antidepressants are sometimes used to treat anxiety, whanxiolyticscan be used to treat depression in clinical practice  In some therapeutic categories, there are some drugs that are labatypicalbecause they show an unusual preclinical or clinical profile  Clozapine is an atypical antipsychotic  Buspirone is an atypical anxiolytic  There are some drugs thatdefy categorizationbecause they show actions that cross many categories, but do not fit easily into any one category  Delta-9-tetrahydrocannabinol (sedative-hypnotic, stimulant, hallucinogen)  MDMA ecstasy (stimulant and hallucinogen)--> think they show put it in a new category (entactogen) o So this system is useful in drug classification as belonging to particular categories based upon behavioural and therapeutic effects, but have to remember the limitations of such categorizations that need flexibility  To measure these effects, in experimental design, control or drug treatments are various doses reflect levels of the IV, while the response to the drug is the DV o In humans, therapeutic effects of drugs are often assessed by rating scales that attempt to measure the symptoms of a particular disorder ( they were originally designed for diagnostic purposes but also measure effects of drugs)  Antidepressant drugs : the Hamilton Depression scale or Beck depression  Anxiolytic drugs : the hamilton anxiety scale  Effects of antipsychotic drugs the Brief psychiatric rating scale and the Positive and Negative Syndrome scale o There are also many animals tests used to test the effects of (Table 2.2)- to test if the drug has a particular set of properties or if it has the likelihood of showing a side effect  Animal models also used in the process of drug development: such as the elevated plus test used as a preclinical test of potential anxiolytic effects in rodents, the more maze time they spend in open arms can indicate anxiolytic effect in humans such with the drugs valium or Xanax o Drugs can also be tested for abuse liability by tests of self-administration through operant conditioning experiments  Drug Classification Based Upon Basic Neurochemical Actions  Describing them in terms of their direct neurochemical actions  In order to induce a behavioural effect, the drug needs to be able to alter the process of chemical transmission in the Nsystem  There are five basic stages of neurotransmiss(synthesis, storage, release, postsynaptic action, and inactivation) and there many neurotransmitters and neuromodulators o So the action of a drug can be described in terms of the transmission process being affected and the neurotransmitter being affected (like increase dopamine synthesis or block serotonin storage)  BUT when combined with a behavioural/therapeutic classification system along with this system, you can get a clearer picture or drug effect  Drug Names and Medical Uses of Drugs  A single drug has several official names o Code name (two or more letters and a series of numbers): initially when pharama company discovers new drug o Chemical name : describes a particular molecule according to rules of organic chemistry o Generic name: the legal, official, or nonproprietary name, which is typically the official name cited in research reports on drug o Brand/Proprietary name : given by manufacture once it has been approved for marketing--> drug can have many brand names o After 20 years, when the patent on a compound runs out, anyone can market it, so it may then have several other brand names, so that’s why we use the generic names in the textbook o When a drug is marketed illicitly or used recreationally, it may have a vastreet names o The Physicians Desk Reference (PDR)--> describes the psychotropic drugs according to their medical uses,it doesn't provide drug prices and comparison info on which of drugs of the same class may be the best for treating a particular condition o The drug has to be approved by the FDA once seen to be safe and effective for particular symptoms:  The FDA has to ensure all statements made by manufacturer are supported with evidence and decides what the manufacturer can recommend the drug for, or if the drug can be obtained through prescription or over the counter  The FDA does not have authority over the practice of medicine: there is no fed law stopping doctors from prescribing an approved drug for anything they choose  Since a new approved use of a drug by the FDA can enhance its marketability, pharma companies will undergo clinical trials to obtain approve for that use, sometimes with a new proprietary name  Schedule Controlled Drugs  Since the passage of tharrison narcotic act in 1914 the fed government has classified psychoactive drugs for legal purposes  The drugs that come under the jurisdiction ofControlled Substances Act are divided into five schedules and are callecontrolled substances o Schedule 1 : haveno currently accepted medical use in treatment in the US, presumed to have a high potential for abuse, and lack accepted safety for use under medical supervision, they can be used only for experimental purposes o Schedule 2: have some currently accepted