Finals Mod 6-9 Flashcards
established to provide
- correct plasma level w/o excessive
fluctuation
- drug accumulation outside the therapeutic window.
Dosage Regimen
Calculating multiple-dose regimen, –> desired/target plasma drug concentration, related to therapeutic response,
multiple-dose regimen must be designed to produce plasma concentrations outside the therapeutic window.
T or F
False
within the therapeutic window
Two Parameters that can be adjusted in developing a dosage regimen?
size of the drug dose & frequency of the drug administration.
initial bolus of a drug is used to obtain desired concentration as rapidly as possible.
LOADING DOSE
Therefore, if an IV loading dose of R/k is given, followed by an IV infusion, steady state
plasma drug concentration is obtained immediately and maintained.
T or F
T
Since extravascular doses require time for absorption into the plasma to occur,
therapeutic effects are delayed until sufficient plasma concentrations are achieved.
T or F
T
To reduce the onset time of the drug-that is, the time it takes to achieve the minimum
effective concentration-a ______ is given.
loading dose (priming) or initial dose of drug
main objective: to achieve desired plasma concentrations as quickly as possible.
Thereafter, a maintenance dose is given to maintain plasma drug concentration.
Intravascular Loading Dose
General Rule: if a drug is normally excreted via the kidneys, its maintenance dose will
need not to be adjusted in patients with renal impairment.
T or F
F
need to
the maintenance rate [mg/h] of drug administered equal to the rate of elimination at steady state.
maintenance dose
- Decrease the dosing interval, dose remains unchanged. Increase the dose, the dosing interval remains unchanged.
T or F
F
Increase…Decrease
The objective is to produce a plasma profile which approaches that normally
achieved in the absence of renal failure.
T or F
T
also defined as the amount of drug required to keep a desired mean steady state concentration in the tissues. It is administered after L.D.
The required ______ may be calculated as: MD = CpCL /F
maintenance dose
It is based on the principle that for some drugs there is a close relationship between the
plasma level of the drug and its clinical effect.
Therapeutic Drug Monitoring
The clinical value of plasma level monitoring depends on how precisely the treatment
outcome can be defined. When a precise therapeutic end point is difficult to define, monitoring of drug levels may be of considerable therapeutic assistance.
T or F
T
Drugs for which relationship between dose and plasma concentration is unpredictable?
Phenytoin
Drugs with a narrow therapeutic window?
Lithium, phenytoin, and digoxin
Drugs with steep dose response curve?
theophylline
Drug with saturable metabolism?
Phenytoin
Drug with poorly defined end point or difficult to clinically predict the response?
immunosuppressant drugs
drug alters the relationship between dose & plasma concentration?
plasma concentration of lithium is increased by thiazide.
It is relative amount of drug from an administered dosage form which
enters the systemic circulation and rate at which the drug appears in the systemic circulation.
Bioavailability (BA)
The extent and rate at which its active moiety is delivered from pharmaceutical form and
becomes available in the systemic circulation
Bioavailability (BA)
4 Possible differences –> Bioinequivalence:
-drug particles size
-excipients
-manufacturing equipment/process
-site of manufacture
Two products are bioequivalent if
➢ They are pharmaceutically equivalent
➢ Bioavailabilities (both rate and extent) after administration in the same molar dose are different to such a degree that their effects can be expected to be essentially the same
T or F
F
similar
THERAPEUTIC EQUIVALENCE:
Two products are therapeutically equivalent if:
➢ Pharmaceutically equivalent
➢ efficacy and safety will be essentially the same as derived from appropriate studies.
T or F
T
Studies involved in therapeutic equivalence:
◦ bioequivalence studies
◦ pharmacodynamic studies
◦ clinical studies
◦ in vitro studies
Original Drug NDA Requirements:
a. Chemistry
b. Manufacturing
c. Controls
d. Labeling
e. Testing
f. Animal Studies
g. Clinical Studies (Bioavailability/Bioequivalence)
Generic Drug ANDA Requirements:
a. Chemistry
b. Manufacturing
c. Controls
d. Labeling
e. Testing
f. Bioequivalence Study (In Vivo, In vitro)
Generic drug applications are termed “_______” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
Instead, generic applicants must scientifically demonstrate that their product is
bioequivalent (i.e., performs in the same manner as the original; drug).
abbreviated
Is an essential pharmacokinetic process, which render lipid soluble and nonpolar compounds to water soluble and polar compounds so that they are excreted by various process from the body.
METABOLISM
It is a specific term used for the chemical transformation of xenobiotics in the living organisms.
Biotransformation
METABOLISM render water soluble and polar compounds to lipid soluble and nonpolar compounds so that they are excreted.
