Drug Disposition Flashcards
What is a xenobiotic? Examples?
any chemical that is considered foreign to a biological system; drugs, pollutants, or other toxic compounds
What is a drug?
any substance that brings about change in biological function through chemical action; treatment, cure or prevention of a disease
what is a prodrug?
an inactive form of a drug that is converted to an active form in the body
What is drug disposition?
qualitative description of how the body handles the drug; includes absorption, distribution, metabolism and elimination (ADME)
What is pharmacodynamics?
actions of the drug on the body; usually mediated thru drug action on specific cellular receptor proteins
What is liberation?
release of drug from formulation
What is absorption?
transport of drugs from site of administration into the general circulation
What is distribution?
delivery of drug via blood to different tissues of the body; drug must be present at adequate concentration at the site of action to produce pharmacologic effect
What is metabolism?
conversion of parental compound (xenobiotic) to metabolites, body’s attempt to make the compound more amenable for excretion, mostly redox enzymes, metabolites typically are inactive but may be pharmacologically active
What is excretion?
removal of compounds and metabolites; usually via kidney or intestine
What factors determine absorption?
property of the drug (size, acid/base, lipophilic/hydrophilic), vehicle/formulation, route of administration and conditions at the route
What is the most desirable drug route? Why? Why might you choose a different one?
oral route; relatively safe, passive diffusion not saturated or energy dependent; poor compound solubility, degraded in stomach or intestine or cannot permeate intestinal wall
What are the different routes of drug administration and their categories?
Enteral- Buccal/Sublingual, Oral, Rectal
Parenteral- injection subcutaneous, intramuscular, intravenous, or intrathecal
Inhalation; Intranasal; Topical- Ophthalmic or Dermal
What factors influence extent and speed drug enters circulation and thus efficacy of buccal/sublingual route?
small SA, highly vascularized, rapid venous absorption, initially bypass the liver; 3-5 min
What factors influence extent and speed drug enters circulation and thus efficacy of Oral route?
most common, convenient, safest and economical; SI major site of absorption due to large SA and high blood flow, absorption can take entire GI length; subject to first pass metabolism (liver); 30-90 min
What factors influence extent and speed drug enters circulation and thus efficacy of Rectal route?
suppository, available when oral precluded by (unconscious, nauseated patients), absorption 50% into hepatic portal (proximal to liver, 1st pass) and 50% direct venous (distal, bypass 1st pass); 5-30min
What factors influence extent and speed drug enters circulation and thus efficacy of subcutaneous (SC) injection?
sustained/slow release, slower absorption rate (poor vascularization), small volumes; 15-30 min
What factors influence extent and speed drug enters circulation and thus efficacy of IM injection?
higher blood flow, prompt absorption, larger volumes or prolonged depot release; blood flow deltoid > gluteal; 10-20 min
What factors influence extent and speed drug enters circulation and thus efficacy of IV?
instantaneous delivery, 100% absorption, bolus- all at once or constant infusion- slower onset but provides steady state concentration; 30-60 sec
What factors influence extent and speed drug enters circulation and thus efficacy of inhalation route? examples?
rapid access to systemic or direct action on bronchioles; volatile anesthetics, aerosols, dry (micronized) powders; 2-3 min
What factors influence extent and speed drug enters circulation and thus efficacy of intranasal route?
local action on nasal mucosa (decongestant or allergy); vaccines
What is the efficacy of ophthalmic topical route?
instillation of drops into eye for local effect
What factors influence extent and speed drug enters circulation and thus efficacy of dermal topical route?
local action; systemic action via transdermal patches applied for prolonged effect- fewer drugs readily penetrate intact epidermis (can be enhanced by oily vehicles), useful for high lipophilicity and potentcy, iontophoretic or phonophoretic too; min to hours
What is transdermal iontophoretic route?
delivery of ionic molecules by passage of e- current; below pain threshold
What is transdermal phonophoretic route?
ultrasound
what is the method of passive transfer across a membrane?
Filtration/bulk flow, passive diffusion, non-ionic diffusion,
What are the characteristics of bulk flow?
through pores/fenestra, restricte by size (<300-500 daltons, ~80% of all drugs), through capillary endothelial membranes important for drug from circulation to tissues everywhere but CNS; includes glomerulus
What are the characteristics of passive diffusion?
directly through membrane by dissolving in and diffusing through membrane down [gradient]; quantitatively most important process (most drugs enteral; which mostly diffuses); uncharged (non-ionized), lipid soluble; net transfer determined by {gradient}; proceed until equilibrium
How is lipophilicty of a drug measured?
by its distribution in an immiscible mixture of organic-aqueous solvent (octanol:water, partition coeff= log Pow)
What are the characteristics of non-ionic diffusion?
non-ionized transfer across the membrane will proceed until the concentration of non-ionized form reaches equilibrium; total concentration of ionizable drug on either side = [nonionized] + [ionized]; only non-ionized can diffuse; separate equilibrium of both species on each side of the membrane.