medical uses in the US but have a high abuse potential o Schedule 3,4,5: thoe with current medical uses and successively lower abuse potentials than those of 1 and 2 o The penalty for nonprescription possession or sale of schedule-controlled drugs increase a lot as one goes from 5 to 1. o Drugs can be placed in different schedules not so much bc of their diffs in their mechanisms of action,but bc of thediffs in pharmacokinetics  Like morphine and heroin have the same action in the brain, they only diff in terms of their ability to penetrate the blood-brain barrier o Placement in these schedules can also be dependent on what a drug is combined with or the concentration of the drug By slightly altering the structure of an already illegal drug,  underground chemists attempted to produce new compounds (designer drugs) with the same properties as illegal drugs o Most designer drugs have been analogues (similar structure) to amphetamines, fentanyl, meperidine, or phencyclidine  Laypersons or the mass media normally refer to some drugs as hard or soft o But it is never clear what characteristics of the drug are being referred to when these terms are used o So describing drugs as hard or soft does not provide one with nay useful info about them  Overall, all psychotropic drugs can be safe or harmful, depending on the circumstances in which they are used, how frequently they are used, or how much is used Chapter 3- Basic Principles of Pharmacology January-22-12 5:30 PM  The definition of the term drug has gradually changed over time, in generaa drug is a chemical that affects one or more biological processest not all chemicals that affect biological processes are considered drugs (carbs, salt)  Due to the 1994 Dietary Supplement Health and Education Act, products labelled dietary supplement may enter the market untested, and the FDA cannot restrict the use of such supplements o Like st. johns wort used as an herbal anti-depressant  Nicotine has been viewed as a drug, but the Supreme court ruled against allowing the FDA to regular tobacco products, this decision was based on politics and not on pharmacological principles  The manufactures of alcohol were prefer not to view it as a ethanolushould be considered a drug in that it affects the normal biological activities of the body  Chemical s originating or produced within an organism that are used to carry out the normal biological functions in the body are not usually though of as drugs--> referred to as endogenous substances,while drugs are referred texogenous substances o But chemists have isolated substances important to the functions of the body and synthesized them and administer them in a purified form to reverse neurological deficits (like the use of l- dopa to make dopamine and l-dopa is viewed as a drug)  From a pharmacological perspective, it seems that the most appropriate way to define drug is as a nonfood, nonmechanical substance (usually a chemical substance) that exerts an effect upon a living system  Basic Chemical Principles related to Psychopharmacology  Water is largest chemical constituent of animals  The chemical structure of water leads many of the chemical characteristics that are evident in living systems o In 3-d the molecule takes v shape o There is an uneven distribution of charge--> water is polar o Water molecules are attracted to each other through hydrogen bonds between oxygen and hydrogen on another molecule of water o This leads to the fluid characteristics of water, it tends to form beads or drops o It is great solvent for other substances that are polar or ionic o Many of the salts that are dissolved in sea water are also present in our body fluilife first evolved in the sea o So a large component of living systems is thaqueous phase , but there is another chemical phase called theorganic phase: chemistry of carbon-based substances, the major part of this phase are hydrocarbons that have C and H bonded together covalently o Lipid soluble substances would dissolve in the fatty organic layer o Cholesterol, triglycerides, and membrane phospholipids (diglycerides with polar head and hydrophobic tail) are important for understanding drug distribution and drug action o Nerve cell membranes are made of phospholipid bilayer --> the polar heads point inward and outward toward the aqueous environment inside and outside the cell , while the fatty chains point towards the center of the membrane  This membrane exerts an influence over brain chemistry and drug distribution because it provides a barrier to the movement of any polar and charged substances o A drug that is highly lipid soluble would be storedadipose tissue and if not metabolized, it would stay there for a long time o The , would be a barrier to diffusion of any cell membrane, which is mostly of a lipid bilayer substance that is too water soluble (lipophobic) o The stomach and intestinal cells would present the first barrier for a pill inentry of the systematic circulation, there also barriers provided by entry in the circulatory system and the metabolic enzymes in the liver o In the brain, thblood brain