Lectures 1 & 2

Question 0

Properties we hope for in a drug

Answer 0

effectiveness, safety, selectivity (drug only works on desired system)

**no such thing as ideal drug - weigh benefits and drawbacks

Question 1

What is the therapeutic objective?

Answer 1

Maximum benefit with minimum harm

Question 2

Factors affecting how a patient will respond to a drug

Answer 2

• route of administration
• pharmacokinetics
• pharmacodynamics

Question 3

5 “rights” of med administration

Answer 3

• giving drug to right patient
• right drug for what you’re treating (drug you intend to administer)
• right dose (look it up if you don’t know)
• right route
• at the right time

Question 4

pharmacokinetics

Answer 4

What the body does to the drug: absorption, distribution, metabolism, excretion

Question 5

pharmacokinetics: absorption

How do drugs cross a cell membrane?

Answer 5

3 ways:

1. Channels and pores - not how most pass. Most are too big.
2. Transport system: P-glycoprotein is the most common. A multi-drug transport system from one side of cell to other
3. Direct penetration of the membrane: most common. Must be lipid soluble.

**polar molecules and ions can’t cross cell membranes

Question 6

What are polar molecules and how do they reach the bloodstream?

Answer 6

Molecules with an uneven distribution of charge, but have no net charge. E.g., water or kanamycin, sugar

PM like sugar dissolves in PM water. Oil is not a PM, sugar will not dissolve in it. –> NOT lipid soluble and so can’t be taken orally. IV solution - dextrose & water.

Question 7

What are ions and how do they reach the bloodstream/how are they absorbed?

Answer 7

Ions are molecules that have a net electrical charge.

Ions cannot cross cell membranes (process of ionizing/de-ionizing is important in absorption)

Question 8

Tell me about acids and bases

Answer 8

Acid- a molecule or compound that is a proton donator.
Base: a molecule or compound that receives or “accepts” a proton.
A key point: Acids are attracted to bases because they are trying to donate a proton. Bases are attracted to acids because they are trying to receive a proton.

Question 9

Why is all this about acid-base, ionization, and polar molecules important?

Answer 9

Whether or not a drug is an acid, a base, an ion or a polar molecule determines absorption of the drug in the body. Ionization of drugs in pH dependent and when the pH of the fluid on one side of a membrane differs from the pH of the fluid on the other side, drug molecules will tend to accumulate on the side where the pH most favors their ionization. Acidic drugs will accumulate on the alkaline side and Basic drugs will accumulate on the acidic side. This phenomena is known as ION TRAPPING OR pH PARTIONING.

Question 10

What factors affect drug absorption?

Answer 10

• rate of dissolution (determines onset of drug - how soon effects will begin)
• surface area available for drug absorption - determines intensity
• blood flow to where drug is absorbed (more rapid where is hight)
• lipid solubility of drug
• pH partitioning

Question 11

Name 5 common routes of drug administration and give pros and cons of each.

Answer 11

1. Intravenous (IV)- no barrier to absorption, almost immediate onset, high cost, inconvenient, risk of infection, risk of blood clot, irreversible, risk of fluid overload
2. Intramuscular (IM)- barrier is capillary wall, rate of absorption determined by blood flow, able to give extended release (depot) preparations via this route, risk of injection site infection and reaction, irreversable
3. Subcutaneous (SQ)- similar to IM; use if we don’t want to get to bloodstream right away, but don’t want to use IM. One example is birth control.
4. Oral- easy to administer and convenient for self administration, variable absorption, PATIENT MUST BE ABLE TO SWALLOW WITHOUT ASPIRATING
5. Rectal- extremely inconvenient, unless patient needs alternative route (e.g. patient vomiting and can’t keep drug down)

Question 12

Define drug distribution

Answer 12

Distribution is the movement of the drug through the body. Drugs must exit the vascular (veins and arteries) system in order to be excreted and metabolized

Question 13

What is protein binding?

