Module 1: Pharmacodyamics Flashcards
Define pharmacodynamics
What a drug does to the body (effects, mechanism of action)
Define pharmacokinetics
How the body handles the drug (absorption, distribution, metabolism, excretion)
What is an example of endogenous ligands?
Hormones or neurotransmitters
Drugs are administered to achieve which two affects?
A beneficial response or a selective toxic effect
What are four common types of receptors?
Regulatory proteins, transporters, enzymes, structural proteins
What are the four common signalling mechanisms of regulatory proteins?
Ligand gated ion channels as receptors
G-protein coupled receptors
Intracellular receptors
Regulated Transmembrane Enzymes
Briefly describe regulatory proteins
Proteins that mediate the actions of endogenous chemical signals.
Generally mediate transmembrane signalling
What is the location of ligand gated ion channels?
Channels span across the cell membrane, with portions protruding out each side
What do ligand gated ion channels transport?
Sodium, chloride, and other ions
How does the ligand-gated ion channel open?
An endogenous ligand or drug binds to the receptor on the outside, causing a conformational change in the protein, opening it and allowing ions to flow through
What is an example of a ligand gated ion channel?
Nicotinic receptors
Where are G-protein coupled receptors located?
They span the outside to inside of the cell membrane
How do G-protein coupled receptors activate?
A drug binds to the receptor on the outside of the cell membrane, a conformational change of the receptor protein occurs and activated the G-protein. The G-protein activates a number of second messenger systems that amplify the signal
T/F - G-protein coupled receptors are a faster process than ligand-gated ion channels
False! G-protein coupled receptors are slower due to the activation of second messengers
What activates G-protein coupled receptors?
Drugs, hormones, neurotransmitters, other signalling molecules
What kinds of molecules activate intracellular receptors?
Lipid-soluble ones (including lipid soluble drugs), such as steroid hormones (cortisol) and thyroid hormones (Thyroxine)
What affect does activating an intracellular receptor have on the cell?
Gene expression is modified and therefore subsequent protein synthesis (whether an increase or decrease)
Why is the intracellular receptor process the slowest?
New proteins have to be synthesized and it takes time for those proteins to accumulate to produce an observed effect
Describe where transmembrane enzymes are located
Located on the outside of the cell, but linked to an enzyme inside the cell
How are regulated transmembrane enzymes activated?
When a drug binds to the extracellular receptor, the change in the receptor-drug complex allows for the activation of an enzyme that activates biochemical reactions to produce a biological effect
Describe: non-competitive antagonist
Binds irreversibly to a receptor but does not activate it. Causes a conformational change of the receptor, inhibiting an agonist from binding
Describe: Competitive antagonist
Bind to the same spot on the receptor as the agonist, but does not produce a response. Does not allow for agonists to bind
Protein kinases are which type of enzyme?
Regulated transmembrane enzymes
Describe: Partial agonist
Bind to the receptor and activate it, but produce a weaker response
T/F - All drugs are mediated by receptors
False. Some drugs interact non-specifically with the biological system.
Ex., antacids use an acid-base neutralization reaction
Ex., Some chemotherapy drugs chemically disrupt cancer cell function
Describe: Agonist
Agonist bind to the receptors and activate it
Describe: Allosteric activator
Binds to a different area of the receptor than the agonist, but makes it easier for the receptor to be activated. Increases the ability of an agonist to activate a receptor
What is the graded dose response relationship?
Describes a drug effect which increases in proportion to increasing the drug dose
Why does the inhibition from a non-competitive antagonist more permanent than that of a competitive antagonist
Because non-competitive antagonists cause a conformational change instead of just fighting for the receptor site, increasing the concentration of agonist does not overcome the inhibition
What is the ED50?
The dose of a drug that will result in 50% of the maximal effect, or the dose of a drug that is effective in 50% of a population
What is the receptor threshold?
The minimum number of receptors that need to be activated to observe a measurable response
T/F - The dose is proportional to the effect only after the receptor threshold has been reached
True!
Describe the maximal response
The response where further increases in dose will no longer correspond to increases in therapeutic effect
Will an agonist, partial agonist, or allosteric activator plus an agonist have the greatest maximal effect?
An allosteric activator plus an agonist, followed by the agonist, followed by the partial agonist
Define efficacy
The maximum pharmacological response that can be produced by a specific drug in that biological system
Define potency
The dose or concentration of a drug that is required to produce a response of a certain magnitude - usually 50% of the maximal response
Drug A produces a response at 40mg, Drug B produces the same response at 20mg. Is drug B more efficacious or more potent?
