TI = LD₅₀/ED₅₀

LD₅₀ - lethal dose that would kill 50% of people.

ED₅₀ - effective dose that would cure 50% people.

The larger the TI, the safer the drug.

So, for a larger TI, the LD₅₀ must be larger, too. If an LD₅₀ is 100mg, this doesn't mean that you're goint to take 100 mg. It means that you can take up to 100 mg before it's lethal. So, you want the LD50 to be big and the ED50to be small.

What is Tolerance?

What are the 2 types of tolerance? 

T or F: Tolerance requires chronic use of a drug over a period of time.

Tolerance occurs when a larger dose is needed to produce the same biologic effect.

Drug disposition tolerance & pharmacodynamic tolerance.

True

What is drug disposition tolerance?

What is pharmacodynamic tolerance?

Drug disposition tolerance occurs when drugs induce more enzymes. Enzymes metabolize the drug faster & the drug is excreted faster. As a result, a larger dose is required to keep up w/ all of the enzymes.

Pharmacodynamic tolerance is an adaption that occurs in the CNS. FYI: It is possibly due to down-regulation of receptors to reduce sensitivity to large amounts of a drug. The body is trying to tell you that it has had enough.

What is antagonism?

What are the three types of antagonism?

Antagonism is where one drug (the antagonist) depresses or inhibits the action of another drug (the agonist).

 1) receptor (aka pharmacological) 2) physiologic 3) chemical

What is receptor antagonism?

What is chemical antagonism?

What is an example?

What is physiological antagonism?

Chemical antagonism is where one drug (the antagonist) reacts w/ another drug (the agonist) and changes its chemical structure so that it cannot bind to a receptor.

An example is when protamine sulfate (a weak base) binds to warfarin (a weak acid) to prevent it from binding to its receptor.

It's a functional antagonist that's actually an agonist, b/c it produces an effect (through a different receptor) opposite to that of the original agonist.

Factors involved in absorption, distribution, & elimination of drug in the body.

What are the 5 major factors involved in drug absorption?

Think ACCDS (ACC DUKE SUCKS)

1)Absorbing surface area - the greater the surface area, the greater the absorption.

2) Concentration - Many drugs are absorbed via passive diffusion. Therefore, the greater the amount of drug, the higher the [gradient] and more drug is absorbed.

3) Circulation to the site - The greater the vasculature, the more the absorption.

4) Dissolution rate - especially solid dosage forms

5) Solubility - especially solid dosage forms

Advantages:

1) its the easiest, safest, & most convenient ROA.

2) Since absorption takes 15-30 minutes, it can be removed via charcoal or vomiting if the wrong drug is given or if negative side effects occr.

Disadvantages:

1) Many drugs are poorly absorbed, some as low as 20-30%.

2) Many drugs, such as protein drugs (eg, insulin), destroy the GI.

3)First pass metabolism - blood first goes directly through the liver. Some drugs are metabolized before they ever reach their destination.

What are two ways that drugs are administered through the oral mucosa?

Name the advantage & disadvantage of this ROA.

Sublingual and buccal (in the cheek)

Advantage:

Avoids first pass metabolism

 Disadvantage:

There is very little surface area for absorption.

What type of ROA includes retention enemas?

What are retention enemas?

Besides retention enemas, what is another dosage form included in this type of ROA? 

What are advantages and disadvantages of this type of ROA?

Rectal

Fluids injected rectally to treat constipation. The fact that it is retentive means it is supposed to stay in the bowel long enough to soften the stool

Suppository

Advantages:

1) Good for pediatrics when swallowing an oral pill is not feasible.

2) No vomiting

3)Avoidance of portal circulation by 50%

Disadvantages:

1)Absorption is incomplete due to feces.

T or F:

IV is the most common parenteral route.

T or F:

IM has good absorption

Why?

Which type of parenteral administration is injected directly into the spinal fluid?

Give an example of when this method is often used

Intrathecal

during labor

Which is easier to do: intravenous or intrathecal?

What type of drugs are normally administered intrathecally?

Intravenous

Toxic drugs

Blood - liver - bile - intestinte - blood

It increases the half life.

T or F:

Rapid absorption occurs when a drug is given nasally due to a large surface area.

Why?

T or F:

Drugs that are taken nasally can cross the BBB.

False

Rapid absorption does occur, but the surface area is actually small.

True

T or F:

The absorptive surface area of the large intestine is the size of a tennis court.

1) mucosal folds

2) villi

3) microvilli

T or F:

Drugs that are poorly ionized display good absorption.

T or F:

Absorption most often occurs via passive diffusion.

Which will have more favorable absorption in the small intestine: weak acids or weak bases?

What is passive filtration? 

T or F:

The brain and placental capillaries are the only tissues that use passive filtration instead of passive diffusion?

