8-5 Pharmacokinectics: Absorption & Distribution Flashcards
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A: Factors affecting drug absorption
1) membrane permeability
2) availability of transport processes (active vs. passive)
3) available surface area (INC surface area = INC rate of transport) - surface area availability can determine 1º absorption site
4) pH and concentration gradients
5) Ion trapping
6) chemical composition and formulation of drug
7) non-specific binding
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A: Factors affecting drug distribution
1) regional differences in blood flow
2) Tissue Mass
3) Transport mechanisms
4) Permeability characteristics (some membranes are more permeable to drugs than others (i.e. blood brain barrier))
5) Ion trapping (local pH differences play a role)
6) Protein binding [acidic drugs binds to albumin] to [Basic Drugs binds to (a1 acid glycoprotein)]
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A: 1 Compartment Distribution= Rapid equilibrium of a drug is achieved between plasma & tissue distribution following drug administration. Plasma concentration to time declines MONO-EXPONENTIALLY
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B: 2 Compartment Distribution= Rapid Distribution to a central compartment is followed by slow distribution to other tissues/binding sites (second compartment).
B2: With repetitive administration, steady-state concentrations are achieved only after 5-6 elimination half-lives. Digoxin, lidocaine and phenytoin are examples of drugs with 2 compartment pharmacokinetics
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- Volume of Distribution = How large a blood volume it takes to contain the entire administered dose of drug. It measures how much of the drug will actually distribute outside of the plasma into other areas.
- Drug Reservoirs = Accumulation of drugs in tissues (fat & muscle) can actually prolong the drug action because it releases out eventually
- AUC (Area under Curve) for plasma to time drug concentration = Bioavailability. [INC Clearance —> DEC AUC]
- Absorption = Process by which drugs move from administration site —> Plasma.
Take drug PO—> disintegration of solids & dissolution of drug in GI fluids–>passage of drug across cells to system
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Aqueous Diffusion:
1) Small molecules [ x
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lipid Diffusion:
1) passive process
2) Driven by concentration gradient - the greater the difference across membrane the more rapid the rate of crossing
3) Lipid solubility is important
- More lipid soluble drugs have faster transport
- lipid solubility is affected by ionization
- degree of ionization depends on pH
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For Acids: pKa = pH + log [AH] / log[A-]
AH is the Pronated Acid (No charge)
B: pKa is the pH at which 50% of the compound is ionized
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For Bases: pKa = pH + log [BH+] / log[B]
B is the DePronated Base (No charge)
B: pKa is the pH at which 50% of the compound is ionized
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A: Most drugs are still absorbed in small intestine
B: Weak acids are WELL absorbed in stomach
C: Weak acids become TRAPPED in small intestine / Alkaline environments because they can’t get across lipid bilayer
D: HIGH pKa = STRONG BASE
E: Local differences in pH will affect absorption
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A: Oral Bioavailability = Fraction of orally administered dose that reaches systemic circulation in its ACTIVE FORM
B: 1st pass effect: metabolism in the liver can inactivate the drug before it ever reaches systemic circulation and so oral doses need to be higher than parenteral doses because of [1st pass effect]
C: Some drugs are absorbed, transported to liver and then secreted into bile where they are deposited back into intestine and ReAbsorbed = Enterohepatic circulation
D: INC gastric emptying time–> INC time for absorption. Some drugs can directly affect gastric emptying time.
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A: Salt Factor = The Fraction of a drug that is delivered in its ACTIVE FORM (only applies to special drugs) to systemic circulation. The desired dose needs to be divided by the Salt Factor.
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Sublingual / buccal
Advantage:
-Not absorbed into portal system
-Mouth is higher pH than found in stomach (allows weak bases to absorb easily)
Disadvantage:
x: Drug Taste
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Rectal
Advantage:
-50-60% bypasses [1st pass effect] by passing the portal vein
Disadvantage:
x:Discomfort & inconvenience
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Inhalation
Advantage:
-passive diffusion
-larger surface area —> INC rate of transport
-voltaile gases driven by partial pressures
-aerosol preparations
-Drug absorption varies with depth and duration of inspiration
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Topical:
- For Local usage
- Highly lipid soluble compounds will ultimately reach general circulation unfortunately
- creams / lotions / gels / ointments
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Transdermal:
1. Passive diffusion of drugs across skin - driven by gradient
- potential benefits
- controlled release of drug into pt which enables steady blood level profile
- user friendly / convenient / painless / multi-day dosing–> improved pt compliance
- bypasses GI tract obviates GI irritation tht occurs with some drugs and avoids first-pass
Limitations/Risks
- Skin barrier limits # of drugs that can be delivered by passive diffusion from adhesive patch
- Discomfort / irritation
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Parenteral Injection
A: Blood flow to area maintains concentration gradient of a drug for Parenteral administration. The drug concentration will remain lower in blood vessels than on tissue because tissue acts as reservoir.