barrier (BBB) is made of tight junctions between endothelial cellsthat compose the outer lining of the blood vessels--> even small diffs in chemical structures can lead to diffs in passage across the BBB, but such compounds that are less likely to penetrate into the brain can be usedstudy peripheral effects of drugs o Ethano l is a substance the easily dissolves iwater and lipid (organic solvents)--> these properties mean that in the body ethanol is easily passed from the stomach into the circulation, easily dissolves in the blood and passes into the brain  It is easily metabolized and the metabolites are easily removed by urine o Delta-9 THC, is highly lipid soluble,it is rapidly absorbed when smoked and passes through the BBB, but is not rapidly metabolized and it not very water soluble (so it stays in adipose tissues for very long) o So lipid or water solubility can lead to difdrug distribution and action , it can affect diffs inonset, intensity, and duration etc.  Morphines lower lipid solubility results in a slower onset and less intensity, but a longer duration of action  In many cases, the effects of a particular drug on an organism rely a lot oaccumulation and the concentration of the drug at its sites of actiond the duration of contact at those sites the dynamic processes involved in the within biological  Pharmakinetics: movement of drugs systems with respect to the drugs absorption, distribution, binding or localization in tissues, metabolic alterations, and excretion from the body o Factors such asroute of administration, metabolism, passage through the BBB, transport and physiological processes related to excretion are all important in regards to pharmakinetics  Pharmacodynamics : thebiochemical and physiological effects of drugs and theirmechanisms of action  Routes of Administration  Most common routes of drug administration is through the mouth (per os or PO), so that it can be absorbed in parts of the GI--> generally safest, cheapest, and most convenient route o Rectal administration (through the rectal mucosa) can serve as an alternativenteral (within the intestine)route for drugs that are destroyed in the stomach or small intestine o There are factors that can affect absorption of drugs from the GI tract:  Drugs are believed topenetrate the GI mucosa by a process of passive diffusion , which is limited mostly by their lipid solubility  Many drugs are mostly weak bases or weak acids, and this alkalinity or acidity results in the drugs being ionized (an atom having a netelectrical charge) , and since proteins embedded in these membranes have a mixture of pos and neg changes tend to repel charged particles, ionization can reduce solubility in cellular membranes for these drugs  So to facilitate their absorption, such drugs are commonly administered in the form of a salt (compound found by the ionic bond between a negative ion and a positive ion) , but since thesalt dissociates in a solutionthe drug may exist as both the nonionized and ionized species  The pH (neg log of hydrogen ion concentration) of the local area determines tratio of ionized to nonionized drug in the area  Weak acids are less ionized in an acid medium and are morelipid soluble through the stomach , while alkaloids like heroin, morphine, and cocaine are poorly absorbed from the stomach  Further down the GI tract in the small intestine, contents are nearly neural or slightly alkaline the environment favours absorption of weak bases  So this explains why the greater surface area of the small intestine, combined with a longer duration of drug contact, favours drug absorption there (that is why ppl get intoxicated faster with carbonated alcoholic drinks, the carbonation forces the alcohol quickly out of the stomach and into the Sintestine where is it absorbed more rapidly  The introduction of a drugintravenous (IV) injection leads to rapid onset of drug action and relatively intense effects , compared to slower absorption after oral administration o An amount of a drug may have minimal effects when taken PO but may be so toxic when taken IV (like heroin) o Fine adjustments in drug dosage are possible with IV , but if an overdose does occur, little can be done about it unless a specific antagonist for the drug is readily available o Drugs injected by IV must also bein a solution and have an aqueous vehicle --> injected illicit drugs mixed with talc (not dissolve in water) can lead to clogging the capillaries in organs and lead to organ failure, clot formation, vessel collapse o High incidence of allergic rxn, cardiovascular action and side effects with this route  Other ways of determining and controlling theintensity and duration of drug action: o Intramuscular (IM) injection: results in more rapid absortion than does the PO route due to good blood supply surrounding the muscle  Drugs in aqueous absorbed faster through the IM than those in oil o : leads to rapid onset of drug action and intense effects becaue the lining of the Drug inhalation inside of the lungs provides a large SA close to many blood vessels  Iteliminates drug loss through first-pass