Introduction Flashcards
Proadifen and cimetidine are significant and related to each other because _. What class of antibiotics have the same effect?
They inhibit drug metabolism
Macrolide antibiotics
Ethanol, phenobarbitol and phentoin are drugs that are significant and related to one another because _. What other agric, product has the same effect?
The enhance / activate drug metabolism.
DDT
The mechanism of action of probenecid is _
It competitively inhibits organic anion transporter
The mechanims of action of cimetidine is _
It competitively inhibits organic cation transporter
Endobiotics and xenobiotics differ because _
Endobiotics and endogenously produced chemicals while xenobiotics are from exogenous sources
The law that required labeling of all active ingredients was _
The pure food and drug act of 1906
The harrison narcotics act of 1914 did what?
Restricted the sale of addictive drugs
What were the 2 goals of the food, drug and cosmetic act of 1938?
- Labeling of inactive ingredients
- Documentation of product safety
The Durham-Humphrey amendment to the food and drug act did what?
Split drugs into legend (prescription) and non-prescription
What was the amendment to the food, drug and cosmetic act that required documentation of drug efficacy?
The Kefauver-Harris amendment
The law that created the DEA, and restricted the manufacture and distribution of controlled substances was _
The controlled substances act
Schedule 1 drugs include heroin, marijuana and LSD. These are all drugs described as _
Having no medical use
What is the goal of phase 1 studies? Who are the subjects?
Establish initial dose and safety
Healthy volunteers
What is the goal of phase 2 studies (2)? Who are the subjects?
Establish efficacy in treating disease and effective dose
Potential patients
What is the goal of phase 3 studies? Who are the subjects?
Compare versus established treatment protocol
Potential patients
What is an NDA regarding drug development?
New drug application, phase 4 which is post market monitoring
What is a category 1 OTC?
Both safe and effective
What is a category 2 OTC?
Not safe, not effective or both
What is a category 3 OTC?
Data on safety or efficacy inconclusive
What law accomplished the following:-
- Vitamins, minerals, herbals, etc are no longer approved / regulated by FDA
- No company responsibility for ensuring effectiveness
- Ensuring safety is manufacturer’s responsibility
The dietary supplement health and education act of 1994
What are the 2 sources of technical information about drugs from the manufacturer?
Package inserts
Physician’s desk reference
What are the 3 sources of technical information about drugs not from the namufacturer?
American hospital formulary service
US Pharmacopeia Dispensing Information
AMA Drug Evaluations
Regarding pharmacology, ADME stands for _. This is related to pharmacokinetics or pharmacodynamics?
Absorption Distribution Metabolism Elimination Pharmacokinetics
Understanding what the body does to a consumed drug is referred to as _
Pharmacokinetics
Understanding what a consumed drug does to the body is referred to as _
Pharmacodynamics
Enteral administration refers to any administration via _. Three types of enteral administration are _
Any thing via GI
Oral, rectal, sublingual
Any drug administration that requires the use of a needle is referred to as _
Parenteral administration
What is the difference between topical and transdermal application?
The intended site of action. Topical has intended site of action of skin, while transdermal is going through skin to get to intended site of action
How would you have to administer a drug so that it avoids the liver before getting to the right heart, lungs and left heart?
Intravenous administration
What is referred to as “complex formation in the GI tract”?
This is when drugs are administered orally, they can form new compounds in the GI tract that affect drug absorption e.g. binding calcium, food, etc
What is the first pass effect?
This accounts for the fact that many drugs are metabolized by the liver upon their “first pass through”, therefore that has to be accounted for when choosing a route of administration
What is an enteral route of admin that completely bypasses the first pass effect? What enteral route reduces it?
Bypasses - sublingual
Reduces - Rectal
What are 2 routes of admin most commonly used for administration of proteins / peptides? What is a consideration with these routes?
SubQ or IM
Activities / surroundings can alter absorption (e.g. cold leading to vasoconstriction)
What is a route of administration that has the advantage of very well controlled rate of admin as well as rapid onset of action, and knowing the entire dose enters the blood?
IV
If you wanted to administer a very high dose of drug to a specific organ, what is a route of admin to take? What is the danger?
Intra-arterial
Hemorrhage
The best way to get a high dose of drug directly into the CNS is via _ admin
Intraspinal
An advantage of topical administration regarding side effects is _. Under what conditions might this advantage be moot?
