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Exam I Study Guide

by: Emma Notetaker

Exam I Study Guide NSCI 4530

Marketplace > Tulane University > NSCI > NSCI 4530 > Exam I Study Guide
Emma Notetaker
GPA 3.975

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About this Document

Comprehensive study guide including all lecture, book and video notes.
Dr. Donhanich
Study Guide
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This 29 page Study Guide was uploaded by Emma Notetaker on Saturday September 24, 2016. The Study Guide belongs to NSCI 4530 at Tulane University taught by Dr. Donhanich in Fall 2016. Since its upload, it has received 168 views. For similar materials see Psychopharmacology in NSCI at Tulane University.


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Date Created: 09/24/16
Drug Administration • psychopharmacology: scientific study of drug actions and effects on mood and behavior • goals: • to place drug at site of action • effective concentration • maintained for appropriate time • cause desired effect • neuropharmacology: drug induced changes in cell function • neuropsychopharmacology: identify substances that act on the nervous system to alter behavior • brain is primary site of action to reduce cough - most drugs act here (some peripheral effects) • ex: cough center: medulla • drug action: specific molecular changes produced by drug • drug effects: physiological or psychological effects • **site of drug action may be different from site of effects** (administration site is NOT the target) • pathways: • administration —> absorbing surface absorbing surface —> vessel (enters blood circulation) • • vessel —> target protein • —> stays in vessel (inactive) • —> storage depots (bone/muscle) • —> kidneys (may reabsorb here) —> elimination • —> liver **look at diagram on slides** • • specific drug effects: based on interactions of drug with target site • nonspecific drug effects: based on unique characteristics of individuals (ex: placebo) • pharmacokinetics: effects of the body on a drug (gaining access to brain - all pharmacokinetic events) • bioavailability: concentration of a drug in the blood that is free to interact at target sites not as important as brain availability, but hard to monitor brain levels • • absorption rates: how quickly drug can access blood circulation • depends on • administration • absorption • properties of drug volume of distribution: how much can actually leave bloodstream and reach targets • • distribution-dependent • plasma concentration of drug over time: • Cmax: peak concentration in blood - may cause side effects • 1/2 life: time required to reduce plasma concentration by 50% • AUC: area under curve managing therapeutic concentration range by repeated dosing • • want to maintain levels between minimum effecting concentration and toxic levels (therapeutic range) • clearance rate: how drug becomes inactive/eliminated • biotransformation • elimination • absorption • most absorption occurs in small intestine • distribution • bonding to receptors • depot binding: bind to plasma proteins • some may be stored in bone or fat • inactivation or biotransformation: metabolic processes of liver • elimination • pharmacodynamics: effects of drug on the body • drug molecules: • agonists: mimics effects of endogenous molecules • antagonists: opposite effects • binding: • drug affinity: drug interactions with proteins • function - broad effects • cellular, systems • physiological • behavioral Routes of administration: influence onset of drug action • enteral: uses alimentary canal - a sealed tube usually slow onset • • can absorb anywhere that there is mucous membrane • variable levels of drug in blood • cells forming alimentary canal: epithelial cell sheets (simple columnar) • intracellular spaces between GI cells very small • 4 angstroms between cells epithelial cells lining GI tract are tightly apposed • • drug passes through lumen of GI cells into capillaries on the other side • capillaries have endothelial cells which are easier to pass into • oral (PO = per os; by mouth) • not absorbed in mouth, but in GI tract (stomach/small intestine) • self-administered, avoids complications usually simple and safe, often most economical • • safe due to ability to throw up toxins • very complex process • properties of drugs absorbed in GI tract • water soluble - must be dissolved • gastric resistant: low pH and enzymes are present in GI tract • • chemical digestion: acid (hydrochloric) and pepsin (enzymes) = gastric juice • mechanical digestion: muscular contractions (peristalsis) • lipid soluble: must be able to pass through the wall • insulin is NOT administered orally because it is a peptide - enzymes in the GI tract break it down (torn apart by pepsin enzyme) first-pass metabolism: drug passing through liver metabolized before reaching general • circulation • liver is the first place where the drug can be degraded repeated doses almost always necessary • • time release oral preparations: via coatings, mixing • sustained release (SR) • sustained action (SA) • extended release (ER, XR, XL) • controls/continuous release (CR) • modified release (MR) • some may irritate gastric mucosa • usually latent period 30-120 minute before maximum concentration in plasma • presence of enough concentration dependent on dissolution and absorption • dissolution is essential - usually in the stomach and may depend on gastric acidity speed of dissolution can affect amount absorbed - faster dissolution usually means • more absorption • sustained release preparations: multi-lamellate erodible polymers, allow slow release continuously • absorption: dependent on physiochemical properties (lipid solubility) • small non-ionized cross easily to absorb acidic areas (ex: weak acids) • most drugs absorbed in duodenum • drugs that affect gastric motility: modify dissolution and rate, NOT extent of absorption • absorption and carrier transport: sometimes requires carrier transport (ex: levodopa absorbed by amino acid transporter) • buccal: drugs via the mouth self-administration • • put in mouth without ingestion/swallowing • ingestion and inhalation necessary • examples: • nicotine (cigar, pipe) • cigars more basic solution, so can be absorbed • chewables (tobacco, nicotine gum, aspirin) • sublingual: • absorbed under tongue • avoids gastric degradation • avoids first-pass liver metabolism (doesn’t go to liver) blood flow goes directly to heart for rapid access • • examples: • antiemetics (anti-nausea) - avoids possibility of vomiting if taken orally • nitroglycerin: dilates coronary artery, which increases oxygen going to heart (helps with angina - reduces chance of heart attack and alleviates plaque issues) • rectal: • substitute for oral (if nausea issues) • can be used for unconscious patients or older patients with swallowing problems • may avoid first-pass metabolism (unless further down near the opening) • often used for emetics and anti-emetics • drawbacks: irregular absorption parenteral: anywhere outside the alimentary canal (often via injection) • • intravenous (IV): • most rapid method - instantaneous absorption • injection into veins because they are more easily accessible at the surface (intraarterial is possible but less common) very precise dosages, most accurate/predictable • • common drugs: anesthetics, drugs of abuse • drawbacks: • risk of overdose due to quick onset(can’t throw it up, take it out, etc.) • allergic reactions • vector for disease • mini-infusion pumps: intermittent intravenous delivery • targeted delivery: selectively goes to desired site of action • intramuscular: • slower release • muscle vascularization more even absorption than IV • • oil vehicles - depot injection: suspended release • constant drug levels for a set period of time • can last for days or weeks • sometimes used to slow absorption rates and prolong duration of action • common drugs: • steroid hormones (birth control, testosterone) • antipsychotic • drawbacks: • usually poorly broken down in the gut • poorly absorbed significant first-pass effects orally • • solution may be irritating • determined by regional blood flow • intraperitoneal (IP): • not done in humans due to chance of infection (bacteria empties from intestine - peritonitis) • injection through peritoneal (abdominal) cavity • rapid, variability in absorption • large volumes • subcutaneous: • injected just below dermal layers skin is very vascularized, which leads to steady absorption • • slow release, determined by regional blood flow • insulin often subcutaneous • drawbacks: • allergic reaction • bruising • painful • silastic capsules: implanted under the skin for contraception, progestin leaks out over time • sustained release (no peaks of high concentration, just keeps it steady) • drawbacks: allergic reactions • • bruising after removal (can stay in for years) • transdermal: administered via a skin patch or gel (self-administered) • controlled and sustained drug delivery • diffusion of medicine across porous membrane onto the skin less invasive • • only works with drugs that are highly lipid soluble/potent • common drugs: • steroids • nicotine • opioid (fentanyl) - used for severe pain • scopolamine (motion sickness) • inhalation: • delivery to lungs • rapid/efficient absorption (effects within seconds) • gases, particulates suspended in gas rapid absorption bc many capillaries on alveoli (lungs are very vascularized) • • drawbacks: • bronchial irritation • pulmonary damage • carcinogenic • spinal administration: • spinal meninges • dura mater • arachnoid mater • subarachnoid space • pia mater - in contact with nervous system, touching spinal/brain cells intrathecal administration • • lumbar puncture (usually between 3rd and 4th lumbar vertebrae) • injected into CSF in subarachnoid space (CSF transports drug into brain - passes through BBB) • drugs: • anesthetics • analgesics • antibiotics (meningitis medications) • drawbacks: specialized injection, cannot self-administer • epidural: • DO NOT penetrate dura (injection between the vertebral column and dura) targets sensory serve roots in epidural space • • drugs: • anesthetics (usually target certain region of the body) • analgesics • anti-inflammatories • drawback: specialized injection, cannot self-administer • intranasal: • self-administration • drugs rapidly absorbed from nasal mucosa to the CSF • avoids: • gastric breakdown first-pass metabolism • • blood brain barrier • drugs: • peptides (ex: oxytocin - 9 amino acids which make it hard to be absorbed in other ways) • causes local and systematic effects while drug moves across epithelial cells • drawbacks: • irregular absorption • nasal irritation • drugs of abuse • topical: • usually local effects - drug will act at the area of administration • transmucosal: • to mucous membranes for topical effects • systemic absorption • intracranial and intracerebroventricular often used in animals Absorption • absorption: getting the drug INTO the blood circulation • rate dependent on administration and absorption water: • • young people consist of 70% water, elderly are 50% water • polar molecule - partial positive and negative sections • electrons spend more time near oxygen, which is more electronegative • polar water molecules are attracted to each other via hydrogen bonds • membranes: 10 nm wide • • fluid mosaic: proteins drift and move through phospholipids continuously • selectively permeable, dynamic • phospholipid bilayer: • POLAR, head (hydrophilic) - polar water molecules attracted to polar heads • glycerol, choline (+) and phosphates (-) NONPOLAR fatty acid lipid tails (hydrophobic) • • form micelle in aqueous solution: sphere with heads on outside and tails on inside • proteins • intrinsic protein: spans entire bilayer • transport proteins • extrinsic protein: go halfway signalling proteins • • peripheral proteins • carbohydrate branches acting as identification markers • glycoproteins • glycolipids • immunological characteristics cholesterol: maintains structural stability, keeps lipids from freezing • • transport across membranes: • simple/passive diffusion: • movement from high to low concentration (down concentration gradient) • no energy needed (passive) • no carrier proteins required transports small molecules and lipid soluble molecules • • rate is directly proportional to the different in concentration • facilitated diffusion: requires proteins (STILL down concentration gradient) • • protein pores/channels • carrier molecules (transporter) • large or charged molecules • passive (NO energy needed) • usually for simple sugars, steroids, amino acids and pyrimidines • active transport • requires energy - ATP • uses carrier protein or protein channel • move from low to high concentration (against concentration gradient) • ex: sodium potassium pump (secondary active transport) random constant motion of molecules: brownian movement • • GI tract: tube lined by epithelial cells • simple columnar • space between these epithelial cells is 4 angstroms (VERY small) • aspirin molecule is only 5 angstroms (one of the smallest you can take orally), but still cannot get through the intercellular space • tightly apposed • drug has to get into the capillaries on the other side of the epithelium - to do this, the drugs have to go through the cells themselves • have to dissolve themselves in the epithelial membranes • properties of drugs absorbed by GI tract: water soluble • • gastric