Pharmacokinetics and Pharmacodynamics
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What is pharmacokinetics?
What the body does to the drug, i.e.: absorption, metabolism, distribution.
What is pharmacodynamics?
What the drug does to the body. Ie: drug receptor interaction.
Transfer of a drug from site of admin to blood
Transfer of blood from blood to ECF and or cells
What affects distribution?
Blood flow, capillary permeability, protein binding, lipophilicity of drug
What is Vd? Does it correlate to a defined compartment?
HYPOTHETICAL volume into which a drug distributes to. It does not correlate to a defined compartment.
How does protein binding affect Vd?
Bound portion is unavailable and forms an inactive reservoir in the intravascular space. Prolongs DOA? Is unavailable for elimination.
How do most drugs get into the blood stream?
Passive diffusion (Fick's Law). Depending on size fat and water soluble drugs can go this way.
How do drugs get absorbed from the GI tract?
What is the bioavailability of IV drugs?
What are determinants of tissue uptake of the drug?
Blood flow, conc. gradient (influences flow into and out of tissues), BBB, physiochemical properties of the drug (ionization, lipid solubility, protein binding)
What are determinants of capacity of tissue to store drug?
Solubility of drug in tissue, tissue mass, binding to macromolecules (proteins), pH
What happens when we continually bolus a patient with a drug?
The tissues get saturated, the drug can't enter the tissues. The DOA now depends NOT on distribution, but on metabolism and elimination (takes much longer than distribution)
T or F, molecules without a charge are lipophilic?
T! Water is polar and has a charge, so molecules with no charge dissolve in lipids.
What is the nonionized form of an acid drug? Of a basic drug?
B and HA
What is the protonated form of an acid drug? Of a basic drug?
Which form of the drug can cross the BBB?
The nonionized form. This is also the ACTIVE form.
What is the significance of the ionization constant?
It's the pKa, important factor in determining drug onset as only the nonionized form will readily cross the BBB.
What is pKa?
The environmental pH at which the drug is 50% ionized and 50% nonionized.
If the pH is LESS THAN the pKa, which form of the drug predominates?
The protonated form predominates. pH refers to pH of the environment.
- Acid drug- HA (non ionized)
- Basic drug- BH+ (ionized)
What form of the drug is able to be renally excreted?
The ionized form.
What is the role of hepatic metabolism?
To convert lipid soluble drugs to water soluble so they can be eliminated by the kidneys.
What are examples of acid drugs? What in the name can alert us that it might be an acid drug?
Thiopental, barbiturates, propofol
Tend to unite with cations, so may be called "sodium ------"
What are examples of basic drugs? What in the name can alert us to this?
All local anesthetics, ketamine, benzos, etomidate, opioids, all amines (so al NT)
Tend to unite with anions, so may be called "----- chloride or sulfate"
What tissue group receives the greatest % of blood flow?
What are the 3 compartments in the body and what is the % and volume of each (for a 70 kg pt)?
- 1) Plasma (6%) 4L
- 2) ECF (20%) 14L (made up of plasma and ISF)
- 3) TBW (60%) 42 L
- 1/3 of TBW is ECF, 2/3 is ICF (28 L)
What characteristics of a drug would lend it to distributing to the plasma?
Large MW, high protein binding, hydrophilic
What characteristics of a drug would lend it to distributing to the ECF?
Low MW, hydrophilic (goes thru slit junctions)
What characteristics of a drug would lend it to distributing to TBW?
Low MW, lipophilic.
T or F, if a drug easily distributes to the TBW, it also easily distributes to the plasma and ECF.
T. It gets progressively more selective as goes from plasma to ECF to TBW.
What's the difference with the barriers of the liver and the BBB?
Liver has slit junctions which are large, easy to pass thru.
Brain has tight junctions which are small. In order to pass drugs must be lipophilic; polar or ionized form can NOT enter.
How do we calculate Vd? What does it tell us?
- Tells us what compartment the drug is likely to distribute to.
- Vd = D /C
- D= total Amt drug in body (amt given)
- C= plasma concentration of drug
What phase is responsible for the clinical effect of a drug?
