Exam 2 Flashcards
Absorption
movement of drugs into the bloodstream from the site of delivery
-stomach
-skin
-vein
Factors accepting absorption
Drug transport
Physicochemical properties
Routes of Administration
When pH is lower than pKa which form will predominate
protonated
pKA - pH
4.2 - 7.4 = (-) what occurs
weak acid
unprotonated form predominates, drug can not cross barrier because it has a negative charge
pKa - pH
9.4 - 1.4 = (+) what occurs
weak base
protonated form predominates
can’t cross barrier, charge
Fractional extent to which a dosage of drug reaches the systemic circulation is dependent on what 3 factors
Route of administration
Absorption
Metabolism
Area under the curve (AUC) indicates what
overall amount of drug in blood after a given dose (over time)
Three factors that impact drug distribution
Protein binding
Tissue binding
Transporters
oral administration: absorption and limitations
absorption: variable, must cross intestinal mucosa
limitations: subject to metabolism
How is uptake governed by pH in oral absorption
-weak acids absorbed from stomach and upper intestine
-weak bases absorbed better from upper intestine rather than from stomach
Oral absorption factors
-accelerating gastric emptying will increase rate of absorption
-delaying gastric emptying will decrease rate of absorption
Controlled release preparations in oral absorption
-designed for slow, uniform absorption of drug
-reduce frequency of administration
-more uniform blood levels
Limitations of controlled release preparations
dose dumping increases toxicity
increase stomach acidity with high-fat meal
sublingual administration
-venous drainage through superior vena cava
-useful with more lipid soluble drugs
transdermal absorption
intact skin provides a lipid barrier for transdermal absorption
oily vehicles (improves permeability)
Rectal administration
absorption may be incomplete
used when patient is vomiting or unconscious
Parenteral administration
-injections allow for absorption by simple diffusion from frug depot into bloodstream
-avoid first-pass metabolism
IV injection
-useful for poor soluble suspensions and depot formulations
-not good for large volumes
-potential pain at injection site
IM injection
-self-administration
-precluded during anticoagulant therapy
-many variabilities
Intraarterial injection
-circumvented to deliver drug directly to tissue or organ
-used for diagnostic agents and chemo
Intrathecal injection
injection into space surrounding spinal cord, useful for drugs that cannot cross the blood brain barrier or limiting effect to spinal cord or meninges
pulmonary absorption
absorption through pulmonary epithelium and mucous membranes of the respiratory tract, avoids first pass hepatic metabolism, directs application of drug to target tissue
Pharmaceutical equivalence
same active form, concentration, dosage form, and route of administration
Bioequivalence
indicated when rates of extent of bioavailability of active pharmaceutical ingredient (API) do not differ significantly
What is drug distribution dependent on
cardiac output, blood flow, capillary permeability, tissue volume
Redistribution of drugs
Rapid distribution to muscle and liver
Slower distribution to adipose tissue
What carriers help drugs bind to plasma protein
albumin for acidic drugs
a1-acid glycoprotein for basic drugs
Tissue binding
-Accumulate by active transport
-Lipid soluble drugs stored in body fat
What drugs bind to bone tissue
Tetracycline and aminoglycoside antibiotics
Blood brain barrier
-composed of capillary endothelial cells
-regulates distribution of chemicals to the brain
membrane transporters (efflux and influx)
What glial cells are located where
BBB
(includes astrocytes and microglia)
what cells separate cerebrospinal fluid from blood
epithelial cells
Phase 1 functionalization reactions
Introduce or expose functional groups
Result in both active and inactive compounds
Net result is water-soluble compounds that can be excreted into urine
Phase 2 biosynthetic (conjugation) reactions
-covalent linkage between functional group on drug
-polar conjugates usually inactive and excreted rapidly
What is first order kinetics?
-constant fraction of drug is eliminated per unit time
-drug metabolism proportional to plasma concentration
What is zero order kinetics?