resistant • stomach is highly acidic • contains many enzymes that may break down drugs • lipid soluble • absorption of oral medication (in GI tract) • plasma concentration of orally administered drugs affected by: • low pH of stomach • gastric enzymes • water solubility • lipid solubility drugs dissolve in stomach • • acidic drugs absorbed in stomach • alkaline are absorbed in duodenum • then drugs go to liver • first mass metabolism • some go back into small intestine • may be broken down • ionized drugs • most drugs weak acids or bases that are ionized in water SO are not very soluble • in physiological conditions, present in ionized and non-ionized form • extent of ionization depends on relative acidity (pH) and intrinsic property of molecule (pKa) • pKa: pH of the aqueous solution that would render the drug 50% ionized • weak acids optimize more readily in alkaline, less ionized in acidic (opposite in bases) • drugs with high charge in both environment are poorly absorbed • Factors affecting rate of absorption by the GI tract: • 1. concentration of drug at site of administration • 2. properties of the drug (acid or base) • weak acids or weak bases exist in 2 forms • ionized form is water soluble (because of polarity - polar water attracts ions) • polar water binds to charged drug —> creates a water shell around the polar drug, which indicates water solubility (no longer a precipitate) • water shell prevents drugs from passing through the membrane due to polarity - lipid tails will prevent movement • unionized form is lipid soluble (nonpolar) • bases: codeine, morphine, cocaine, amphetamine, nicotine, caffeine • weak acid is LESS ionized at low pH (high concentration of H+ ions) • weak base is LESS ionized at high pH (low concentration of H+ ions) • **weak bases are more efficiently absorbed in the small intestine than the stomach** • small intestine is more basic • 3. pH of absorbing surface • low pH means a high concentration of H+ molecules (pH represents concentration of H + ions) • pH ranges from 0-14 • at pH 7.0, [H+] = [OH-] • low pH: high [H+] • high pH: low [H+] • H+ will associate with acid to unionize it (protonation) - this causes lipid solubility • acids: HA <—> H + A + - • bases: BH <—> H + B + • low pH favors ACID ABSORPTION (less ionization) • acids better absorbed in stomach • high pH favors BASE ABSORPTION (less ionization) • bases better absorbed in small intestine • pH gradient across GI tract: low in stomach, gets higher as you go on towards the colon • epithelial lining of stomach between gastric fluid and blood plasma • stomach fluid is pH 1.4 —> when acid placed in stomach, most exists in unionized form (due to high concentration of H+) • blood is pH 7.4, so when acids pass the epithelial layer, these unionized ions associate with H+ become ionized now, more ionized acid molecules than unionized • • this maintains the concentration gradient going into the blood (ionized acids cannot pass back through the membrane back into the stomach) • promotes absorption • ion trapping: once protons are lost, acids cannot dissolve back into the membranes due to water shell (ionized acids) • small intestine has pH 5.0-6.6, so bases are less ionized than in stomach • 4. pKa of the drug • pKa: pH at which 50% of the drug is ionized (acid OR base) • pKa unique for each drug molecule changing pH changes % of molecules that become ionized - as pH rises, acid more • and more ionized (because fewer H+ leads to more associations) • pKa of acids is below 7, pKa of bases is above 7 • Henderson-Hasselback equation (**don’t need to know for exam) • weak acids: pH = pKa + log ([A-]/[AH]) • weak bases: pH = pKa + log ([B]/[BH+]) • 5. area of absorbing surface: most important factor • small intestine made for absorption - goes for many feet • folds (3x increase), villi (30x) and microvilli (600x) of small intestine increase the surface area • pentobarbital (acid) - 23.7% absorbed from stomach in 1 hour, 54.6 absorbed from duodenum in 10 minutes • this is because surface area of small intestine is so large, and even though acid base rules are important, surface area trumps all • promethazine (base) - 0% absorbed from stomach in 1 hour, 38% from small intestine in 10 minutes • ethanol (neither) - 37.7% absorbed in stomach in 1 hour, 64.1 absorbed from duodenum in 10 minutes (SA most important) • this is why drinking on empty stomach is absorbed so quickly • lipid solubility facilitates movement of drug molecules through lining into circulation • H+ ions will associate with ionized acid molecules to neutralize the charge —> this makes the drug lipid soluble • lipid soluble drugs: pass through membranes via passive diffusion (high to low concentration) • • concentration gradient: difference on each side of the membrane • higher gradient = more rapid diffusion • partition coefficient: predicts relative rate of movement of drug through cell membrane • ratio of amount of drug dissolved in oil divided by the concentration in the water • higher concentration in oil means it’s more lipid soluble, will pass more quickly through ex: acetylsalicylic acid: unionized form is lipid soluble, ionized form is water soluble • • other factors: • surface area • movement speed • size of individual (larger = more diluted drug, so you will need more) • sex final step of absorption: blood enters the bloodstream • • drug molecules pass through epithelial layer of GI tract to the capillaries • capillaries need to be accessed in order to be distributed through the body • capillaries are made up of endothelial cells, which have larger gaps • endothelial cells not as tightly pushed together - spaces between cells which allows for easy access into capillaries some drug distribution happens through the lymph system • Oral Absorption Review Questions • what drives the movement of most drugs across cell membranes? • passive or facilitated diffusion (down the concentration gradient) • active transport does occur BUT is rare • why does lipid solubility affect movement of most drugs across cell membranes of the GI tract? very narrow space between epithelial cells; requires molecules to dissolve in the lipid • bilayer of the cell membrane in order to get through the GI lining • why does ionization state affect drug absorption by the GI tract? • ionized drugs are water soluble, so polar water shell forms around it so it cannot pass through the membrane • unionized drugs are lipid soluble • what types of drugs can exist in both ionized or unionized states? • weak acids • aspirin, penicillin, warfarin, phenobarbital • ionized form is water soluble • unionized form is lipid soluble (when acids pick up a proton they are unionized) • weak bases • codeine, morphine, cocaine, amphetamines, nicotine, caffeine • ionized form is water soluble (when bases pick up a proton, become ionized) • unionized form is lipid soluble • what does pH represent? • concentration of hydrogen ions in a solution • as pH increases, [H+] decreases • how does pH affect the rate of absorption of a weak acid? • low pH (higher [H+]) increases % of unionized acids, which are readily absorbed • acids absorbed better at low pH —> less ionized • because acids are unionized when they pick up an H+ how does pH affect the rate of absorption of a weak base? • • high pH (lower [H+]) increases % of unionized bases, which are readily absorbed • bases absorbed better at high pH —> less ionized • low hydrogen concentration (because bases become ionized by picking up H+) • what does pKa represent? • pH at which 50% of drug is ionized and 50% is unionized depends on strength of acid or base • • what is ion trapping? • ionization that occurs when acid enters capillaries lining GI tract, which prevents reabsorption into GI lumen • when an unionized drug passes from stomach into blood, becomes trapped because it has now been ionized what is the most critical factor determining the rate of drug absorption by the GI tract? • • surface area of the absorbing surface (intestines have the most SA due to folds, villi and microvilli) • factors favoring absorption by small intestine over stomach • larger surface area • longer transit time - time moving through the structure less mucous in small intestine (mucous impedes absorption) • • higher pH, which helps with absorption of weak bases • absorption: drug enters bloodstream Distribution • final step of absorption: blood enters the bloodstream • drug molecules pass through epithelial layer of GI tract to the capillaries • capillaries need to be accessed in order to be distributed through the body capillaries are made up of endothelial cells, which have larger gaps • • endothelial cells not as tightly pushed together - spaces between cells which allows for easy access into capillaries some drug distribution happens through the lymph system • • once drugs pass the epithelial layer, they can pass into the endothelial cells with little trouble - SO if drugs are injected (IV, intramuscular, etc) they can easily be absorbed • parts of the body with the most blood flow have the highest concentration of the drug • brain gets 13.9% of immediate cardiac output • drugs can potentially go anywhere with blood circulation • after administration/absorption, drugs are located in plasma (possibly bound to proteins) • when distribution complete, concentration of plasma water and ECF is equal • general capillary (capillaries outside CNS): • single layer of endothelial cells • larger spaces between cells drug molecules can easily enter and exit circulation (even if water soluble molecules) • • types of structures • continuous - still have intracellular spaces (but smaller) • fenestrations - holes in the endothelial cells that allow drugs to enter • right under epithelial layer in GI tract • sinusoid: LARGE intercellular gaps and incomplete basement membranes • these are found in the liver (has to metabolize many things, such a large proteins) • water soluble cells can go through fenestrations or intercellular spaces • lipid soluble can go through membrane, space or fenestration • drugs exit general capillaries through various routes • intracellular spaces pinocytosis • • invaginations pick up drug molecules (vesicles) and transport them across membrane into extracellular space in • fenestrations: pores in the endothelial cells • lipid transport: lipids can pass through all membranes • molecules travel through vascular and hepatic veins • lipid-soluble drugs with low mol. weight are distributed widely • may be uneven when • differences in blood perfusion • pH • permeability of cell membranes plasma protein binding: proteins in the blood bind drug molecules • • this prevents them from exiting circulation (cannot pass through endothelial cell layer) • albumin: most important role in drug binding (lots of binding sites with affinity for various drugs) • mainly binds acidic and neutral compounds • beta-globulin: bind many basic drugs • this binding ends up transporting drugs around the body • most drugs poorly soluble in plasma water, so they need to bind to plasma proteins for transport in plasma • if binding can escape, THEN it can have effect on target area • protein binding reduces bioavailability (concentration that is FREE to interact with targets) prevent action - tie up drug molecules in plasma • • reduce action • prolong action - may be weaker effect, but can keep drug in system longer • excessive protein binding only decreases elimination if the liver is deficient • factors that can affect plasma protein binging and increase pharmacological effects of drug presence of a second drug in competition • • drug interactions: one drug displaced by another • finite number of plasma protein sites • drug B competes for sites occupied by drug A • now more of drug A becomes bioavailable to the tissues - stronger effect • reduction in albumin and beta-globulin synthesis • liver dieseases (ex: cirrhosis) • liver pathologies can reduce production of plasma proteins, which causes greater bioavailability of the drug • increased concentration of the drug so all proteins are at 100% capacity • drug storage depots: inactive sites where no measurable biological effect is initiated drugs stuck here cannot reach active sites - reduces concentration of drug at action sites • because only free drugs can react • drug molecules bind to muscle, fat and bone • thiopental distribution over time after IV injection • initially flows to tissues with lots of blood flow - goes to brain very quickly, but doesn’t last there very long • because so lipid soluble, spreads to rest of the body (muscle and fat) • gets stuck in muscle and fat, and spreads to the whole body • grogginess for a while after, because the drug is stuck in fat and slowly leaking out • lead binds to bone - can cause mental retardation • remains in bone for long periods of time (years) tetracycline: binds to enamel • • stains teeth while still developing • binding is nonselective, so competition is involved —> this can lead to more free drug than expected and can cause overdose • drugs that are bound cannot be metabolized by liver • reversible - when blood level drops, the drugs can unbind • depot binding extends the time the drug stays in the body • depot binding may be responsible for terminating drug action • protein binding: • blood brain barrier: • protects, stabilizes and preserves brain environment structural feature: tight junctions between endothelial cells • • primarily accounted for by the narrow