Answer 13

While circulating in the blood, some drugs attach themselves to proteins. The most common protein is albumin. While the drug is attached to a protein it is not “doing its thing” on the body. This can be a problem when a patient is taking two or more drugs that use the same protein to bind. These drugs can compete for a protein and can displace each other. This means that free standing levels of one drug or both drugs can increase leading to trouble (toxicity or increased adverse effects, drug interaction).

Question 14

Define drug metabolism

Answer 14

The alteration of a drug by the body. This is done by enzymes. Leads to the breakdown of a drug or, if it is a Pro-drug, an alteration that makes the drug active in the body. Most metabolism occurs in the liver.

Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, aka the P450 system. A common enzyme is 3A4.

Question 15

Why is it important to consider enzyme metabolism when administering multiple drugs?

Answer 15

The body can only make so much of an enzyme at a time. So, if a patient is taking multiple drugs that use the same enzyme for metabolism, then the drugs may compete for this enzyme, which can affect the drug level of one or both. This can lead to unwanted effects.

In general, some drugs are enzyme INDUCERS, which makes them speed up the metabolism of other drugs. This can cause the other drug to get broken down more quickly and therefore have a reduced therapeutic effect. On the other hand, some drugs are enzyme INHIBITORS. They can prevent or slow down the breakdown of other drugs thereby causing them to build up in the body and cause toxic effects.

Question 16

Metabolism: What is 1st pass effect?

Answer 16

The first-pass effect (also known as first-pass metabolism) is where the concentration of a drug is greatly reduced before it reaches the systemic circulation. After a drug is given orally it must first pass through the liver which reduces the amount of the drug before it reaches the rest of the body.

Question 17

Define drug excretion. Include steps to renal excretion and factors that modify excretion

Answer 17

The expulsion of a drug or its metabolized products from the body. Most common route is renal (kidney). Other routes include via GI, breast milk, sweat, etc.

Steps in renal drug excretion: Glomerular filtration, passive tubular reabsorption, active tubular reabsorption

Factors that modify:
1- pH dependent ionization - can accelerate b/c not lipid soluble so won’t be reabsorbed. Will remain in renal tubule and be excreted via urine.
2 - competition for active tubular transport
3 - Age (old kidneys are shot, young kidneys immature)

Question 18

Name and describe 3 Plasma (blood) levels of a drug

Answer 18

i. Minimum effective concentration (MEC)- the minimum plasma level of a drug needed for a therapeutic effect to occur. In other words, if the plasma level is below this point the patient is not getting any benefit from the drug.
ii. Toxic concentration- the plasma level at which the patient begins to show signs of toxicity from a drug. Plasma levels must be kept below this point.
iii. Therapeutic range- The range between the MEC and toxic concentration. The objective of drug dosing is to maintain plasma blood levels in the therapeutic range.

Question 19

Drug half life

Answer 19

The time required for the amount of drug in the body to decrease by 50%. Determines the dosing interval of a drug (amt of time between each dose) - you want to administer before the minimum effective concentration.

At 4 to 5 halve lives, a steady state (plateau) will be achieved.

Question 20

What is a plateau, when is it reached, when does it decline, when is it at peak concentration? What is trough concentration and what is a loading dose?

Answer 20

Plateau (steady state)- when the amount of drug eliminated between doses equals the dose administered. Plasma drug level is constant (ie at a plateau).

i. Time to plateau- reached in 4 to 5 half lives when a drug is administered at the same dose repeatedly.
ii. Decline from plateau- when a drug is discontinued it will be eliminated from the body in 4 to 5 half lives
iii. Peak concentration- highest blood level of a drug
iv. Trough concentration- lowest blood level.
v. Loading dose- large initial dose given to establish a therapeutic drug level

Question 21

The trifecta of dose reduction

Answer 21

the elderly, people with liver issues, people with kidney issues: all good candidates for dose reduction

Question 22

Dose response relationship and dose response curve

Answer 22

The relationship between size of dose and intensity of response to it. Determines minimum amt of drug that can be used. Basic components- DOSE RESPONSE RELATIONSHIP IS GRADED ie. Increased dose→ increased response. It is plotted on a curve called the dose response curve. This curve is described in three phases.

