Exam 1 Flashcards
Define pharmacology
The study of the effects of drugs on the function of living systems. The science that deals with the physical and chemical properties,
Drug
A chemical substance of known structure, other than a nutrient or an essential
Xenobiotic
A chemical substance found within an organism that is not
naturally produced or expected to be present within the organism.
Drug action
Molecular interaction between drugs and cell components
• Drug must be “delivered” to site of action
Drug effect
Biochemical and physiological consequences of drug action
• Desirable or undesirable
general ways in which molecules of drugs interact with their target molecules.
Non-cellular and cellular
Non-cellular
no interaction with cellular components
- Physical action – protective, adsorbent or lubricant properties of drug
- Chemical reaction – chemical reaction between drug and an endogenous chemical
- Physicochemical action – alteration of biophysical properties of a biofluid
- Modification of body fluid composition – produce osmotic changes, alter pH of body fluids
Cellular
interaction with cellular components
Correctly list the four kinds of molecules commonly serving as molecular targets for drugs.
Receptors, enzymes. carrier molecules, ion channels
Receptors
proteins or protein complexes that act as transducers
Transducer: converts “information” in one form into another form
Enzyme
proteins that serve as catalysts for biochemical reactions
Carrier molecules (transporters)
proteins or protein complexes that move chemicals across membranes
Ion channels
protein complexes that control movement of ions across membranes
proteins are protein complexes that move chemicals across membranes
Dose-response curves
dose is administered, response is measured, and response is plotted against dose
What is this arrow pointing to?
- Rmax –> doses producing maximal response; increase in dose no longer produces increased response
What is this arrow pointing to?
“threshold dose”; no response is detectable until a “threshold” dose is reached
What is this arrow pointing to?
ED50 or EC50 –> effective dose 50; dose that produces a defined effect in 50% of population taking drug or 50% of maximum effect`
Potency
dose necessary to elicit a defined response
- Higher dose, lower potency
- Lower dose, higher potency
Which one is less potent?
Green line –> has a lower response at higher concentration
What is MTC?
MTC is the minimum toxicity concentration and can be shown as a horizontal line where that concentration is on a curve
What is MEC?
The MEC is the minimum effective concentration, again this can be represented by a horizontal line at this concentration.
What is the goal of therapeutic treatments in terms of MTC and MEC?
The goal of therapeutic drug treatment is to keep the concentration of the drug in the body between these two horizontal lines. If the concentration goes above the MTC line we may see toxicity and if the concentration goes below the MEC line, its not therapeutic.
How to tell what is the best drug regimens using MEC and MTC?
So if you were given a dose response curve with two lines representing two different dosing regimens for Drug A or even two different Drugs. The drug or the dosing regimen that stays between the lines is most efficacious. If one of the dosing regimens goes above the MTC and the other doesn’t, the one that doesn’t go above MTC threshold is most efficacious (because no toxicity). If both regimens are between the lines, the one that stays above the MEC threshold the longest, I think would be most efficacious because it would require fewer doses per day for example.
What is the two state receptor model?
The two-state model is a simple linear model to describe the interaction between a ligand and its receptor, but also the active receptor
- Describe a receptor agonist
- Endogenous or exogeneous chemical
- Has affinity and efficacy
- Elicits a response
- Full agonist = maximal response
Describe a receptor partial agonist
- Chemical eliciting a less than maximal response
- Has affinity and partial efficacy
- Describe a receptor antagonist
- Endogenous or exogenous chemical that
Interacts with the receptor
Does not elicit a tissue response
Has affinity but no efficacy!
Describe inverse agonism.
Measurable effect in the absence of an agonist (background effect)
- Constitutively active receptor adopts active state in absence of agonist
Association favors the inactivated receptor. Shifts equilibrium so more receptors adapt the R state. Reduces magnitude of background effect.
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist, but induces a pharmacological response opposite to that of the agonist
Which one is the agonist, antagonist, or inverse agonist?
green –> Ag
Red –> Antag
Blue –> Part Ag
Is this a reversible or irreversible competitive antagonist graph?
Reversible
Is this a reversible or irreversible competitive antagonist graph?
Irreversible
What is an irreversible and reversible antagonist?
Irreversible –> increasing [A] does not overcome antagonism
Reversible –> Increasing [A] will overcoming the antagonism
What is another word for Desensitization?
Desensitization = tachyphylaxis
• Tachy –> “swift”
• Phylaxis –> “body defense”
What is drug desensitization or tachyphylaxis?
Drug effect decreases over time when drug is continually administered (at same dose)
Develops quickly
Correctly describe the mechanisms of drug desensitization or tachyphylaxis.