spacing between the endothelial cells of the capillaries • tight end gap junctions between endothelial cells which restrict passive diffusion • many different proteins that anchor the 2 proteins to each other • most proteins made by glial cells • manipulating this junction (tightening or loosening) is an area of current research for drug penetrance • pericytes • no fenestrations (larger openings) or pinocytotic vesicles • basement membrane enzymatic feature: enzymes inside • • if compounds get through the barrier into endothelial cell, can be destroyed by enzymes inside • peripheral astrocyte processes metabolize neurotoxins (these produce the enzymes) trophic factors secreted by astrocytes • • export pumps expel foreign materials • glial cells: • manufacture proteins that anchor junctions together • takes up different substances (uptake mechanisms) • enzymes can also degrade unwanted substances • not a great structural barrier - gaps between their foot processes • bidirectional transport • some active transporters: • glucose • amino acids drug permeability: • • diffusion and transport of molecules across BBB • lipid-soluble diffusion • lipid-soluble agents • facilitated transport • glucose, amino acids, nucleosides • transcytotic transport (for smaller proteins) - similar to pinocytosis • insulin, transferrin (peptides) • endocytosis/carrier transport can help some substrates pass • many low molecular weight/lipid soluble drugs can pass • alcohol, ecstasy, nicotine, heroin ecstasy actually damages barrier as it goes through • • some cells trick the BBB by attacking proteins on the endothelial cells which “opens” gate • other drugs can widen the gaps between endothelial cells • new developments: liposomes that can sneak drugs through the walls like “trojan horses” • some transporters (glycoprotein) can pick up things in membrane and push it back it into the blood • areas with weak or no blood brain barrier (AKA circumventricular organs): accessible by water-soluble drugs • subfornical organ: important for fluid regulation detects angiotensin levels • • area postrema • in medulla (vomiting center) • aka chemical trigger zone - induces vomiting when toxic substances in blood • only useful if drug is in the GI tract • median eminence • in hypothalamus • allows neurohormones to travel to pituitary gland • pineal gland • choroid plexus • ependyma weakened by: • • multiple sclerosis - antibodies can weaken BBB by opening intercellular spaces • antibodies cause deterioration of the myelin • bacteria • viruses • ecstasy • placental barrier: between blood circulation of mother and fetus • acute toxicity: high drug blood level of mother affects fetus - remains in body for a long time due to slow metabolism • ex: opiates (heroin) • teratogens: agents that induce developmental abnormalities in the fetus • at term, compartments between the fetus and mother are separated by one layer of chorion • most low molecular weight and lipid soluble drugs can pass • removal from maternal blood depends on placental blood flow Biotransformation and Elimination • biotransformation: metabolism • alteration in the chemical structure of a drug molecule by the action of enzymes • common sites: stomach • • intestine • blood • kidney • brain • liver - most drugs metabolized in the liver liver • • lobule • hepatocytes: active area • contain enzymes necessary for biotransformation • spaces in between hepatocytes: sinusoids • these are filled with blood - all cells have lots of exposure to circulation enzymes: very complex structure within hepatocytes • • proteins - act on a substrate • form new metabolite • reusable - catalyze reactions and then are free to act again • can catalyze 10,000s of reactions/second • reduce energy needed for chemical reaction (lower the activation energy) extensive blood vessels and cells • • liver gets more blood flow than any other structure • capillary structures - intercellular spaces • large molecules can access hepatocytes due to sinusoid capillaries - large gaps • 1000A (GI epithelium is only 4A) • Kuppfer cell: macrophage stellate cell: form scar tissue (cirrhosis) • • caused by heavy drinking • 80% of blood flow from portal venule • biotransformation by liver microsomal enzymes • enzymatic conversion of lipid-soluble nonpolar drugs into water-soluble compounds • these can be filtered by the renal glomerulus or secreted into liver or bile water solubility makes elimination easier • • drug —> metabolite #1—> metabolite #2 • highest number of chemical changes occur in the liver phase I: simplifies drug molecules • • non-synthetic modification of drug molecule (aka functionalization) • most reactions in SER or microsomes • catabolic reactions: • oxidation • hydroxylation • dealkylation • deamination • usually via cytochrome P450 (microsomal enzyme system) • mixed function oxidases • on smooth ER non-specific • • inducible - if exposed to a drug repeatedly, may start making more enzymes • this leads to metabolic TOLERANCE • many isoforms - can metabolize many foreign chemicals • metabolizes most psychoactive drugs • some endogenous compounds metabolized by monoamine oxidase • most esters and amides broken down via hydrolysis • phase II: synthetic or conjugation reactions (BUILDING bigger molecules) • anabolic: adding to phase I product • -COOH - carboxylation • -OCCH3 - -CH3 - methyl group • • -C6H10O7 - glucuronic acid • -SH4 - sulfate • -NH4 - amino • via transferases • transfer groups to drug molecule • specific - more specific than phase I • inducible - leads to metabolic tolerance • can either activate or deactivate molecule • glucuronide conjugation: • dependent on enzymes in hepatic ER many polar groups attached, which makes molecule more water soluble/hydrophilic • • results in acidic drug metabolites with low pKa - increases water solubility • sulfate conjugation in gut wall or cytoplasm of liver • ultimately, both phases produce one or more inactive metabolites which are lipid soluble (so they are easily excreted) • example: aspirin • phase I: cytochrome P450 hydrolyzes aspirin into salicylic acid • salicylic acid gets glucuronic acid group, which can now be excreted by kidneys • at the end of phase I and phase II - lipid solubility has been altered to make excretion more or less likely • ex: metabolism of aspirin (acetylsalicylic acid) aspirin inactive, but body converts it to active form • • phase I: hydrolysis via cytochrome P450 (add OH) • aspirin (acetylsalicylic acid) —> salicylic acid (active form) • phase II: conjugations via glucuronic acid transferase • this transforms it back to inactive forms salicylic acid to ether glucuronide (added to OH) OR ester glucuronide (added to • COOH) • now in a state more likely to be