-limited metabolic capacity
-constant amount of drug metabolized per unit of time
some drugs alter metabolism of other drugs through
-induction of enzymes (increased expression of drug metabolizing enzymes)
-inhibition of enzymes (blockade of drug metabolizing enzymes)
Glomerular filtration
only unbound drug filtered into tubular lumen from the blood
Active proximal tubular secretion
-ATP-binding cassette transporters secrete anions and metabolizes into tubular fluid
-Other ABC transporters are more selective for organic cations or neutral substrates
Active distal tubular reabsorption
-From tubular lumen to systemic circulation by membrane transporters
-most reabsorption is by nonionic diffusion
Renal excretion
concomitant reabsorption of non-ionized weak acids and weak bases, depends on pH
Biliary excretion
potential recycling through reabsorption from GI tract to systemic circulation
What is F (bioavailability)
fraction of a drug absorbed into the systemic circulation
-depends on route of administration, absorption, metabolism, excretion
What is V (volume of distribution)
apparent space of body available to contain a drug based on amount given and concentration in systemic circulation
-impact by plasma binding protein, age, gender, body composition
What is CL (clearance)
measures body efficiency in drug elimination
-use in designing dosing regimens
-can follow either first order or zero order
Steady State Concentration (Css)
Concentration achieved when intake of drug is in dynamic equilibrium with elimination of drug
Km and vm
Km is the concentration at which half max rate of elimination is reached
vm is the max rate of elimination
Clinical pharmacokinetics parameters can be utilized to design dosing regimens
maintain plasma concentrations within therapy window
maintenance doses can be adjusted
loading doses used to achieve rapid onset
Maintenance Dose
Series of repetitive doses or continuous infusion to maintain steady state
What can polymorphisms impact
Protein structure
Function
Pattern of expression in
SNPs
May change coding for proteins or impact expression
Insertions or deletions (indels)
Like SNPs (change coding)
Copy number variations
Gene duplications or deletions
Non-synonymous (missense)
Change impacts protein sequence
Amina acid substitution or stop translation
Synonymous (sense)
Change does not impact protein structure
May impact expression
Non-coding SNPs
3’ or 5’ untranslated regions (promoter or enhancer regions)
Intronic/intergenic regions
UGT1A1
TA repeats (insertions) in promoter impact expression of enzyme
-range is from 4 to 9 repeats
-6 or 7 repeats most common
CYP2D6
Ultra rapid metabolized phenotype implicated in variable responses to antidepressants therapy
CYP2D6
20-25% of drugs are metabolized by the enzyme
Can have poor or ultra-rapid metabolism
What does poor drug metabolism do in your body
Can’t eliminate drugs so they stay in the system and produce toxic effects
CYP3A5 expressed in higher percentage of individuals of ________ descent than in caucasians
african
SNP in intron __ encode stop codon, resulting in truncated protein
3
What are the two main classes of transporters and what do they do
SLC-include both active and non-active transporters
ABC-active transporters needing ATP
What are the three adverse effects of membrane transporters
decreased uptake in clearance drugs
enhanced uptake or reduced efflux from target organs
decreased efflux of endogenous compounds
Passive diffusion
electrochemical potential gradient
Facilitated diffusion
Membrane SLC transporters facilitate diffusion
Primary active transport
ABC transporters hydrolyze ATP through intrinsic ATPase activity
Secondary active transport
SLC transporters move one solute against ECG by transporting another solute with ECG
Vectorial transport
The net flow of drugs from one compartment to another depending opinion the relative orientation and function of multiple transporters
ADME transport of vectorial transport
Absorption - absorb in small intestine
Distribution - CNS penetration at the BBB
Metabolism - Hepatobiliary transport in the liver
Elimination - tubular secretion in the kidney
Role for type 2 nuclear receptors
Ligand binding and formation of heterodimers
Binding to specific elements in enhancer regions of target genes
Changes in transcription or transporters and other proteins
Altered transporter function has been linked to human disease what receptor is tangier disease
ABCA
Altered transporter function has been linked to human disease what receptor malfunction results in amyotrophic lateral sclerosis
High affinity glutamine and neutral amino acid transporter
7 ABC transporters are identified. Which two play important roles in drug transport
ABCB1
ABCC
ABCG
Induction of ________ can decrease systemic exposure to substrates such as digoxin
ABCB1
Inhibition can reduced _________ of digoxin
Excretion
Role:
OATP, OAT
OCT
OATP, OAT- transport anions
OCT- transports cations
Role of NTCP
Transports bile salts
Phase 1 bio transformation reactions
Increase water solubility by exposing functional groups
CYP 450 enzymes
Epoxied hydrolases
Flavin containing monooxygenases
Phase 2 conjugating enzymes
Increase hydrophilicity and molecular weight
Inactive compounds
Transferases (UPD, sulfur, glutathione, acetyl, methyl)
CYP 3A 4/5 involved with metabolism of _____% of all drugs
50
UDP UGT1A1 is important for metabolizing drugs and bilirubin what disease can it cause and what is it effects
Gilbert’s syndrome
Toxic for patients with low binding levels
Induction of drug metabolizing enzymes increase metabolism thereby ________ drug exposure and _________ clearance
Decreasing
Enhancing
