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Chapter 1-3

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Carleton University
PSYC 3604
Tarry Ahuja

PYSC3406Addiction Chapter 1 Pharmacokinetics: How Drugs are Handled by the Body Pharmacokinetics 1. Absorption 2. Distribution 3. Metabolism 4. Elimination These four processes determine the bioavailability of a drug, how much of the drug is administered actually reaches its target Understanding pharmacokinetics allows determination of the concentration of a drug at its receptor sites and the intensity of drug effect on the receptors as a function of time DrugAbsorption Refers to process and mechanisms by which drugs pass from the external world into the blood stream 1. Enteral routes refer to administration involving the gastrointestinal tract a. Orally b. Rectally 2. Parenteral routes refer to administration that does not involve the GI tract a. Injected b. Inhaled as gases, vapours, or particles carried in smoke or in an aerosol c.Absorbed through the skin d. Absorbed through mucous membrane OralAdministration Drug must be soluble, able to dissolve Must be stable in stomach fluid, not to be destroyed by gastric acids Liquid form tends to be absorbed more rapidly than those given in tablet or capsule form Oral formulation may contain a precursor of a drug called a prodrug − prodrug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent After the tablet dissolved, drug molecules are carried into the upper intestine, are then absorbed across the intestinal mucosa by a process of passive diffusion − passing from an area of high concentration to an area of low concentration Drug molecules must be lipid soluble Disadvantages − may lead to vomiting and stomach distress − how much of the drug that will be absorbed into the blood stream cannot be accurately predicted because of genetic differences − acid in the stomach destroys some orally administered drugs before they can be absorbed RectalAdministration If the patient is vomiting, unconscious, or unable to swallow Absorption is often irregular, unpredictable, and incomplete, and many drugs irritate the membranes that line the rectum Administration by Inhalation Lung tissues have a large surface area through which large amounts of blood flow, allowing for rapid absorption of drugs from lungs into blood Drugs absorbed into pulmonary capillaries are carries in the pulmonary veins directly to the left side of the heart and form there directly into the aorta and the arteries carrying blood to the brain Administration Through Mucous Membranes Of the mouth of nose Examples, Cocaine powder, Nasal decongestants, Nicotine, Caffeine (gum). Administration Through the Skin Transdermal patches- provide continuous, controlled release of a drug from a reservoir through a semipermeable membrane Minimizes side effects associated with rapid rises and falls in plasma concentration Administration by Injection Intravenous, intramuscular, subcutaneous Produces a more prompt response than oral because absorption is faster Permits a more accurate dose because the unpredictable process of absorption through the stomach and intestine are bypassed Disadvantages − Rapid rate of absorption leaves little time to respond to unexpected drug reaction or overdose − Requires sterile techniques − Once administered, cannot be recalled Intravenous Administration Directly into the bloodstream Can be injected slowly, dosage can be precise Most dangerous of all routes because it has the fastest speed of onset of pharmacological action Drugs that are not completely solubilized before injection cannot be given intravenously because of blood clots Intramuscular Administration Injected into skeletal muscle, usually in arm, thigh or buttock, are absorbed fairly rapidly More rapid than from the stomach Are two types (1) fairly rapid onset and short duration of action - drug is dissolved in an aqueous solution, water and dissolved drug are quite rapidly absorbed (2) slow onset and prolonged action - drug is suspended in an oily solution, oil and dissolved drug solution is slowly absorbed, complete absorption can take days to week vs hours Subcutaneous Administration Injected under the skin is rapid Exact rate depends mainly on the ease of blood vessel penetration and the rate of blood flow through the skin Drug Distribution Drug is distributed throughout the body by the circulating blood, passing across various barriers to reach its target site of action − only a very small portion of the total amount of a drug actually contacts with its receptors Action of the Bloodstream The entire blood volume circulates in the body about once every minute • Blood returning to the heart through the veins is first pumped into the pulmonary (lung) circulation system, where carbon dioxide is removed and replaced by oxygen • Oxygenated blood returns to the heart and is pumped into the great artery (aorta) • From there blood flows into the smaller arteries and finally into the capillaries, where nutrients and drugs are exchanged between the blood and the cells of the body • After blood