T or F
F
render lipid soluble and nonpolar compounds to water soluble and polar compounds
These are all chemical substances that are not nutrient for the body (foreign body) and which enter the body through ingestion, inhalation or dermal exposure.
Xenobiotics
Drug Metabolism
* Most organic compounds entering the body are relatively water soluble (hydrophilic).
* To be absorbed, they must traverse the lipoprotein membranes of the ______ walls of the gastrointestinal (GI) tract.
T or F
F…..lumen
lipid soluble (lipophilic).
Because of ________, lipophilic compounds are not excreted to any substantial extent in the urine.
reabsorption in the renal tubules
Thus, the formation of water-soluble metabolites not only enhances drug elimination, but also leads to compounds that are generally pharmacologically inactive and relatively nontoxic.
T or F
T
If lipophilic drugs, or xenobiotics, were not metabolized to polar, readily excretable water-
soluble products, they would remain indefinitely in the body, eliciting their biological effects.
T or F
T
Consequently, drug metabolism reactions have traditionally been regarded as detoxication (or detoxification) processes. Therefore, it is assumed that drug metabolism reactions are always detoxifying.
T or F
F
not all drug metabolism reactions are always detoxifying.
substances that result from metabolism?
It may be inactive, or they may be similar to or different from the original drug in therapeutic activity or toxicity.
metabolites
FACTORS INFLUENCING DRUG METABOLISM:
Physicochemical properties of the drug
Chemical factors
Biological factors
the parent compound is inactive when administered and must be metabolically converted to a biologically active drug (metabolite), these types of
compounds are referred to as ____?
Prodrugs
The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and thereby may activate or deactivate the drug is called ________
biotransformation
Active to Inactive:
Phenobarbitone→Hydroxyphenobarbitone
Inactive (prodrug) to Active:
L-Dopa ————–→ Dopamine
Parathion ———-→ Paraoxon
Talampicillin ——→ Ampicillin
“initial site of drug metabolism”.
Intestines
“metabolite clearing house”
Liver
major organ/site for drug metabolism
Liver
The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the intestine. Drug metabolism rates vary among patients.
T or F
F
liver
rapid metabolism: therapeutically effective blood and tissue
concentrations are not reached;
slow metabolism: usual doses have toxic effects.
T or F
T
The enzymes responsible for oxidation and reduction of drugs and certain natural metabolites, such as steroids,
monooxygenase enzyme known as MFOs (mixed-function oxidases).
describes the oxidation of many xenobiotics (R-H) to their corresponding oxidized metabolites (R-OH)
General stoichiometry
the reducing agent in mixed-function
oxidase or monooxygenases?
NADPH
O2 + (introduced) R-H = R-OH; O2 + H2O
mixed-function oxidase or monooxygenases.
responsible for transferring an oxygen atom to the substrate RH.
CYP enzymes
Nomenclature:
Arabic # - Family > 40% i a.a. s
Capital letter - Subfamily >55% i a.a. s
Arabic # - individual enzyme > 90% i a.a. s
N/A
these enzymes are best known for metabolizing clinically useful drugs in humans.
CYP 1-3
oxidation of caffeine
Cytochrome P-450 IA2 (CYP1 A2)
metabolism of vindesine, vinblastine, and other vinca alkaloids.
CYP3A
oxidation of codeine, propanolol, and dextromethorphan. Responsible for
debrisoquine metabolism among individuals showing genetic polymorphism.
CYP2D6
EM – extensive metabolism
PM – poor metabolism lacks functional ____?
CYP2D6
Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.
N/A
Phase I is called Conjugation Reaction. Functionalization Reaction. Phase II is called Functionalization Reaction.
T or F
F
Phase I: Functionalization Reaction
Phase II: Conjugation Reaction.
This can be achieved by direct introduction of the functional group (e.g., aromatic and aliphatic
hydroxylation) or by modifying or “unmasking” existing functionalities
Phase I: Functionalization Reaction.
Reduction of ketones and aldehydes to alcohols
Phase I
Oxidation of alcohols to acids
Phase I
Hydrolysis of ester and amides to yield COOH, NH2, and OH groups
Phase I
Reduction of azo and nitro compounds to give NH2 moieties.
Phase I
Oxidative N-, O-, and S de-alkylation to give NH2, OH, and SH groups.
Phase I
Conjugation of functional groups of a compound or its metabolites with
endogenous substrate to form water soluble conjugated products.
Phase II: Conjugation Reaction
Phase II Reaction type:
Glucuronidation, Sulfation, Glutathione conjugation, Acetylation and
Methylation.
terminate or attenuate biological activity,
Methylation and Acetylation
protects the body against chemically
reactive compounds or metabolites
glutathione conjugation
Products called as ______ are water soluble metabolites and are easily excreted from the body.
conjugates
are generated by mutations in the genes for these enzymes, which cause decreased, or absent enzyme expression or activity by multiple molecular.