excreted by the kidneys • drug clearance: • first order kinetics • constant fraction (50%) of the free drug is removed in each time interval • most common • the amount of drug metabolized depends on the concentration of the drug • half life: amount of time needed to remove 50% of drug in blood • determined time interval between doses (shorter half life means more frequent doses) 90% of the drug lost in 3.32 half lives • • different types of drug metabolism • half life is affected by physiologic, pathologic and environmental factors • each person has their own half life values for each drug • steady state plasma level: desired blood concentration of drug achieved when the absorption/distribution phase is equal to the metabolism/excretion phase • reached after 5 half lives for any given daily dose • zero-order kinetics: drug molecules are cleared at a constant rate regardless of concentration (straight line in a graph) • constant amount (NOT PERCENT) is removed at each interval • ex: high doses of ethyl alcohol rare • • factors influencing drug metabolism: • enzyme induction • drugs used repeatedly can cause increase in particular liver enzyme • this speed up rate of biotransformation for these drugs AND can also increase metabolic rate for all other drugs modified by that enzyme • increases liver weight, microsomal protein content and biliary secretion • increases conjugation due to increase in activity in glucuronyl transferase • ex: heavy smokers need higher doses of antidepressants and caffeine • enzyme inhibition • some drugs inhibit enzyme action reduces metabolism of other drugs taken at the same time with the same enzyme • • ex: grapefruit juice inhibits metabolism of some psychiatric medications • first-pass metabolism • drug competition • drugs that share the same metabolic system compete • elevated concentration of either drug reduces the metabolic rate of the second • individual differences (age, gender, genetics) • age: rates reduced in very young and very old • sex: genetic and hormone effects • species: wide variations • genetic polymorphisms: genetic differences that produce different forms of the same protein • differences in nutrition • drug history: enzymes induced by prior drug exposure • metabolic tolerance cross tolerance - one drug affects tolerance of another drug (smokers often need • larger doses of drugs) • pathological differences: • liver cirrhosis • renal disease • decrease in cardiac output • hyperthyroidism/hypothyroidism • fever • elimination: • urine • bile feces • • saliva • sweat • breast milk • expired air • renal elimination: through kidneys • most important route of elimination is through urine (via kidneys) • usually lower molecular weight • kidney —> ureter —> bladder —> urethra • aquaporins: pores through which water moves • nephron: tangle of tubes and blood vessels 1.5 million/kidney • • renal tubules: aqueous solution carrying various solutes • go through these, down to collecting duct and out through bladder • lined by epithelial cells - simple cuboidal epithelial cells • right up against each other - substances need to cross through this cell layer (same as in the GI tract) • blood vessels in close proximity to tubules • blood cells and plasma proteins are too large to enter kidney tubules • renal corpuscule • Bowman’s capsule containing glomerulus • water and solutes enter kidney tubules through Bowman’s capsule proximal tubule initiates at Bowman’s capsule • • loops of Henle • ascending and descending tubules have different permeabilities to water and sodium • distal tubule • low water permeability • collecting duct fine-tunes water reabsorption • glomerulus: knot of blood vessels • Bowman’s capsule surrounds it - this connects it to tube structures • interface between blood circulation to enter kidney tubules (via Bowman’s capsule) space between glomerular endothelium: 75-100 A • • involves some fenestration - many things can move out • only things that don’t move out are typically proteins and blood cells • 99% filtrate reabsorbed by blood • reabsorbed from tubule system back into circulation about 1% is excreted • • 1.5 liters of fluid excreted daily - water + solutes • glomerular filtration: • Bowman’s capsule interface • intercellular spaces • renal corpuscle and the filtration membrane • eliminates poorly-lipid soluble drugs/metabolites • only unbound drug is transferred from plasma to tubular cells • proximal tubular secretion: • rapid secretion • carrier transport - against concentration gradient acids and bases are transported separately • • only unbound drug is transferred from plasma to tubular cells • distal tubular secretion: • non-ionic diffusion • large H+ gradient between plasma and urine • acidic drugs excreted in alkaline urine • basic drugs excreted in acidic urine because they are ready diffuse from plasma to urine (providing gradient) • most drug molecules that are lipid-soluble when in the kidney tubule are reabsorbed by blood • factors affecting rate of elimination by kidneys - determine whether reabsorption or excretion will occur • 1. acid or base • ionization reduces reabsorption • ionized (water soluble) molecules are excreted in urine • water shell prevents reabsorption through renal epithelium • unionized (lipid soluble) molecules are reabsorbed by blood • 2. pKa of drug • 3. pH of tubules • ranges from 4-8 (varies over time) • at higher pH, acids are more ionized and excreted more quickly • at low pH, acid will be less ionized and will be reabsorbed at low pH, bases are more ionized and excreted at faster rates • • at high pH, bases are less ionized and reabsorbed • pH gradient within kidneys • upper nephron tends to be closer to neutral • closer to ureter, lower pH • genetic variability • dietary factors • drug interactions • biological rhythms • other - ex: stress causes more acidic urine • nicotine is a base - stress causes more acidic urine, so basic nicotine may bring pH back up • FIGURE THIS OUT for exam • ex: weak acid will be excreted more rapidly by the kidneys when the acid is highly water- soluble • ex: weak base will be excreted more rapidly by the kidneys when • low pH of renal tubule • concentration of H+ ions in tubule is high • base is not lipid soluble • base is highly ionized • regulators of renal absorption • anti-diuretic hormone (peptide hormone) - aka vasopressin (increased blood pressure) • synthesized by hypothalamus • stored in/released from posterior pituitary • facilitates/increases water reabsorption in the kidney collecting duct • increases number of aquaporins at collecting tubule • aquaporins: protein channels in renal epithelial cells allowing passage of water molecules • aldosterone (steroid hormone - 4 ring structure) • synthesized