A2: This maintains a steady rate of absorption until local reservoir is depleted
B: For Parenteral injection: Drug has be in solution form
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SubQ Advantage: -slow even absorption -may be used as a depot -rate of absorption is modified by blood flow
Disadvantage:
x: of little value in peripheral circulatory failure (shock) because it relies on blood flow
x: only small volumes can be administered
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Intramuscular Advantage: -more rapid absorption than with SubQ -Rate of Absorption can be modified by altering blood flow -AVOIDS 1st pass effect
Disadvantage:
x: [n. damage] or potential infection
x: less than 100% bioavailability
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IV:
Advantage: The only route of administration that has 100% Bioavailability
Disadvantage:
must avoid bolus effect (excessively high plasma concentration that comes from rapid IV drug administration). Is necessary to administer dose over long period of time
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A: During distribution phase of [2-compartment distribution] the drug is cleared form plasma by inter compartmental distribution (bi-directional) and by elimination (unidirectional)
B: As plasma concentration DEC…tissue concentration INC and the net inter compartmental clearnace approaches 0. When inter compartmental clearnace is actually 0 = end of distribution phase. At this point plasma concentration starts to DEC because of elimination clearance, and this happens in a mono-exponential way
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A: Distribution is bi-phasic with initial distribution going to organs w/rich blood supply (kidney/heart/lungs/brain) and then later distribution to other tissues with less rich blood (fat, muscles, bone, bladder)
B: Fat & Muscles can act as drug reservoirs and store large amounts of a drug (especially obese pt). In some cases, there’s more in Fat/Muscles than in the system. This will limit the fraction of drug available for actual use in the system AND for excretion of the drug.
B2: When plasma levels of a drug DEC from metabolism or excretion, the reservoirs will release more into the circulation and this can cause
1) longer therapeutic effects
OR
2) toxicity
B3: Plasma proteins can ALSO serve as a drug reservoir. Only Unbound proteins can cross over into tissue.
C: Bone can accumulate certain toxins such as lead and tetracycline abx
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A: Although many drugs bind to albumin in the plasma, very few of these actually “knock” other drugs off albumin and prevent binding. This is because most of them only bind to a SMALL fraction of albumin proteins (which leaves plenty of albumin to go around for everyone).
B: The exception to this is Sulfonamides! They occupy 50% of the plasma albumin binding sites! They’re greedy! This causes abnormally high levels of other drugs since they’re going to be unbound!
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A: Loading Dose does NOT DEC amount of time it takes for a drug to reach Steady State in body.
B: At Steady State, the [rate of drug administration = rate of Drug clearance]. Amount of time it takes to get to Steady state does NOT depend on Loading Dose or Dosage in general.
C: [1st Order Kinetics] = Body varies clearance of a drug so that a CONSTANT Fraction of the drug remains in the plasma even if we give more drug to the pt = elimination half life remains constant! Most drugs obey [1st Order Kinetics]
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A: Drugs that are mostly eliminated via metabolism (and not renal excretion) typically undergo [ZERO order Kinetics] = elimination half-life will vary and a CONSTANT amount of drug can only be eliminated per hour. It’s capped!
B: Caveat to this is that drugs mostly eliminated via metabolism BUT also have a Concentration MUCH lower than the metabolic enzyme Km—>undergo [1st Order Kinetics]. If their Concentration exceed the Km for the [metabolic enzymes] they’ll CAP OFF at a MAX–> [ZERO order Kinetics]
(ex. ASA / phenytoin / Ethanol)
C: Creatinine Clearance only indicates RENAL FUNCTION. It does NOT represent Clearance Rate of a drug
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Liver Clearnace depends on 3 things:
1) Rate of hepatic blood flow to deliver the drug
2) Protein binding of the drug = how much drug is free to metabolize
3) hepatocellular capabilities of hepatocytes and/or biliary excretion = intrinsic clearance
B: Restrictive Hepatic Clearance= Hepatic Clearnace of the drug has to be RESTRICTED by us because the drug has low hepatic extraction(passes right thru the liver w/out being metabolized first) and doesn’t incur the first pass effect.
C: Restrictive Hepatic Clearance can only really be sensitive to [Protein binding] since regardless of blood flow speed the drug will pass right thru liver. Capacity-limited Clearance
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A: NON-Restrictive Hepatic Clearance= because drug has HIGH hepatic extraction, there is no restriction on the clearance once actually inside the liver
B: In this case, NON-Restrictive Hepatic Clearance will be sensitive to
-changes in hepatic blood flow
(CHF/hypOtension will reduce hepatic clearance)
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A: Scientific basis for Dosing of a drug and time course of a drug fall under pharmacokinetics
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A: Ligand Gated Channel Receptors = 1 of the FASTEST Cell Receptors because once one of the subunits are bound by ligand, center cation channel opens and allows RUSH of Na+ to go into cell–>Changes cell membrane electrical potential (ex. Nicotinic Cholinergic Receptor and [AcH ligand] )