metabolism by the liver, but irritants or oils can cause pneumonia or cancer like with cigars o Subcutaneous (SC) drug injection: the injection of a drug underneath the skin into tissue between the skin and muscle  This method can be used with nonirritating substances to produce slow and even absorption due to the poor blood supply in fatty tissue  The rate of absorption can be controlled through the form of the drug:  It can be in aqueous: fast absorption  In suspension: slower absorption  Solid form: very slow absorption o Sublingual or buccal administration: through the oral mucosa under the tongue or between the cheek and gum  Can be used with drugs that are destroyed in the stomach of intestines, like nitroglycerin and nicotine o Rarely used routes: o Intra-arterial administration:very hazardous because the drug is so concentrated o Bone marrow administration: used in infants or when the veins are collapsed o Rubbing drugs over a large surface area of the skin o Intranasal administration: applying the drugs to the mucous membranes of the nose, or you can apply drugs to mucous membranes of the vagina or urethra or through the eye o Intraperitoneal injection: injecting into the abdominal cavity (mostly used with small animals such mice and rats  Absorption is faster and more uniform than with PO, and drug is not affected by enzymes in stomach or Sintestine o All the routes listed above involsystemic administration, but there are routes tdeliver drugs directly to the NS:  Intrathecal administration: injection of the drug into the subdural spaces of the spinal cord  Intracerebroventricular injection:into the ventricular spaces of the brcan be used to bypass BBB and directly administer into the NS tissue  Intracranial administration: direct infusion of a drug into a discrete brain area  Some experiments done to facilitate a drug's ability to cross the BBB, like making it more lipid soluble  Controlled release system s that are better than osustained-release or slow-release preparations in maintaining drug plasma levels have been developed  Drugs can be administered aPro-drugs , where the active compound is covalently bound to another chemical structure and is relatively inert when combined with other substituent, but after administration the active compound is then gradually liberated by spontaneous or enzymatic chemical reactions  Although the skin is often considered a barrier to all agents, including drutransdermal delivery systemshave been dev to allow clinically relevant doses of drugs to penetrate the skin o It is useful alternative to conventional formsof admin as iavoids degradation in the GI tract and first-pass metabolism, allows steady or time varying controlled delivery, and improves patient compliance o Very few drugs that are charged or large molecules can be admin transdermally due to low permeability of the skin  Importance of the BBB in Psychopharmacology  It provides stability from fluctuations in blood concentrations of many chemicals, and it provides defence The faster the drug penetrates the BBB, the greater the likelihood of it being abused and producing  dependence  The BBB is a feature of the physical structure of the capillaries supplying blood to the brain, unlike endothelial cells in other parts of the body, the ones livascular wall of the brain capillaries are tightly linked with junctional complexeshat eliminate gaps or spaces between cells and prevent any free diffusion of blood-borne substances into the brain extracellular space  The endothelial cells in the brain hvery few apertures like small poresnlike other capillary lining endothelial cells  Each brain capillary also hlipid sheaths made up of glial feet extensionsm nearby astrocytes that surrounds the brain capillary  Endothelial cellselectively transport nutrientsto the brain by wayf carrier mediated or active transport systems o Active transport systems: ions or molecules are transported by proteins that expend energy in order to pump the substance across a membrane, these systems allow nutritive but nonlipid- soluble substances such as glucose, vitamins and minerals to get into the brain o Carrier-mediated transport systems: transports substances across biological membranes o In order for a drug (which is administered any way but directly to the brain) to have access to CNS neurons it must be:  Lipid solubleto some degree  Compatible with one of several carrier mediated or active transport systems developed in the capillary and astrocyte cells  A part of the BBB in the capillaries bybrain stem where the vomiting centre is locatedare permeable to chemicals because it is where the neurons must monitor for deadly poisons, to then induce vomiting  The BBB can breakdown temporarily due to injury  Dose Response Relationships  Amount of drug available depends on the dose of drug given  Besideschemical structure and neurochemical effect of the drug itself, dose given is the most important when considering the effect of the drug  Dose-response function : expresses the relationship betwedose administered and the response observed o So you take the