Introduction/Drug Action Flashcards
what is pharmacology?
the study of all compounds that interact with the body and includes knowledge of the interactions between these compounds and body constituents at any level of organization
what is a drug?
any chemical substance that affects a living system
what is toxicology?
the study of harmful effects of drugs
why are children more vulnerable to toxins?
because their metabolism isn’t as efficient and have different surface/area ratio
what is the risk-benefit evaluation?
all drugs will have side effects, but we must make sure that the benefits outweigh the risks
what is proteomics?
the study of proteomes, or the entire complement of proteins expressed in a certain cell, tissue, organ system, or the body
what is pharmacogenomics?
understanding genetic differences amongst people and how these differences influence one’s response to drugs
what are the types of drug names?
- chemical
- generic
- trade
what is pharmacodynamics?
what the drug does to the body
what is pharmacokinetics?
what the body does to the drug
what is therapeutics? what are indications and contraindications?
- therapeutics: using a drug to treat or prevent disease
- ind: when you should use the drug and what it is used for
- cont: when you should not use the drugs
what is bioavailability?
how much of the drug is available to get into the systemic circulation, after getting through the liver
what are the methods of administration?
- oral
- parenteral (injection)
- inhalation
- topical
- sublingual
what are the advantages and disadvantages of oral administration?
- adv: easy, cheap, convenient
- dis: stomach acidity may destroy the chemical composition of certain drugs (particularly biologicals), and liver inactivation can act really strongly on some compounds
what are the different injection methods?
- subcutaneous (under skin)
- intravenous (in bloodstream)
- intramuscular
- in cerebrospinal fluid
- intraperitoneal
what are the advantages of injecting a drug?
fast, accurate, and controlled absorption
what are the advantages of inhaling a drug?
- easy to administer
- rapid systemic effect since lungs have huge surface area
what are the advantages of sublingual drug administration?
- rapid
- no first-pass
what does the time course and peak concentration look like for Iv, oral, and rectal?
- IV: high initial peak and drops quickly as it gets distributed
- oral: slower rise since it takes time for it to be absorbed by GI and lower peak due to first-pass
- rectal: slow absorption and lower peak level
what are the two types of drug selectivity?
- selective: mostly targets one area
- generalized: acts on all systems
what is the a drug receptor?
a macromolecular protein target to which endogenous ligand or exogenous agonist/antagonists can bin to to cause cellular response
what are the different action of receptors?
- autocrine (acts on itself)
- endocrine (chemical transported through blood)
- paracrine (chemical acts on nearby cell)
- juxtracrine (chemical that acts on neighboring cell via connection)
what does the affinity of a drug to an ion channel depend on? what does this tell us about the drug?
- depends on the membrane potential and channel cycling frequency
- tells us how quickly the drug will bind
where do natriuretic peptide receptors activate cellular responses?
kidney and the heart
how do the response times differ on different types of receptors?
- ion: fast to respond (msecs)
- GPCR: 2nd messenger must be activated (secs)
- enzymes: blocking or stimulating enzymes (mins)
- DNA-linked: translocation, transcription, translation, enzymatic activity (hrs)
what do cancer treatments affect/alter?
alter cell division/reproduction process with microtubule destabilizers/stabilizers (alters mitosis)
are receptors static or dynamics? explain.
they are dynamic
- there is constant turnover (synthesis, transport, stimulation, recycling, resynthesis, etc. )
- cell can respond by changing number of receptors at the PM
explain the concept of biological variation and how that connects to quantifying and comparing the effect of a drug (what type of graphs are used?).
- everyone is different due to their genetics and the environment
- graph plotting drug dosage and number of people responding we see a normal distribution since most people will respond with moderate dose but others need more or less
- dose-response curve: plots the cumulative percentage of people responding to a dose (usually log scale is used)
what is the ED-50?
the dose required to produce an effect on 50% of the population
what do you use a dose response curve for?
- comparing drugs: some may be more potent than other (use a lower dose for same effect) and might want to use the least or most potent depending on other factors
- studying the magnitude of drug effect: study effect on single cell, organ system, or in an individual
what is the following on a dose response curve: threshold, ceiling dose, potency
- threshold: it is the minimum dose to see an effect
- ceiling dose: does where effect levels off and cannot get higher
- potency: if more towards the left is more potent and if more to the right, less potent
what is receptor occupancy? what are spare receptors?
- it is the percent of receptors that are occupied for a specific response - usually less than 100%
- spare receptors are the ‘fail-safe’ mechanisms - they are the receptors that are not being used
what is the efficacy of a drug?
the proportion of receptors that are forced into their active conformation when occupied by a drug and that give the desired effect
what is a partial vs full agonist? what are the benefits of partial agonists?
