Lectures in Review and Lecture 4-11 Objectives

Question 1

Drugg Effects Lecture

There are two “S” dose-response curves side by side on a drug concentration log dose graph, which curve has a higher potency? (left or right?)

Answer 1

the curve on the left will be more potent than the curve on the right.

Question 2

True or false

antagonists cause an effect

Answer 2

False.

Antagonists block th effect of the agonist and shifts the response curve to the right.

Question 3

True or false

Effects are always proportional to receptor binding.

support your answer

Answer 3

False

There are complex interactions like
Cascades of 2nd messengers and Spare receptors that Only need to activate a small fraction of receptors to get maximal response like in the Neuromuscular junction.

There is also Tolerance/desensitization from
Previous exposure to a drug that may cause decreased effects

Question 4

Variability lecture

What are the two main types of transporters?

Answer 4

ABC (ATP binding cassette)
Pumps that remove drugs from cells
ATP used up (1° active transport)
P-glycoprotein (MDR1)

SLC (solute carrier)
Many examples: glutamate transporters
Many use 2 ° active transport (Na+ gradients)
Many use facilitated diffusion

Question 5

Exotic Animal Pharmacology Lecture

What is a good chemical restraint for fish?

Answer 5

Tricaine methanesulfonate (MS-222)
Approved for use in fish
Local anesthetic that blocks voltage-gated sodium channels in both PNS and CNS
Should be buffered (makes water acidic)
Eugenol (Clove oil)
Unknown mechanism of action
Narrow margin of safety

Question 6

Lecture 4: Drug Elimination

Be able to describe how Phase I and Phase II reactions by the liver may decrease the concentration of a drug in the body. Be able to recognize some of the typical types of reactions that occur in each phase.

Answer 6

Both phases increase renal elimination. Oxidation happens in one and conjugation happens in two.

Question 7

Lecture 4: Drug Elimination

Be able to describe how the excretion of drugs by the kidney and liver may decrease the concentration of a drug in the body.

Answer 7

If the kidney is not functioning properly, expect elimination to not be as high. The liver metabolizes the majority of drugs given orally.

if more than 80% of liver is not functioning, will start casuing a decrease in metabolism.

Question 8

Lecture 4: Drug Elimination

Be able to compare and contrast the mechanisms by which filtration and secretion move drugs from the blood into the urine.

Answer 8

Secretion happens in the proximal convoluted tubule.

Question 9

Lecture 4: Drug Elimination

Be able to define the 3 measures of elimination (half-life, clearance, and the rate constant of elimination) & how they are related.

Answer 9

Half-life: (t1/2) Time it takes to reduce the drug concentration to ½ of the original concentration
Used to calculate withholding times for milk etc.
t1/2 ~ 0.693Vd/CL

Clearance: Volume of blood cleared by an organ per unit time
CL = CLrenal + CLhepatic + CLother
If you know of organ dysfunction, you can estimate changes in clearance
Example: Clearance of creatinine by kidney

Rate constant of elimination: Kel = 0.693/t1/2

Question 10

Lecture 4: Drug Elimination

Be able to use half-life and clearance to predict changes in drug concentration.

Answer 10

Half life example: You withhold milk until the concentration gets below the required level of 1 μg/ml. If the milk is at a level of 16 μg/ml and the half-life is 4 hrs, how long will you wait?
> 4 half-lives or > 16 hrs

Clearance example: You are treating a dog with renal disease with a reduced renal clearance. The clearance of creatinine is about 50% of normal. What does the decreased clearance do to the half-life of the drug?
t1/2 ~ 0.693Vd/CL : Half life will be twice as long (If fluid volumes stay the same)

Question 11

Lecture 5: Blood Concentrations

Be able to define a loading dose and describe why it is useful.

Answer 11

What can be done about the time it takes to get to a steady-state concentration?
Give a loading dose
Calculate the loading dose based on Vd and the desired plasma concentration.
Loading dose = target C.Vd/F
Give that dose at the beginning of treatment
If toxicity may be a problem, divide the dose and monitor for toxicity or blood levels

Question 12

Lecture 5: Blood Concentrations

Be able to describe/calculate the effects of the following on the fluctuations induced by repeated doses at steady state: Dose interval, Half life (or clearance or rate constant of elimination), Slow absorption

Answer 12

Proportional to dose interval
Inversely proportional to half-life
Decreased by slow absorption

Question 13

Lecture 5: Blood Concentrations

Be able to describe/calculate the effects of the following on steady state concentrations: dosage, does intervals, bioavailability, clearance (or half life or rate constant of elimination)

Answer 13

Proportional to dosage (twice the dose, twice the blood level) & inversely proportional to dose interval (number of hours apart dose is given- if went from every two hours to four… it would be half of blood concentration, every 8 would be a fourth)
Proportional to bioavailability (F) & inversely proportional to clearance (CL)

Question 14

Lecture 5: Blood Concentrations

Be able to describe how giving repeated doses rather than continuous infusion affects the steady state levels of a drug.

Answer 14

A continuous infusion eventually reaches a steady state after 4 half lives Giving repeated doses gives you something of a plateau but with fluctuations.

Question 15

Lecture 5: Blood Concentrations

Be able to describe the effect of increasing the dose rate on the steady state plasma concentration.

