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Week 3 Psychopharm

by: Emma Notetaker

Week 3 Psychopharm NSCI 4530

Marketplace > Tulane University > NSCI > NSCI 4530 > Week 3 Psychopharm
Emma Notetaker
GPA 3.975

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Week 3 notes, covering both lecture and readings.
Dr. Donhanich
Class Notes
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This 10 page Class Notes was uploaded by Emma Notetaker on Thursday September 15, 2016. The Class Notes belongs to NSCI 4530 at Tulane University taught by Dr. Donhanich in Fall 2016. Since its upload, it has received 18 views. For similar materials see Psychopharmacology in NSCI at Tulane University.


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Date Created: 09/15/16
Thursday, September 8, 2016 Week 3 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 1 Thursday, September 8, 2016 • 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) 2 Thursday, September 8, 2016 • 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 3 Thursday, September 8, 2016 • 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 4 Thursday, September 8, 2016 • 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 **look at full diagram on slides** 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 5 Thursday, September 8, 2016 • 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 6 Thursday, September 8, 2016 • 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 7 Thursday, September 8, 2016 • 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 • renal elimination: • most important route of elimination is through urine (via kidneys) • usually lower molecular weight • nephron: • renal corpuscule • Bowman’s capsule containing glomerulus • proximal tubule initiates at Bowman’s capsule • loops of Henle • ascending and descending have different permeabilities to water and sodium • distal tubule • low water permeability • collecting duct fine-tunes water reabsorption • water and solutes enter kidney tubules through Bowman’s capsule • blood cells and plasma proteins are too large to enter kidneys • 99% filtrate reabsorbed by blood • 1.5 liters of fluid excreted daily • ionization reduces reabsorption • unionized (lipid soluble) molecules are reabsorbed by blood • ionized (water soluble) molecules are excreted in urine • at higher pH, acids are more ionized and excreted more quickly • at low pH, bases are more ionized and excreted at faster rates • pH of kidney tubules ranges from 4-8 (varies over time) • glomerular filtration: Bowman’s capsule interface 8 Thursday, September 8, 2016 • intercellular spaces • glomerular-capsule interface 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) • factors affecting rate of elimination by kidneys • acid or base • pKa of drug • pH of tubules pH gradient • • genetic variability • dietary factors • drug interactions • biological rhythms • other • regulators of renal absorption • anti-diuretic hormone (peptide hormone) • synthesized by hypothalamus • stores in posterior pituitary • facilitates water reabsorption • increases aquaporins at collecting tubule • aquaporins: protein channels in renal epithelial cells allowing passage of water molecules • aldosterone (steroid hormone) • synthesized and released by adrenal cortex • facilitates sodium reabsorption • acts on collecting tubule • diuretics • ethanol: inhibits ADH release from posterior pituitary • caffeine: acts on blood vessels of glomerulus to increase glomerular flow? • 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 9 Thursday, September 8, 2016 • 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 10


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