Local effects, minimal systemic effects
Use too much drug, then some gets into blood stream, now have systemic effects
The options are arteries, arterioles, capillaries, venules and veins. The majority of drug absorption occurs across _. Why?
Capillaries
Have the thinnest walls
Biomembranes can be considered as lipoprotein barriers
containing small pores. What type of transport depends mainly on lipid solubility of the drug in question?
Passive diffusion
What is the major difference between active and facilitated diffusion? What is the main similarity?
Difference - Active is coupled to an energy source, facilitated is not directly coupled to an energy source
Similarity - Both require the use of channels
Movement of drugs between cells (vs. through cells) refers to what type of transport?
Aqueous diffusion
The type of transport that can be used to highly concentrate a drug in a compartment regardless of its concentration gradient is _
Active diffusion
What is the major requirement for pinocytosis / exocytosis to work?
The molecule has to be large enough to be recognized by the cell
Between the ionized and non-ionized form of a drug, which is more likely to be able to cross a lipid barrier? Which is more likely to be water soluble?
Cross barrier - non-ionized
Water soluble - Ionized
pH = pKa + log ([ionized]/[non-ionized]). This represents the equation for acids or for bases?
Acids
pH = pKa + log ([non-ionized]/[ionized]). This represents the equation for acids or for bases?
Bases
What is the definition of the pKa?
The pH at which the ratio of ionized to non-ionized form of a drug is equal to 1
Consider the ionized and the non ionized form of an acid. What is happening to these 2 elements as you increase the pH of a solution?
Know that the ionized form of the acid is A-, non ionized is HA. As the pH goes up, more free H+, therefore more free A-, therefore as pH increases, more ionized acid
Consider the ionized and the non ionized form of a base. What is happening to these 2 elements as you increase the pH of a solution?
Know that ionized form of the base is BH+. Therefore as pH goes up (more free H+), that means you’ll have more free B. Therefore as pH goes up, less ionized form is present in solution.
For thinking about the henderson hassellbach, know that for the equations, it is A- and B. Think that the what makes it an acid is that it is able to donate a proton, while a base is able to accept a proton
HA H+ and A-
B and H+ BH+
For weak organic acids, what are the 2 functional groups that are able to donate a proton? What is the main functional group of the base that make it able to accept a proton?
Acids - COOH and OH (Become COO- and O-)
Base - NH2, (become NH3+)
Can you draw the graphical form of the henderson hasselbach equation?
See ppt. pg 21
What is the pH partition hypothesis?
For Weak Organic Acids or Weak Organic Bases, the Non-Ionized, more Lipid-Soluble form crosses biomembranes much more readily than does the Ionized,
more Water-Soluble form*
For a lumen pH of 1.4 and a pKa of 3.4, calculate the ratio of ionized to non-ionized aspirin, a weak organic acid
pH = pKa + log [i]/[ni]
1.4 = 3.4 + log [i]/[ni]
log [i]/[ni] = 1.4 – 3.4 = –2
[i]/[ni] = 10–2 = 1/100
For a plasma pH of 7.4 and a pKa of 3.4, calculate the ratio of ionized to non-ionized aspirin, a weak organic acid
pH = pKa + log [i]/[ni]
7.4 = 3.4 + log [i]/[ni]
log [i]/[ni] = 7.4 – 3.4 = 4
[i]/[ni] = 104 = 10000/1
Both active transport and facilitated diffusion rely on channels. What is the major difference between the 2?
Facilitated diffusion uses no energy, transports substrates from areas of high to low concentration
Glucose, some amino acids and ion transporters work by _ type of transport
Facilitated diffusion
What are the 2 types of active transport transporters mentioned in the notes? What is the major difference regarding their energy source?
MDR / MDP - has ATPase activity
SLC - indirect energy source
There are 2 examples of active transport receptors provided. Which is most likely to be an antiporter protein?
The SLC, it uses existing gradient to transport its substrates
Majority of drug transport occurs using what type of transporter?
ABC transporters
The blood brain barrier is very tight. What is a means which this structure can be circumvented as discussed in this class?
Drug transporters
Generally speaking, between the SLCs and the ABC type pumps, which is likely to be an influx pump (into cell) and which is likely to be an efflux pump?