populations your interested in, give them diff dose of the drug being studied, wait for sufficient time for drug to act, and assess the degree of effect or the number of ppl displaying a specific effect of the drug  For comparison, one group getsa placebo, or a substance that has no physiological effect ppl display physical or psychological symptoms if they expect to receive a drug o In some situations giving a placebo in a clinical trial can be unethical, sometimes it may be necessary to give those placed in a control group a substance that has a medically accepted level of effectiveness in case they know they could be receiving a placebo (then you compare experimental drug to the control drug)  Foranimals , the control consists ovehicle solution which is mostly the solution the drug itself is dissolved in like saline  An active placebo, is a substance tmimics some of the noticeable physiological characteristics of the drugbeing used but without the effects on the brain that the researcher is interested in (usually given to a person who may be knowledgeable about some of the characteristics of a drug they are taking) o Like if looking at an antidepressant drug with sedative properties, you could give an antihistamines drugs with sedative properties but has no efficacy at reducing depression  Double blind procedure: neither subject, not person giving drug knows if it is a drug or a placebo  Efficacy : refers to the magnitude of the effect of a drug at the system or organism level, most expressed as maximal effect of the drug o A commonly used example is the therapeutic efficacy of a drug,hich refers to the magnitude of the therapeutic effect, but efficacy can be used to describe effects of drugs that are not necessarily therapeutic o Sometimes the term is used to describe the basic effect of a drug or neurotransmitter at the receptor level, but some drugs have efficacy at the systems or behavioural level (bc they induce an effect, but not due to binding to a receptor)--> so we should use the term intrinsic biological activity or signal transduction when defining the effects at the cellular level that occur directly as a result of receptor binding, and use the term efficacy to describe the magnitude of any effect seen at the systems or organism level  Potency: the dose at which the effect occurs o How much of a drug is needed to produce an effect? o Highly potent drugs produce a effects at low doses: LSD o Potency is usually defined by tED50 (effective dose 50), the dose that produces an effect that is 50% of the maximal effect o It is inversely related to ED50, a lower ED50 value is more potent  Responses can be measured: o In terms of the units that are appropriate for the behavioural measure being used (like locomotor counts, operant response rate) o Expressed in terms of the % of subjects that show a particular effect --> so 50% of subjects showed the therapeutic effect expected  Figure 3.2--> typical dose-response curve o The shape issigmoidal (s-shaped) or hyperbolic in nature o Generally, as the dose gets higher, response gets higher, up to a point o There is alinear portionof the curve, but as the dose gets higher , the effect begins to reach an asymptote as the maximal levels of the response are seen o Efficacy and potency can be extracted from the graph  Efficacy of drug effect from the y axis, and potency (like ED50) is given from the x axis dose units  From figure 3.4--> o A indicates ththreshold dose or minimally effective dose --> the dose just large enough to produce a detectable change in response o B indicates thmaximal response , which is the greatest degree of a given response that can be achieved with that drug  This maximum response does not have to been produced with the highest doses of the drugs, bc higher doses can interfere with response brought about from the lower doses o C indicatesED50 --> a drug can have several ED50's since it can be used for diff therapeutic contexts o D indicatesLD50 --> it is the dose that cadeath in 50% of the population , so it is the ED50 when the response is death o You hope to have an LD50 that is much larger than an ED50:therapeutic index : the drug's LD50 relative to its ED50 o A drug with a where the LD50 is 100 times larger than the ED50 is therapeutic index of 100- considered safe, an Tindex under 10 is hazardous o Some drugs have potential side effects that can occur at doses much lower than the LD50 o A drug can have a therapeutic index higher than another drug, but it can also have properties that can increase the chance of a person self-administering a lethal amount o In Figure as the dose of amphetamine increases, the % of rats that exhibit stereotypy 3.5 a--> (a repetitive, ritualistic, or compulsive set of behaviours ) also increases o 3.5b-->locomotor activity will increase as dose of amphetamine increases but only up to a point , then with larger doses of amphetamine activity occurs less, to with sometimes at higher doses there may be no activity at all--> biphasic/curvilinear functions o 3.5c-->effect of amphetamine on a schedule controlled behaviour (operant responses