and released by adrenal cortex • facilitates sodium reabsorption • acts on collecting tubule • diuretics: increase water elimination (increase renal output) • ethanol: inhibits ADH release from posterior pituitary • promotes excretion (because ADH can no longer facilitate reabsorption into blood) affects BRAIN - may affect GABA system • • caffeine: acts on blood vessels of glomerulus to increase glomerular flow?? • controversial • affects KIDNEYS themselves • biliary excretion: less important than renal excretion • for molecular weight above 400-500 Da ionized drugs eliminated from liver cells via active transport - dependent on Na+/K+ • ATPase • non-specific • saturable • can be competitively or non-competitively inhibited by other drugs • enterohepatic circulation many compounds eliminated in bile are hydrolyzed in small intestine and reabsorbed • after • this circulation may occur many times before final elimination from the body Drug-Target Interactions • pharmacokinetics: effects of the body on a drug • pharmacodynamics: effects of drug on the body • physical and biochemical interactions with tissue that’s responsible for effects of drug includes binding and effects of the drug • • drug molecule —> binding to organic molecule —> change in cellular activity —> change in behavior • drug molecules: • ligand: molecule that binds to a receptor with selectivity • agonist mimic effects of specific neurotransmitter • • stimulate cellular response similar to neurotransmitter • stimulate receptors fully (full agonist) or partially (partial agonistic effect) known as intrinsic activity - effect SIMILAR to the neurotransmitter • • partial agonists: doesn’t have full effect - may fit just enough to cause some, but not all, changes • may not exactly mimic transmitter exactly • can do other things than just activating receptor • can enhance synaptic function by increasing nt synthesis or release • antagonist • block specific neurotransmitter receptors • doesn’t have to be the same shape, just enough to block the target site • prevent cell response induced by neurotransmitter • do not stimulate receptors (no intrinsic activity) still has a biological effect, but not activating intrinsic activity like the transmitter • would • competitive antagonists: compete with agonists for receptor sites • noncompetitive antagonists: reduce agonist effects in other ways • ex: bind to other part of protein and change shape • physiological antagonism: 2 drugs that act in different ways but interact so that they reduce each other’s effectiveness • receptors: large protein molecules on the surface OR within cells • extracellular • intracellular • cytoplasm nucleus: hormone receptors • • binding is temporary • ligands binding to receptors make a physical change in the shape of protein • modifications: • long-term (modifications in number) • up regulation • down regulation • rapid regulation: modification in sensitivity • often due to 2nd messenger cascades • receptor binding • drug affinity drug effects • • cellular • physiological • behavioral • additive effects: sum of 2 individual effects • potentiation: combination of 2 drugs produces effects that re greater than the sum of their individual effects • standard dose-response curve: describes extent of biological or behavioral effect produced by a drug • classic S shape • threshold dose: lowest dose that produces given effect potency: dose necessary to produce effect • • farther to the left - more potent (requires smaller dose to get to ED or produc50 maximum effects) • farther to the right is less potent • response measurement methods: all based on given dose • percent of subjects responding • intensity of response itself (maybe within one subject) • ED :50ffective dose that produces 50% response - produces half of the maximal effect • expressed as a dosage that produces the response (NOT as the response itself) • ED 100: maximum response • TD: toxic dose • TD 50produces toxicity in 50% of patients • LD: lethal dose therapeutic index (TI): calculates drug safety (look at dosage curves) • • compares adverse effects to therapeutic effects • therapeutic index inside ED and50D 50 • OR between lethal dosage and effective dose (inside ED and LD ) 50 50 • based on ratio of TD /E50 50 or TD 1ED 99 higher TI ratio = greater drug safety • • can differ for different side effects • should have indices for ALL different side effects (what does drug do in terms of sedation, nausea, etc.) • can change as tolerance develops - desirable curve can start moving toward toxic curve (this decreases index window) • can vary between individuals • TI is a measure of drug safety most useful during drug development • factors determining drug potency: accessibility (pharmacokinetics) - depends on how much access drug has to target sites • • affinity (pharmacodynamics): attraction between drug and receptor • drug interacting with target (receptor) • binding leads to cellular effect • drug molecule locks onto receptor site to form a drug-receptor complex drug + receptor —k1—> DR complex —> effect • <—k2— • intrinsic activity (pharmacodynamics): aka efficacy • activation of cellular processes by neurotransmitter or agonist • after drug has boded to molecule, receptor changes conformation/shape which leads to cellular effects —> these effects are the intrinsic activity • NOT from antagonists - can only be from nt or agonist • neurotransmitters: LEARN THIS SLIDE —WILL BE ON EXAM (table 3.1) • acetylcholine - CNS functions, ANS, motor neurons amino acid transmitters: contain amino group and carboxylic acid • • involved in most nervous system functions • examples: • GABA - inhibitory • glutamate - excitatory glycine - inhibitory • • monoamines (aka biogenic): attention, consciousness, cognition, etc. • catecholamines: benzene ring with 2 hydroxyl groups • norepinephrine • dopamine • epinephrine • indoleamines • serotonin histamine • • peptide transmitters: chains of amino acids • opioids - pain perception • endorphins • substance P • adenosine: purine • **general understanding of CHAPTER 3 p. 77-90** • synaptic mechanisms: • 1. neurotransmitter is synthesized and stored in vesicles • 2. action potential invades presynaptic terminal • 3. depolarization of presynaptic terminal causes opening of voltage gated calcium channels • 4. influx of calcium ions through channels • 5. calcium causes vesicles to fuse with presynaptic membrane • 6. neurotransmitter is released into synaptic cleft cis exocytosis • 7. neurotransmitter binds to receptor molecules in postsynaptic membrane • 8. opening or closing of postsynaptic channels • 9. postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes excitability of the postsynaptic cell • 10. retrieval of