ABC - efflux, think drug resistance
SLC - Influx pump
Diffusion that occurs between cells via channels is called _
Aqueous diffusion
How do increased gastric emptying time, decreased intestinal transit time and binding to drugs to mucus or food affect absorbtion?
Reduce it
Where is a drug most likely to accumulate, in a compartment with or without receptors?
In a compartment without receptors
What role does the presence of drug receptors have on if a drug will accumulate in a compartment?
None, its is mainly an issue to transporters / permeability
What types of molecules are most likely to accumulate in the brain and adipose tissue?
Non-polar drugs
If you were to graph the concentration of free drug in plasma of a drug that could bind plasma proteins, at what point will the rate of increase of free drug markedly change?
At the point when the plasma proteins are saturated, more drug added to the system will increase plasma concentrations more than before saturation
What kind of effects can be observed when 2 drugs compete for binding on plasma proteins?
increased biologic effects, metabolism and toxicity
Tight junctions that form the blood brain barrier are formed between what type of cell? Selective permeability of the BBB means that _ soluble drugs are more likely to end up in the brain
Endothelial cells
Lipid soluble
Which is more restrictive, the blood BB or the blood-placenta barrier?
BBB
What is the difference between a quantal drug response and a graded drug response?
Quantal - All or nothing
Graded - A continuous range of possibilities
A dose response curve may be plotted of quantal responses, paradoxical as that may seem. What change has to be made to the graph variable for this to be possible?
The Y axis that to now plot responders within a POPULATION
an ED50 and a TD50 is common to both a graded and quantal dose response curve. Which of the two types of responses can also be used to generate LD50 data?
Quantal dose response curve of entire population. Hard to calculate dose that kills 50% of a population of 1 (graded curve)
What is the Emax of a dose response curve? For a single drug, what is the main determinant of Emax?
The maximal effect that can be elicited in response to a drug
The number of receptors engaged
Changes in efficacy are reflected by curves that shift along the _ axis, while changes in potency are reflected by curves that shift along the _ axis
Efficacy is Y axis (Think Emax)
Potency is X axis (Think different ED50s)
What is a potency ratio?
A ratio of the ED50s of 2 drugs
What is a therapeutic index?
A measure of how far apart the ED and LD 50 curves are
Both an agonist and an antagonist bind the receptor. What differentiates them? While an agonist will likely have a sigmodal curve, what is the shape of an antagonist curve?
Agonist elicits an effect, while the antagonist has no effect by itself
Flat line
What is intrinsic efficacy?
The ability of an individual drug to generate a response, regardless of whether it is a full or partial agonist
What is an inverse agonist? What condition has to be met for you to observe the effects of an inverse agonist?
It is a molecule that is able to reduce receptor activity below basal levels
You need to have some basal receptor activity that the inverse agonist can reduce
In terms of Emax and ED50, what effect does a competitive antagonist have on those parameters?
A competitive antagonist will change the ED50 (more agonist needed for same effect) but won’t change the Emax since you can outcompete it with enough agonist
In terms of Emax and ED50, what effect does a non- competitive antagonist have on those parameters?
A non-competitive antagonist will change the Emax (will reduce the max effect) but will not change the ED50
In what conditions can a partial agonist be used as an antagonist?
When a partial agonist is mixed with an agonist, it will reduce the number of receptors activated to the max, therefore acting as an antagonist
Why do the effect of non-competitive antagonists take longer to reverse?
They work by covalent binding to the receptor, therefore usually require new receptor synthesis
What is a chemical antagonist?
An antagonist that exerts its effects by directly modifying the agonist in question, vs by acting at the receptor
What is a physiological antagonist?
An antagonist that acts at a receptor exerting an opposite effect of the agonist
What is the difference between a selective and a specific drug?
Selective - can bind many receptors, has a preference
Specific - Interacts with only one receptor subtype
What is an idiosyncratic drug response?
An unusual / atypical response to the drug, usually occurs in a small subset of the population
Arrange in order of increasing severity: Toxic effect, side effect, adverse effect
Side effect - minor, undesired
Adverse effect - major, serious medical consequence
Toxic effect - very serious adverse effect
What are the 4 basic sources of side effects?
Chemical property of drug
Drug acting at multiple receptors
Drug acting at many subtypes of receptors
Drug acting at receptor in unintended tissue
What are the 3 mechanism by which drug actions are stopped? Which is responsible for stopping majority of drug actions?