What factors effect the equilibrium of non-ionic and ionic drugs?
whether it is an acid or a base, the pKa of the drug, pH of environment (plasma, cytosol, etc)
What determines the ionization tendency of a drug? How is Non-ionized/Ionized calculated easily?
pKa, pH at which 1/2 is ionized; each pH unit from pKa the N/I ratio changes by 10 fold
What side to acidic drugs accumulate? bases?
A: high pH side
B: low pH side
What are the characteristics of carrier mediated transport?
~200 genes, broad substrate specificity (anions or cations or uncharged, organic or inorganic), gram or mM needed for saturation, competes with xenobiotics and endogenous compounds
What are the characteristics of facilitated diffusion?
transport down chemical gradient to equilibrium, energy dependent, protein saturable by structurally selective substrates, bivectorial (both ways only down gradient); most SLC (solute carrier) family
What are the characteristics of active transport?
membrane transport proteins, saturable, against gradient, ATP dependent, amenable to competitive inhibition by structurally similar, form an intermediate complex with drug substrate-> conformational change that results in translocation of substrate; transfer proceeds until ATP or drug depleted,
What are the two kinds of active transport? Characteristics?
1- coupled with ATPase, self contained ATPase; ABC (ATP Binding Cassette) transporters
2- driven by transport of another with its gradient, either symport or antiport, ATP provided by another source, SLC transporter, most ion-coupled
What is an ABC transporter? Where is it found?
7 families, mediate vectorial (unidirectional) transport across monolayer polarized cells (endothelial or epithelial); from cytosol to other extracellular or from cytosol to other intracellular comp.
What are three isoforms of ABC transporters involved in disposition? Characteristics?
MDR (Multi-Drug Resistance) proteins, MDR1, efflux transporter selective for organic cations and neutral bulky; apical membranes, pump into urine, bile and intestinal lumen
MRP (Multi-Drug Resistance-associated Protein), efflux for organic anions, found same as MDR
BCRP (Breast Cancer Resistant Protein)- neutral or negatively charged
What are general characteristics of SLC transporters? Isotype examples?
bidirectional, 2 types: facilitated diffusion or secondary active (anion exchangers); OAT, OCT, and Neurotransmitter reuptake
What are OAT’s? Characteristics?
Organic Anion Transporter, organic anions; primarily expressed on the basolateral membrane of renal proximal tubule
What are OCT’s? Characteristics?
Organic Cation Transporter, organic cations, similar tissue/cellular distribution as OAT
What are the characteristics of Neurotransmitter reuptake transporters? Examples.
transport excess NT; DAT (dopamine transporter) and SERT (serotonin transporter)- target of SSRI antidepressants
What are the characteristics of clathirin dependent endocytosis?
drug binds specific receptor, drug-receptor complex engulfed by cell membrane, vesicle formation and pulled into cell, active transport modality ( requires energy to rearrange cell); limited to transport of large polypeptides and proteins
What effects drug dissolution in gastric juices?
formulation (immediate v slow release), different salt forms can have different dissolution rates, other material can render dissolved drug non-absorbable (food, antacid, activated charcoal)
What properties effect drug absorption in GI?
low lipophilicity, , low N/I ratio, always ionized drugs poorly absorbed
What SI surface properties affect absorption?
large SA allows highly ionized to be absorbed some extent, high perfusion rate- maintains concentration gradient preventing equilibrium, SI absorbs better than stomach due to thick wall, mucus layer, and low SA; delayed gastric emptying also reduces absorption
Characteristics of GI tract to systemic circulation?
buccal/distal rectum- absorbed directly into venous system; Stomach, SI, and proximal rectum- transported to capillaries and portal vein
What happens to a drug in the liver?
1st pass metabolism, % parent drug that survives depends on drug properties and enzymes; remaining non-metabolized drug transported via hepatic vein into systemic circulation
What is bioavailability? Factors affecting it?