vesicular membrane from plasma membrane • neurotransmitter release: • cluster of proteins in the membrane of the synaptic vesicle (vesicles bud off endosome) vesicles fill with neurotransmitters • • vesicles are docked and primed • when calcium enters the presynaptic membrane, the membranes sure and the molecules of the neurotransmitter leave • removal of transmitter: • enzymatic breakdown • presynaptic uptake • glial reuptake • synapses are excitatory or inhibitory • dendritic synapses usually excitatory • somatic synapses usually inhibitory axonal usually mix of both • • association: biding of transmitter or drug to receptor • dissociation: transmitter or drug leaves receptor • ionotropic receptors: • ligand gated ion channels on cell membranes • when ligand binds, then channel opens and allow ions to pass through receptor gate • conformation change due to receptor binding • Na+ goes in, K+ comes out • when ligand leaves, channel closes quickly • cause graded potentials when activated • Na or Ca in will excite Cl in or K out will inhibit • • rapid synaptic transmission (milliseconds) • receptor-ion channel unit • desensitization: channel remains closed even though there are ligands bonded - must resensitize before opening again protein subunits arranged around central ion channel (4-5 subunits) • • acetylcholine (nicotinic), GABAA, 5HT3 • NMDA glutamate receptor • metabotropic receptors (G-protein receptors) • G protein linked (alpha, beta and gamma subunits) • alpha or beta-gamma subunits activate effectors • 7 peptide domains span membrane • 2nd messenger channels - NO pore/channel • can affect proteins and genes • slower (seconds), longer lasting response • ligand binds, which changes receptor shape this changes shape of G-protein • • activates other enzymes and effector proteins • mechanisms of G protein operation: • stimulate or inhibit the opening of other ion channels in the cell membrane • stimulate/inhibit effector enzymes in the membrane - these produce biochemical and physiological effects • these enzymes usually involved in the synthesis or breakdown of 2nd messengers • process: biochemical cascade • activation of G protein (via ligand) • agonist-receptor binding > G-protein dissociation • this stimulates or inhibits adenylyl cyclase this up regulates or down regulates cAMP (2nd messenger) • • ^^ increased synthesis or breakdown of 2nd messenger • 2nd messenger causes protein kinases phosphorylate other proteins (transfers phosphate group) • these proteins are effector enzymes • some processes regulated by protein phosphorylation • receptor up or down regulation • ion channel opening or closing • enzyme activation or deactivation • neurotransmitter release • dendritic growth cellular metabolism • • —> biochemical or physiological changes in cell • ACh (muscarinic), monoamines, peptides • many nt and hormones bind to GPCR • Gs protein activation releases GDP (which binds GTP) • alpha subunit binds to adenylyl cyclase, which hydrolyzes ATP to cAMP • cAMP is 2nd messenger to signal intracellular events • Gs protein coupled receptors stimulate cAMP • ligands: heart - epinephrine, norepinephrine • Gi protein coupled receptors inhibit cAMP • ligands: heart - ACh, adenosine Gq protein coupled receptors activate the inositol triphosphate pathway (IP3) • • ligand: blood vessels - norepinephrine, angiotensin II, endothelin-1 • 2nd messenger is IP3 instead of cAMP • enzyme-linked receptor • ligand binds to receptor • enzymes inside cell activated • GTP becomes cAMP • downstream signaling of other 2nd messengers in cell • intracellular receptor: • ligands that can pass through the cellular membrane enter the cell • after entering nucleus, bind to intracellular receptors • this can alter transcription of DNA Receptor Measurement • measurement of receptor binding • radioligand: compound that binds to specific receptors in membranes allows for us to measure receptor binding via radioactive labelling of drug molecules • • measuring the amount of radioactive isotope in the samples tells us how much drug molecule is there • forms of hydrogen • hydrogen: one proton deuterium: one proton, one neutron • 3 • tritium [ H]: one proton, 2 neutrons • able to trace presence as it decays • can replace any hydrogen in a molecule with tritium • unstable tritium decay: gives off energy in radiation • • decays into stable atom • emits beta particle (radioactive energy) • tritiated radioligand - radioactive compound • substitute for hydrogen • specific receptor binding • radioligand binds to receptor • ionotropic or metabotropic • after experiment, can detect presence of radioactive drug to receptor • radioligand binding method • tissue dissection • tissue homogenation • in buffered solution • incubate tissue (receptors) with radioligand • [ H] ligand with receptors • incubation for 1 hour results • some binds to receptors, some doesn’t (bound3and unbound ligands together) • this labels receptors with radioactive tag [ H] • separation of unbound and bound radioligands (via filtration) • bound = radioactive drug bound to receptor • bound ligands become trapped on filter paper 3 • buffer solution with unbound/free [ H] ligand at bottom • scintillation counting of bound radioligand • place filters in scintillation vials • add scintillation fluid for counting • beta particles excite contents of scintillation fluid - this is given off as light 3 • amount of bound [ H] this is measured (counted) using scintillation counter • properties of receptor binding • transient - short-lived • reversible • drug + receptor —k1—> DR complex —> effect <—k2— • k1: association rate • fast association rate = higher affinity • k2: dissociation rate • fast dissociation rate = lower affinity • there are irreversible drugs, not typically given to humans • selective: certain drugs like certain receptors • drug-receptor affinity: quantitative measure of attraction between drug molecules and receptors • Kd (dissociation constant): measure of drug affinity for specific receptor • takes into account both k1 and k2 • determined empirically • 2 methods of determination: • 1. Kd = k2 • k1 • 2. Kd = concentration of radioligand that labels 50% of total receptors in a sample of homogenate • lower Kd, higher the affinity and vice versa • to measure specificity, add high concentrations of nonradioactive competing ligand to some tubes to show that most of the radioactive binding is being replaced • saturable: finite number of receptors in given amount of tissue • Bmax: point of maximum binding • saturation experiment goals: • 1. determine number of receptors that bind drug (Bmax) • 2. determine affinity of drug for receptors (Kd) • process


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