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Pharm 1 - Pharmacokinetics

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ginnie8's version from 2016-06-25 15:19

Pharmacokinetics

Question Answer
What is pharmacokinetics?"What happens to the drug in the animal's body." Official def. = study of characteristics of the time course & extent of drug exposure in individuals & populations
5 big words in pharmacokinetics?Absorption, Distribution, Metab, Excretion, Xport
2 things pharmacokinetics dictate?Dose regiments, routes of admin (how much & where)
9 routes of admin.?Enteral (oral or rectal), local, SQ, topical (skin), intramuscular, inhalation, intra-abdominal, intra-osseous, intra-arterial
What does oral bioavailability depend on? (7)pKa of drug, pH at site of absorption, surface area, feeding, Dz, drug xporters, 1st pass effect.
What type of bioavailability is oral admin? Rectal?Oral = systemic or local, Rectal = systemic
Examples of local admin?Intra-articular, intramammary, intra-uterine, regional perfusion (temp. cut off veins & admin for a ↑ conc. locally. 30min max), subconjunctival, epidural
Advantages of local admin?Drugs stay local! Higher conc. achieved, less drug is needed. Prevention of systemic conc.
Disadvantages of local admin?Possible systemic escape
What is SQ absorbency like? How is it influenced?Absorbance is like IM but more variable. Influenced by autonomic control over blood flow
Advantages of SQ admin?Potential for slow & prolonged absorption (such as testosterone pellets giving linear absorption over 2mo.), used for drugs that cant be admin. orally & Lg amts can be given (owner compliance)
1 thing a drug must be for topical admin?LIPID SOLUABLE!
Topical admin - Where? What does it avoid? Speed? Penetration is dependent on?Admin in areas of ↑ blood flow, avoids 1st pass, slow & variable, penetration is dependent on lipid/water partition coefficients
IM injxn depends on?Site of injxn! Muscle used more frequently = more perfusion means better uptake (ex: graph, serratus (best) → biceps → pecs → gluts → SQ)
What is critical about inhalation admin? Benefits?Sm particle size. Lg surface area, rapid absorption & onset of action
What animals is intra-abdominal admin used on? Benefits? Type of effect?Usually sm animals. Lg surface area, rapid uptake, systemic effects.
Where does a drug reach to be considered bioavailable?Central compartment (blood/heart)
3 major influences on drug absorption?Drug factors, Pt factors, Site of injxn
What is an ABC?ATP Binding Cassette xporter. Outwards xport of endogenous & exogenous compounds (xports drug out before its absorbed)
ABC xporters prevent?"Prevent the absorption of certain types of toxins, xenobiotics, or drugs," 1st pass effect & enterohepatic circulation is partly regulated by xporters in the liver & GI tract
What do all drugs need to cross? What drugs inherently easier to process?Lipid bilayers of membranes - which means hydrophobic drugs are easier to absorb
Define bioavailabilityThe proportion of the admin. dose that reaches the central compartment
Least bioavailable admin is?Orally
Role of food intake w/ drugs?Feeding has influence on absorption!
Drug distribution is dictated by what 5 things?1) Membrane permeability
2) Plasma protein binding (acidic drugs bind to albumin, basic bind to α-1-acid glycoprotein)
3) Blood flow
4) Depot storage (fat storage)
5) Apparent volume of distribution
Plasma protein acidic drugs bind to?Albumin (A-A)
Plasma protein basic drugs bind to?α -1-acid glycoprotein (A1AG)
What should be noted about plasma protein binding as a distribution method?Proteins are big! Gets you close but not into cell
Depot storage means?Fat storage
3 groups of drugs based on distribution?1) Confined to plasma
2) Limited distribution
3) Extensive distribution
Examples/types of drugs confined to plasma?Dexx, mannitol, highly protein bound drugs (Dexter, a bound man, eats a lot of protein)
Types of drugs w/ limited distribution?Lg non-lipid soluble drugs, polar drugs
Type of drugs w/ extensive distribution?Lipid soluble drugs
What compartment of the body is difficult for drugs to get in & out of?Deep compartment
What is Vd? What does a ↑ or ↓ Vd mean?Apparent volume of distribution. ↑ Vd= wider distribution=↑ bioavailability. ↓ Vd = stays in blood= ↓ bioavailability
*What is the formula for calculated volume? What do the parts of the formula mean?Calculated volume is: Cl = Vd*Kel. Cl= clearance, Vd= apparent volume of distribution, Kel= elim constant
Vd (volume of distribution) Clinical significance for what 2 main things?1) Effective conc. (does the drug reach the problem area? intracellular spaces? accumulation in the tissues?)
2) Vulnerable structures (CNA, eye, embryo, testis, milk) & side effects
What is the total plasma conc. formula? Which frxn is active?C = C-free + C-bound. Only free frxn is active
Describe albumin in terms of a plasma protein which can bind drugsLg capacity. 50% of plasma proteins & mult. binding sites. Most weak acids, neutral substances, some weak bases.