% drug administered that reaches systemic circulation by any route (IV = 100%); Other routes effected by chemical form of drug, time of contact with absorbing surface, presence of efflux transporters/ metabolizing enzymes before circulation (lumen, mucosal wall and microflora in stomach, int., rectum, lung and nasal)
Is drug distribution uniform? What factors effect rate and extent of distribution?
no; blood flow and tissue mass/vol, capillary permeability, lipid solubility of drug, extent of ionization and tissue pH, transport mechanism available and extent of drug binding to plasma and tissue proteins
What is critical concentration?
concentration at which pharmaceutical effect is reached
What effect does a rapidly redistributed drug have?
may be terminated due to movement out of a tissue rather than by actual elimination (metabolism/excretion)
How is distribution effected by blood flow and tissue mass volume?
(high perfusion sec to min - liver and brain, low perfusion- muscle and skin 15-30 min, larger mass longer to fill), allows more drug, longer to fill, longer to reach critical concentration
How is distribution effected by capillary permeability?
peripheral are porous (esp liver and kidney), filtration into interstitial fluid is rapid, CNS and placenta capillaries are non-porous, provides some limits to distribution to these tissues; BBB- preclude filtration of large hydrophilic drugs, limited to carrier mediated and passive diffusion, efflux to pump out drugs
How does lipid solubility v lipid content if tissue effect distribution?
highly lipophilic drugs can accumulate in adipose tissue
How does extent of ionization and tissue pH effect distribution?
pH lower in cells compared to plasma; weak acidic drugs accumulate in plasma and weak base in cells, pH and accumulation usually not clinically significant; but may shift drug site of action if in acidosis or alkalosis
What is ion trapping?
concentration of ionized form of drug is higher in tissue than in plasma and drug accumulates there.
How can transport mechanism available effect distribution?
saturation of carrier mediated transport mechanisms can also cause accumulation
What is Vd? how is it calculated?
apparent volume of distribution; X0 (amount of drug in body mg)/ Cp (concentration of drug in blood mg/mL at time zero {Vd (L)= X0 (mg)/ Cp (mg/L)
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of 3 L means?
drug remains in blood compartment
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of 15 L means?
drug leaves blood compartment, enters ECF compartment but not ICF
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of 42 L means?
drug leaves blood compartment and enters cells but is not bound to albumin or stored in fat
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of 3-15 L means?
drug leaves blood compartment and enters ECF but is bound to plasma protein
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of 15-42 L means?
drug distributed to TBW and bound to plasma protein
For a 70kg male BW= 42 L , ECW=12L and Plasma = 3L then a Vd of >42L means?
distributed to TBW and binds tissue and/or stored in fat
What clinical info is provided by Vd?
est. proportion readily available for therapeutic effect or excretion;
What are characteristics of drugs with higher Vd?
more lipophilic, accumulate in fat and tissues, easier to cross BBB, maintained in body longer, require hepatic metabolism for elimination
What are characteristics of drugs with lower Vd?
more hydrophilic, large MW or bind plasma protein, more remains in blood, little accumulation in fat, tissue or brain, eliminated primarily by kidney
What factors effect the equilibrium of drug bound to plasma protein?
affinity, determined by weak binding forces ( ionic, hydrogen and van der Walls;
How is percent bound to plasma protein determined?
characteristic of drug, binding is saturable, when all binding sites taken up [free drug] increases; can be displaced by other drugs
Which plasma proteins bind drugs?
Albumin- mainly to acidic; Alpha-1-acid glycoprotein- mainly basic
What are some consequences of drug binding to proteins?
only free drug crosses membrane to enter tissue or be eliminated, or bind to receptors and produce pharmacological effect, after drug leaves circulation reestablish equilibrium, changes in free drug concentration can lead to transient changes in therapeutic response and Vd
What cellular constituents can drug bind to? Example. What is the characteristics of the bond?
protein- functional (receptors or non-functional, reversible or irreversible (drug dependent); Lipids- highly lipophilic drugs can accumulate (important for more toxic)
The liver has a high extraction rate for what type of drugs? Why?
lipophilic; due to affinity for transporter proteins and metabolizing enzymes
What drugs have a tendency to bind in the lung?
basic amines with lipophilic groups and pKa >8
What types of drugs get bound in the bones?
complexes with calcium and bone matrix
What factors effects most xenobiotics including in diet effecting their elimination?
too lipid soluble to be excreted rapidly enough to avoid accumulating to toxic levels; prevented by metabolizing enzymes
When metabolized how are lipophilic xenobiotics changed to facilitate elimination?
converted to metabolites that are more polar, add or expose hydrophilic functional group; occurs in biphasic steps; thus eliminating the parent drug; metabolite may be active or toxic
What is a phase one reaction? Possible consequences?