How does Vd affect half life and duration?
Any factor that increases Vd, increases half life and extends duration.
What is 1st order kinetics?
This applies to most drugs. A constant FRACTION of available drug is metabolized per unit time.
What is the main purpose of metabolism?
Converting pharmacologically active and lipid soluble drugs to (usually) inactive and water soluble form.
What is zero-order kinetics? When does this occur?
- Constant AMOUNT of drug metabolized per unit time.
- Occurs when plasma conc. of drug exceeds capacity of enzymes.
T or F, metabolism equals inactivation or detoxification?
F! Drug can have active metabolites.
What is metabolic rate of drug dependent on?
Determined by conc. of drug at site of metabolism, rate of metabolism itself, and liver blood flow.
What drugs are metabolized by zero order kinetics?
- ETOH, phenytoin, ASA
- Or any drug at a high enough dose that all the enzymes are saturated.
What types of chemical reactions occur with phase 1 metabolism? What is the goal?
- Goal- convert lipophilic drug to MORE POLAR molecule by changing the chemical structure
- -This can increase, decrease, or leave unaltered the drug's pharmacologic activity
What is phase 2 metabolism?
conjugation (making a substance hydrophilic)
if after phase 1 the drug is not polar enough to be eliminated it will undergo phase 2
What is the CP450 system? Where does it occur?
CP450 system, AKA mixed oxydase system, involves oxidation and reduction (phase 1)
What happens to the CP450 system with enzyme induction (ex: ETOH abuse)?
Chronic ETOH abuse causes enzyme induction of CP450 enzyme, the enzymes are stimulated, so pt "chews thru" meds
What happens if a lipid drug isn't converted to a water soluble (polar) drug?
It will be reabsorbed by the peritubular capillaries and reenter the systemic circulation
What is steady state concentration? (Css)
- -plasma concentration is constant
- -input = output
What factors influence steady state concentration?
- 1) rate of drug infusion (css is directly proportional to infusion rate and inversely proportional to drug clearance)
- 2) time to reach steady state
- -independent of the rate of infusion (css is achieved at the same rate, only difference is what the conc. is once css is reached).
What is metabolism by phase 1 and phase 2 also called?
T or F, half life applies to drugs metabolized by zero order kinetics only?
F, it only applies to 1st order kinetics.
At what interval are drugs usually given at? (how many half times)?
5 half times
T or F, half life depends on dose or total amt of drug in the body?
F, it does NOT depend on dose or total amt
T or F, the Css and how quickly it is achieved depends on frequency of dosing?
F, Css and how quickly it is achieved does NOT depend on frequency of dosing.
What is redistribution?
The drug reentering the plasma from the tissues
Describe the 3-compartment model of pharmacokinetics.
- Alpha- rapid (re)distribution; drug from plasma rapidly equilibrates with tissues (VRG and MG)
- Beta- slower distribution phase, gradual decline in plasma conc.
- Gamma- terminal or elimination phase, drug returns from periphery to plasma, rate of elimination is slower than earlier phases due to decreased plasma concentration (1st order kinetics)
- -The above compartments do not correlate with the various tissue groups
Alpha, beta, and gamma phases of the 3 compartment model all apply to half time, T or F?
What is effect-site equilibration?
- -AKA effect compartment modelling
- -Pertains to onset, time needed for the drug to be delivered to the site of action (the brain).
- -Short effect site equilibration = fast onset, ex: propofol, alfentinil, remifentinil
- -Important for us to know timing and when to expect med to have clinical effect
What is context sensitive half-time?
- -Refers to infusion duration.
- -Time for plasma drug conc. to decrease by 50%
- -No constant relationship with elimination half time
How many half times does it take for most of a drug (97%) to be eliminated?
What is the advantage of context sensitive half time over elimination half time?
Context sensitive half time takes into account the combined effects of distribution and metabolism and duration of a continuous infusion
T or F, clearance is multifactorial?
- total clearance = hepatic cl + renal cl + pulm cl + other cl
What are the 2 major sites of clearance?
Kidney (elimination of UNCHANGED drug in the urine) and liver (biotransformation)
What's the formula for clearance?