Describe α-I-glycoprotein in terms of a PP which can bind drugs1 specific binding site. Levels ↑ during inflammation (acute Phase proteins: APPs) Bind MOST weak bases.
Example of how plasma protein ↓ affects active conc.?If drug binds to PP 99%, then PP conc ↓, then only 95% is bound so instead of 1% being active, 5% is. This means there was a 500% ↑ of active component, which can be bad
How does ↓ Vd affect depot storage?↓ Vd won’t get into fat storage
How is drug distribution affected by inflammation?1) ↑ membrane permeability (more drug gets into tissue)
2) ↑ blood flow (↑ leakage)
How is drug distribution affected by local anesthetics?1) Basic drugs (pKa 7.6 - 8.9) diff of pH & pKa ↑, drug gets ionized, gets a charge & can’t pass membrane
2) Bind to Na-channel inside axon (Less distribution)
Examples of the BBB failing during distribution?The BBB protects against absorption of toxins, drugs, etc. has xporters which as soon as something passes the membrane, are pumped back out
1) Less protected during inflammation - tight jxns lose their integrity
2) Certain dog’s breeds are sensitive to ivermectin bc the PgP (permeability glycoprotein - an 'out' exporter) is not as effective so ivermectin crosses BBB
Why is drug elim a difficult process?Most drugs are lipophilic & most exits from the body are watery
10 elim routesLiver (bile), Kidney (urine), GI tract (feces), Lung (exhalation), Saliva (ruminants), Skin (lipophilic drugs), Milk (public health concern), Eggs (public health concern), Sweat glands, Tears
2 ways drugs are eliminated?Changed or Unchanged
Drug metab (in terms of elim) can be in what 5 places?Liver, Kidney, GI tract, Lungs, Skin
What is 1st pass effect? It ONLY happens when?Only after ORAL admin. A phenomenon of drug metab whereby the conc. of a drug is greatly ↓ before it reaches the systemic circulation. It is the frxn of lost drug during the process of absorption which is generally related to the liver & gut wall. It affects oral bioavailability of drugs
3 ways 1st pass can occur?1) Metab of drugs into inactive compounds by the liver
2) Metab of drugs into inactive compounds in gut wall
3) Immediate outward xport of drugs by xporter proteins (ABC xporters) - they stay in the GI & are excreted
What is enterohepatic circulation? How is it different from 1st pass?Occurs w/ ALL ROUTES of admin. Drug *already entered* systemic circulation, then it goes to the liver to be metabolized, then flora in intestine reverse liver metab & drug is taken up again
How can liver Dz affect bioavailability?Can be more bioavail, bc 1st pass & enterohepatic circ ↓
How does metab work?Metab eliminates the substrate, but leaves the product (metabolite) in circ (more polar = excreteable)
What is a metabolite?Product of metab, left over after substrate is eliminated
3 types of metabolites left after metab?1) Inactive metabolites
2) Active metabolites (benzodiazepines)
3) Toxic metabolites
Example of an active metabolite?Benzodiazepines
What is a prodrug?An inactive drug that can be metabolized into an active drug
Two examples of prodrugs & their metabolites?1) Inactive netobimine → active albendazole sulphoxine (use prodrug bc poor oral bioavailibity)
2) Olaslazine → 5-amino salacylic acid
3 Phases of drug metab? (List)PHASE I: Fxnalism
PHASE II: Conjugation (PHASE IIb-biotransformation of Phase II conjugates)
PHASE III: interaction w/ xport proteins
(FCBI - Fuck cunt bitch itch)
Phase I (fxnalism) of drug metab: 2 main purposes it serves?Makes drugs more water soluble, creates substrates for Phase II
Rxn for Phase I (fxnalization) of drug metab? 2 examples?Oxidation-reduction-hydrolytic rxns. Ex: cytochrome p450 enzymes: monooxygenases (metabs 75% of all compounds). (Ex: mixed fxn oxidases: N-oxidation, S-oxidation rxns (MFOs) (Phase I of passing this test - take 450 oxys)
What causes 70% of all side effects?Variations in biotransformation capabilities (ex: species & gender diffs)
Enzyme inhibition causes? (Part of biotransformation) what drugs can cause this?↑ Toxicity, ↑ Side effects. Ex: erythromycin, ketoconazole
Enzyme induction causes? What drugs can cause this?↓ Effectivity/tolerance (speed up metab) ex: barbiturates, dioxin, phenytoin
What is phytotherapeutics? How can you do this?Phtx is modulation of endogenous (hormones) & exogenous substances. You can put inhibitors & inducers in animal's foodstuffs. (Use of extracts of natural origin as medicines or health-promoting agents)
What is Phase II? Whats it mean?Conjugation. Conjugation w/ GLUCURONIC ACID (or glutathione, sulfate, methyl, acetyl, methionine, etc) to make it more water soluble = easily excreted via kidney or liver (bile/urine)
Biotransformation clinical relevance. 4 major factors that will influence it?1) Species diffs (Little glucuronidation in cats, little acetylation in dogs, little sulfatation in pigs, no flutathion conjugation in g-pigs)
2) Age diffs influence biotransformation
3) Substrate competition for biotransformation enzymes (co-medication)
4) Dz processes will influence the effectiveness of the biotransformation process (species, age, competition, dz)
What cant cats do in terms of metab?Only a little glucuronidation
What cant dogs do (metab)Only a little acetylation
What cant pigs do (metab)Only a little sulfatation (pigs)
What cant G-pigs do (metab?)No flutathion conj
3 parts of renal clearance? Active or passive?1) Glomerular filtration (PASSIVE diffusion- free frxn)
2) Tubular secr (ACTIVE xport. competition=probenicide) (from blood to tubule) (penicillins, frusemide, procaine, trimethoprim).
