Flashcards in Exam 1 Deck (184):
what is pharmacology
scientific study of substances that interact with living systems through CHEMICAL processes
chemicals typically bind to _____ and activate or inhibit many normal body processes
drugs are typically what kind of molecules ?
small organic molecules
4 main classifications of drugs
1. pharmacological effect
2. chemical structure
3. target system
4. site of action
criteria for a good drug?
1. do what it is meant to do
2. no side effects
4. easy to take
why should drugs work?
drugs = tiny chemicals of simple structure
organism = huge array of chemical reactions that keep the body healthy and functioning properly
- drugs enter this chemical world
where do drugs act
upon or within cells
3 main molecules targets of drugs
1. lipids/cell membranes
2. proteins (imbedded in membrane or cytosolic)
3. nucleic acids (DNA/RNA)
what happens when lipids are a drugs target?
lipid structure of cell membrane is disrupted
order from most common to least common molecular targets of drugs
1. Proteins (enzymes/receptors)
2. Nucleic acids
what protein structure is most important with respect to drug action
what are the major protein drug target
how do enzymes facilitate reactions
1. provide a reaction environment
2. bringing reactants together
3. positioning reactants properly for reaction
4. weakening bonds
5. participating intimately in the reaction mechanism
most drugs are enzyme ___(activators/inhibitors)
control and communication of cells comes primarily from what?
the brain and spinal column (CNS)
in a synapse how are messages transferred
via neurotransmitter/receptor system
how do synapses allow for an electrical message sent via nerves to become a chemical message? (allows a potential site for drug interaction
because of the neurotransmitter/receptor system
neurotransmitters are usually ___(+/-) charged small molecules
how can drugs increase/decrease neurotransmission
1. stimulate receptor (agonist)
2. block receptor (antagonist)
3. block transport/reuptake of NT
4. block metabolism of NT
5. block synthesis of NT
6. open/close ion channels
Nucleic acids as drug targets are drugs that interfere with either ____, ____, or ____ in some way.
typically drug interactions with nucleic acids leads to what
three types of agents that are drugs that act on DNA
1. intercalating cytostatic agents
2. alkylating agents
3. chain "cutters"
what do intercalating cytostatic agents do?
insert between strands/layers of base pairs
disrupt the shape of the double helix
prevent replication and translation
what do alkylating agents do?
electrophiles attacked by nucleophiles to form strong, covalent bonds to DNA
drugs with 2 alkylating groups can cross-link DNA strands to prevent unraveling
what do chain "cutters" do?
agents that cut DNA strands and then prevent DNA ligase from repairing the damage
relays codes for particular proteins from DNA to protein production site (rRNA)
constructs protein molecule from message on mRNA-moves along mRNA to "decode" it
links triplet code on mRNA to a specific amino acid (different molecule for each AA)
drugs that interact with RNA with interfere with what?
transcription and translation
commonly see interference with ribosomal action
what about a drug and a receptor must be complementary?
functional (chemical) groups
- chirality is important
drugs and receptors interact chemically, intimately, and specifically at the ___ level
what are pharmacodynamic processes
how drugs act on the body
plays a major role in deciding if drug class is appropriate therapy
what are pharmacokinetic processes
how the body acts on the drug
absorption, distribution, metabolism and elimination of drugs from the body
important in choosing and administering drugs for particular patients
what is the duration of drug action denoted by
actions of a drug is terminated by what?
1) dissociation of drug from receptor
2) destruction of a drug-receptor complex (endocytosis)
3) desensitization mechanisms activated
receptors must be _1_-specific and _2_
2. change shape
what do inert binding sites affect?
distribution and concentration of drug
- drug becomes less available to act and to be metabolized
effective concentration eliciting a response
inhibitory concentration = 50% enzyme inhibition
effective dose in 50% of subjects
lethal dose that kills 50% of subjects
EC50, IC50, ED50, LD50 all relate to what?
EC50, IC50, ED50, LD50 are all measures of what?
what is Kd
measure of receptor binding affinity
what is therapeutic index?
conc. that kills/conc. that heals
does a higher or lower therapeutic index = safer drug?
what does potency differentiate?
differentiates compounds based on their concentration-response relationships
is potency a precise or relative measure?
specific ability of drug to bind to a receptor
affinity is a _1_(relative/precise) measure relating to _2_ responses
affinity = ?
relates the magnitudes of the max effects of a series of drugs
does a more efficacious drug produce a lesser or greater response?
what are partial agonists
drugs of low efficacy
appear to bind to receptors, but don't fully activate the system as full agonists
4 types of drug antagonism?
