Exam 1 Flashcards
Define endogenous?
A chemical produced from within the body
The first recorded physician?
Imhotep
Coined the “Father of Western Medicine”?
Hippocrates
Famous quote from the “Father of Toxicology?”
“The dose makes the poison”
The “Father of Toxicology”?
Paracelsus
Pharmacokinetics is defined as?
What the body does to a drug
Pharmacodynamics is defined as?
What a drug does to the body
Define what an agonist is?
Activates a response from a receptor; similar to native ligand.
Define what an antagonist is?
Blocks an endogenous ligand from eliciting a response / Does not activate a response
Define exogenous?
A chemical that is produced outside of the body
Describe a toxin?
A biologic chemical that produces undesirable effcts
Describe a poison?
A non-biologic chemical that produces undesirable effects
What are the three main types of bonding in pharmacology?
Covalent, Electrostatic, and Hydrophobic
Most drugs are what molecular weight?
100-1000 MW (daltons)
> 1000 MW has difficulty due permeability
What is the strongest bond?
Covalent bonds
What is the weakest bond?
Hydrophobic bonds
Describe the relationship between the type of bond and their receptor specificity?
The stronger the bonds, the less specific. The weaker the bonds the more specific. (Inverse relationship)
What are racemic mixtures made of?
50/50 of each stereoisomer
This is the most potent stereoisomer of ketamine?
The (S) stereoisomer, named Esketamine
Describe an orthosteric receptor interaction?
Orthosteric interactions occur at the active site
Describe an allosteric receptor interaction?
Allosteric interactions occur away from the active site
What are the primary components of Pharmacokinetics?
Adsorption, Distribution, Metabolism, and Excretion
What is the EC50?
The concentration of a drug when 50% of the maximal effect (Emax) is achieved
What is the distribution coefficient (Kd)?
The concentration of a drug when 50% of the maximal binding is achieved
Explain why Kd does not have to equal EC50?
Because they are not proportional. You may achieve EC50 when Kd is only at 5%, or you may achieve Kd and not have any effect achieved.
Describe the meaning of a low Kd?
A low Kd means that the drug has a high affinity for that receptor. A small amount of drug required to reach 50% receptor binding.
Describe a competitive inhibitor?
A drug that stops the agonist from binding at the active site and decreases response.
Describe an allosteric activator?
A drug that does not bind to the active site, but improves binding and increases the response.
Describe an allosteric inhibitor?
A drug that does not work at the active site that non-competitively blocks binding at the active site and decreases response greatly.
Causes change in conformation at the receptor site.
Describe the role of an “agonist mimic” or “indirect agonist”?
They increase the activation or response intracellularly by downstream inhibition. (Ex: Binds to an enzyme that breaks down an intracellular second messenger).
What does it mean for an antagonist to be “surmountable”?
A competitive antagonist’s inhibiting effects can be countered by increasing the amount of the agonist to activate a receptor
eventually the same effect as agonist alone
What does it mean for a antagonist to be “insurmountable”?
The agonist can never overcome the inhibiting effects of the antagonist. No matter how much agonist given, will not achieve same effect as agonist given alone.
Due to covalent bonding, which is very stong and wont be broken
Describe a non-competitve antagonist?
An allosteric receptor interaction that can never be overcome by the agonist.
Describe what this diagram is showing?
Competive Inhibitior (antagonist, propanolol) is overcome by addition of more agonist (Isoproterenol) to achieve the same effect. EC50 is increasing due to higher amounts of the drug being required to overcome the competitive antagonist.
Describe what this diagram is showing?
Noncompetitive inhibitors are insurmountable, adding more of the agonist will never reach the same effect as the agonist acting alone. There is no change in EC50 because the maximum effect is now lower.
Describe a partial agonist?
Competes with the full agonist and produces a lower response than full agonist when all receptors are bound.
In the prescene of a full agonist, it acts as an antagonist. In the abscence of a full agonist, it acts as an agonist.
Describe physiologic antagonism?
Drugs that inhibit the effect of another drug without binding to the same receptor.
Acetylcholine opposes the effects of epinephrine
Insulin opposes gluccocorticoid hormones
Explain active (Ra) and inactive (Ri) receptor congigurations?
Receptors switch between Ra and Ri on their own, even in the abscence of a drug - favors Ri.
Agonist favors Ra and Inverse Agonist favors Ri
Describe an inverse agonist?
An agonist that has a greater affinity for the Ri state, which inactivates the receptor site. Reduces constitutive activity which may producing an opposing physiologic effect.
In clinical practice it is just an antagonist.
Antagonistic activity (beta blockers, H1/H2 blockers)
What is the Materia Medica?
Collection of works describing the preparation and use of botany and medical substances
Precursor to pharamcology
Correlate stereoisomerism and differences in drug effects
One enantiomer is typically much more potent than the other, they can elicit differing respones from the receptor.
one enantiomer fits better into the receptor than the other
What is Bmax on a drug response curve?