functionalization, structural modification via oxidation, reduction or hydrolysis (OH, COOH, SH, O or NH2); inactivation of parent, active drug to active metabolite, toxic metabolite, reactive metabolite (antigenic hapten or mutagen/carcinogen), or inactive drug to active metabolite (bioactivation)
What is a phase 2 reaction?
conjugation reactions; covalently conjugates large endogenous compound to functional group from phase 1; almost always results in conversion of drug to inactive, highly ionized, polar, hydrophilic metabolites
What is an exception to the end metabolite characteristics of a phase 2 reaction?
acetylation yields less water soluble product but inactive drug
what kind of drug is often eliminated without metabolism?
inhaled anesthetics
What do phase 3 reactions do?
action of drug efflux transporters regulates bioavailability, distribution and excretion, acts in concert with phase 1 and 2, contributes to endothelial barrier function in brain, placenta and testes, cause resistance to anti-cancer and antibiotic drugs (decreased uptake and increased efflux in neoplastic and bacterial), also reuptake of NT (SERT, DAT)
What are all the sites that contribute to 1st pass metabolism?
liver (most), SI epithelium 6%, Nasal and Lung epithelium 20-30%, Skin 1 %, Placenta, and Kidney *%
What are the subcellular locations of phase 1 transporters?
rxns occur within lipid bilayer of SER, enzymes membrane bound, microsomes- isolated preps of SER allowing for metabolites of drugs to be id in vitro
What are the subcellular locations of phase 2 transporters?
cytosol, enzymes are soluble, except UGT
What are the subcellular locations of phase 3 transporters?
apical (luminal) side and basolateral (blood) side membranes of GI and renal tubular epithelium, plasma and canalicular membranes of hepatocytes
What phase 1 enzyme is responsible for most drug metabolism?
CYP450- 2 SER enzymes CYP450 (heme containing monooxegenase requires NADPH, O2, and phospholipid) and CYP reductase (e- transfer from NADPH, 3 isoforms accounts for most metabolism and 3A4 >50%;
What are the other phase 1 enzymes?
Amine oxidase, Dehydrogenase, Flavin containing monooxygenase, Reductases, hydrolytic, carboxylertserases, amidase, and epoxide hydrolase
Give and example of an amine oxidase and metabolism.
(MO) catecholamine metabolism
What does Flavin containing monooxygenase do?
(FMO) oxidizes N, S, or P moieties, similar to CYPS;
Give an example of dehydrogenase phase 1 enzymes and action.
(ADH, ALDH) oxidize alcohols and aldehydes
Give an example of reductase phase 1 enzymes and action.
reduction of azo, nitro and carbonyl (liver and anaerobic B)
Give an example of hydrolytic phase 1 enzymes and action.
inactivates some parent esters but activates others
Give an example of carboxylesterase phase 1 enzymes and action.
ACE (neurons) and butyrylcholinesterase (plasma)
Give an example of amidase phase 1 enzymes and action.
hydrolyze amide linkages
Give an example of epoxide hydrolase phase 1 enzymes and action.
EH, hydrolyze epoxide metabolites, close to CYP to prevent escape of reactive epoxide
What are phase 2 enzyme functional groups? Endogenous donors? Effects on drug?
hydroxyl, epoxide, nitrite, amine, or sulfide; glucuronic acid, sulfate, glutathione, amino acids or acetate; inactivates, usually drug more polar (except acetylation and methylation), greater molecular weight and more easily secreted in bile or urine
What are the various phase 2 enzymes?
UGT, SULT, GST, NAT, and MT; NAT, GST, UGT and SULT metabolize 80% drugs
What are the characteristics of phase 2 enzyme UGT?
only 2 phase SER enzyme, close to CYPs, attache glucuronic acid to OH, NH2, COOH, and sulfonamide to form glucuronic conjugate; cofactor UDP-glucuronic acid from glucose, can be cleaved by B-glucuronidase in anaer. B (enterohepatic recirculation)
What are the characteristics of phase 2 enzyme SULT?
attaches sulfate to OH acceptor sites producing sulate conjugate, cofactor PAPS (3’phosphoadenosine-5’-phosphosulfate)
What are the characteristics of phase 2 enzyme GST?
attaches GSH (glutathione) to acceptor sites, GSH conjugate, cofactor GSH(gamma-glutamyl-cysteinyl-glycine), often further metabolized to mercapturates in the kidney (Glu/Gly cleavage then acetylation), toxicity occurs if GSH is depleted from liver (detox electrophilic reactive metabolites; acetaminophen)
What are the characteristics of phase 2 enzyme NAT?
attaches acetate to aromatic amine and hydrazine; acetylated metabolite; cofactor- acetyl CoA
What are the characteristics of phase 2 enzyme MT?
methylates various substrates; cofactor s-adenosylmethionine; isoforms TPMT , COMT, and PNMT
What are the phase 3 transporters?
