Test 3 Flashcards
Absorption
Process by which unchanged drug proceeds from the SOA to the site of measurement within the body.
Factors influencing absorption
Dose Dosage form Route of Administration Physicochemical properties of drug A&P at the site of abosrption
Barrier usually passed through in abosrption
Biological membrane of tissue barrier
Diffusion
Passive. Depends on downward gradient. Obeys Ficks law.
Facilitated diffusion
Uses carrier molecules. Still needs gradient.
Active transport
Carrier mediated. Needs energy, ATP. Can go against gradient.
Fick’s Law
Quantifies amount of substance that diffuses across a given surface area in an amount of time under certain concentration gradient.
Gi Drug absorption
Transcellular- Through cells
Paracellular- In between cells. Small polar molecules.
Transcytosis- Uses Vesicle
M-cells- absorb it into lymphatic system. Microfolds of peyers patch
Gastric transit times
Stomach- 1 hr fasting, meal 2-8
Small intestine- 2-4
Large- 12-24
What effect does gastric emptying have on drug absorption?
Can speed or delay it.
Factors that effect drug permeability.
Lipophilicity- -1 to 4 best
Charge - neutral or unionized
size - less than 500mw
Presence of transporters
Absorption may be limited by…
Permeability or dissolution
Blood flow can limit the rate of absorption for..
Highly permiable drugs
Highly permeable drugs are referred to as…
High extraction ration drugs. 70% or more taken up in single pass.
Eternal routes
By mouth, sublingual, Rectal (50% first pass)
Parenternal routes
IV, IM, Sub-Q, Intraspinal, Intraatrial,
How many genes code for transporters or transporter supporters?
2000 or 1/8 total
ABC transporter
ATP binding casette. Active, need ATP. P-glycoprotein efflux system and CFTR.
SLC transporters
Solute carrier type. Facilitated and ion coupling. Can be drug targets or alter ADME. Serotonin and dopamine reuptake systems.
Distribution is…
Reversible. Also non homogeneous, tissues differ in the rate and efficacy of drug uptake
Metabolism and Elimination are…
Non-Reversible
Drug distribution refers to?
The reversible transfer of free drug circulating in the body
Factor affecting drug distribution
Blood flow to clearance organisms, organ size, capillary bed surface area, capillary permeability, Influx and efflux systems, plasma protein binding, and presence of a disease in an organ.
Organ with high rates of blood flow
Lung, kidney, brain, and liver. Have high capillary surface area.
Organs with low rates of blood flow.
Resting muscle, skin, bone, and fat.
Perfusion or flow limited
Compounds in which uptake is sufficiently rapid that transfer is limited by delivery, not permeability. Usually smaller lipid soluble compounds with “high extraction ratios”
Permeability limited
Transfer across membrane is rate limiting. Polar, charged, and low lipid solubility usually. “Low extraction ratio”
Fenestra
Small porous membranes in some capillaries.
Free drug concentration can be affected by these 2 important factors.
Binding to plasma protein, ex, albumin.
Active transport back out of tissues by efflux pumps, ex. P-glycoprotein and MDRP4 systems.
Plasma protein binding
Binding by these reduces free fraction of drug. Rarely leads to adverse drug events because of different binding sites.
Albumin
Has 3 binding domains each with 2 subdomains.
Sudlow site 1 at 2a, warfarin binds here.
Sudlow site 2 at 3a, diazepam and ibu.
Lipoproteins
Allow drugs to piggy back
Exchange between plasma and tissue is based upon…
Free drug concentration
Blood Brain Barrier.
Very picky to what it allows in. Capillaries lack pores and fenestra. Compounds must dissolve and diffuse across lipoid cell membrane.
CSF sink effect
Small amounts of some molecules that do cross barrier can be carried out with the more CSF flow so brain extracellular levels remain lower than those in the plasma.
Xenobiotics
Things that can he harmful to us. The body has mechanisms to excrete such substances.
Drug metabolism
Modifications made to drugs in order to get them excreted.Drugs can be activated (prodrugs) or inactivated by metabolism. Each metabolite of a drug had the possibility to be toxic.
Top 2 drug metabolizing organs.
Liver and Gi tract.
Phase 1 metabolism
Oxidation, reduction, hydrolysis. Small changes to make substance more polar. Usually add O or N.
Phase 2 metabolism
Bigger changes to make more hydrophilic.
Phase 3 metabolism
Excretion. Biliary or renal.
Where are phase 1 and 2 enzymes located?
Phase 1 - In the Endoplasmic reticulum
Phase 2 - In the cytosol
Cyclophosphamide
Pro drug. Induces apoptosis in cancer cells.
Methotrexate and 5-fluorouracil
prodrugs. Block dTMP in cancer cells.
Methotrexate is folic acid analog that is polyglutamated in a cell.
Cytochrome P450
Major phase 1 enzyme system located in smooth ER. NADPH cofactor required. Phase 2 UGT is nearby, exception to cytsol rule. Causes coupling between these phase 1 and 2 processes.
What is homology percentage?
How many amino acids are the same in a CYP family.
Enzymes that mediate Phase 1 but not CYP
Flavin monooxygenase isoenzymes
Alcohol Dehydrogenase
Aldehyde oxidase
Mooamine oxidase
Three concers of CYP450 in drug therapy.
Inhibition of drug metabolism
induction of drug metabolism
Genetic polymorphism in population
Inhibition of P450
Some substances compete for P450. EX. one drug can inhibit P450 while another being taken needs it to metabolize. May show saturation if inhibitor is a substrate, usually competitive inhibition, maybe allosteric, and slow parent drug metabolism can raise plasma conc.