Redistribution
Biotransformation (Majority)
Excretion
What are the 2 goals of biotransformation reactions?
make compounds more hydrophillic
Make compounds less pharmacologically active (usually)
What are the functional groups that are either unmasked or introduced in phase 1 reactions?
Unmasked - NH2 and SH
Introduced - OH
What are the 3 reaction classes for phase 1 reactions? Which is most prevalent?
Oxidation (most prevalent)
Reduction
Hydrolysis
What are the enzymes responsible for the majority of phase 1 oxidation reactions? What are 2 other names?
CYPs
MFOs (mixed function oxidases)
Liver / hepatic oxidases
Beyond the CYPs, what other oxidases are important in metabolism?
MAO-A and MAO-B
What enzymes carry out reduction reactions? What enzymes carry out hydrolysis (2)
Reductions - oxidoreductase
Hydrolysis - Plasma and acetyl - cholinesterases
Where are you most likely to find acetyl cholinesterase? What type of compound is the substrate for plasma cholinesterase?
The synaptic cleft of cholinergic synapses
Ester drugs
How many steps / reactions are involved in the Phase 1 reactions? What is the main co-factor of the first reaction?
2 reactions
NADPH is required for the first reaction
Which reaction in the series of phase 1 reactions is catalyzed by CYPs? What are the 2 flavoproteins usually involved in this reaction?
Catalyzes reaction 2
FAD and FMN
What is the goal of phase 2 reactions? What are the 4 examples of substrates that can be added during this phase?
Add an endogenous polar substance to the substrate
- glucuronic acid
- sulfate
- amino acid
- glutathione (GSH)
WHat are the class of enzymes that catalze the phase 2 reactions? What are the 5 examples provided and which is most common?
Transferases Glucuronyl transferase (most common) Sulfotransferase COMT Acetyltransferase Glutathione Transferase
How many steps are involved in Phase 2 reactions? What step is usually catalyzed by the transferases?
2 reactions
Transferases catalyze step 2
The first reaction of the phase 2 reactions usually generates a substrate required in subsequent steps. What is this substrate in for the glucuronyl transferases (UGTs)? What about for the sulfotransferases (STs)?
UGTs - UDP-alpha-glucuronic acid (UDPGA)
STs - 3 phosphoadenosine-5-phosphosulfate (PAPS)
What us the difference between an active metabolite and a reactive metabolite?
Active - drug metabolite with more activity than parent compound
Reactive - drug metabolite that is toxic produced from relatively inert precursor
What is the only known role of proadifen?
It is an inhibitor of drug metabolism
What are 3 drugs provided as examples of metabolic enzyme activators? What are 2 other non-drugs with the same effect?
Drugs - Ethanol, phenobarbital, phenytoin
Others - Pesticides, DDT
How does hepatic disease affect metabolism and duration of action?
Decreased metabolism and increased duration of action
What are the 4 major routes of administration provided?
Kidney
Liver
GI
Lungs
What is the primary means for reducing drug concentration in tissues and thus in terminating drug action?
Excretion
What are the 3 processes involved in drug excretion?
Filtration
Passive diffusion
Active secretion
What is the main site of filtration? What are 2 limitations?
Glomerulus in kidney
Size and binding to protein
What are 2 mechanisms to increase filtration?
Increase urinary volume
Increase blood flow to the kidneys
What can occur to non-ionized lipophillic drugs in the renal tubule?
Can be reabsorbed from the tubule lumen into plasma
What is the major determinant of whether weak organic acids or bases diffuse across the lumen? What are 2 drugs that can modify this?
pH in the various partitions
Ascorbic acid can acidify the lumen
Sodium bicarb can make the lumen more basic
What are 2 of the major transporter systems in the renal tubule for transporting ions? What are their substrates (3) and (1)?
OAT - acids, glucuronide conjugates, sulfate conjugates (negatively charged)
OCT - bases
What is the drug that is known to be a competitive inhibitor of the OAT? What about the OCT?
OAT - Probenecid
OCT - Cimetidine
Which is able to filter larger substances, the liver or kidneys? What are 3 transporters found in the liver?
Kidney filters larger substances
OCTs, MRPs, OATs
What is the enterohepatic circulation? What is the source of enzymes that makes this possible?
A metabolized drug may become “unmetabolized” as it transverses the GI, allowing its reabsorption
Enteric bacteria