ABC and SLC
What is enzyme induction? Examples? How does enzyme induction effect drug biotransformation?
reversible adaptive response that increases rate of drug biotransformation by increase [enzymes and transporters], certain drugs, pollutants, chemicals, and food comp. induce drug metabolism (Tobacco, Charcoal-broiled food, Ethanol, St Johns Wort), lipid soluble, bind and activate nuclear transcrtiption factors, DNA response elements, 24hr to increase and 24-48 to return to pre-induction levels
What are the consequences of enzyme induction?
usually accelerates elimination of xenobiotic causing induction (autoinduction) and possibly others; may reduce therapeutic blood level (adjust dose), may increase production of toxic metabolites (tissue damage), long term may induce levels that never return to normal after cessation (tobacco)
How does enzyme inhibition effect biotransformation? clinical consequences?
decreased metabolism or transport, M-M competitive and non-competitive (irreversible inhibition), immediate or rapidly occurring; decrease further metabolism or elimination, may lead to toxicity, need to monitor effects and lower dose, major Drug-Drug interactions mechanism
What is pharmacogenetics?
variability in drug responses; most normal enzyme activity but can have slower or faster in certain populations; SNP, deletions or duplications can cause this; CYP polymorphism (not all the same activity); NAT polymorphism- fast or slow, toxicity in slow can resemble OD, (45% US W and B, 90% US Asians are fast); UGT polymorphism- 70-80% decreased UGT-> CAD; most significant for narrow therapuetic windows
How does age effect biotransformation?
rxn rates slower in young children and elderly; decreased glucuronidation capacity-> jaundice
How does Nutrition and diet effect biotransformation?
impaired metabolism->protein deficiency (diminished CYP, phase 2 variably effected; fat free diet->decrease FA incorporation in ER lipid bilayer diminished anchor of CYP leads to decrease in content and activity; chronic consumption induces enzyme-> ethanol, and charcoaled foods
How does disease effect biotransformation?
metabolic funct. decreased with altered blood to liver, loss of liver function or cellular architecture, and effects on enzyme regulation (heavy metal toxicities); phase 1 more sensitive than phase 2
How does hormonal effects effect biotransformation?
hypothyroid diminishes, hyperthyroid increases, pregnancy increases
How does intestinal microflora effect biotransformation?
produce both phase 1 and 2, depletion of flora can increase [drug] leading to toxicity risk; diminished b-glucuronidases- increases elimination of drug-glucuronides in feces and less reabsorption, less [drug] in circulation
What are the methods of renal elimination?
GF, passive diffusion (can be both ways), carrier-mediated transport (PCT can be both ways),
What factors effect drug filtration in glomerulus?
only unbound small molecular weight (<500 D= 80% of drugs), dependent on blood flow, glomerulonephritis can increase permeability, filtration and rate of drug excretion effectively decreasing plasma levels
What factors effect passive diffusion of drugs in the kidney?
down gradient, btwn blood and DT if non-ionic and lipid soluble, can be secretion (high albumin binding) or reabsorption(low albumin binding), also pKa and urine pH dependent (ionized more likely to be retained in urine; more acidic urine more excretion of weak bases than acids, and vice versa); can acidify (IV ammoniumCL, amphetamine) or alkalize (IV Nabicarb, Phenobarbitol) to effect elimination
What factors effect carrier-mediated transport in renal secretion?
drug must cross 2 membranes, PT many uptake and efflux transporters (OCT, OAT, MDR, MRAP) balance of transport favors efflux but reuptake can occur( E higher affinity than reuptake), low competitor concentration can block secretory but not reabsorption, greater reabsorption and drug retention, high competitor concentrations blocks both more retained in urine and excreted
How is biliary excretion achieved?
metabolized drug now larger, more ionized and polar (no bulk flow or PD)active transport from hepatocyte: anionic (OAT), bile aid transporter, cationic (OCT) and neutral organic transp.; NB:ABC transporters predominate transport to canaliculi; can have enterohepatic recirculation of glucuronide conjugates (prolong presence and effects of drug)
What utilizes pulmonary excretion?
anesthetic gases, exhaled as non-metabolized, ethanol <5% exhaled as a vapor
How else can drugs be eliminated?
saliva, sweat (lipophilic/uncharged passively and hydrophilic through aqueous pores), breast milk (mostly passive diffusion)