whose rate of occurrence is determined by the schedule of reinforcement) --> shows that responses that occur at a fairly high rate to begin with become relatively less frequent with increasingly larger doses of amphetamine, whereas responses that occur somewhat infrequently become relatively to more frequent with low-to-moderate doses of amphetamine and then decrease with high doses of amphetamine (known as rate dependency)  i--> might occur if there were no reinforcement provided  Ii--> might occur if responses were only reinforced if the animal spaced its responses with some minimum interval between them  Iii--> might occur if responses were reinforced ager variable periods of time had elapsed  Iv--> might occur if responses were reinforced after a specified number of responses had occurred  In each of these cases, the direction of amphetamine's effect at each dose depends on the normal rate of responding that occurs without the drug  If a bipolar DR function is shown, it can be said that there are actually two diff DR curves present, each with its own efficacy and potency  When doing a DR function of a drug, one must take into consideration the route of administration, the time since the drug was administered, and the number and spacing of drug exposures  Once a drug is administered, the type of effect and the magnitude of a given effect will vary across time becausethe concentration of a drug is rarely sufficient to exert much of an effect if the time period is too short or too long o So time-response curves are graphed similarly to dose-response curves  Neuroadaptations can occur if a drug is taken more than once o Tolerance : taking drug results in lower potency or efficacy--> so a higher dose is generally needed to produce the effect o Sensitization: if repeated administration of a drug leads to increases in potency or efficacy o Both tolerance and sensitization are influencedpsychological factors--> like conditioning mechanisms can also be involved  Drug Metabolism and Excretion  Metabolism (biotransformation) refers to any process resulting in any chemical change in the drug in the body o Can lead to drug becoming more active or less active or unchangedin terms of its activity at its binding sites, so metabolism does not mean inactivation o Drugs may be affected by all three types of metabolizaton: more active, less active, or become equally active  Catabolism: when complex chemical compounds are metabolized or broken down into simpler ones o The reverse process ianabolism  Since thetermination of a drug's action is also dependent to extent on its being excreted from the body , metabolism of the drug into a more water soluble compound must generally take place  The major metabolic processes are: o Cleavage reactions: the splitting of the molecule into two or more simpler molecules o Oxidation: combing the molecule with oxygen or increase the electropositive charge of the molecule through the loss of hydrogen or one more of the electrons o Conjugation: the combing of the molecule witglucuronic or sulfuric acid o Reduction: the opposite of oxidation in the which the molecule becomes more negatively charged by gaining one or more electrons  The most active tissues are mostly those involved in the excretion of drugs--> the liver, kidneys, lungs and the GI tract  Some drugs are excreted intact,ith only minimal metabolic transformation o : the mushroom can be toxic in large quantities, but hallucinogenic in Amanita muscaria smaller ones  Before drugs are eliminated from body, even if lipid soluble in nature, thbecome more water solublebecause the drugs and their metabolites are excreted by way of the kidney and into the urine, so volume is important  Drug passes through the GI tract (enzymes metabolize them)--> drug molecules cross the membrane of cells on the GI tract--> move into blood circulation that takes them to the liver--> then goes to body or the brain o First pass- metabolism: when molecules are further metabolized in the liver (hepatic system)  It is the reason plasma or brain concentrations of the drugs taken orally or generally lower than those drugs taken through other routes  For most drugs first pass metabolism occurs in liver, but for some others it can occur at another site o By far theorgan most responsible for metabolizing drugs is tliver  In the membrane of the primary liver cells are a large complex of enzymes--> called the hepatic microsomal enzyme system (it has been developed through years of evolution to deal with toxic substances that animals may be exposed to)  The actions of these enzymes are nonspecific in nature, they may act on diff types of substances such as drugs  Many drug-metabolizing enzymes are comprised of a large family of proteins calledthe cytochrome P450 enzymes --> found in high concentrations in the liver and in every cell in the body  So drug passes through and diffused into liver cells and are acted on by drug metabolizing enzymes , then themetabolites or the unchanged drugs diffuse back into the plasma or are secreted into the bile  Water soluble metabolites in plasma are excreted