- full: binds to receptor and leads to large response
- partial: binds but leads to small response (low efficacy)
- benefit: can lead to less adverse effects, can block access to full agonist by giving a partial agonist
what is a competitive vs non-competitive antagonist and how do they affect the dose-response curve?
- competitive: bind to same site, will shift the curve to the right and when given at VERY high concentration, it can decrease the maximum response agonist
- non-competitive: bind to different site (allosteric), will lower the peak of the curve
what is an irreversible vs reversible antagonist?
- irreversible: binds irreversibly and decreases the number of available receptors, so body has to synthesize more/ increase turnover
- reversible: binds reversibly, is most common one (irreversible can cause toxicity)
what is TD50?
the dose required to produce a toxic effect in 50% of the population
what is LD50?
the dose required to produce a lethal effect in 50% of the population
what is the therapeutic index?
the ratio of toxic to the therapeutic effect; TI = TD50/ED50
what is considered a good vs bad TI?
- the larger the Ti, the better it is
what is the therapeutic window?
the dose range within which most people get therapeutic effects without side effects
what is the safety factor?
TD1/ED99
what is a benefit and a toxicity outlier?
- benefit: respond to the drug a much lower (or much higher dose)
- toxicity: have toxic effect at much lower (or higher) dose
what are the 5 parts of pharmacokinetics?
- liberation
- absorption
- distribution
- metabolism
- excretion
what is absorption of a drug?
the transfer from the site of administration to the bloodstream
what are ways that drugs can pass through the plasma membrane?
- aqueous pores (small molecules, water soluble molecules, ions)
- diffusion (passive, lipid soluble molecules, gases, small polar molecules)
- transporters (large molecules and charged particles)
what is the effect of the stomach on drugs?
- has low pH and little absorption happens, mostly a reservoir
- weak acids: will be non-ionized in low pH so will be able to cross lipid membrane of stomach cells
- weak bases: will be in ionized forms in low pH so won’t be able to cross membrane and will be absorbed in the intestine
what is the effect of the small intestine on drugs?
- has a higher pH
- has much more absorptive surface so absorbs pretty much all drugs
what is the effect of the liver on drugs?
- “scans” what gets absorbed before going into circulation
- metabolized/detoxifies chemicals
- firsts-pass metabolism
how are the drugs distributed and in what form?
- go through body by blood stream and rate of blood flow varies with different organs
- will only be free to move through plasma membrane when is a free drug, cannot when it is bound (there is equilibrium between two forms)
are drugs equally distributed throughout the body?
no because blood flow varies with tissue type (will go in brain first, then muscles, then fat)
what is the duration of action?
time that spans the onset of effect and the time when the effect ceases
what is the lag period?
time until concentration of drug becomes high enough to get therapeutic effect
what are variables that affect drug concentration? how would that look relative to the MEC for toxicity and MEC for therapeutic effect?
- increase concentration: will go above MEC for toxicity
- drug absorbed quickly: will peak very fast and will be at MEC for toxicity but then will also go down quickly
- drug that is eliminated quickly: does not stay above MEC for therapeutic effect long
what are mechanisms by which the BBB protects the brain?
- tight junctions between capillaries
- astrocytes help regulate blood flow into the brain
- very tightly controlled active transport
is the placenta a good barrier?
no, lipid soluble drugs diffuse rapidly and water-soluble drugs can pass slowly
which proteins can drugs be bound to? in which situation can this be altered?
- bind to albumin (impaired in liver disease)
- bind to glycoproteins (elevated in inflammation)
what is the apparent volume of distribution?
amount of drug in body (in mg)/concentration of drug in plasma (in mg/L)
what does a high and a low AVD mean?
- low: high protein binding (most in plasma)
- high: high tissue binding (most is in tissue)
what are variations in AVD due to?
- properties of the drug (e.g. absorption efficiency)
- protein binding
- tissue binding
what is the loading dose and how can you determine the loading dose of a drug?
- is amount of drug to administer
- can figure out with AVD and required concentration in plasma for effect
what is drug metabolism?
the alteration of the chemical structure by an enzyme
what are changes that can be done to a drug during metabolism?
- conversion from a nonpolar, lipid-soluble compound to a more polar form that is more water-soluble (so can be excreted more readily by kidney)
- converted to less active or inactive metabolites
- conversion of a prodrug into active form
what are the two phases of drug metabolism? which enzymes catalyze reaction in each phase?
- phase 1: oxidation/reduction/hydrolysis and renders the drug inactive - done by cytochrome p450 enzymes
- phase 2: conjugation, which couples drug molecules to endogenous substituent group to make it more water-soluble for renal elimination - catalyzed by transferases
where are cytochrome p450 enzymes usually found?
smooth er of hepatocytes by can also be found in GI tract, lungs, skin, kidneys, and brains
how are cytochrome p450 enzymes named?