Phase 1: low dose—flat because no response. NOT GRADED.
Phase 2: increase in dose results in corresponding increase in response. GRADED PART OF CURVE.
Phase 3: Plateau of response. NOT GRADED.

Question 23

Maximal efficacy & relative potency

Answer 23

Maximal efficacy- largest effect a drug can produce. INDICATED BY HEIGHT OF DOSE RESPONSE CURVE.

Relative potency- the amt of drug that must be given to produce a response.

Question 24

What are drug receptors and what do they allow drugs to do?

Answer 24

Functional macromolecules in/on a cell to which a drug binds to produce it’s effect. Usually binding of a drug to a receptor is reversible (although it can be irreversible).

Drugs can do two things by using receptors:

i. Mimic the actions that our hormones, neurotransmitters and other endogenous compounds produce
ii. “plug” the receptor used by an endogenous compound in order to block the effect of the endogenous compound.

Question 25

4 primary (most common) receptor families

Answer 25

i. Cell membrane embedded enzymes (span cell membrane. Bind and mimic/block compounds)
ii. Ligand gated ion channels (span cell membrane, regulate flow in and out of cell)
iii. G-protein coupled receptor systems (chain reaction)
iv. Transcription factors (work more slowly than first three) (has to get into cell then nucleus then start affecting RNA and DNA)

Question 26

Theories of drug-receptor interactions:

Answer 26

Simple occupancy theory-

1) intensity of a response to a drug is proportional to the number of receptors occupied by the drug
2) maximal response occurs when all receptors are occupied by the drug

Modified occupancy theory-

1) Affinity: strength of the attraction between a drug and its receptor. Reflected in potency. High affinity drugs tend to be very potent.
2) Intrinsic activity: ability of drug to activate receptor upon binding. Reflected in maximal efficacy. High intrinsic activity= high maximal efficacy

**both theories are correct - just depends on the situation. (e.g., noncompetitive vs competitive antagonists)

Question 27

Agonist vs Antagonist

Answer 27

Agonist- molecules that activate receptors

Antagonists- molecules that block receptors

i. Non-competitive antagonist: can bind irreversibly to receptors, and therefore reduces the total number of receptors available for activation by an agonist.
ii. Competitive antagonist- typically binds reversibly to receptors. Only will block if in higher concentration than the compound it is trying to block.
iii. Partial agonist- agonist with moderate intrinsic activity. Can act as antagonists and agonists!!

Question 28

ED50 vs LD50

Answer 28

ED50 (average effective dose)- the dose required to produce a therapeutic response in 50% of the population.

LD50 (average lethal dose)- dose required to produce a lethal response in 50% of the population.

Question 29

Therapeutic index

Answer 29

A measure of drug safety. It is the ratio of the drug’s LD50 to the drug’s ED50.

A large therapeutic index means the drug is pretty safe. A small index means you can overdose your patient pretty quickly. This means that you want to be keeping a close eye on the patient taking a drug with a small therapeutic index (e.g. by monitoring signs and symptoms of toxicity and taking blood levels)

Question 30

Examples of physiologic changes brought on by pregnancy that can alter drug disposition

Answer 30

o By the third trimester, renal blood flow is doubled, causing a large increase in glomerular filtration rate, which can accelerate clearance of drugs. Therefore the dosage of some drugs may need to be increased during this time.

o For some drugs, hepatic metabolism increases during pregnancy.

o Tone and motility of the bowel can decrease in pregnancy causing intestinal transit time to increase, increasing drug absorption, and therefore a reduction in dose may be needed for some drugs.

