Pharmacokinetics and Pharmacodynamics Flashcards
Mathematical description of plasma concentration-time course
Pharmacokinetics
What are components of the dosage regimen?
Dosage
Route of administration
Frequency
Duration of administration
What is an optimum dosage regimen?
Effective and Nontoxic (within the therapeutic window)
Without prolonged drug residues in tissue of food animals
Time to peak plasma concentration
Rate of absorption (tmax)
_______________ is the fraction of the dose which reaches the systemic circulation intact
Systemic bioavailability
How is systemic bioavailability calculated?
Systemic bioavailability (F%)= (AUC extravascular x100) / (AUC IV)
AUC= area under the plasma concentration-time curve
What is the one-compartment model?
All tissues and organs that the drug penetrates (good enough reason to use penetrate???) behave as if they were in ready equilibrium with the blood
What is the two-compartment model?
Peripheral and central compartments behave differently
Initial decent (distribution phase): distribution from central compartment to peripheral compartment
Second decent (elimination phase): metabolism and excretion of the drug
_________________ is estimated by the distribution phase half-time(t1/2a) in the two compartment model
Rate of distribution
_______________ is measured by the apparent volume of distribution
Extent of distribution (Vd)
what is the volume of fluid which would be required to contain the amount of the drug in the body if it were uniformly distributed, and the concentration in that fluid was equal to the concentration of the plasma
Apparent volume of distribution (Vd)
How is apparent volume of distribution calculated?
IV: Vd (L/kg)= amount of drug in body (Dose)/ plasma drug concentration (cp)
Extravascular: Vd= dose x F% / Cp
Vd < 1L/kg means?
Drug has limited distribution (tends to stay in plasma)
Vd = 1L/kg means?
Drug has a wide distribution (concentration of drug in tissue is the same as the plasma)
Vd > 1L/kg means?
Drug has a very wide distribution (concentration is greater in the tissue than plasma)
___________ is the time required for the body to eliminate one-half of the drug it contains
Half life
Elimination in first order kinetics means?
Rate of removal of drug from the plasma is proportional to concentration present at a given time (a constant percent of drug is eliminated per unit time)
What is elimination by zero-order kinetics?
Rate of elimination remains constant regardless of the amount of body in the drug (a constant amount of drug is eliminated per unit time)
Aspirin in cats follows (first/zero) order kinetics of elimination ?
Zero
What determines the rate at which plasma concentration of a drug rises during constant IV infusion to attain a steady state concentration ?
Half life
Plasma concentration when the maintenance rate of drug administration is equal to the rate of elimination
Steady state plasma concentration / plateau
How many half life’s does it take for a drug to reach 90% of the steady-state concentration
3.3
What percent of the steady state concentration is achieved after 4 half lives ?
93.75%
T/F: A faster rate of infusion will change the time needed to achieve steady state concentration
False
The drug will have a higher steady state concentration if the rate of infusion is faster
Rate of drug elimination from the body, by all routes, relative to the concentration of drug in the plasma
Total body clearance
CL(B) = CL (r) + CL (nr)
What is plasma clearance?
Volume of plasma cleared of the drug per unit time
How is plasma clearance calculated?
CL (p)= rate of elimination(mg/min)/ plasma drug concentration (mg/mL)
How is rate of elimination calculated?
Rate of elimination (mg/min) = urine flow (mL/min) x concentration of drug in urine (mg/mL)
How is total body clearance calculated?
CL (B)= Vd x k / T1/2
K= 0.693
Fraction of the drug removed from the perfusion blood by an organ
Extraction ratio
E= C(A) - C(v) / C(A)
C(A) = concentration of drug in arterial blood entering the organ C(v)= concentration of drug in venous blood leaving the organ
Organ clearance
CL(organ)= extraction ratio x blood flow to the organ
What are examples of drugs that have high hepatic extraction ratios??
Lidocaine, propranolol, diazepam, and nitroglycerin
What is the maintenance dose
Dose required to maintain steady state plasma concentrations
Dose x F / dosing interval = CL(B) x C(p-ss)
What is the loading dose ?
Dose required to achieve therapeutic concentration quickly
Loading dose = Vd x desired serum drug concentration
To adjust a dose and dose interval due to renal disease, the calculation is?
Adjusted dose= normal dose x (patient renal clearance/normal renal clearance)
Adjusted interval= normal dose interval x (normal renal clearance / patients renal clearance)
What are the targets for drug action?
Physical interactions:
-non-specific effects
Biological interaction:
- non receptors
- receptors (single transduction)
What are non specific effects of drug action due to physical interactions?