Induction of P450
Stuff to be broken down does so faster, stuff to get activated gets activated faster. Substance makes more P450 be made.
Genetic polymorphism of P450
Some people just metabolize slower and some faster.
APAP toxicity
Due to saturation of normal detox path. NAPQI metabolite binds to sulfhyryl groups in important proteins. Loss of intracellular calcium, disruption of mitochondrial function, and cell death.
What protects cells form APA toxocity?
Glutathione reacts with toxic metabolites.
Phase 2 metabolism
Covalent conjugation reactions, mostly in cytosol. Attach large hydrophilic endogenous groups. Ex. Glucuronic acid, glutathione, sulfate, acetic acid, and some amino acids.
Enzymes that help conjugation?
Mainly UGT, sulfotranserases, methyl-T, Acetyl-T, Amino acid-T, Glutathione-T, and fatty acid conjugation.
Glucuronidation
Most important in phase 2. Glucose and UTP make UDP-Glucose. UDP gulcose dehydrogenase makes UDP glucuronic acid. Finally UGT makes O-Glucuronide.
Gilberts syndrome
Deffective UGT1A1. Bilirubin cant be conjugated.
Enterophepatic Recycling
Drug glucuronide complexes excreted to gut can be broken down by B-glucuronidase. The released drug can be returned back to body, forming cycle and increasing drug half life.
Acyl Glucuronides
Are unstable and can undergo hydrolysis or rearangment from C1 to C2, or C3 to C4 at neutral or alkaline PH. Can create toxic species.
Sulfation
Done by sulfotransferases. Critical metabolism route for some drugs. Uses energy rigch sulfur donor PAPS.
Sulfotransferases.
SULT or ST. Cytosolic enzyme in liver, kidney, gut, and brain. High affinity, low capacity.
Acetaminophen
Is sulfated with sulfotransferase and PAPS. Estrone also does this.
Methytransferase
Cystolic. Co-factor SAM. COMT is metabolism of catetholamines. Also done in desmethylimipramine.
Thipourine methyl transferase.
TPMT. Significant metabolism of 6-Mercaptopurine with this is normal person. If genetically defective low activity of TPMT causes toxicity because of 6-thioguanine nucleotides.
Phase 2 acetylations
Acetyl-CoA cofactor. Cystolic, NAT-1 and NAT-2 isoforms. In kupffer cells. CoASH left over after RXN.
Glutathione conjugation
Bonds through nucleophilic cysteine thiol group. Very reactive with electrophilic substances.
Fatty acid conjugation
Adds hydrocarbon tail onto site of phase 1 metabolism. Defies what we think of phase two because it makes drug more lipophilic.
Drug elimination
Irreversible loss of drug from the body via metabolism or excretion.
Metabolism
Loss of drug by chemical conversion.
Excretion
Loss of drug by diffusion, filtration, evaporation, or transport process.
Pharmacokinetics
Rate of elimination of a drug as the change in drug concentration with the passage of time. dC/dT.
Rate of elimination =
-Ke*C^n
If n=0
Zero order kinetics. aka. saturation kinetics
If n=1
First order kinetics
Zero order elimination
Independent of drug concentration.
Half life increases and clearance falls with increased drug conc.
First order elimination
Dependent on drug concentration
Half life in independent of conc and constant.
Clearance is constant and not related to conc
Rate constant, Ke
Function of slope of elimination time as conc falls. Dont confuse with elimination rate.
Volume of distribution
Apparent volume in which a drug appears to be dissolved.
Clearance
amount of blood from which drug can be metabolized or otherwise eliminated in a unit of time.
Cl=Rate of elimination / Drug Concentration
Renal excretion
Glomerular filtration- Creates plasma like blood filtration
Tubular reabsorption- Takes useful stuff from filtrate back to blood
Tubular secretion- Removes additional blood waste and adds to filtrate
Renal Elimination =
Glomerular filtration + tubular secretion - tubular reabsorption
Macular densa
Special group of cells at distal tubules. Last check
Juxtaglomerular apartaus
Macula densa and juxtaglomerular cells
Clearance depends upon what?
Renal funtion. GFR.
Free drug clears easier than bound drug
99% of filtered fluid is…
reabsorbed in the renal tubules. Occure by passive diffusion and active transport.
Factors that influence reabsorption
Urine flow
Urine pH
Lipophilicity of Drug
Transport modulation
Hepatic Excretion
Drugs actively transported from plasma to bile. Bilary excretion not good for drugs under 400 daltons. Conjugating to glucuronic acid helps with this excretion
Enterohepatic circulation
Drugs excreted in bile un-conjugated by enzymes in GI tract. Reabsorbed in blood and re used. Increases half-life.
Mammary secretion
Passive diffusion. Milk slightly acidic compared to blood.
Toxicology
Study of adverse effects on living organisms. Includes symtoms, mechanisms, treatments, and detection of poisoning. Chief criteria for toxicity is amount or dose of substance that causes it.
Procrustean Approach
Drugs often interact with multiple receptors.
Therapeutic index
LD50/ED50 . Higher the ratio the safer the drug.
Adverse drug reaction
Negative outcome due to drug.
Adverse drug event
A negative outcome that occurs while taking a drug, but not necessarily attributed to it.
Basis of allergic drug reactions
Most small drugs do not cause reactions. Must be presented to T-cell receptor via MHC. Must react covalently with protein to for a hapten.
Acute toxicity
Uses a variety of doses and two animal species to determine LD50
Subacute toxicity
Three doses in two species. Doses try to match those expected to be used clinically
Chronic toxicty
Rodent and non rodent species, studies 6 months or longer.