Mechanisms of desensitization:
Change in receptors Loss of receptors –> down-regulation: gradual decrease in # of receptors on or in the cell upon prolonged exposure to drug.
Deletion of mediators –> drug exposure causes mediator to become depleted; rate of loss of mediator is faster than at its rate of replacement
Altered drug metabolism –> exposure to drug increases metabolic degradation in tissues, usually the liver, reduces effect
Physiological adaptation –> Homeostatic response, often seen with side effects; they gradually decrease as therapy continues.
Advantages and disadvantages of oral (per os, PO)
Advantages –> ease of administration
Disadvantages –> pills must disintegrate and dissolve first, subjected to acidic stomach fluid, subjected to first-pass effect, affected by GI motility and presence of food
Advantages and disadvantages of sublingual
Advantages–> rapid response possible, provides acidic environment of stomach fluid, avoids first-pass metabolism
Disadvantage –> taste
Advantages and disadvantages of rectal
Advantages –> relative ease of administration, first-pass effect may be avoided, use when other routes not possible
Disadvantages –> patient acceptance, unreliable absorption for systemic effects
Advantages and disadvantages of topical
Advantage –> achieves local effect, convenient, avoids first pass
Disadvantage –> challenge to apply to skin
Advantages and disadvantages of inhalation
Advantage –> large surface area for absorption, ease of access to blood + rapid change of drug concentration in blood, rapid access to heard via pulmonary vein
Disadvantage –> introduction of non-volatile drugs or drugs that are not gases
Advantages and disadvantages of injection Subcutaneous (SC, SQ)
Advantages –> convenient, less painful than IM (low volume), absorption rates similar to IM
Disadvantages –> similar to IM
Advantages and disadvantages of injection Intramuscular (IM)
Advantages –> convenient (for the administrator), longer duration of effects than IV, oily or irritating drug preps
Disadvantages –> invasive, requires aseptic technique, pain, tissue damage
Advantages and disadvantages of injection Intraveneous (IV)
Advantages –> bypasses absorption barriers, rapid onset of effects, when drug cannot be administered p.o.
Disadvantages –> rapid onset of effects, suspensions or oils cannot be used, invasive + requires sterile technique
Describe how entry of poisons into the body can differ from entry of drugs into the body.
Routes of drug administration:
- Parenteral = other than alimentary canal
- Enteral = alimentary canal
- Topical
- Inhalation
- Intrathecal = spinal canal
- Intramammary
- Intravaginal
- Intrauterine
Routes of exposure to poisons:
- Parenteral is rare, but possible –> insect or animal bites, venom injected into tissues
- Eternal is common –> p.o. (very important)
- Topical is relatively common –> dermal (poison ivy), transdermal
- Inhalation for vapors, gases, fine particles
4 main ways small molecules cross cell membranes
- Passive transport (diffusion)
- Facillitated diffusion
- Active transport
- Pinocytosis
Passive transport (diffusion)
–> movement is down concentration gradient. Requires no energy. Most common means of absorption. Lipids through bilayer, hydrophilics through pores in membranes
Facilitated diffusion
–> requires a transporter, requires NO energy, moves chemicals DOWN gradient
Active transport
–> requires a “pump” of energy, pumps against concentration gradient
Pinocytosis
–> cell membrane engulfment after association with receptor
- Given the pKa or pKb of a drug, the pH of two fluid compartments separated by a biological membrane, and the Henderson-Hasselbalch equation, predict the relative drug distribution in those compartments across that membrane.
HA <—-> H+ + A-
Ka = [H+][A-] / [HA]
Pka = pH + log {[HA]/ [A-]} Pkb + Pka = 14
Given Pka and pH, ratio of {[HA]/ [A-]} can be calculated. Higher the ratio, the better the absorption
Correctly explain why absorption differs between ionic and charge-neutral molecules.
- Ionic compounds do not pass through membranes without “help.”
Drugs that are un-ionized will be better able to diffuse through a lipid cellular membrane, cross a biologic barrier, and enter the bloodstream (e.g. be absorbed) compared to drugs that are ionized.
Given two drugs administered concurrently, each of which bind to plasma proteins, describe or predict how that drug binding might affect their pharmacodynamics, distribution, and elimination
Rates of distribution depends upon: physical and chemical properties of xenobiotic, blood flow through tissue, mass of tissue (organ), affinity of drug or toxin for components of tissue, barriers to distribution
- Lipid solubility
- Ionization
- Molecular weight
Blood flow – xenobiotics with high affinity for a tissue may “concentrate” in that tissue
Describe the blood-brain barrier
The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream.