1. competitive antagonism (irreversible/reversible)
2. noncompetitive antagonism
3. functional antagonism ("physiologic antagonist)
4. chemical antagonism
what is the most common type of antagonist drug
what is functional antagonism?
represents interaction of two different agonists with opposite pharmacological effects
what is chemical antagonism?
direct interaction between agonist and antagonists
what are the four major types of transmembrane signaling mechanisms ?`
1. receptors are intracellular
2. receptors on membrane-spanning enzymes
3. receptors on membrane ion channels
4. receptors linked to effector via G-proteins
what type of drug agents acts on receptors that are intracellular?
lipid soluble or diffusible agents (steroids or nitric oxide)
what kind of receptor would insulin act on
receptor on membrane-spanning enzymes
how do receptors on membrane-spanning enzymes work
drug combines with an extracellular receptor which affects intracellular enzymatic activity
how do receptors on membrane ion channels work
receptors may directly cause the opening of an ion channel or modify the channel's response to other agents
how do receptors linked to effector via G-proteins work
G-protein couples the receptor to its effector
what is idiosyncratic response?
an unusual response in an individual
hyp- or hyperactive responses
how does drug tolerance occur due to excess stimulation (agonists)?
A cell will remove receptors and decrease their production
how does drug tolerance occur due to reduced stimulation (antagonists)
cell will increase receptor population
what is anaphylaxis
immediate reaction to a drug
- IgE antibodies --> release histamine and serotonin
placebo effect is evident in what percentage of patients
what is placebo toxicity
patients will experience side effect symptoms of a drug that believe they are taking
what causes the primary effect for drugs?
side effects and toxic effects
what is the main therapeutic goal of drugs?
to achieve a desired beneficial effect with minimal adverse effects
concentration D -->effect/response (receptor level)
what type of pharmacological process?
dose-->concentration at receptor (organismal level)
what type of pharmacological process?
what is the sum reaction of the pharmacodynamic and pharmacokinetic processes?
aka ___ ---> ____
dose --> effect/response
what does pharmacokinetics deal with?
deals with drug concentration and how they vary overtime
"fate" of drugs
4 pillars of drug-body interactions/processes in pharmacokinetics?
what are the common routes of administration?
Enteral or parenteral
route of administration via the GI tract
most common route of administration
route of administration other than GI tract
rapid onset/reduced metabolism
abbreviation for by mouth
what does IV stand for
what does IM stand for
what does SC, SQ stand for
what does IA stand for
what is intrathecal?
injection into the subarachnoid space (beneath membrane envelope of brain)
administering a drug via aerosol or inhalation would be what kind of route?
after administration, the drug must be...?
1. absorbed in the blood stream
2. distributed to its target by permeating through barriers/membranes
3. metabolized and/or...
movement of drug from site of administration to the plasma
movement of drug within an organism to the sites of action
what does the rate of drug action depend on
absorption and distribution
what is permeation and what are the 4 primary mechanisms
Movement of a drug through system and proceeds through 4 primary mechanisms:
Passive (most common)
1. aqueous diffusion
2. lipid diffusion
3. special carriers (proteins)
4. endocytosis and exocytosis
major functions of membranes
1. barriers - contain essential molecules within cells/nuclei/organelles and exclude non-essential molecules
2. support matrix for macromolecules
solubility in a lipid (neutral) environment
logP = ??
measure of a drug molecules hydrophobicity
logP = lipid/water partition coeffiction
what factors should be considered with hydrophobicity/lipidphilicity?
- ionizability of molecules (+/-)
pH = ?
Ka = ?
[A- or B][H+]/[AH or BH+]
what is the henderson hasselbach equation
pH = pKa + log [Base]/[Acid]
are most drugs acids or bases
what are 2 special membranes
blood brain barrier (bbb)
characteristics of blood brain barrier (bbb)
- very hydrophobic
- drugs must be highly non polar to pass
- psychoactive drugs
- compromised in very young and old
characteristics of placental barrier
- similar to bbb
- many drugs readily enter placenta (and may get trapped)
what are the major mechanisms to terminate drug action
3. metabolism (or biotransformation)
metabolism is the most important determinant of _1_ of drug action and _2_ of response
metabolism alters pharmacological _1_ and _2_
metabolism greatly increases the ability to ____ drugs
what are the types of metabolism
inactivation - metabolite is less active (or inactive)
activation - metabolite is more active (Pro-drugs)
combination of activation and inactivation - different activity
location of metabolism
drug metabolism is also known as what
(drug = xenobiotic)
goal of xenobiotic metabolism?
hydrophobic molecule --> hydrophilic molecule
want to increase drug excretability and decrease drug activity
what happens to drug in phase I of xenobiotic metabolism?
increase functionality (activity)
increase water solubility
what happens to drug in phase II of xenobiotic metabolism?
increate water solubility
what phase in metabolism is oxidative?
what phase in metabolism is synthetic?