Polymorphism
is a drug- or chemical-stimulated increase in enzyme activity, usually due
to an increase in the amount of enzyme present. Requires some onset time for the synthesis of enzyme protein.
Enzyme induction
due to substrate competition or direct inhibition of drug-metabolizing enzymes, particularly one of several of the cytochrome P-450 enzymes.
Enzyme inhibition
Example of Enzyme inhibition:
SSRis – inhibit the CYP2D6 system, resulting in significantly elevated plasma
concentration of co-administered psychotropic drugs.
Fluoxetine – decreases the clearance of imipramine and desipramine.
Ideally, drug doses should be given at evenly space intervals. However, to improve patient compliance, dosage regimens may be designed to fit with the lifestyle of the patient.
T or F
T
Is designed by physicians based on empirical data, Personal experience and Clinical observations. This method is however not very accurate.
Empirical Dosage regimen
Is designed by physicians based on empirical data, Personal experience and Clinical observations. This method is however not very accurate.
Empirical Dosage regimen
Is the most accurate approach and is based on the pharmacokinetics of drug in the individual patient. The approach is suitable for hospitalized patients but is quite expensive.
Individualization of Dosage regimen
Most often used approach.
Dosage regimen on population Averages
The magnitude of both therapeutic and toxic responses depends upon dose frequency.
T or F
F
Dose Size
If the interval is increased and dose is unchanged, Cmax, Cmin, Cav decreases but the ratio Cmax/Cmin increases. Opposite is observed when the dosing interval is reduced or dosing frequency is increased. It also results in greater accumulation of drug in the body and toxicity.
T or F
T
Greater the dose size greater the fluctuations between Cssmax and Cssmin during each dosing interval and greater the chances of toxicity.
T or F
T
The Dosing Interval (inverse of dosage frequency) is calculated on the basis of ____of the drug.
half-life
If the interval is increased and dose is unchanged, Cmax, Cmin, Cav decreases but the ratio Cmax/Cmin increases.
Opposite is observed when the dosing interval is reduced or dosing frequency is increased. It also results in greater accumulation of drug in the body and toxicity.
N/A
For drugs with wide therapeutic index such as penicillin’s, Larger doses may be administered at longer intervals (more than half life of drug) without any toxicity effects.
T or F
T
It is both the synthesizing and an excreting organ.
LIVER
drug removed in changed form
Metabolism
drug is removed in unchanged form
Excretion
Provides a direct measurement of drug removal from the liver after oral administration of a drug.
Liver Extraction Ratio
Plays an important role in the amount of drug metabolized after an oral administration.
Provides a reasonable approach for evaluating the reduced bioavailability due to first-pass effect.
Blood Flow to the Liver
Blood flow to an organ is directly proportional to the arteriovenous pressure difference (perfusion pressure) across the vascular bed and indirectly proportional to the vascular
resistance.
T or F
T
Normal Renal Arterial Pressure? 45 to 60 mm Hg in the glomerulus.
100 mm Hg
refers to the maintenance of a constant blood flow in the presence of large
fluctuations in arterial blood pressure.
Autoregulation
filters the blood that passes through the kidneys
Renal corpuscles:
-glomerulus
-Bowman’s capsule
specialized for secretion and reabsorption.
Renal tubules:
-proximal convoluted tubule
-loop of Henle
-distal convoluted tubule
-collecting tubule
effective renal plasma flow (ERPF)
425-650 mL/min
is the major route of elimination for many drugs.
Renal drug excretion
normal adult male GFR
125 mL/min
The major driving force for glomerular filtration is the ______within the glomerular capillaries.
hydrostatic pressure
a substance administered to determine GFR that is primarily excreted by the kidney by glomerular filtration and not by reabsorption and secretion.
inulin
a compound that is created by the body at a constant rate from the breakdown of creatine phosphate. It is however secreted by the peritubular capillaries in small amounts.
Creatine
A carrier mediated system that requires energy input, because the drug is transported against a concentration gradient.
Active Tubular Secretion
Occurs after the drug is filtered through the glomerulus and can be an active or a passive process involving transporting back into the plasma.
Tubular Reabsorption
defined as “the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely in a specific period of time”. Expressed in ml/min.
Clearance
“the volume of blood or plasma which is completely cleared of the unchanged
drug by the kidney per unit time”.
Renal clearance
passively affects glomerular filtration and reabsorption.
PLASMA CONCENTRATION OF DRUG
liver metabolize and excrete into __ many compounds and toxins,
thus, eliminating them (usually) from the body.
bile
Irreversible transfer of drug or drug metabolites from the plasma to the bile through the hepatocytes
BILIARY EXCRETION
intestinal reabsorption of the active drug
ENTEROHEPATIC CYCLE