The drug concentration when the maximum number of receptors are bound.
What is Emax on a drug response curve?
The drug concentration when maximal effectiveness is achieved.
How can a partial agonist also behave as an antagonist?
Partial agonists compete for the same receptors as the full agonist, preventing the full agonist from binding.
Describe a receptor site?
A protien on the cell surface that can bind to specific molecules, which activates a chemical reaction.
The “lock” to the drug “key”
What would a high Kd indicate?
That the drug has a low affinity for the receptor.
Describe antagonism with opposite charge?
A drug is given with an opposite charge that will bind and inhibit its effects.
Protamine (+) binds to and inhibits the effects of heparin (-)
What is constitutive activity?
The spontaneous activation of receptors without the binding of agonist.
What are properties of a “good” receptor?
It is selective and can activate an alteration in function (initiate downstream effects.)
What are “bad” receptor properties and some examples?
They bind with drugs but do not cause a change in function. Examples are inert binding sites and drug carriers.
Describe a drug carrier’s funtion?
A drug carrier can bind to a drug at it’s inert binding sites to transport a drug around the body.
What are the differences in bound and unbound drugs?
Drugs bound to a drug carrier cannot cross membranes, only the unbound drug can cross.
Unbound too large to cross membranes
What changes in drug administration for drugs that are highly protein bound?
A highly bound drug may require a higher dose to increase free drug concentration.
This is pharmacokinetics
Desribe plasma protein and drug effects in malnutrition and liver damage?
In malnutrition/liver damage plasma albumin levels are lower, so there will be more free drug with an equal dose = increased effect and toixc effects.
What may be the effect if 2 drugs are given that are both highly bound to proteins?
One drug may displace the other off of the protein it is bound to.
What are the most common drug carriers?
Albumin (most important), a1-acid glycoprotein, and lipoproteins.
What does albumin mostly bind to?
Acidic drugs
What does a1-acid glycoproptein mostly bind to?
Basic drugs
What does lipoprotein mostly bind to?
Neutral drugs.
What is drug potency?
Potency is the concentration or dose of a drug need to get to 50% of maxmimal effect.
Low does and high effect = more potent
What is the drug efficacy?
The maximal response a drug can deliver. Depends on receptor interactions.
More important clinically than potency
Compare the efficacy and potency of these drugs.
Drug B is the most potent drug, but drugs A,C, and D are more and equally efficacious. Potency of the drugs is such that B>A>C>D.
What is TD50?
Median Toxic Dose
What is LD50?
Medican Lethal Dose.
How can you calculate therapeutic index?
TD50 divided by ED50.
What does the therapeutic index indicate?
The safety of a drug. A high Ti means the drug is safer than a low Ti.
What are the 4 main causes of drug variation?
- Variations in concentration of drug that makes it to the receptor (ADME, age, sex, disease).
- Variation in concentration of endogenous ligands.
- Variation in number or function of receptors.
- Variations in downstream responses (most important).
What charge must a drug have to cross a barrier?
Uncharged
Describe weak acids?
They release a proton (H+) into solution
Describe weak bases?
They absorb protons (H+) from a solution.
Draw the basic structure of a monoclonal antibody.
antibodY, drawn like a Y. Binding sites at the tips.
What are the steps to bring a presription to market?
In vitro studies (lead compound isolated and patent submitted), animal testing (investigational new drug submission), Phase 1, Phase 2, Phase 3 human clinical testing (new drug application), and Phase 4.
Describe the cell signaling process.
- Signaling molecule (drug or endogenous ligand)
- Molecule activates the receptor.
- Signal transduction proteins and 2nd messengers (cAMP, IP3, DAG)
- Effector protein (causes the change intracellulary)
Draw the phosphorylation cascasde.
Drug activates the receptor, this causes a conformational change and becomes an activated effector protein and starts a chain of activated second messengers by phosphorylation through kinases.
What are the 4 transmembrane signaling methods by drug-receptor interations?
- Lipid soluble molecule crosses and attaches intracellularly.
- Enzyme activation (catalytic)
- Ion channels
- GPCR’s
Explain the mechanism of GPCR signaling.
Drug binds to the receptor, this causes a conformational change and GDP leaves the alpha strand and GTP attaches - activating it. The activated G protein activates the effector protein releasing the second messengers like cAMP that activates the effector protein that invokes a response.
The drug does not have to stay attached, it can leave an another can bind - the downstream effects still occur.
Draw and describe the GPCR pathway involving adenyl cyclase?
Describe how GCPRs cause desensitization?
Drug activates GPCR. The carboxyl tail becomes phosphorlated by G protein kinases. This promotes binding of beta arestin and prevents further interactions with G proteins. This complex binds with a clatherin coated pit which internalizes the receptor. Then the drug unbinds form the receptor causing dephosphorylation and detachment of beta arestin. Then either 1. the receptor can be returned to the plasma membrane and bound again or 2. be taken to a lysosome for destruction.