what reactions happen in phase I metabolism
where does oxidation (and reduction) happen in phase I metabolism
where does hydrolysis take place in phase I metabolism
what reactions occur in phase II metabolism
where does conjugation/synthetic happen in phase II metabolism
ER and cytosol
what enzyme superfamily mediates oxidation in phase I metabolism
what cytochrome P450 independent enzymes perform oxidation in phase I metabolism
1. flavin monooxygenase
2. amine oxidase
phase I metabolism reactions creates polar _1_ and phase 2 metabolism reactions add _2_ to handles
2. polar molecules
phase I metabolism reactions make drugs more polar by adding/revealing ____
what does N-dealkylation form
amines and aldehydes
what does O-dealkylation form
phenols and aldehydes
what does N-oxidation form
primary, secondary, and tertiary amines
major enzymes for the breakdown of neurotransmitters that are primary amines
what happens in phase II metabolism
form new covalent bonds to drug or metabolite via handles
add larger structural/functional units to the handles created in phase I
what phase II metabolism reaction is the major route in all mammals?
what enzyme catalyzes glucuronidation (phase II)?
what cofactor is required in glucuronidation (phase II)?
what is happening in glutathione (tripeptide) conjugation
add glutathione (tripeptide) to electrophilic drugs to yield mercapturic acid derivatives
what catalyzes sulfation in phase II
what cofactor is required for sulfation in phase II
what enzyme catalyzes glutathione conjugation
what enzymes catalyze amino acid conjugation (phase II)
in methylation, coenzyme _1_ is used to add _2_ to _3_, _4_, and _5_ atoms
in acetylation, _1_ are formed by adding an _2_ group to _3_.
1. inactive amides
2. acetyl (CH3CO-)
3. primary amines
acetylation is catalyzed by what enzyme
how do we use the sequenced human genome
genetic testing for:
- genetic diseases
- adverse response to specific drugs
measuring gene expression in response to drugs
development of more specific drugs (pharmacogenomics)
diagnosis by biochemical markers
what are these biochemical markers
biochemical genetic testing
- loss of enzyme activity
- increase or decrease in a metabolite
what form of genetic testing is good for detection of carriers
what form of genetic testing helps with understanding disease pathway
what form of genetic testing provides a diagnosis before symptoms appear
what form of genetic testing test DNA for causative mutation
what is pharmacogenomics
study of how an individuals genetic inheritance affects the body's response to a drug
what holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own genetic makeup
understanding an individual's ___ ____ is thought to be the key to creating personalized drugs with greater efficacy and safety.
Mutations in proteins that metabolize drugs can affect ____
Mutations in proteins that are drug targets can affect ____
ex vivo = ?
in vivo = ?
viruses and liposomes
how could someone watch and follow a drug through the body?
radio labeling drugs --> positron emission
what are inborn error of metabolism
recessively inherited enzymopathies
disorders of intermediate metabolism
how is inborn error of metabolism inherited
In the metabolic pathway, what happens if you do not have enough of a functional enzyme?
Failure of formation
albinism is what kind of inborn error of metabolism?
failure of formation
(no tyrosinase to produce melanin)
Goitrous cretinism is what kind of inborn error of metabolism?
failure of formation
(lack of thyroid hormone)
if there is an inborn error of metabolism where there is an accumulation of precursors, what happens if the precursor is soluble (hydrophilic)?
- diffuse increase in bodily fluids and tissues
- increased excretion in urine
if there is an inborn error of metabolism where there is an accumulation of precursors, what happens if the precursor is insoluble (hydrophobic)?
- stored in various tissues or tissue organelles
- accumulation leads to progressive problems
alkaptonuria is what kind of inborn error of metabolism?
accumulation of precursors
phenylketonuria is what kind of inborn error of metabolism?
accumulation of precursor
examples of accumulation of precursors insoluble?
lipid storage disease
glycogen storage disease
lysosomal storage disease
(lets make ghost levitate pronto)
Hurler syndrom MPS-1 is what kind of inborn error of metabolism?
accumulation of precursors
congenital adrenal hyperplasia is what kind of inborn error of metabolism?
increase alternate products
cystinuria is what kind of inborn error of metabolism?
disorder of transport
cystic fibrosis is what kind of inborn error of metabolism?
disorder of transport
hyperlipidemia is what kind of inborn error of metabolism?
familial gout is what kind of inborn error of metabolism?
inborn errors are individual _1_ but _2_ common
what kinds of inborn errors of metabolism are there?
1. failure of formation
2. accumulation of precursor
3. increase alternate products
4. disorders of transport
5. excess production
6. receptor disorders
advantages of recombinant proteins over those purified from natural sources
2. human protein
3. decrease viral hazard
how are recombinant proteins produced
microbes - yeast/bacteria
pharming - introduce human gene behind a whey promoter into a farm animal and purify protein from milk
characteristics of using animals cells to produce a recombinant protein
- complex proteins that require secondary modifications
- growth factors (serum)
characteristics of using microbes (bacteria/yeast) to produce recombinant protein
- use fermentor
- large amounts
characteristics of pharming to produce recombinant protein
- introduce human gene behind a whey promoter into a farm animal and purify protein from milk
how is insulin produced
examples of recombinant proteins
erythropoietin - anemia
human growth hormone - dwarfism
tissue plasminogen activator (t-PA) - strokes
clotting factor VIII - hemophilia
what are not many protein drugs effective orally?
proteins are digested in the stomach by amide hydrolysis
how must blood proteins being injected
how can insulin be injected