- CYP
- family: number between 1-17
- sub-family: letter
- enzyme or gene: number
what are xenobiotics?
substances that are foreign or exogenous to a system
what do CYP1/CYP2/CYP3 do? what do CYP4/CYP5/CYP8 do? what do the others do?
- 1,2,3: drugs, xenobiotics
- 4,5,8: internal breakdown
- others: steroid hormone breakdown
What does the relative concentration of CYP enzymes in the liver tell us?
nothing, there is no relation between the amount and its importance
which CYP enzymes are the most important in drug metabolism?
CYP3A, CYP2C, CYP2D6
what are factors that influence enzyme function/drug effect in individuals?
- polymorphisms
- drug interactions
- age
- environmental factors
- diseases
what are the consequences of genetic polymorphisms?
- altered drug effect
- altered sensitivity to stereoselective metabolism
- altered sensitivity to interactions
- altered production of active metabolites
what are the effect of drug metabolism enzyme inducers and inhibitors? what mechanism may they have?
- inducer: high exposure stimulates synthesis of drug-metabolizing enzymes to increase speed (can increase clearance)
- inhibitor: inhibition leads to rapid overdose because cannot be broken down (reduces clearance)
excretion is predominantly done by what?
the nephrons in the kidney
where can drug elimination occur?
- kidney (goes to urine)
- exhaled (breathalyzer)
- secreted in saliva
- secreted in sweat
what is drug clearance?
the quantity of blood that is cleared of a drug in a given amount of time
what is the T1/2? and how many half lives to get rid of dug in body completely?
the half life, which is the time taken to get rid of half of the drug in the body - it takes 4
what is first-order kinetics vs zero-order kinetics?
- first: constant fraction per time unit
- zero: constant amount of drug eliminated (this is due to saturation of enzymes)
when should you get another dose of drug? when is steady state achieved?
- usually at internals of the half-life
- steady state after 4.5 half lives (so 4 doses)
how can tolerance be studied?
animal models: seen by frequency of how often the animal takes the drug
what is tolerance? what are the types?
- the need of more and more drug to get the same effect
- chronic: repeated administration leads to decrease response
- acute: even with one dose, have adaptation in body to fight drug (usually seen in CNS)
what is pharmacokinetic tolerance, pharmacodynamic tolerance, and behavioral tolerance?
- kinet: increase metabolism or decrease absorption / shift to right of dose-response curve but no shift for concentration-response curve
- dyn: adapting site of action (# of drug receptors can increase/decrease) / shift to right for both dose-response and concentration-response curve
- beh: lower effct of drug as result of conditioned response
what is withdrawal?
a series of reactions that are opposite to the effects of the drug
what is neuroplasticity? why is that significant?
the ability to adapt quickly to any new information
- there are lots of stages of communication that can adapt to create tolerance
what are some presynaptic and postsynaptic adaptations that may occur?
- pre: neurotransmitter released from presynaptic neurons in vesicles and go to cleft, and at that cleft can have many fates – binding to receptors, reuptake, diffusion, autoreceptors, synthesis, storage
- post: alter number of receptors – if agonist will downregulate, if antagonist will upregulate
what is cross tolerance?
tolerance for drug of same family develops at same time
what is differential tolerance?
ability to produce tolerance depends on location in body, and differences with the different affects of the same drug (e.g. we usually don’t become tolerant to lethality)
what is behavioral tolerance?
the decrease of potency in affecting a specified behavior after repeated or continuous exposure (learned or conditioned behaviour)
what is the time course for withdrawal?
intensity of symptoms gradually rises and falls unsymmetrically
intensity of withdrawal is related to what?
the dose that was taken and the half-life of the drug (short-acting drugs will have bigger counter-effect)
what are acute and long-term withdrawal effects?
- acute: worst of the symptoms
- long: less intense but may last a very long time
what are the stages of the addiction cycle?
- craving
- ritual
- consumption of drug
- guilt
- emotional trigger
what can you do to treat drug dependance?
- slowly decrease the drug
- substitute to a safer drug, then decrease dose
- prevent relapse with antagonist or agonist
- reduce craving with therapy and altered lifestyle
what are two systems that appear to modulate drug dependance?
- gain reward: activate dopaminergic pathway
- avoid punishment: withdrawal
how can nasal sprays cause dependance?
they constrict blood vessels so that don’t secrete as much mucus, and nerve endings adapt such that vasodilation occurs when not using spray, s have to keep using to breath properly
what are signs of addiction?
- tolerance
- obsession
- increase intake
- loss of control
- abuse despite harm (like risk of cancer)
- withdrawal symptoms
drugs are more addictive when?
onset of effects is rapid and blood concentration rises quickly
where is the dopaminergic pathway located and what is associated with?
located in midbrain and is associated classical reward pathway (which goes from ventral tegmental area to nucleus accumbens (where dop. neurons synapse) to prefrontal cortex)