passes through the capillaries, it is collected by the veins and returned to the heart to circulate again First pass metabolism- drug-metabolizing enzymes in the cells of either the GI tract or the liver can markedly reduce the amount of drug that reaches the bloodstream − alcohol dehydrogenase is found in the cells lining the GI tract and in cells of the liver Body Membranes The Affect Drug Distribution (1) Cell membranes (2) Walls of the capillary vessels in the circulatory system (3) Blood-brain barrier and (4) Placental barrier Cell Membranes • Adrug must penetrate the cell membrane to be absorbed from the intestine or to gain access to the interior of a cell • Consist of protein and fat • Provide a physical barrier that is permeable to small, lipid-soluble drug molecules but is impermeable to large, lipid-insoluble drug molecules • Are important for the passage of drugs from (1) the stomach and intestine into the blood stream (2) the fluid that closely surrounds tissue cells into the interior of cells (3) the interior of cells back into the body water (4) kidneys back into the bloodstream Capillaries • After a drug is distributed throughout the entire blood volume, drugs leave the bloodstream and are exchanged between blood capillaries and body tissues • Capillaries are tiny, cylindrical blood vessels with walls that are formed by a thin, single layer of cells packed tightly together • Between the cells are small pores that allow passage of small molecules between blood and the body tissues • Membrane pores are large enough for even fat-insoluble drugs molecules to penetrate Blood-Brain Barrier The capillary walls in the brain do not have pores Adrug leaving the capillaries in the brain has to traverse both the wall of the capillary itself and the membrane of the astrocytes The rate of passage of a drug into the brain is determined by two factors (1) the size of the drug molecule (2) its lipid solubility Large substances can be transported across the capillary wall by a process called transcytosis − the substances attach to a receptor that is located in the well wall membrane − a small segment of this membrane then forms a vesicle, which crosses over to, and fuses with the membrane on the opposite side of the capillary wall, after which the receptor releases the substance into the brain Placental Barrier • Drugs cross the placenta primarily by passive diffusion • The fetus obtains essential nutrients and eliminates metabolic waste products through the placenta without depending on its own organs, many which are not yet functioning Termination of DrugAction 1. kidneys 2. lungs 3. bile 4. skin Most leave in urine, either as the unchanged molecule, or as a broken-down metabolite of the original drug For a lipid-soluble drug to be eliminated, it must be metabolically transformed into a form that can by excreted rapidly and reliably Role of the Kidneys Kidneys perform two major functions (1) they excrete most of the products of body metabolism (2) they closely regulate the levels of most substances found in body fluids The kidneys alone are not capable of eliminating psychoactive drugs from the body; some other mechanisms must overcome this process of passive renal reabsorption of the drug Role of the Liver The reabsorbed drug is eventually picked up by liver cells and enzymatically biotransformed into metabolites that are less fat soluble, less capable of being reabsorbed, and capable of being excreted in urine As the drug is carried to the liver, a portion is cleared from blood by hepatocytes and metabolized to by-products that are then returned to the blood-stream The metabolites are carried in the bloodstream to the kidneys, are filtered into the renal tubules, and are poorly reabsorbed, remaining in the urine for excretion The cytochrome P450 enzyme family is the major system involved in drug metabolism • CYP-3A4 catalyzed about 50% of drug biotransformations • CYP-2D6 catalyzes about 20% of drugs • CYP-2C variants catalyze 20% Factors Affecting Drug Biotransformation Genetic, environmental, cultural, physiological DNAtesting can identify whether a person is a normal metabolizer of a specific drug, slow or fast metabolizer If more than one drug is present in the body the drugs may interact with one another Aconsequence of metabolic tolerance is that any other drug that is metabolized by the same enzyme will also be broken down more rapidly- cross-tolerance Time Course of Drug Distribution and Elimination: Concept of Drug Half-Life Is essential for (1) predicting the optimal dosages and dose intervals needed to reach a therapeutic effect (2) maintaining a therapeutic drug level for the desired period of time and (3) determining the time needed to eliminate the drug The process if redistribution takes only minutes to spread a drug nearly equally throughout the major tissues of the body Knowledge of a drug's half-life is important because it tells us how long a drug remains in the body The drug persists in the body at low levels for a least six half-lives; the so-called drug hangover is a result The drug half-life is the time for