Drug B is more potent, as it is producing the same response, but at a lower dose
Drug A can treat pain patients say is a 10/10. Drug B can treat pain that is described as a 3/10. Is Drug A more efficacious or potent?
Drug A is more efficacious. It can produce a greater maximum effect.
T/F - Clinically, efficacy is more important than potency
True! Maximal effectiveness of a drug is generally what determines which drug is chosen to treat a condition. The potency doesn’t matter as much, as doses can be adjusted
Describe the therapeutic range
The range of drug concentration in the plasma that is above the minimum concentration to produce a response, but below toxic concentrations
What are the four processes of pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Describe absorption
The movement of a drug from the site of administration into the blood
Describe distribution
The movement of a drug from the blood to the site of action and other tissues
Describe metabolism (biotransformation)
The conversion of a drug into a different compounds, usually a more water-soluble one
What is bioavailability?
The percentage of an administered dose that reaches the blood in active form
The unionized form of a drug is ___ soluble
Lipid soluble
Describe excretion
The removal of a drug and its products from the body
What route of administration guarantees 100% bioavailability?
Intravenous administration
What is a weak base?
A neutral molecule that can combine with protons to become positively charged
What are some of the key components of the absorption?
Breakdown of excipients (medium for the drug to enter the body), dissolution in GI fluids, crossing of biological membranes
In an acidic environment, will the ionized or unionized form of a weak base predominate?
The ionized - as there are plenty of protons available
What is a weak acid?
A drug that is a neutral molecule that can dissociate into a negatively charged molecule and a proton
The ionized form of a drug is ___ soluble
Water soluble
In an acidic environment, will the ionized or unionized form of a weak acid predominate?
The unionized
In a basic environment, will the ionized or unionized form of a weak base predominate?
unionized
In a basic environment, will the ionized or unionized form of a weak acid predominate?
Ionized
Under acidic conditions, which drug (acid or base) is lipid soluble?
Weak acid
Under basic conditions, which drug (acid or base) is lipid soluble?
Weak base
Where are most dugs absorbed? Why?
The small intestine - due to its permeability, large surface area, and high blood flow
If the concentration of a drug in the blood drops below the concentration at any of its distribution sites - what happens?
The drug will move from the site back into the blood to maintain an equilibrium
T/F When a drug is bound to a protein it cannot act and will be excreted
True! Only free drugs are able to act - as drugs bound to proteins cannot reach their site of action
What is the organ where most biotransformation reactions occur?
The liver
What is a phase 1 reaction
The addition or unmasking of a functional group so phase 2 reactions can proceed
What enzyme performs the majority of biotransformation reactions?
Cytochrome P450 (CYPs) - specifically CYP3A4
What is the issue with most drugs using the same enzyme to metabolize its products?
Drugs can compete for the attention of CYP3A4
What are the 4 chemical reactions that can be used for biotransformation
Oxidative reactions using CYPs, oxidative reactions of amines, dehydrogenation of alcohol to aldehydes, hydrolysis of esters and amides
What are phase 2 reactions?
The addition of a large water-soluble moiety to the product from phase 1 - making it water-soluble so the kidney can excrete it
What is the first pass effect?
The biotransformation and inactivation of a drug during absorption from the intestine. The biotransformation of a drug as its absorbed due to the intestine’s biotransformation enzymes
What is a consequence of the first pass effect?
A reduction in the amount of active drug reaching the blood and therefore site of action
What are 4 factors that can affect biotransformation
Other drugs being taken competing for the same enzyme
Genetic factors (slow vs fast metabolizers)
Age (decrease in biotranformation enzymes at birth and in ppl >60)
Disease states (diseases that affect the liver)
If someone has kidney disease - how will this affect drug elimination?
Glomerular filtration will be decreased and therefore excretion will be decreased
If someone has basic urine, what drugs (acidic or basic) will be excreted more?
Acidic
What are the three processes that occur in renal excretion?
Glomerular filtration, passive tubular reabsorption, active tubular secretion
What is first order kinetics?
A constant fraction of the drug is eliminated over a set period of time (if there is [20mg] of drug in the blood and the body eliminates 50% over 4 hours - there will be [10mg] at the end of the 4 hours. After another 4 hours, [5mg] will be left
What is zero-order kinetics?
A constant amount of the drug is eliminated in set period of time because the enzymes responsible are saturated. (ex., no matter how much alcohol is consumed - only 10-13mL will be eliminated per hour)
What is the plateau principle?