It's where drugs that are small, water-soluble ions move through small membrane channels or small para-cellular spaces.

False, it's actually the peripheral capillaries that use passive filtration (they also use passive diffusion). The brain and placental capillaries use passive diffusion only.

T or F:

Facilitated diffusion moves with a concentration gradient.

What is facilitated diffusion? Is it selective? Is it saturable?

True

It's where a drug uses a carrier

(eg, transport protein) to get across the membrane. Carrier types include antiporters, symporters, and uniporters. It is selective and saturable.

How is active transport similar to facilitated diffusion?

They both require selective and saturable carriers.

Multi-Drug efflux is a type of               transport in which a selective/non-selective transport protein, such as a                    transporter, moves drugs and other                in/out of the cell.

T or F:

Multi-drug efflux functions in cancer cells and pathogens to produce drug resistance.

Multi-Drug efflux is a type of active transport in which a non-selective transport protein, such as a MDR (multi-drug resistance) transporter, moves drugs and other toxins out of the cell

True

Choose one: Plasma proteins can increase/decrease a drugs half life by binding to it. Why?

Which protein binds to weak acids? Which protein binds to weak bases?

What type of bonds are involved in protein binding?

It increases its half life, b/c it makes it more difficult for the drug to cross cell membranes and be metabolized.

Serum albumin - a1-glycoprotein

Weak bonds such as H-bonds, VDW's, etc. - not covalent or ionic bonds.

1)Protein binding

2)Adipose tissue

3)Bones and/or teeth

Martin Luther King Healed Forlorn Spirits 

1) Milk 

2) Lungs

3) Kidneys

4) Hair and skin

5) Feces

6) Sweat, saliva, tears

What is the primary route of excretion?

T or F:

Drugs that are non-ionized are readily excreted.

False. As a general rule, they are usually reabsorbed so they can be metabolized to a more polar metabolite.

T or F:

All molecules of less than 80k MW are filtered by the glomerulus.

False, all molecules of less than 70k MW are filtered by the glomerulus.

pH changes - drug A may increase pH while drug B requires a lower pH

altered absorption - drug A may extend gastric emptying time. Then, drug B ends up in the stomach for an extended period of time. Since drug B is slow in getting to the small intestine, this delays absorption.

altered peristalsis - drug A may speed up motility, causing drug B to go through the small intestine faster. The faster it moves through, the less it is absorbed.

Absorption

protein binding

Metabolism

Excretion

Drugs may compete for a protein. Drug displacement is where drug A kicks drug B off of a protein and drug B is absorbed (maybe faster than it should have been)

nonspecific enzyme induction - drug A may induce more of an enzyme that will degrade drug B.

Metabolic competition - self-explanatory

1) pH changes - if drug A lowered the pH, a weak base would ionize and it would be excreted faster.

2) Impairment of renal secretion.

The level of measurement that we use depends on the amount of info that is available. 

An anesthetic will be used to describe the levels of measurement.

Symptomatic - If we know very little, the action is described on a symptomatic level. Fe, the pt feels no pain.

Physiological - If we know a little more, we can describe the effects on a physiological level. Fe, we may know that nerve impulses are not being conducted.

Cellular - If we know more, we may be able to describe actions on a cellular level. Fe, we may be able to tell that a membrane potential is stabilized.

Molecular - The most specific level measurement. Fe, there may be a decreased capacity of Na channels.

Specific drugs are aimed directly at a disease. Non-specific drugs ameliorate symptoms. They are used for syndromes in which no clear cause is known.

Examples of specific drugs are most chemotherapeutic drugs. Examples of non-specific drugs are APAP and hypertension drugs.

T or F:

Chemotherapeutic agents have to be lethal to an invader to be effective. 

False, chemotherapeutic agents can be suppressive and still be effective.

T or F: 

Chemotherapeutic agents are always selective for organs

What is the hallmark of chemotherapy?

False, Abx are often selective for invaders.

Selective toxicity b/w host and invader

T or F:

Pharmacotherapeutic agents are always reversible.

False. It's rare, but they are sometimes irreversible. When they are , they are associated w/ toxicity.

T or F:

Anti-growth cancer drugs are very effective for slow growing tumors.

False

Anti-growth cancer drugs are NOT very effective for slow growing tumors

T or F:

Pharmacotherapeutic agents will increase or decrease activity of the organ function when producing its therapeutic effect.

T or F:

Any Abx that doesn't inhibit cell wall synthesis will only suppress bacterial growth.

1) They can replace naturally occurring substances in your body that are either gone or not working sufficiently. These drugs would be mostly hormones, but some neuromediators.

 2)There are drugs that change regulation of body functions. Examples would include the treatment of symptoms, antihypertensives,diuretics, antivonvulsants, etc.