the plasma level of drug to fall by 50 percent First-order elimination or kinetics, the metabolism rate of the drug is a constant fraction of the drug remaining in the body, rather than a constant amount of drug per hour Drug Half-Life, Accumulation, and Steady State The biological half-life of a drug is also required to determine the length of time necessary to reach a steady-state concentration − can be reached is about six times the drug's elimination half-life and is independent of the actual dosage of the drug − is reached when the amount administered per unit time equals the amount eliminated per unit time Therapeutic Drug Monitoring • Can aid a clinician in making critical decisions in therapeutic application • Can improve the prognosis of psychological disorders, making previous difficult to treat disorders much more treatable • Basic underlying principle is that a threshold plasma concentration of a drug is needed at the receptor site to initiate and maintain a pharmacological response • It is important that plasma concentrations of psychoactive drugs correlate well with tissue or receptor concentrations • is an indirect measurement of drug concentration at the receptor site Goals of TDM • To asses whether a patient is taking medication as prescribed • To avoid toxicity • Enhance therapeutic response by focusing not on the amount of drug taken but on the measured amount of drug in the plasma • Possible reductions in the cost of therapy Drug Tolerance and Dependence Drug tolerance is a state of progressively decreasing responsiveness to a drug − tolerance requires a larger dose of the drug to achieve the effect − three mechanisms are involved in the development of drug tolerance Metabolic tolerance, more enzyme is available to metabolize a drug and as a result more drug must be administered to maintain the same level of drug in the body Cellular-adaptive, or pharmacodynamic tolerance; receptor in the brain adapt to the continued presence of the drug, neurons adapting to excess drug either by reducing the number of receptors available or reducing their sensitivity to the drug − down regulation is the reduction in numbers or sensitivity Behavioural conditioning processes; when a drug is administered in the context of usual pre-drug cues but not in the context of alternative cues Physical dependence- a person who needs the drug to avoid the withdrawal symptoms that occus if the drug is not taken Chapter 2 Pharmacodynamics: How DrugsAct Pharmacodynamics involved exploring the mechanisms of drug action that occur at the molecular level − what the drug does to the body Adrug must bind to and interact with specialized receptors to produce an effect In most cases, drug-receptor binding is both ionic and reversible in nature − strength of ionic attachment is determined by the fit of the three-dimensional structure of the drug to the three-dimensional site of the receptor When a psychoactive drug binds to a receptor and alters the normal functions of the receptor, the neuronal response is one of two types (1) an immediate response to the presence of the drug on the receptor or (2) when the drug is given over a longer period of time, long-term changes in the properties of the receptors resulting in long-term changes in neuronal, brain, and behavioural functioning Immediate responses follow from the acute binding of a drug to its receptor with initiation of an immediate neuronal response Longer-term responses to a drug require that a dug be taken continually over a period of time • as a result, neurons adapt to the presence of a drug, resulting in long-term changes in neuronal functioning Receptors for Drug Action Areceptor is a large molecule on the surface of or within a cell that is the site where biologically active, naturally occurring endogenous compounds (transmitters) produce their normal biological effects Only one neurotransmitter might be specific enough to fit or bind to a specific receptor protein Drug receptors are proteins − with this understanding it became possible to isolate a specific receptor protein from the rest of the brain, purify it, determine its amino acid sequence, isolate the portion of DNA responsible for making the protein, and clone the protein receptor to produce sufficient quantities of receptor against which drugs could be screened for affinity and activity Agiven drug may be more specific for a given set of receptors that is the endogenous neurotransmitter binding of a drug to a receptor results in one of three actions: (1) binding to a receptor site normally occupied by the endogenous neurotransmitter can initiate a cellular response similar or identical to that exerted by the transmitter; the drug thus mimics the action of the transmitter- called an agonistic action, and the drug is an agonist (2) Binding to a site near the binding site for the endogenous transmitter can facilitate transmitter binding, this is also an agonistic action, termed an allosteric action (3) Binding to a receptor site normally occupied by a neurotransmitter, but not initiating a transmitter like action, blocks access of