##Footnote
This causes desensitization because the receptor cannot be bound during this period
What is the structure of a RTK (receptor tyrosine kinase)? How does it function?
The receptor becomes dimerized when activated (two seperate receptor monomers combine). Each monomer has 3 tyrosine sites. These 6 tyrosine site are phosphorylated by 6 ATP and become active. Once active, can activate an effector proteins and second messengers.
Describe voltage gated ion channels and where they’re found?
1.Found in excitable cells like neurons, muscle, and endocrine. 2.They are closed at resting membrane potential and open when the threshold is met.
3.They are selctive based on the ion.
Describe ionotropic ligand gated ion channels?
The protein has a ligand binding site and channel. Ligand binding opens the gate and allows ions to cross.
Describe metabotropic ligand gated ion channels?
The ligand activates a GPCR which activates and EP that releases second messengers that open the ion channel.
What are the metric system converion factors?
Practice Vd problems
Describe first order elimination?
Applies to most drugs, rate of elimination varies with concentration. **Clearance remains constant. **
Describe Zero order elimination?
Rate of elimination is constant. Clearance varies with concentration.
Occurs when ability to eliminate drugs is at max capacity.
All transporters are being used.
How are rate of elimination and clearance effected by drug concentration?
At inital drug concentrations, rate of clearence remains the same and elimination changes based upon drug concentration (First order). Then as drug concentration increases, the body switches to zero order and rate of elimination remains the same and clearance changes based upon drug concentration.
Describe how flow dependent elimation relates to extraction ratio?
Blood flow x extraction ratio = clearance
The only time you have a high clearance is when you have high extraction and high blood flow.
What is steady state dosing?
Dosing the drug in a way that replaces the eliminated amount and still keeps therapetic effects.
What is the route of blood through the liver?
Oral: GI - local veins - hepatic portal vein - Sinusoids - Hepatic vein - vena cava - systemic circulation
All drugs: Systemic circulation - hepatic artery - Sinusoids - hepatic vein - vena cava - systemic circulation
What is the generic pathway of CYP450 metabolism?
Note: Flavoprotein is oxidized by reducing PY450 and then is reduced by use of NADPH so the reaction and happen again.
Describe PY450 induction?
A drug may induce CYP450, increasing its activity. If a drug becomes inactive by P450 then it will be inactivated faster.
If a drug is activated by P450 (prodrug), it will taken to its active form faster.
Describe P450 inhibition?
A drug may inhibit P450, decreasing its activity. For a drug that is inactivated by P450 it may be active longer or have less inactivation.
For a drug that is activated by P450 (Prodrug), much less of the the drug will be activated.
Describe glucoronidation?
Adds glucuronic acid to a drug via UGT’s (uridine diphosphate glucuronyltransferases) to make a drug more hydrophilic (more water soluble) which increases urinary excretion.
Describe the pathways that acetaminophen is metabolized to harmless products? What happens if you are low on glutathione?
Normally, acetaminophen will undergo Phase II reactions of glucorondiation and Sulfation and be excreted as nontoxic byproducts.
You can give N-acetylcistine which causes recycling of glutathione.
Describe the pathway that acetaminophen is metabolized to hepatotoxic products during an overdose?
In and overdose acetaminophen will be metabloized in Phase I reactions (CYP2E1/CYP3A4) that creates a toxic intermediate. This will undergo GSH conjugation to mercapturic acid and be excreted (backup plan) but, when glutathione runs out the intermediate will bind to cell macromolecules (proteins), inactivate them, and lead to liver cell death.
Desribe the role of drug efflux transporters?
They pump drugs out of the cell. Most are ATP Binding Cassette (ABC) transporters.
Describe drug transporters in the intestine?
Most transporters are positioned on the apical membrane (micrvilli) allowing transport of drugs from the intestine to the blood stream. There are a few that efflux some drugs (which prevents them from being taken orally, like glucoronidation).
Describe drug transporters in the placenta?
Most transporters are positioned to efflux drugs from the placental membrane back into the mother’s blood stream. The placental barrier is the only pathway for fetal nutrients.
Describe drug transporters in the liver?
Most transporters move drugs into the liver for metabolism.
Describe drug transporters in the blood-CSF barrier?
Has less efflux than the BBB, drugs like bupivicaine work here.
Describe drug transporters in the BBB?
The vascular epithelium is primary site of exclusion due to tight junctions and multiple transporters. Most transporters efflux drugs back into the blood.
Describe drug transporters in the kidneys?
Primarily located on the apical side that leads to excretion in the renal tuble from the glomerulus.
What are the components of an intact brain barrier?
Vascular space, vascular epithelium (tight junctions), astrocyte, podocyte.
Describe the pathway of tylenol in the gut before and after biotransformation?
Tylenol is absorbed into the blood by transporters in the microvilli. It then travels to the liver where it undergoes First Pass Effect and becomes a non-toxic glucoronide (Phase II; glucoronidation). Then it is effluxed back into the intestine for excretion by ABCC that are specialized for glucuronides.
