Pharmacokinetic Principles of Pharmacology Flashcards
what the body does to the drug
pharmacokinetics
what the drug does to the body
pharmacodynamics
clinical pharmacokinetics is the discipline that describes the 1 2 3 4
absorption, distribution, metabolism, excretion
half life is the time required for serum concentration of a drug to decrease by ____ after absorption and distribution are complete
example drug A half life is 2 hours - 100%
1 hour is 50%
50%
a drug given orally has to first pass through this organ _____________ before it reaches its site of action
hepatic first pass effect
___________ is a generic name for the group of enzymes that are responsible for most drug metabolism _______ reactions. They are produced in the _______
cytochrome p450
oxidation
physiologic barriers
physical, chemical and biological barriers
epithelial lining of GIT is a __________
pH difference between stomach and fundal veins is a _________
blood barrier/blood placental barrier is a _________
bi-lipid layer: _________, ______, ________
transmembrane proteins (__ proteins)
___________ core and 2 _______ surfaces
physical barrier chemical barrier biological barrier phospholipids, sterols, glycolipids G proteins hydrophobic hydrophilic
drug concentration at sites of action influenced by several factors such as:
1
2
3
route of administration
dose
characteristics of drug molecules
drug absorption routes of drug administration 1 2 - vapors, gases, smoke 3 - \_\_\_\_\_\_\_ - \_\_\_\_\_\_\_\_ -\_\_\_\_\_ suppositories 4. injection (parenteral) - \_\_\_\_\_\_\_ -\_\_\_\_\_\_\_\_ -\_\_\_\_\_\_ -\_\_\_\_\_\_\_\_ -\_\_\_\_\_\_ -\_\_\_\_\_\_\_\_ 5. \_\_\_\_\_\_\_\_\_
oral inhalation mucous membranews intranasal sulingual rectal intravenous intramuscular subcutaneous intraperitoneal intra-arterial intra-articular transdermal
drug absorption
lipid solubility
pKa = pH at which __% of drug molecules are ionized
-uncharged (_______) molecules are lipid ______
-the pKa of a molecule influences its rate of ________ through tissues into the blood stream
-pH trapping (___________ equation)
-consider a weakly acidic drug ___
pH trapping
- aspirin is _______ in an acidic environment and 1000x faster in diffused through the GI mucosa into the plasma which has a pH of 7.4
- once in the plasma, this acidic drug is _______ and cannot reneter the GI trapped
pH varies: _______ (1-2), intestines (6-7)
50 unprontonated soluble absorption henderson-hasselbalch equation neutral pH trapped stomach intestines
routes of drug administration
oral drug administration:
advantages:
safe, economical, convenient, practical
disadvantages
- ___________
- _____ levels are difficult to predict due to multiple factors that limit absorption
- some drugs are destroyed by _________
- drugs may get activated and then broken down
- some drugs irritate the ___ system
first pass effect
blood
stomach acids
GI
routes of drug administration
advantages of injection routs
- absorption is more ____ than with oral administration
-rate of absorption depends on blood flow to particular tissue site (___> ___ > ___)
advantages specific to IV injection
- no absorption involved ( inject directly into blood)
- rate of _____ can be controlled
- a more accurate prediction of ____ is obtained
rapid
IP, IM, SC
infusion
dose
routes of drug administration
disadvantages/risks of injection
-a rapid onset of action can be dangerous if _______ occurs
-recovery from ________ or shock
-if administered too fast, ____ and ____ function could be compromised
-drugs insoluble in water or dissolved in oily liquids can not be given ___
-_______ techniques are neccessary
overdosing dehydration heart, respiratory IV sterile
______: the fraction of an administered dose of drug that reaches the blood stream
- physical properties of the drug (______, ______, ________)
- drug formulation (_______, ______, ______)
- _____ state
- _______ emptying rate
- interactions with other drugs
- ____ and ___
- _____
- genetic, disease, ethnocultural, socioeconomic
bioavailability hydrophobicity, pKA, solubility sustained release, troche, pessary fasting gastric age, gender diet
__________: the passage of drug from site of administration into the circulation
__________: drugs given in solid form muset dissolve in the _______ bio-phase before they are absorbed. poorly water soluble drugs (______)
- passive transport depends on the _________ gradient
- area of absorbing surface: if the area is _____, the absorption is faster
- ________ of absorbing surface. Blood circulation _____ the drug from the site of absorption and maintains concentration gradient across the ________. _____ blood flow hastens drug absorption