the transmitter to its binding site, inhibits the normal physiological action of the transmitter. Called an antagonistic action, drug is termed an agonist Drugs do not created any unique effects; they merely modulate normal neuronal functioning; mimicking or antagonizing the actions of specific neurotransmitters Receptor Structure Ion Channel Receptors- ionotropic The central portion of the receptor forms a pore that spans the membrane of the neuron, which enlarges in size when either an endogenous neurotransmitter and exogenous drug attaches to the receptor- binding sire Attachment allows flow of a specific ion Ionotropic receptor is composed of five subunits • Benzodiazepines serve as agonists by binding to a site near the GABA-binding site and by facilitating the action of GABAin increasing the flow of chloride ions into the neuron, this inward flow hyperpolarizes the neuron and inhibits neuronal function G-Protein Couples Receptors- metabotropic Activation of these receptors induces the release of an attached intracellular protein (G protein) then controls enzymatic function within the postsynaptic neuron Asingle protein chain of 400 to 500 amino acids possessing seven transmembrane alpha helices Neurotransmitter attaches inside the space between these coils and is held in place by ionic attractions Do not form a membrane spanning pore that can allow the direct passage ions − when a neurotransmitter associates with the extracellular recognition site, an intermediate molecule within the postsynaptic cell, the G protein, is activated, either directly or indirectly, through a series of enzymatic reactions, − is not as immediate as ionotropic, action is slower Process starts when a receptor binds to its proper hormone or neurotransmitter, this changes the shape of the receptor, which then binds to the three-chain G protein inside the cell membrane and activates it The G protein can then directly activate an ion channel or can trigger several biochemical reactions that will cause the G protein to move along the membrane until it finds and then activates (indirectly) the enzyme adenylyl cyclase Adenylyl cyclase produces lots of cyclicAMP, which spread the signal through the cell and affects can ion channels − cyclicAMP is the second messenger Advantage of this approach is that it allows the signal to be amplified; a single molecule can stimulate the production of many molecules of cyclicAMP G-protein-couples receptors are the middlemen, effect communication between the neurotransmitter- receptor complex and intracellular enzymes or adjacent ion channels Control many cellular processes such as ion channel functioning, energy metabolism, cell division, and differentiations, and neuronal excitability Carrier Proteins • Transports small organic molecules, such as neurotransmitters, across cell membranes against concentrations gradients • Are the presynaptic carrier proteins that bind dopamine, norepinephrine, or serotonin in the synaptic cleft and transport them back into the presynaptic nerve terminal, terminating the synaptic transmitter action of these neurotransmitters • The transporter must exist in at least three ionic states (1) open to the synapse (2) occluded with the transmitter trapped inside, (3) open to the cytoplasm of the presynaptic neuron Enzymes Break down neurotransmitters and their inhibition by drugs increases transmitter availability Acetylcholine esterase, enzyme that breaks down acetylcholine within the synaptic cleft Monoamine oxidase, enzyme that breaks own norepinephrine and dopamine in presynaptic nerve terminals, controlling the amount available for release Irreversible acetylcholine esterase inhibitors form covalent bonds with the enzyme, preventing it from functioning Monoamine Oxidase Inhibitors- drugs that irreversibly inhibit the enzyme monoamine oxidase - used as antidepressants Drug-Receptor Specificity Receptors exhibit high specificity both for one particular neurotransmitter and for certain drug molecules − making only modest variations in the chemical structure of a drug may greatly alter the intensity of a receptor's response to it Adrug may be more potent than another because a lower absolute achieves the same level of response as a higher dose of the other drug − a more potent drug is not necessarily a more effective drug, it merely produces its effects at a lower dose Isomers; molecules formed around a carbon atoms that have the same molecular formula but have a different arrangement of their atoms in space − isomers represent forms of a molecule that are mirror images of each other − the isomer that rotates the light in a clockwise direction is designated as the (+) isomer, the isomer that rotates that light in a counterclockwise direction has the (-) designation Only one of these optical isomers is biologically active − optical isomers behave the same way chemically but not biologically Dose-Response Relationships Use dose-response curves to quantify drug-receptor interactions Dose-response curves demonstrate several characteristics • Po
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