mostly iurine, if not water soluble they can undergo more metabolization in the liver  Metabolites in bile are delivered in tintestines,if water soluble can be excreted as feces, if not will be reabsorbed by the intestines to under more metabolism In most cases, the of the  rate of drug metabolization is proportional to the plasma concentration drug (in log units)--> first-order kinetics  Some drugs show zero-order kinetics: they are metabolized at a fairly constant rate regardless of the amount taken  Rate of metabolism is also dependent on the amount of P450 enzymes in the liver --> this level can be elevated with continuous exposure to certain drugs o This is an important factor drug tolerance, in which the effects of a given amount of drug are decreased bc of previous exposure to the drug o Because allpsychotropic medications (except lithium) are metabolized by these enzymes, their plasma levels can be considerably reduced due to this factor o Chronic use of drugs that depress brain function tend to induce higher levels of the P450 , but this effect is not limited to sedative type drugs only enzymes o Drugs can alsoinhibit the metabolism of other drugs through various mechanisms  Antabuse , drug used the treatment of alcohol, mcombine with the active sites of enzymes and prevent them from being available for metabolizing other drugs, alcohol gets broken down into acetaldehyde which is toxic, but normally acetaldehyde is metabolized into acetic acid which is not toxic, but antabuse competes for the enzymes that changes acetaldehyde into acetic acid o One drug can inhibit the metabolization of another because the two drugsshare a common metabolic pathway- the enzymes might be busy metabolizing another drug and that allows higher than normal levels of the other drug  Since most psychotropic drugs involved the same P450 enzymes, this phenomenon is responsible for the increased blood levels and potentially serious drug interactions that occur with many psychotropic drugs  The presence of one drug may alter the types of metabolites formed from another drug  Since there armany diffs in the ways in which species metabolize drugs , it is very difficult to predict the response of humans to drugs on the basis of other animals  In humans, there are marked between and within race diffs in the level of drug metabolizing enzymes and the rates of metabolizing drugs, and this diff coul50% due to genetics  They have also found thaindividual diffs in response to a particular drug is due to diffs in the number of P450 enzymes in the body that are active , for some ppl particular enzymes may be missing o This is a likely reason as to why there oftenlack of correlation between the dosages of drugs used in the treatment of mental illness and their therapeutic response, why there are diffs in the side effects experienced, an d why ethnic and racial groups differ in term of their responses  P450 enzymes can activate or deactivate drugs of abuse , sopharmacogenetic variations in the patterns of metabolism among individuals can also modulate the risk of dependence o For example, ppl with gene mutations that resultlittle or no activity of the CYP2D6 (activates codeine to morphine) enzyme may also have less risk of dependenceof oral opiates (like codeine) bc of lower levels of metabolites (morphine) with greater psychoactivity  Age is another factor in drug metabolism because older ppl tend to lose their ability to produce many of these enzymes , making them more susceptible to the toxic effects of drugs o In the fetus and newborn infants, the concentration and activity of drug metabolizing enzymes is less than in adults  Nutrition and Disease are important factors in drug metabolization o In first stages starvation drug metabolization can be enhancedliver disease an reduce the ability of the organism to metabolize drugs  Some studies saythere can be diffs in the way men and women metabolize drugs, some studies indicate otherwise o Some gender diffs in metabolism can be the result of hormonal diffs but also due to diffs in body composition, weight, ratio of fat to total body water which may affect the pharmakinetic processes other than metabolism  Renal kidney excretion of drugs , mostly theimetabolites is the primary way in which they are removed from the body  The metabolitesrate of excretiondepends on theirlipid-solubility, on whether they are actively secreted (compared to being passively diffused) into the urine or kidney cells, and one their PH and that of the urine o Due to theirlipid solubility, psychotropic drugsre excretedslowly in their active forms o The rate of excretion oacidic drugs can be enhanced by alkalinization of the urine, while the excretion of alkaline drugs can be enhanced by acidification --> called ion-trapping o One's ability to excrete drugs will vary a lotage, the plasma half-life of most drugs progressively increases from childhood to old age,bc they are decreasing ability to being excreted  Implications of the Pharmacokinetics in the Fetus and Neonate  The developing fetus or newborn of a women who takes psychotropic drugs