Osmotic diuretics (attract water)
Antacids that act by direct neutralization of acid in the GItract
Radioactive iodine
What are non-receptor targets of drug action through biological interaction?
Ion channels -physically obstruct or modulate opening and closing
Enzymes - compete for binding sites or produce abnormal metabolites
Carrier proteins - alter proteins and inhibit their actions
What are the receptor interactions for drug action?
Specific recognition sites fore endogenous chemical messengers :
Ion channels (inotropic receptors)
G protein coupled (metabotrophic receptors)
Kinase linked
Nuclear receptors (transcription factor receptors)
Drugs that bind ligand-gated channels have what affect?
Allows/prevents ions passing through
Eg Nicotinic ACh r)eceptors or GABA receptors (neurotransmitters
What is a G protein coupled receptor and what affects does its activation have?
Transducer an extracellular signal to an intracellular one
-ligand binds to the receptor which displaces GDP from the Gprotein and it is replaced with GTP
GTP regulates enzyme/ion channel activity
GTP->GDP stops the action
What are the intracellular systems of a Gprotien coupled receptor?
- cAMP: adenylyl cylase catalyzes ATP to cAMP-> protein kinase A
- PIP2: phospholipase C -> cleaves PIP2 to IP3 and DAG -> IP3 works on ER to release Ca and DAG activates membrane protein kinase C
What are the Gprotein subunits?
S- stimulators
I- inhibitory
q- couples to PLC
If a drug couples to G(s) protein receptor what affect will it have?
Positive
Increase cAMp
Phosphorylation cellular constituents
If a drug couples of G(i) protein receptor what will the effects be?
Negative
Decrease cAMP
Increased outward K+ and close Ca and K channels
If a drug couples of G(q) protein receptor what effect will it have?
Positive
Couple to phospholipase C
Increase Ca release from SER
Drugs that bind to kinase-linked receptors will have what affect?
Extracellular receptor -> intracellular kinase domain ->phosphorylation and activation of proteins => insulin, IGF-1, cytokines (generally growth promoting hormones and factors)
_________________ receptors are in the cytoplasm and on binding they will trans locate to nucelus to bind to DNA and alter specific gene transcription
Nuclear receptors
How are receptors up regulated ?
Increased number at cell surface
How are receptors down regulated ?
Decrease in number of receptors and effect
Internalization
Recycling
Sequestration
Degradation
____________ is a gradual decrease in responsiveness to a drug when given repeatedly over days to months
Tolerance
___________________ is an acute tolerance that develops over a short period of time
Tachyphylaxis
What are the types of ligand?
Agonist
Antagonist
Inverse agonist
Mixed agonist-antagonist
what is an agonist
Mimics the effect of an endogenous ligand
Affinity and efficacy
What is the difference between a full agonist and a partial agonist?
Full agonist- spare receptors (receptor reserve) and titrational effect (Eg Methadone)
Partial agonist- binds to receptor but does not cause as much effect as a full agonist, still blocks that receptor from full agonist binding “ceiling effect” (once fill effect is reached adding more will not cause a change) (Eg Buprenorphine)
A ___________ binds to the same receptor, prevents an agonist from binding, and inhibits the effects of the receptor
Antagonist
Naloxone
What time of antagonism is reversible and has concentration-dependent binding
Competitive
What type of antagonism is irreversible and prevents action of antagonist at ANY concentration.
Noncompetitive
‘Covalently bound to receptor’
___________ binds to the same receptor site and produces the opposite effect as agonist. Give an example
Inverse agonist
B- carboline
___________________ acts as an agonist on one type of receptor and as an antagonist on other types of receptors. Give an example.
Mixed agonist-antagonist
Butorphanol - k opioid agonist (sedation) and u opioid antagonist (analgesic)
__________ is the concentration of a drug needed to produce the effect
Potency
Point at which increasing concentration does not yield greater response
Maximal effect (ceiling)
What is the efficacy of a drug
Maximal effect a drug can have
Partial agonist may never be able to achieve full efficacy
What is the effective concentration
50% of maximal response in vitro
Relates to the concentration of the drug at the site
What is the effective dose
Desired effect in 50% of the population
Relates to the dose given to individuals and observed effect
What is the does between the lethal dose and the effective dose?
Therapeutic index
TI=LD50 / ED50
___________ means that the dose required to cause death is close to the dose required to have a therapeutic effect
Narrow therapeutic index
________________ means that the dose required to cause death is much higher than the dose required to have a therapeutic effect
Wide therapeutic index
How is the standard safety margin calculated?
SSM= (LD1-ED99) / ED99
___________ is the time required after drug administration for a response to be observed (latent period)
Onset of action
____________ is the length of time that a drug is effective
Duration of action