Prevents movement of xenobiotics from blood into brain
Describe how disease or genetics can alter BBB function.
- Malfunction due to damage / lack of development –> xenobiotic can enter brain tissue; causes toxicological effects
Causes: immaturity (neonate), inhibition of pump, mutation (pump defective), infection in brain tissue
Correctly explain the interrelationship between excretion and metabolism in xenobiotic elimination
Xenobiotic elimination is a combination of excretion and metabolism
Excretion
movement of drug/toxin (parent compound) out of the body by various routes
Metabolism
chemical reaction changing parent drug/toxin into another chemical (metabolite)
Correctly describe clearance and its relationship to elimination.
Is a fundamental PK parameter describing drug elimination
- Volume of blood cleared of the drug / unit of time
Sum of various clearances by all routes of elimination
Phase I Reactions
- Oxidation –> e loss, O gain, H loss
- Reduction –> e gain, ) loss, H gain
- Hydrolysis –> reaction with water
- Cytochrome P450 (cP450, P450)
Phase II Reactions
- Glucuronidation
- Sulfation
- Acetylation
- Methylation
- Glutathionation
- Amino acid conjugation
Correctly identify the Phase I reaction that produces a toxic product and how a follow-on Phase II reaction protects against the toxic damage; explain how the Phase II protection can be lost resulting in a toxicosis.
Given two drugs concurrently administered, with one affecting the metabolism of the other, correctly predict and explain how the elimination of those two drugs would change upon concurrent administration.
Consequences of xenobiotic metabolism –> usually increases hydrophilicity, enhancing excretion. BUT, metabolite(s) may be
- Biologically inactive; terminating effect, reducing toxicity
- Biologically active; effect, toxic
Given a xenobiotic and information about its elimination, correctly predict or explain how hepatic disease or genetic differences could affect the elimination of that xenobiotic.
Hepatobiliary: secreted into bile via liver and reabsorbed
Excretion: elimination from body of parent xenobiotic or its metabolites
Drug metabolizing enzymes are primarily decreased due to loss of liver tissue.
Hepatic clearance of drug decreases. Half-life increases
Correctly explain enterohepatic circulation and its effect on drug elimination.
Refers to the process whereby a drug or metabolite in the liver is secreted into the bile, stored in the gall bladder, and subsequently released into the small intestine, where the drug can be reabsorbed back into circulation and returned to liver.
Effect –-> increases the elimination half-life of many drugs (thus prolonging their action).
Correctly name the three processes by which xenobiotics are eliminated renally.
Glomerular filtration
Tubular secretion
Diffusion across renal tube
Glomerular filtration
–> glomerular capillaries allow plasma to pass into nephron. Protein bound drugs DO NOT pass through
Tubular secretion
Tubular secretion
–> . Can remove protein bound drugs (mass action: removal causes dissociation from protein).
Diffusion across renal tube
–> lipid soluble drugs are likely to be reabsorbed by passive diffusion. Urinary pH adjustment used to promote secretion.
Given a xenobiotic and information about its elimination, correctly predict or explain how renal disease or genetic differences could affect the elimination of that xenobiotic.
Since severe renal disease causes a reduction in the plasma protein binding of many drugs, the metabolic clearance of such drugs will be increased
Renal disease alters the effects of many drugs, particularly when active drug moieties are renally cleared. Drug doses should usually be reduced in renal disease in proportion to the predicted reduction in clearance of the active drug moiety.
Correctly classify its elimination as either zero- or first-order and explain why you so classified that elimination
- Given the equations for half-life calculations, correctly calculate the elimination t½ for the drug.
Correctly identify the classical pharmacokinetic model that would describe the concentration vs time data.
Pharmacokinetic two-compartment model
divides the body into central and peripheral compartment. The central compartment (compartment 1) consists of the plasma and tissues where the distribution of the drug is practically instantaneous
Open vs closed model
Open –> administered dose is eliminated from the body by an excretory mechanism
Closed –> the drug dose is not eliminated from the body
determine Route of administration as either IV or a route involving an absorptive step on graph
Explain the rationale for enteric-coated and time-release capsules.
Enteric coatings are primarily used for the purpose of: Maintaining the stability of APIs that are unstable when exposed to the acidic conditions of the gastric milieu. Such APIs include erythromycin, pancreatin, and the class of proton pump inhibitors, such as omeprazole.
Time-release medications are drugs that are released slowly over time within the body rather than all at once. This enables a sustained or delayed action within the body, making sure that the individual doesn’t get too much of the drug at once or doesn’t get it right away