Question 31

Drug risks to fetus

Answer 31

• Some drugs can cross the placenta. The factors that determine drug passage across the membranes of the placenta are essentially the same factors that determine drug passage across all other membranes. Accordingly, drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar or protein bound cross with difficulty. One should assume however, that any drug taken during pregnancy will reach the fetus.
• Drugs taken during pregnancy can adversely affect both the mother and fetus. The greatest concern is teratogenesis (production of birth defects).
• FDA pregnancy risk categories: The FDA established a system for classifying drugs according to their probable risks to the fetus. According to this system, drugs can be put into one of 5 categories: A, B, C, D, X

A: there are no risk free drugs
B: animal studies have revealed no harm to fetus, but no adequate studies in pregnant women OR animal studies do show risk but pregnant women studies don’t
C: animal studies show risk, no adequate studies in preg women OR no animal or adequate preg women studies (do not use if safer drugs available)
D: Studies show risk but benefits may outweigh (do not use if safer available)
***X: studies of animals and pregnant women show evidence of abnormalities. DO NOT ADMINISTER

Question 32

Drug therapy during breast feeding

Answer 32

Drugs taken by lactating women can be excreted in breast milk. If drug concentrations are high enough a pharmacologic effect can occur, raising the possibility of harm to the baby. The factors that determine entry into breast milk, determine passage of drugs across membranes; drugs that are lipid soluble tend to enter breast milk more readily, whereas drugs that are ionized, highly polar, or protein bound tend to be excluded.

Question 33

Pediatric considerations

Answer 33

Pediatric patients are usually defined as younger than 16 years of age and weighing less than 50 kilograms.
• Adverse drug reactions: Pediatric patients are particularly sensitive to drug interactions resulting in increased concentrations as well as being vulnerable to unique adverse effects that may affect an immature body system.
• Promoting adherence: special considerations like dosing schedule, tablet size and technique of administration (e.g. asthma inhalers) need to be addressed in order to promote adherence to therapy.
• Pharmacodynamics: In very young children, immature organ systems have less than optimal functioning, which may necessitate increasing or decreasing drug doses to prevent toxicity and to achieve a therapeutic drug level.
• Pharmacokinetics:
-Neonates and infants: Because organ systems are not fully developed in the very young, these patients are at risk for drug effects that are unusually intense and prolonged.
-Children aged 1 year and older: By the age of 1 year, most pharmacokinetic parameters in children are similar to those in adults. Although they do differ in that they tend to metabolize drugs faster than adults until the age of 2 when it begins to decline. A further sharp decline takes place at puberty, when adult values are reached. Therefore dose adjusting may be necessary.
-Dosing may be based on weight or BSA (body surface area) depending on the drug.

Question 34

Considerations for Elderly patients: ADME

Answer 34

• Absorption: Rate of absorption may be slowed and therefore drug responses may be delayed. Gastric acidity is reduced which may alter the absorption of certain drugs.
• Distribution: The increase in body fat seen in the elderly provides a storage depot for lipid soluble drugs, which can reduce plasma levels and cause a reduction in response. A decline in lean body mass & total body water causes water soluble drugs to become distributed in a smaller volume. This can increase drug concentrations creating a more intense effect. Although albumin levels are only slightly reduced in healthy adults, these levels can be significantly reduced in adults who are malnourished. Because of reduced albumin levels, protein binding of drugs decreases causing levels of free drug to rise, making drug effects to be more intense.
• Metabolism: Rates of hepatic metabolism tend to decline with age therefore the half lives of certain drugs may be increased.
• Excretion: Drug accumulation secondary to reduced renal excretion is a major cause of adverse drug reactions in the elderly.

Question 35

Individual variations in drug responses

Answer 35

• body weight & composition (e.g., body fat/lean mass - some drugs reside in fat cells and remain active)
• Age (underdevelopment, failing system, fewer receptors)
• Pathophysiology (kidney disease/excretion, liver disease/metabolism, acid/base imbalance, altered electrolyte status
• Tolerance: pharmacodynamic tolerance, metabolic tolerance
• placebo effect
• variability in absorption, e.g., bioavailability
• genetics: altered drug metabolism, altered drug targets, etc.
• gender: e.g., alcohol metabolized more slowly by women, certain opioid analgesics more effective in women
• diet
• adherence to prescription directions