does not have the choice, if the mom the takes the drugs, they will face the consequences, and as many as 80% of pregnant women take prescribed drugs  The placenta is the tissue in which most psychotropic drugs can easily pass o This tissue is specialized to allow transport of oxygen, nutrients, and waste between the women and the fetus, but it is not different from other cell membranes in its general permeability to drugs o Drugs can even pass the placentra through passive diffusion, even more easily then they penetrate the BBB in the adult brain o So any psychoactive drug can pass through the placenta and accumulate in the developing fetus in high quantities o Passive diffusion through the placenta is dependent upon characteristics of the drug (molecular size, lipid solubility), drug concentration, and duration of exposure  The fetus has a less developed BBB and less plasma membrane proteins for binding (more complete and rapid exposure of the drug to the infant brain), there is a lower level of hepatic metabolizing enzymes, so the fetus and newborn are much more susceptible to the potential toxic effects of drugs than adults  Risks to the fetus inclteretogenic effectsbnormal development--> or could be present immediately causing spontaneous abortion), long term behavioural effects, and direct toxic effects o Majority of drugs of abuse have been linked to lower birth weights and shorter gestational periods  Psychotropic drugs can distnerve cell proliferation, differentiation, and neurotransmitter concentrationthat lead to disruptions in psychomotor activity, behavioural development, and performance  Whether subtle or transient, behavioural effects may still cause probs ones may be evidenced if the infant is exposed to certain improverished types of environments, transient effects can lead to psychological probs for the child  But some moms have mental disorders or medical conditions that require them to be on drugs in order to protect the fetus  Pharmacogenetic and Ethnic Factors in Drug Action  There are many variable drug responses  There is more evidence that drug responsiveness is capolymorphisms (variations) in multiple genes protein products of which are involved in critical metabolic or physiologic pathway - the disciplines of pharmacogenetics and pharmadynamics have evolved  Pharmacogenetics attempt to discover differential effects of a drug in diff patients, depending on the presence of inherited variations in genes, with the goal of providing more patient/disease specific health care  Pharmacogenomics: wants to discover the differential effects of compounds, either in vivo or in vitro, on gene expression among all the genes that are expressed in the humans, with the goal of finding the best drug candidate from a given series of compounds under evaluation  It appears that pharmacokinetic variability in humans is substantial and may be more pronounced then pharmacokinetic variability  A personsethnic heritagean be a source of variability in drug action, response to drugs can vary across various populations groups and so it is important that experiments should include diverse subjects  Ppl from differeethnic backgrounds can have diffs in response to ethyl alcohol  On mice,genetic characteristiccan exert a powerful influence on drug effeso its not only on humans Chapter 4: Excitability and Chemical Signalling in Nerve Cells January-25-12 10:00 AM  Neurons are mixed with nonneuronal cellular elemgial cells o Astrocytesensheath synaptic connections between neurons and are needed for synaptic formation and maintenance o Oligodendrocytes wrap layers of myelin membrane around axons to insulate them for impulse conduction  Neurons act ttransduceinfor about their physical and chemical environment transmitinfo  Neurons areelectrically active they generate electrical signals, andchemically active  The Neuron  Dendrite-->soma-->axon hillock-->axon-->terminals/varicosities  The point of functional connection between the neurons is csynapse, and it consists of a presynaptic membrane, the synaptic cleft, and the postsynaptic membrane  Electrical excitability of neurons: the resting membrane potential  At baseline, the neuron is polarized (voltage diff between inside and out-s restinga membrane potential )  The voltage diff between in and out is about 70mV, sininside of the cell membrane is neg relative to the outside of the cell membraneu say -70mV  Factors that drive the resting membrane potential: o The electrical characteristics of the ions  Looking at important ions such as Na, K, and Cl, Ca o The physical forces that drive the movements of the ions  Movement a long a concentration gradient diffuse  Movement along an electrical gradientdriven by electrical forces like charges o The characteristics of nerve cell membrane: protein and lipid concentrations  The lipid portions act as a barrier to ions or polar substances  Protein parts can be enzymes, receptors (initial detection process for the presence of neurotransmitter), channels and transportersacts as pump to move substances
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