3) Tubular reabsorption (active or passive)
What happens w/ the excretion of weak acids if ↓ urinary pH? ↑ pH?↓ pH= excretion of weak acids ↓ bc similar, not ionized, can be reabsorbed (ex: glucose has no charge = rebasorbed). ↑ Urinary pH means it's easier to excrete weak acids bc they are ionized & won’t leave tubule
What happens w/ the excretion of weak bases if urinary pH is ↓? pH is ↑?↓ pH = ↑ excretion of weak base. ↑ pH= ↓ excretion of weak base
What’s the average pH of carnivore urine? Carnivores have trouble eliminating? Herbivores?Carnivores have acidic urine, they have delayed elim of ↓ pKa drugs. Herbivores are the opposite
Explain Henderson-Hasselbalch equationDegree of ionization depends on pH of environment & pKa of drug. If the difference is big, the drug is ionized & can’t pass membranes. If the difference is Sm, the drug is non-ionized & won’t pass through membranes
State the Henderson-Hasselbalch equation?pH-pKa= log ([base]/[acid]) ratio of non-ionized to ionized drug (ppk- BA)
What is the equation for body clearance? The definition?Cl-total = Cl-hepatic + Cl-renal + Cl-trans. It is the plasma vol that is completely cleared per min. Can be dependent on intrinsic clearance (biotransformation capacity), organ blood flow & organ fxn.
How is dose affected in renal failure? Hepatic failure?Renal failure = 75% of normal dose. Hepatic= 50% of normal dose.
What is the equation for F=?F= [AUCpo/AUCiv] F means bioavailability, AUC means area under curve, po means per os (oral admin) & IV means intravenously.
What is F= [AUCpo/AUCiv] about? How do we use it?It is for determining bioavailability, if IV's AUC (say, "2") is bigger than PO's AUC (say, "1"), then its 1/2) according to the formula (PO is over IV) so F = 1/2) so F is less than 1, 1 would be 100%)
Short words for what each drug metab Phase is actually doing?1) More water soluble- kidney
2) More water soluble- kidney & liver
2b) Use enzymes on Phase 2
3) Attach to things to help get it out
What is AUC?Area under the curve/ AMT OF DRUG IN BODY
What does the plasma conc. time curve look like?Bell curve w/ long tapering rt side
Part 1, 2 & 3 of the plasma conc. time curve are what?Absorption, Distribution, Elim
What is happening during the distribution portion of the curve in the plasma conc time curve?Moving from blood to tissues
In the plasma conc time curve, what is the portion under the graph the MEC (minimum effective conc) passes through?Duration of action of drug
What would a plasma conc. time curve look like in IV infusion?Ski slope
Ka is what?Absorption constant
Kel is what?Elim constant
Distribution (Vd) calculated how?Vd= D / (AUCxCl)
Zero order kinetics is a _ processSATURABLE
In Zero order kinetics, what is fixed?Elim rate
What does the line look like w/ Zero order kinetics?Straight
What’s the half-life like in a Zero order kinetics graph?↓w/ ↓conc.
2 drugs w/ Zero order kinetics?Ethanol, Phenytoin
1st order kinetics inherently imply?1 compartment
Whats the line look like w/ 1st order kinetics?Gradual slope downwards
What is constant in 1st order kinetics?Half-life (t1/2= 0.693/Kel)
Example of 1st order kinetics?Renal filtration
Rate of elim in Zero order kinetics? 1st order?0=K (constant), 1st= kC (constant but conc dependent)
Conc-time curve in Zero order is what? 1st order?Linear, decaying exponentially
C= (?) in Zero order? 1st order?Zero: C= C (0) – kt
1st: C= C(0)*e^(-kt)
How does drug conc ↓ w/ time in Zero order kinetics? 1st?0= linearly, 1= exponentially
Rate of elim in Zero order kinetics? 1st?0= constant
1st= rate proportional to conc of drug
When is the plot linear from Zero order kinetics? 1st?0 is linear already. 1st when plot= conc as a log
Which order (zero or 1st) has a constant half-life?1st
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