Fundamental Principles of Pharmacology :)

Define spare receptors

don't need to bind all receptors to get max cellular response (effect)

statements most accurately describes a system having spare receptors?

"A single drug-receptor interaction results in many cellular response elements being activated" One explanation for the existence of spare receptors is that any one agonist-receptor binding event can lead to the activation of many more cellular response elements. Thus, only a small fraction of the total receptors need to be bound to elicit a maximum cellular response.

Non-receptor antagonist

*Physiological* (antagonized by an opposite response produced by another drug acting on a different receptor - ex. Histamine bronchoconstricting vs norepinephrine bronchodilating) *Chemical* (inactivates agonist chemically before it can act - ex. Magnesium hydroxide neutralizes effects of acid on stomach)

Define tachyphylaxis

*acute response* Repeated administration of the same dose of a drug results in a reduced effect of the drug over time. This depletion is caused by the cell's reducing the number of receptors in response to their saturation

Define desensitization

decreased ability of a receptor to respond to stimulation by a drug or ligand - Mechanism that leads to tolerance or tachyphylaxis. - the loss of responsiveness to the continuing or increasing dose of a drug

Theraputic Window

definition for the range of doses that have a high probability of therapeutic success

Maintenance dose

dose required to maintain the drug concentration within the therapeutic range (Maintenance dose = Clearance x c-steady state) , if you have inactive liver enzymes, you need a lower maintenance dose so that the drug doesn't reach toxic levels.

Describe how diet and environment affects drug metabolism

grapefruit can inhibit certain P450 enzymes

Define bioavailability

how much drug reached the circulation for the amount of drug administered (NOT how much is getting to receptors) this is important for the dosage needed. IV is 100% bioavailability

Explain the term partial agonist

less efficacy than a full agonist - gives less of a response - can act as an antagonist (competing for same binding sites) - shifts dose response curve to the right

Describe the pathways of drug metabolism: oxidation/reduction reactions

mainly via heme-protein oxidases (Cytochrome P450), drug becomes hydroxylated which renders it inactive or makes it more hydrophilic (dissolves in the urine to be excreted)

Explain what happens during an acetaminophen overdose

normal phase II reactions are saturated and a phase I reaction with a P450 enzyme which is usually minimal makes a toxic metabolite NAPQI. Under normal conditions NAPQUI can be excreted when conjugated to glutathione. If glutathione runs out, NAPQI can accumulate at toxic levels - give N-acetyl cysteine which is a precursor to glutathione.

Define pharmacokinetics and how it relates to absorption, distribution, metabolism and excretion (ADME)

pharmacokinetics is how to get the drug to the site of action (receptor) - have to cross membranes, get into systemic circulation or lymphatic system, what is the best way to do that

Describe the membrane effects on drug-receptor interactions

polar drugs can't cross the membrane to affect receptors inside the membrane therefore most polar drug receptors are on the exterior surface of the membrane. Many polar molecules have receptors located within the cell

Review the forces that govern protein conformation

primary structure (sequence)

Define down regulation

repeated or persistent drug-receptor interaction results in removal of the receptor sites where subsequent drug-receptor interactions could take place

Describe the different mechanisms by which drugs cross the membranes

small non-polar (hydrophobic) molecules can cross directly (steroid hormones), negative molecules can use carriers (facilitated diffusion or active transport) or can enter by endocytosis. Membrane diffusion is favored by concentration gradient and positive charge on drug

Briefly describe biliary excretion

some drugs are excreted from the liver into the bile duct via *ABC transporters* (some oral also excreted in feces)

Explain the term tolerance

some people have a natural or innate tolerance, others is acquired. Pharmacokinetic tolerance has to do with the ADME of the drug, pharmacodynamic has to do with the receptor (down regulation or desensitization), or the tolerance can be learned (alcohol or other substance abuse)

Describe the factors that contribute to drug selectivity

Cell type of receptors (b2 in heart is different than b2 in bronchioles), cell-type specificity of receptor-effector coupling (drugs have diverse responses between cells)

Which of the following names best describes an antagonist that interacts directly with the agonist and not at all, or only incidentally, with the receptor?

Chemical antagonist chemical antagonist interacts directly (chemically) with the agonist drug and not with a receptor.

Carbamazepine, a drug used in the treatment of epilepsy is metabolized by the one of the cytochrome P450 enzymes. However, it also induces this enzyme such thatover time, the therapeutic effectiveness of carbamazepine is reduced. Which of the following best describes this phenomenon?