3)Some pharmacotherapeutic drugs alter mood.

Methotrexate and Trimethoprim

are inhibitors of                 .

folic acid reductase

T or F: 

Receptors for pharmacotherapeutic drugs are often binding sites for a variety of endogenous, normally occurring, compounds including hormones and neurotransmitters

Structural complementation - Receptors are very specific. Fe, vasopressin and Qytocin are both 8 aa proteins that vary by 2 aa's. They act w/ different receptors.

Orientation in space - (stereoselectivity) chiral isomers are mirror images and  have identical properties, but differ in the receptors they bind to. Quite often, one isomer is active and the other is inactive.

cis-trans isomers - they differ in their properties and in their ability to bind to receptors.

T or F:

Antagonists must be identical to agonists.

False

Most often, antagonists hardly resemble the endogenous molecule they are trying to inhibit.

T or F:

With pharmacotherapeutic agents, toxicity is often an extension of therapeutic effect.

T or F:

Unlike geometric isomers, stereoisomers are easily isolated as pure substances, b/c they are racemic.

False

Geometric isomers are easily isolated as pure substances. Stereoisomers are not.

T or F:

An allosteric effect can either increase or decrease the binding of a ligand.

What is positive cooperativity?

What is negative cooperativity?

Cooperativity involves identical ligands.

Positive cooperativity is where one ligands binds to a receptor and causes another receptor on the same molecule to fit with an identical ligand. An example involves Hb's affinity for oxygen.

Negative cooperativity is where one of the ligands binds to the allosteric site and consequently changes the shape of the active site so that the other ligand cannot bind.  

What are membrane transporters?

What is Cystic Fibrosis?

What are the 2 types of transporters?

They are transporters in the membranes that help maintain the plasma concentrations of drugs. They have nothing to do with mediating drug effects.

CF is due to a genetic defect in ABC's. The defective ABC's can't efflux the chloride ions.

ATP Binding Cassettes (ABC's) and Solute Carrier Transporters (SLC's)

What are ABC's

What are SLC's

ATP binding cassettes (ABCs) are primary active transporters that are responsible for causing an efflux from cells in the liver, kidney, intestine, and BBB. The most important ABC is the MDR.

SLC's are solute carrier transporters. They use facilitated transporters or ion-coupled secondary active transporters. They are involved in the reuptake of nt's, transport of organic anions (OATs) and organic cations (OCTs)

Organic anion transporters are important in what organ?

What popular class of drugs uses these OATs?

Liver

Statins

T or F:

All drug actions require that a drug bind with a receptor.

False

Chelating agents, osmotic cathartics, & anesthetic agents act through physical or chemical processes.

Cholinesterase inhibitors and MAOIs act through enzymatic mechanisms.

Since penicillin is a water soluble drug, it doesn't absorb well. If it's given orally, it will have more time to be absorbed.

Why is drug metabolism necessary?

Most drugs are lipid soluble, meaning they would stay in the body for a long time and become very toxic. Metabolism converts the drugs into water soluble metabolites that can be excreted.

What is the main difference b/w the Phase I and Phase II proportions of metabolism?

Which one is synthetic (or conjugated) and which one is nonsynthetic?

Phase I involves small chemical changes occurring in one or more functional grps of a drug. Phase II is where a molecule provided by the body is added to the drug. 

 Phase II is synthetic (or conjugated) b/c there are many changes. Phase I is non-synthetic b/c there are minor changes.

T or F:

Phase I rxns always precede PhaseII rxns

False

The purpose of phase I rxns is to prepare drugs for phase II rxns by making them more reactive. Some drugs already have plenty of reactive grps and can be directly metabolized by phase II conjugation.

What are the main types of metabolic

phase 1 rxns?  What types of groups are commonly added b/c of these rxns?

oxidation, reduction, and hydrolysis

Think SHAC

Sulfhydryl (SH), hydroxyl, amino, & carboxyl.

T or F:

Only metabolic phase II rxns involve conjugation.

T or F:

Any drug that is modified by a metabolic phase I rxn will lose its biological activity.

Oxidation

FYI: Biotransformation = metabolism

T or F:

Most oxidations take place in the SER of cells in metabolizing organs such as the liver and kidneys.

They are enzymes found in the SER

What are the products after an ester undergoes hydrolysis? What enzyme catalyzes this rxn? 

What are the products after an amide undergoes hydrolysis? What enzyme catalyzes this rxn?

An esterase hydrolyzes an ester to an alcohol and a carboxylic acid. 

An amidase hydrolyzes an amide to an amine & a carboxylic acid.

Why are phase I rxns nonsynthetic?

Why are phase II rxns called synthetic or conjugated?

It's b/c only small changes occur in one or more functional groups on a drug.

It's b/c the body provides a highly polar molecule or group to be attached to the drug.