absorption aqueous solubility aqueous Griseofulvin concentration larger vascularity membrane increased
route of administration affects drug absorption because each route has its own pecularities
oral application
- unionized lipid soluble drugs (______) are readily absorbed from GIT
- acid drugs (____) acid drug absorption from the stomach is faster due to non-ionized properties
- basic drugs (______, ______) are largely ionized in the _______ and are absorbed only from the ______
ethanol aspirin atropine, morphine stomach duodenum
presence of food
-dilutes the ____ and retards ______
-_______ with calcium present in milk
-_______ hormone (_______: synthroid USP)
-food delays gastric _______. Most drugs are absorbed better if taken on an empty stomach
-certain drugs are degraded in the GIT _______ by acid, _____ by peptidases - ineffective _____
-enteric coated tablets (______ coating)
and sustained released preparations can be used to overcome ______ ability, _____ irritancy and ____ duration of action
drug, absorption tetracyclines thyroxine levothyroxine emptying penicillin G, insulin orally acid resistant acid, gastric, brief
presence of other drugs
-drugs can also alter absorption by gut wall:
altering motility (_______, ________)
-causing mucosal damage (_______)
-alteration of gut flora by _______ may disrupt the __________ circulation
intestinal absorption
-ileum (_, _, _, _)
motility atropine, metoclopramide methotrexate antibiotics enterohepatic ADEK
Subcutaneous and IM
- drug deposited in the vicinity of the _________
- _______ drugs pass readily across the surface of the capillary endothelium
- absorption from SC site is ______ than that from IM
- application of ___ and ______ accelerate drug absorption by increasing blood flow
- _____ preparations (preparations with a long action) such as _______ and __________ can be given by these routes
vaccines
capillaries lipid soluble slower heat, muscular exercise depot benzyl penicillin protamine zinc insulin
topical application
(skin, cornea, mucous membrane)
systemic absorption depends on ________
only a few drugs significantly penetrate intact skin
-_______, ______, and _______
-______ applied over extensive areas can produce systemic effects and ________ suppression
-mucous membranes of the mouth, rectum, and vagina absorb ______ drugs (example: ______)
lipid solubility
nitroglycerine, scopolamine, estradiol
glucocorticosteroids
estrogen creams
______: passage of a drug from the circulation to the tissue and the site of its action
-the extent of distribution of a drug depends on its _______, _______ at physiological pH, extent of binding to _____ and ________, and differences in regional _______
movement of a drug proceeds until an ______ is established between unbound drug in plasma and tissue fluids
distribution lipid solubility ionization plasma, tissue proteins blood flow equilibrium
the total body water as a perccentage of body mass varies from __ to __%, being rather less in _____ than ____
body water is distributed into the following main compartments
1. _______ (20% of body mass)
2. _______ fluid (15%)
3. ______ fluid (35%)
4. _________ fluid (__%)
5. ___ (20%)
50, 70 plasma intestinal intracellular transcellular fat
apparrent volume of distribution
if drug given IV the body behaves as a single ______ compartment with a volume (Vd) where the drug gets immediately distributed
vd = _________/_________
homogenous
dose administered
plasma concentration
drugs extensively bound to plasma proteins are largely restricted to the _______ compartment and have low __ (______ is 99% bound to plasma proteins therefore its Vd is 0.1)
drugs sequestrated in other tissues may have Vd much more than the ___ or even body mass (________)
- drugs may be present in other tissues, and the plasma concentration is low (___________)
- drug poisoning: Drugs with large Vd are not easily removed by ___________ and need a plasma antidote to chelate them
- chelating agents: _________ for Lead
- _________ for copper (______ disease)
vascular compartment Vd TBW Digoxin biphosphonates hemodialysis Ca++ EDTA penicillamine Wilson's disease
Blood Brain Barrier
- Lipid based and limits the entry of non-lipid soluble drugs (_______)
- efflux carriers like P-gp (_______) present in brain capillary endothelial cells extrude drugs that enter the brain by other processes
- inflammation of the meninges of the brain ______ permeability of the BBB
- Drugs: ________ does not enter the brain, but its precursor ______ does
- use in _________
amoxicillin glycoprotein increases dopamine parkinsonism
blood placental barrier
- _________. Placental membranes are _____ soluble and allow free passage of ________ drug, while restricting ______ drugs