Pharmocokinetic Tolerance where one drug affects the metabolism of another drug. Pharmacodynamic tolerance would be a drug that interacts with another drug at the receptor level.

Drug Response Curve Tells us

Potency, Efficancy The potency of a drug is inversely proportional to the concentration of drug that is required to produce 50% of the maximum response (EC50). The lower the EC50 is, the greater the potency is.

Explain the term prodrug

Prodrug is inactive until it is metabolized

Explain the term toxic metabolites

can cause side effects, react with DNA and cause cancer, can also trigger regulatory responses (fibrosis, necrosis, apoptosis, proactive response/repair)

Describe how drugs are eliminated by the kidneys

can either be 1)filtered in the glomerulus 2)secreted from the peritubular capillary to the tubules (tubular secretion). 3)Drugs can also be reabsorbed back into the blood from the tubules. 4) Urine

Define refractoriness

cannot be restimulated for a certain period of time (voltage gated sodium channels)

Explain the term agonist

binds to a receptor and produces an effect in the cell

Describe transmembrane receptors with enzymatic cytosolic domains

binds to an enzyme which has a general cellular response (ex. Insulin binds to receptor tyrosine kinase causing as dephosphorlyation/phos). No coupled protein.

Receptor antagonist

binds to either the active site (reversibly/competitively or irreversibly/noncompetitively) or allosterically (noncompetitively)

Describe the different body compartments

blood/plasma, fat, interstitial and intracellular fluid, bones and teeth

Define the term clearance and how it can be calculated

clearance (from all sources i.e. Kidney, liver) = (metabolism + excretion) / [drug] in plasma.

What are the advantages and disadvantages of parenteral administration?

A: rapid onset and high bioavailability. D: Infection, skilled personnel, hurts(compliance), irreversible (danger)

What are the advantages and disadvantages of enteral administration?

A: simple, cheap, self-administer and low infection rate. Dis: passes through GIT, first pass metabolism, relatively slow delivery, compliance

ACE inhibitor blocks

ACE and Kininase II leading to an increase in Bradykinin (kininase is off-target)

Explain, giving examples, how transmembrane ion channels are influenced by drugs

Ach can bind directly to a channel which increases affinity for another Ach molecule to bind (Needs 2 to activate). Can also act through a G protein - b1 agonist binds to G protein that start a cascade of effects (adenylyl cyclase -> cAMP -> PKA) that eventually phosphorylates and opens a calcium channel in the membrane

patient is prescribed the drug dobutamine that binds to a receptor leading to an increase in the activity of adenylyl cyclase. From this you can ascertain that dobutamine is a

Agonist - Ga s receptor (we memorize its a B1 agonist)

action of a noncompetitive antagonist?

Decrease the maximum response of the agonist (decrease efficancy)

Describe the factors that influence half life

Decreasing clearance (liver, kidney or cardiac failure; inhibition of CYP450), increasing VD (Obesity, Edema/Ascites)

Describe the kinetics of drug distribution

Distribution and elimination happen together, blood distributes fast then the vessel rich group, then muscle takes longer to reach maximum concentration but is slower to distribute and eliminate, fat is the slowest to reach maximum concentration and has very poor perfusion and distributes and eliminates very slowly

The drug has been starting to lose it's effectiveness due to receptor sequestration decreasing the number of receptors on the target cell membrane. This process of receptor sequestration is known as:

Down-regulation

Drug X in a dose of 5 mg produces the same magnitude of diuresis as 500 mg of drug Y using same mechanism. Which of the following statements best describes these results?

Drug X is about 100 times more potent than Drug Y

Describe the pathways of drug metabolism: conjugation/hydrolysis reactions

Drug conjugates with a group (glucuronate, sulfate, methyl, glutathione, acetate, and glycine) which makes it more polar and hydrophilic which allows for it to be excreted

Define potency and identify it on a dose-response curve

EC50 (potency) is the concentration of drug to get 50% of max response, low EC50 = more potent drug

Define effective dose

ED50 is the dose where 50% of patients show therapeutic response

Describe Dose-Response curves

Effect/maximum effect (y-axis), ligand (x-axis),

Explain how half life can be calculated from knowing the volume of distribution and clearance

Half life t1/2 = 0.693 x VD / Clearance (if the drug has high clearance, it has a short half life, if it has a large volume of distribution it will have a longer half life)