Cl = rate of drug elimination / plasma drug conc.
What formula calculates 1/2 time, taking into account clearance, half-life, and Vd?
1/2 time = 0.693 x Vd/ Cl
A factor that increases Vd does what to half life?
A factor that decreases clearance does what to half life?
How do most drugs cause their effect? Is this pharmacokinetics or pharmacodynamics?
Interact with a receptor (often in the lipid bilayer of the cell membrane) to alter function and initiate a biochemical or physiologic change
What are the 4 families of drug receptors?
- 1) cell membrane embedded enzymes
- 2) ligand gated ion channels
- 3) G protein coupled receptor system
- 4) Transcription factors
What's an example of a ligand gated ion channel? (hint: Ach)
Nicotinic Ach channel; when Ach binds to alpha subunit on the receptor, it causes internal aqueous pore to transiently open and for Na+ to enter.
In general, how does a ligand gated ion channel work?
drug binds to cell surface, regulates flow of ions in and out according to conc. gradient, spec. for an individual ion, Ach and GABA act via this mechanism
What is the agonist and what's the antagonist for the Ach nicotinic receptor?
- Agonist- succ (depolarizing muscle blocker)
- Antagonist- NDMR
T or F, receptors are selective in that only a drug with the proper size, shape, and properties will stimulate a receptor?
What is potency?
The AMOUNT of drug required to produce a particular effect. Ex: morphine is more potent than demerol.
What is efficacy?
The MAXIMUM effect that can be produced by a drug independent of dose. Ex: morphine is more efficacious than advil
What's an agonist?
Binds to and activates a receptor to cause an effect
What's an antagonist?
Binds to receptor preventing binding by an agonist (blocks agonist).
What's a partial agonist?
Binds to receptor but does not evoke as strong as a response, less efficacious than an agonist.
What are the 3 types of antagonists?
- 1) competitive antag.
- 2) noncompetitive antag
- 3) partial agonist
How does a competitive antagonist work?
- -Interacts with receptors at the same site as the agonist. Shifts curve to right so drug appears less potent.
- -Need more of drug to get same effect
- -Can be overcome by high conc. of an agonist
How does a non-competitive antagonist work?
- -PREVENTS binding of agonist or activation of receptor. Decreases maximal response of the drug. Drug appears less efficacious.
- -Drug can't exert same effect regardless of concentration.
- -Reversed only by synthesis of new receptor molecules
How does a partial agonist work?
Blocks binding site, decreases response as compared to full agonist.
What is the therapeutic index?
- -Difference btw the dose of the drug that produces desired effect and toxic effect
- -Margin of safety
- -LD 50 / ED 50
- -Less safe drugs have a narrow therapeutic index
What is down-regulation?
- -Exposure of a receptor to agonist drug can cause desensitization due to down-regulation, or destruction of receptors.
- -Body becomes refractory to additional drug.
- -Ex: epi gtt, can give more drug but no further response
What is up-regulation?
- -Exposure of a receptor to antagonist drug can cause hypersensitivity due to synthesis of new receptors.
- -Ex: abrupt withdrawal of beta blocker causes exaggerated response to agonist
What signs would indicate anaphylaxis?
hypotension (distributive shock due to vasodilation), erythema, tachycardia, urticaria, flushing
T or F, anaphylaxis is an immediate type 1 hypersensitivity reaction that is mediated by IgE?
Anaphylactoid reaction has the same clinical presentation as anaphylaxis, but is non-immunologic and chemically mediated, T or F?
What are the 2 phases of anaphylaxis?
- 1) sensitization phase- antigen triggers B cell production of IgE, antibodies bind to receptors on surface of effector cells
- 2) elicitation phase- reintroduction of antigen causes activation of effector cells and histamine release
What is atopy?
Risk for histamine release in presence of histamine releasing drugs, ex: morphine, cis-atrocurium
Who is at most risk for an anaphylactic run?
Women in their 40's to 50's
What is the treatment for anaphylaxis?
- D/c drug
- 100% O2
- Epi 0.01 - 0.5 mg
benadryl and hydrocortisone
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