- the placental P-gp also serves to limit fetal exposure to maternally administered drugs
- _______ amounts of non-lipid soluble drugs when present in high concentration gain access to the fetus
- it is an ______ barrier
- ________, ________, ______ cross easily
- _______, _______, and _______ do not affect the fetus and may be used during pregnancy
placental barrier lipid lipophilic hydrophilic restricted incomplete benzodiazepines, alcohol, cannabis penicillins, azithromycin, erythromycin
storage of drugs
-drugs may also accumulate in specific organs or get bound to specific tissue constituents
- heart and skeletal muscles - ______
- liver - _______
- kidney - ______
- thyroid gland - _______
- brain - _________
- retina - ________
- bones and teeth - _______, _______
- Adipose tissue - _______
digoxin chloroquine NSAIDs iodine isoniazid chloroquine tetracyclines, heavy metals DDT
Metabolism (biotransformation)
-chemical alteration of the drugs in the body
- the primary sites for drug metabolism is the ______, ______, ______, _____, and _______
metabolism of drugs may lead to the following:
a) ______ - most drugs are converted to less active or inactive metabolites (_______)
b active ______ from an active drug - many drugs are converted to one or more active metabolites (______, ______)
c) activation of ________ drug - _____ are inactive and need conversion to one or more active metabolites (_____ to ______) their active forms may be more stable; have better _______ less side effects and toxicity
liver, kidney, intestine, lungs and plasma inactivation morphine metabolite diazepam, codeine inactive prodrugs levodopa to dopamine bioavailability
biotransformation reactions can be classified into two phases Phase I (\_\_\_\_\_\_\_) and II (\_\_\_\_\_, \_\_\_\_\_\_\_)
Phase I
a) _______ is the most important drug metabolizing reaction
- various oxidation reactions are ________; oxygenation at __, __ or __ atoms
- oxidative reactions are mostly carried out by ______ enzymes in the liver (___________)
- there are more than 200 cytochrome p450 isoenzyes, differing in their affinity for various substances
non-synthetic synthetic, conjugation oxidation hydroxylation C-, N-, S- atoms cytochrome cytochrome p450 reductase
cytochrome p450
- ______/_______ carry out biotransformationo f the largest number (=50%) of drugs
- in addition to the . liver, these isoforms are expressed in the ______ and the _____
- inhibition of CYP ___ by _______, _______, ______, ______, ______ and a constituent of _______ are responsible for unwanted interactions
- _______, _____, _________
- inducers of the _______
CYP 3A4, CYP3A5 intestine, kidney 3A4 erythromycin, clarithromycin, ketoconazole, ltraconazole, diltiazem, grapefruit juice rifampicin, phenytoin, carbamazepine
cyp3a4/5 inhibitors slide 30
ketoconazole, gestodene
b) Reduction.
this reaction is the converse of oxidation and involves _____ enzyme in working in the opposite direction
-drugs, primarily reduced are ______, ______
CYP450
levodopa, halothane
c) _______ - this is cleavage of a drug molecule by raking up a molecule of water
ester + h20 —-> (esterase) acid + alcohol
similarly _____ and ______ are hydrolyzed by _______ and _______. Hydrolysis occurs in the ______, ______, ____ and other tissues (_______, ______)
hydrolsis amides, polypeptides amidase, peptidases liver, intestines, plasma lidocaine, oxytocin
d) _______ - opening up of a ring structure of the cyclic molecule (_______)
decyclization
phenytoin
Phase II - synthetic (conjugation) reaction
these involve conjugation of the drug or its phase I metabolite with an _______ substrate to form a ____, highly _____ compound, excreted in ____ or ___
-conjugation reactions have ____ energy requirements
1) ___________ is the most important synthetic reaction. Compounds with a ________ or ________ group are easily conjugated with glucoronic acid (ex. _______)
- the liberated drug is reabsorbed and underrgoes the same fate. This _________________ of some drugs (__________) prolongs their actions
endogenous polar, ionized urine, bile high glucuronide conjugation hydroxyl, carboxylic bile salts enterohepatic recirculation oral contraceptives
phase II - synthetic (________) reactions
2) ________. compounds having ____ residues are conjugated with the help of _________ (ex. _______) multiple genes control the ________ and rate of acetylation shows genetic _______ (slow and fast acetylators)
3) _________/________ synthesis is important for the activation of many ____ and ______ antimetabolites used in ________ (ex ________)
4) __________
- alcohol by __________
- epinephrine by ____________ (__)