Define the terms induction and inhibition of cytochrome P450 enzymes

Induction is when the drug induces P450 transcription and causes an increase in P450 enzymes, this can lead to toxic levels of metabolites. Inhibition can be competitive or non-competitive and prevents drug from binding to receptor which can lead to toxic levels of the drug in the circulation

Define lethal dose

LD50 is the dose that causes 50% fatality

Describe Drug-receptor binding curves and identify KD

LR/R0 = receptors bound with ligand/ total # of receptors (y axis), Ligand (X axis), KD is the dissociation constant - low KD = High affinity of ligand for receptor

Explain how drug metabolism can be influenced by disease

Liver disease - decreased drug metabolism, cardiac failure - decreased drug delivery to liver (less metabolism, hyperthyroidism - increases metabolism

Explain the concept of loading dose

Loading dose is a higher initial dose that allows you to get into therapeutic range quicker (Loading dose = VD x c-steady state), the higher the VD, the higher the loading dose that is needed.

Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body

Pharmacokinetics- includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body and the effects and routes of excretion of the metabolites of the drug.

Describe how age and gender affects drug metabolism

as you get older, metabolism decreases, gender effects are less clear

Describe mechanisms by which drugs do not interact with receptors

Osmotic diuretics (sits in kidneys, increase water in kidneys -> increase urination), Antacids (bicarbonate reacts directly with stomach acids)

Describe how pharmacogenomics affects drug metabolism

P450 2D6 enzyme converts codeine to morphine, TPMT defect allows thiopurines to cause less bone marrow activity, ALOX5 defect - no response to zileuton in patients with asthma, EGFR defect causes tumors

drug X has an intrinsic activity of 40%. X is most likely a...

Partial agonist Intrinsic activity denotes the ability of a drug to "activate" (cause a conformational change) the receptor. A drug with a reduced ability to activate the receptor is classified as a partial agonist. A full agonist has 100% intrinsic activity and an antagonist has no intrinsic activity

Which of the following terms best describes a drug that blocks the action of epinephrine at its vascular α receptors by occupying the epinephrine receptor-binding sites without activating them?

Pharmacologic antagonist A pharmacologic antagonist occupies the agonist receptor sites without activating them.

Variation in the sensitivity of a population of individuals to increasing doses of a drug is best determined by which of the following?

Quantal Dose - Response Curve Only a quantal dose-response curve gives information about differences in the sensitivity of individuals to increasing doses of a drug. Also Quantal dose-response curves provide information about the statistical distribution of sensitivity to a drug.

Quantal dose-response curve

Quantal dose-response curve shows individuals responding to drug (y-axis) vs. Dose (x-axis)

What does the term tachyphylaxis mean?

Rapid development of tolerance to the drug's effects.Tachyphylaxis is loosely defined as rapidly developing tolerance to the effects of a drug that is administered repeatedly, even if the dosages given after the first one are not changed or even progressively increased to overcome the phenomenon.

Explain the dose-response curve for a noncompetitive antagonist

Shift down - potency is the same (even though response is less), maximum efficacy is lowered (decreasing # of receptors agonist can bind to) *assuming no spare receptors*

Explain the dose-response curve for a competitive antagonist

Shift to the right - can still reach maximum efficacy but takes more agonist, *potency is decreased* takes more dose to ellict response (antagonist at a set concentration)

Define toxic dose

TD50 is the dose where 50% of patients show toxic effect (want to keep this as far from ED50 as possible for a safe drug)

A competitive Agonist INCREASES the ED50

TRUE In the presence of a competitive antagonist, a higher concentration of drug is required to elicit a given response.

describes quantal dose-response covers?

Used to determine the therapeutic index of a drug. Quantal dose-response curves show only the frequency of occurrence of a specified response, which may be therapeutically effective (ED) or toxic (TD). Dividing the TD50 by the ED50 (both obtained from quantal dose-response curves) gives the therapeutic index.