After about 5 half-lives, the rate of drug input is equal to drug output. The plasma concentration of the drug has reached a steady state
What is the therapeutic index?
An index telling you how safe a drug is.
How do you calculate the therapeutic index?
TD50 (toxic dose to 50% of the population) / ED50 (effective dose to 50% of the population)
Can you name the 8 common adverse drug reactions? (I def can’t)
Extension of therapeutic effect
Effects in non-target areas
Unrelated to main drug action
Drug idiosyncrasy
Allergic reactions
Adverse biotransformation reactions
Tolerance, withdrawal and addiction
Teratogenesis (Birth defects)
Describe the adverse effect, give an example & solution: Extension of therapeutic effect
Occurs when too much of the drug is in the blood (drug overdose)
In order to stop this adverse reaction, you can reduce the dose of the drug
Too much of an anticoagulant will cause bleeding
Describe the adverse effect, give an example & solution: Effects in non-target tissues
When receptors for the drug exist in more areas than just the target tissues - effects will occur in these other areas
Ex., morphine produces analgesic effects by acting on opioid receptors in the CNS, but also act on opioid receptors in the GI tract causing constipation
Solution: Decrease dose
Describe the adverse effect: Unrelated to main drug action
Effects that are unexpected and unrelated to the intended pharmacological action of the drug. Drug acts on other receptors other than the ones involved in therapeutic effect
Similar to effects in non-target tissues - but different in the drug is acting on different types of receptors
Describe the adverse effect: Drug idiosyncrasy
A genetic condition causing an unusual response to a drug
Describe the adverse effect: Allergic reactions
Adverse effect mediated by the immune system. An antigen-antibody combination provokes an unwanted reaction
Describe the adverse effect, give an example & solution: Adverse biotransformation reactions
A drug is converted into a chemically reactive metabolite that can cause damage.
Ex., overdose of acetaminophen leads to production of chemically reactive metabolites that cause liver injury
Solution: Take only recommended dose
Describe the adverse effect & solution: Teratogenesis
Refers to drug-induced defects in the developing fetus
Solution: avoid drugs with these effects during pregnancy
Describe an antagonistic drug-drug interaction
One drug reduces the pharmacological effect of another drug by competing for the same receptor to produce a different response
Who are at greater risks for adverse reactions?
Newborns and those over 60 years of age
Those with multiple diseases
Genetics (particularly slow metabolizers)
Give some reasons why drug toxicity can be difficult to predict
Rare adverse effects
Toxic reactions only occur after prolonged use
Toxic effect is not detectable in animals
Adverse effect is unique to only a particular period (ex., when pregnant)
Describe an additive drug-drug interaction
The combined pharmacological effect of the two drugs is the sum of the individual effects (1+1=2). Occurs when the drugs bind the same receptor
Describe an altered physiology drug-drug interaction
One drug may alter the normal physiology of the body so that the response of another drug is altered
What are the five types of drug-drug interactions?
Additive
Synergistic
Potentiation
Antagonism
Altered physiology
Describe a potentiation drug-drug interaction
The pharmacological effect of one drug is increased by a second drug
Describe a synergistic drug-drug interaction
The combined pharmacological effect of two drugs is greater than the sum of the individual effects (1+1 =3). Occurs when the drugs bind different receptors, but have the same overall effect
What are some risk factors for drug-drug interactions?
Age - decreased liver and kidney function causing drugs to stay around longer
Polypharmacy (taking multiple drugs)
Genetic factors (slow metabolizers)
Drug properties (low therapeutic index, extensive blood protein binding)
What is preclinical testing?
Testing of compounds to determine their safety and potential efficacy
What does a phase 1 clinical trial look for
Safety and tolerability in a few healthy individuals
What does a phase 2 clinical trial look for?
Effectiveness, safety and pharmacokinetics in those with the disease its meant to treat. Divided into control groups and treatment groups
What does a phase 3 clinical trial look for?
Effectiveness and safety in a large amount of people with the disease
What does a phase 4 clinical trial look for?
Long term safety - after marketing and distribution to the public
What does an acute toxicity study look into?
Looks into determining the toxicity of a drug after a single administration over a short period of time (a few days) with several different doses
What does a sub-chronic toxicity study look into?
Toxicity over a longer period of time (few weeks to 3 months) with about 3 different doses
What does a chronic toxicity study look into?
Toxicity over a longer period of time (6 months - 2 years) with about 3 different doses