conjugation acetylation amino acetyl coA isoniazid acetyl transferases polymorphism ribonuceloside/nucleotide purine, pyrimidine cancer chemotherapy 5-fluroacil dehydrogenases monoamine oxidase (MAO)
first pass (presystemic) metabolism
- metabolism of a drug during its passage from the site of absorption into the systemic circulation
- all orally administered drugs are exposed to drug metabolism in the __________ and ____ in different extent
- _______, _______, ______, _______
- oral dose of these drugs is higher than _______ dose
- there is individual variation in the oral dose due to differences in the extent of first pass metabolism
- oral _________ is _______ patients with severe liver disease
intestinal wall, liver propranolol, verapamil, albuterol, nitroglycerine parenteral bioavailability increased
iv \_\_\_\_\_\_ - the passage of systemically absorbed drugs out of the body drugs and their metabolites are excreted by: 1 2 3 4 5 6
excretion urine (kidney) bile and feces exhaled air saliva sweat milk skin
urinary/renal excretion 1 2 3 4 5 - urinary antiseptic
aminoglycosides beta-lactams sulfonamides quinolones nitrofurantoin (Macrobid)
hepatic excretion 1 2 3 4
macrolides
lincosamines
rifampicin
tetracyclines
pulmonary excretion 1. general \_\_\_\_\_\_\_\_\_\_\_ 2 3 4 5
inhalation anesthetics nicotine albuterol deriphylline alcohol
salivary excretion
1
2
3
nicotine
phenytoin
nifedipine
first order (exponential kinetics)
- this occurs for ________ of drugs
- the processes involved involved in elimination are not ______ over the clinically obtained concentrations
- their rate of elimination is directly proportional to the _________ concentration
- drugs are ______ at the rate at which they are ______
majority saturated plasma drug removed absorbed
zero order (linear) kinetics
- some drugs are inactivated by metabolic degradation (_______, ______, _______ and _______)
- time-course elimination of drug from plasma is initially ____ and then the ________ get saturated
- these drugs are removed at constant rate of which is ________ of plasma concentration
ethanol, phenytoin, theophylline, warfarin
linear
excretory mechanisms
independent
first order elimination
- drug decreases _______ with time
- rate of elimination is _______ to drug
- t 1/2 is _______ regardless of drug
zero order elimination
- drug decreases ______ with time
- rate of elimanation is ______
- rate of elimination is _______ of a drug
- no true t 1/2
exponentially proportional constant linearly constant independent
__________ is the time in which the plasma concentration of a drug declines by 1/2. drugs with long t 1/2 can ______
_______ < 2 sec
________ up to 8-10 years
plasma half life t1/2
accumulate
adenosine
alendronate
tolerance (desensitization)/tachyphylaxis
- rapid tolerance development: ________
- ______ response to same dose with repeated (______) exposure
- or more drug needed to achieve same effect
- may occur with an acute dose (ex. ______)
- can develop across drugs (_________)
- caused by ________ mechanisms that oppose the effects of the drug
- ________ and ______
tachyphylaxis decreased constant alcohol cross-tolerance compensatory nitroglycerine, nicotine
drug-drug interactions
pharmacokinetic, pharmacodynamic
_________ drug interactions - one drug affects the absorptionl distribution metabolism or excretion of another
_________ drug interactions: two drugs have interactive effects at the site of drug action (___ and ______)
either type of drug interaction can result in adverse effects in individuals
-________, _____, _______ and _________
pharmacokinetic
pharmacodynamic
BZDs and alcohol
cumulative, additive, synergistic, antagonistic
______ effects
the condition in which repeated admin of a drug may produce effects that are more pronounced than those produced by the fiirst dose
________: ______
cumulative
antipsychotics
haloperidol
_______ effects
the effect of two chemicals is equal to the sum of the effect of the two chemicals taken separately
ex _______ and _____
additive
acetominophen, ibuprofen
________ effects
the effect of two chemic als taken together is greater than the sum of the separate effect at the same doses
ex:
alcohol and marijuana
________ effects
the effects of two chemicals taken together is less than the sum of their separate effect at the same doses (_______ drugs such as ______ may antagonize effects of _____ drugs such as _______)
antagonistic
bacteriostatic, macrolides
bactericidal, vancomycin
_____ - median ____ ____ 50: the dose at which 50% of the population or sample manifests the desired effect
____ - median _______ ___ 50 - dose which kills or causes toxicity in 50% of the subject
ED50, median effective
LD50, median lethal
therapeutic index equation:
TD50 or LD50/ ED50