Define efficacy and identify it on a dose-response curve

a drug is efficacious if it reaches maximum effectiveness, some drugs can't get to max efficacy

Explain the effects of an alpha-q subunit on the G-protein coupled transduction pathway

activates PLC in the membrane -> PLC cleaves PIP2 to IP3 and DAG -> IP3 increases calcium levels which together with DAG activates PKC. Calcium activates CAM kinases, PKC increases protein phosphorylation and gene transcription

Explain the effects of an alpha-stimulatory subunit on the G-protein coupled transduction pathway

activates adenylate cyclase -> increases cAMP -> activates PKA -> increases protein phosphorylation and gene transcription

Describe the action of a generic G-protein coupled receptor

agonist binding -> GTP-GDP exchange -> G-protein is activated -> a-GTP diffuses to effector -> effector is activated -> Agonist unbinds -> GTP is hydrolyzed to GDP -> Heterotrimeric G-protein reconstituted

List enzymes that can be inhibited by drugs

angiotensin converting enzyme (ACE) in the lung, Cholinesterase (anticholinesterases) in synaptic clefts and neuromuscular junctions, Vitamin K epoxides reductase (Warfarin) in the cytosol

List the sites of drug metabolism

any organs with enzymes but MOSTLY THE LIVER!

Describe intracellular receptors and how they operate

drug has to diffuse through the membrane (usually non-polar molecule). Receptor is either already in the nucleus or in cytosol, binds then moves to the nucleus to allow for a change in *gene transcription* (cortisol, steroids)

Explain the impact of drugs binding to plasma proteins

drugs that have high affinity for plasma proteins keep Volume Distribution low but free drug low

Describe how race and ethnicity affects drug metabolism

e.g. Warfarin sensitivity (Asians - more sensitive, Africans are less sensitive)

Describe the different routes of administration

enteral (Per os, oral, by mouth) or parenteral (intravenous, intramuscular, subcutaneous, intrathecal/into brain past bb barrier, mucous membranes, transdermal)

C-steady state

equilibrium between drug in plasma and areas that the drug is distributing to (VD has no effect)

Describe how cells integrate various signals to produce a coherent response

few second messengers provide the cell with a common point for which numerous outside stimuli could converge to generate a coordinated cellular effect

Explain what is meant by the terms first order kinetics, zero order kinetics

first order kinetics is the amount of drug excreted is proportional to the concentration in the plasma (logarithmic relationship), zero order is rare, but after high doses, the clearance mechanism gets saturated and when there are low doses it shows first order kinetics again

What are the factors that influence renal excretion

increased urine flow can increase excretion (diuretics), pH trapping (give bicarbonate for aspirin overdose to increase urine pH and ionize aspirin and trap it in the kidney so it can't be reabsorbed into peritubular capillary)

Explain the terms therapeutic index and therapeutic window

index = toxic dose/therapeutic effect (TD50/ED50); the larger the TI, the safer the drug. Window is just the distance between toxic dose and therapeutic effect

Theraputic Index

indicate the ability of a drug to produce the desired therapeutic effect relative to a toxic effect

Describe the impact of drug binding on the receptor

induced fit at the active site causes a conformational change that can lead to activation (agonist), inactivation (inverse agonist) or nothing (antagonist)

Describe the mechanisms of drug interactions

inhibition and induction of enzymes, induction of enzymes that metabolize drug itself (can cause a decreased response - pharmacokinetic tolerance), same enzyme metabolizes two prescribed drugs (competition can elevate drug levels and increase response)

Explain the effects of an alpha-inhibitory subunit on the G-protein coupled transduction pathway

inhibits adenylate cyclase (Drug is still an agonist since it produces an effect) -> decreases cAMP -> deactivates PKA -> decreases protein phosphorylation and gene transcription

Explain the term antagonist

inhibits the action of an agonist, but has no effect in the absence of the agonist

List the major types of drug receptors

ion channels, G-protein coupled receptors, enzymatic cytosolic domains, intracellular

Explain the term half life

the amount of time over which the drug concentration in the plasma decreases to one half its original value

Explain the term volume of distribution (VD) and how it can be calculated

the dose given compared to the concentration of drug in the plasma. Tell us how much of the drug administered remains in the circulation, high distribution means less concentration of drug in plasma for any given dose.

Explain the principles of therapeutic dosing and frequency

therapeutic dosing is getting the right concentration to the targeted receptors. Frequency affects the dose needed, if there is less frequent administrations of a drug, a higher dose is needed (elimination will become more rapid). If there is frequent administration of a drug, it is easier to keep it within therapeutic range

Explain the concept of pH trapping

use Henderson-Hesselbach equation to determine difference between pKa and pH (ex. 3 means 1000 times more HA than A, -3 means 1000 times more A than HA), use protonation of acids to have them cross membranes and become trapped because of pH (ex. Aspirin has pKa of 3.5, goes from stomach [1.5] to systemic circulation [7.4])

Tolerance

when repeated administration of a drug leads to an increased dose being required to produce the same effect. This is the same as saying the same dose gives a diminished response after time.