What are the 6 types of conjugation rxns involved in phase II of biotransformation?

Which is the most common?

Think GASMAG 

Glucuronidation

Amino acid conjugation

sulfation

methylation

acetylation

glutathione conjugation

Glucuronidation is the most common

Explain the process of glucuronidation in phase II rxns.

Why is this the most common phase II rxn?

With the help of a microsomal enzyme, the GA attached to UDPGA is transferred to the drug, making it a glucuronide. The glucuronide is a weak acid that will ionize at physiological pH, and be excreted.

It's the most common rxn, b/c UDPGA is not selective and it comes from glucose (which the body has plenty of).

During biotransformation, what type of cmpds are sulfated?

Explain sulfation.

aromatic hydroxyl cmpds (eg, phenols and catechols) and some amines

First, sulfate combines w/ ATP to convert to its active form, PAPS. Sulfotransferases then catalyze the conjugation rxn b/w PAPS & the drug (or the phase I derivative), making it more water soluble and readily excreted in the urine and bile.

Concerning biotransformation, explain amino acid conjugation.

T or F:

Concerning biotransformation, glutathione conjugates are rarely excreted in bile, but are excreted only in urine.

False

They're rarely excreted in urine b/c of their large MW. They can be excreted in bile.

T or F:

There is absolutely no barrier in the hepatic sinusoids to limit the uptake of solutes.

T or F:

Polar and ionized drugs cannot enter hepatocytes.

False

they can, but they have to enter via carriers or specific transporters.

Environmental or therapeutic factors can cause enzyme induction. Examples of therapeutic factors would be barbituates & rifampin increasing CYP3A4.

Genetic mutations can also increase metabolism.

How many CYP450's are there?

How are they distributed?

57

15 metabolize xenobiotics

14 are involved with sterol metabolism

4 oxidize fat soluble vitamins

9 oxidize fatty acids in addition to synthesizing prostaglandins

15 have no xenobiotic substrate

What 2 drugs induce CYP3A4 and CYP2CP/19?

What CYP is most abundant? Most polymorphic?

Rifampin and phenobarbital. This is one of the few examples of where metabolism is increased. If anything, metabolism is more often decreased

CYP3A4; CYP2D6

Compare zero and first order kinetics

zero order kinetics                              first order kinetics

-there is a constant amount of drug      -there is a constant % of drug lost  

lost per unit time                                  per unit time

-It's dose dependent, b/c the half-life   -It's dose-independent, b/c the 1/2

increases as [plasma] increases.           life remains steady at any [plasma]

-The graph is non-linear, b/c as the      -The graph is linear, b/c as the  

dosage increases, the [plasma]             dosage rate increases, the

increases exponentially.                        [plasma] stays the same. 

-the saturation of an enzyme is            -There is no saturation.

associated w/ its rate of excretion,         

thus the disappearance is a constant

amount per unit time.

-The exponential increase occurs b/c     -The linear increase occurs b/c the

the [plasma] is > Km.                           [plasma] is < than the Km.

-Prediction of [plasma] is difficult          -Prediction of [plasma] is easy and

                                                          toxicity is avoided.

What does steady state mean?

What is the steady state formula?

It means that a drug has equilibrated in all fluids.

1.5 X dose/time X t1/2

Vd

When given data, find the mass/volume and multiply it by 1.5

1) Rates of absorption and elimination - [peak] occurs when rates absorption and elimination are =.

2) ROA - [peak] will occur soon after an IV. For all other ROA's, the [peak] varies.

3) Target tissue

4) Apparent Vd - it's apparent, b/c it's not accurate. It's = to the dose / [plasma]. If the [plasma] is low (due to drug being stored in tissues), the Vd will be high. If the [plasma] is high, the Vd will be low.

5) Clearance - the volume of blood (ml's) from which drug is removed per unit time (minutes).

6) Half life - the time for the agent to decrease in concentration by one-half.

C = K_e * Vd

t_1/2 = .693/k_e

Dose rate = ?

Loading dose = ?

Dose/Time = Cl (mL/min) * [plasma] (in mg/ml) 

Loading dose = [plasma] (in mg/L) * Vd (in L)

For drugs that follow first order kinetics, the time to reach the final concentration is dependent on                  .

If a drug has a long/short (choose) half life, you can give a priming dose of the drug to reach the therapeutic concentration faster.

half-life

long

T or F

A prodrug has to be administered as inactive

False

It can be significantly less active

What is the main purpose of NO?

What are some of the other actions of NO?

Vasodilation via cGMP.

It acts as a NT in the CNS. NO alters platelet activation and has roles in inflammation and septic shock.

cGMP

NO; increased by ACh through the production of NO; and, phosphodiesterase V inhibitors (viagra)

T or F

Drugs made for hypertension are non-specific