Answer 15

Time to steady state independent of dosage (even if a little bit of drug, still take 4 half lives but just at a lower dose)

Question 16

Lecture 5: Blood Concentrations

Be able to describe how the steady state blood concentrations are related to the half life of a drug.

Answer 16

steady state is reached in about 4 half lives

Question 17

Lecture 5: Blood Concentrations

Be able to describe in approximate terms how blood levels of a drug will vary over time if the drug is given by i.v. bolus or by continuous rate of infusion.

Answer 17

Bolus: All the drug goes in at once
After a bit of redistribution, plasma levels depend on clearance

Constant rate of infusion:
Plasma levels start low and eventually approach a steady state

Question 18

Lecture 6: Variability and Transport

Be able to list three factors whose variations contribute to the typical 9-fold range in blood-levels (pharmacokinetics) seen in many drugs.

Answer 18

Bioavailability, clearance, and volume of distribution.

Question 19

Lecture 6: Variability and Transport

Be able to explain using a population dose-response curve and a dose-toxicity curve how variation may contribute to adverse effects.

Answer 19

Variation, even in species, can create different effects. What works for one, may not work for the other. For instance, a len vs an obese animal.

Question 20

Lecture 6: Variability and Transport

Be able to contrast the types of molecules that move across membranes without transporters with those that may be carried across membranes by transporters. Which type is saturable?

Answer 20

Movements across membrane without transporters: Types of molecules: Hydrophobic molecules (Includes uncharged form of acids, bases) and Small molecules (Nitric oxide, Water)
Depends on diffusion: surface area, concentration. Not saturable
Movement with transporters: Types of molecules: Any size, charge. May be very efficient, rapid. Almost 100% of the penicillin in blood is removed by a single pass through the kidney. Saturable Other drugs may compete for transport.

Question 21

Lecture 6: Variability and Transport

Be able to list important drugs transported by the p glycoprotein and explain how variations in p glycoprotein expression contribute to toxicities.

Answer 21

P-glycoprotein removes ivermectin from the brain.
Also transports quinidine, verapamil, digoxin, spironolactone, etc
Ivermectin & perhaps other compounds may be toxic in some collies & other breeds because of decreased P-glycoprotein.

Question 22

Lecture 6: Variability and Transport

Describe where in the kidney that transporters are important for drug secretion. What types of molecules are secreted at this site? What types of molecules will diffuse back out of the urine?

Answer 22

SLC & ABC usually on opposite sides of cell (get a flux across an epithelium) Enables efficient drug elimination into urine, bile.
Acidic drugs (organic anions) Penicillin, ampicillin, cephalosporins, thiazine diuretics, furosemide, probenicid, salicylate, etc. Basic drugs (organic cations) Histamine, amiloride, cometidine, procainamide, neostigmine, trimethoprim, atropine, etc

slc: solute bindin carrier
abc: atp binding cassette

Question 23

Lecture 7: Adverse Drug Reactions

Be able to distinguish between the different types of adverse drug reactions.

Answer 23

Lack of efficacy
Side effects
Allergic reaction
Toxic drug reaction
Ideosyncratic reaction (not as important) - something that does not fit in with other reactions… Peculiar or individual

Question 24

Lecture 7: Adverse Drug Reactions

Be able to use a population dose-response curve to estimate what fraction of animals remains unresponsive at any dose and explain how this may contribute to ineffective drug therapy.

Answer 24

Dose response curves for populations
Typical pharmacokinetic variability may lead to some animals needing 10 times as much of a drug as other animals to respond

If we also have similar degrees of variability in pharmacodynamics, it may take 100 times as much drug to get 90% of animals to respond as it took to get 10% to respond

Question 25

# Lecture 7: Adverse Drug Reactions Be able to describe the mechanisms by which a drug could produce atopy (rash), anaphylactic shock, cytotoxicity and other types of hypersensitivity.

Answer 25

Type I-IV hypersensitivity: Type I (anaphylaxis-atopy) IgEs → mast cells, basophils Type II (cytotoxic) Other Igs & complement Type III (immune complex mediated) Big antigens form precipitates with aby Type IV (cell mediated) T cells

Question 26

# Lecture 7: Adverse Drug Reactions Be able to define a therapeutic index. If you are given a dose-response curve and a dose-toxicity curve, at a given dose be able to estimate what fraction of animals are responding to the drug and what fraction of animals are showing a toxic reaction.

Answer 26

Activate receptors with too high a dose: * Problem with a narrow therapeutic index * Too many “normal” receptors activated (excitotoxicity): Too much activation may be bad (overstimulation) * Activate wrong receptors (might be most toxic): Activate low affinity receptors, Ivermectin can act as a GABA agonist Non-receptor mediated mechanism * Form nasty compounds during metabolism: Acetaminophen forms alkylating agents that inactivate important proteins & DNA, There doesn’t seem to be high affinity binding to any receptor

Question 27

# Lecture 8: Toxicity Be able to describe receptor mediated and non-receptor mediated toxicities.

Answer 27

Receptor mediated: **Drug binds to important receptors/enzymes** Disrupt normal activity → damage/death **Overstimulation of “normal” receptors** Example: excitotoxicity **Low-affinity binding to “abnormal” receptors** High dose causes binding to receptors with low affinity for drug Non-receptor mediated: **Not very selective, usually not very potent** Toxic metabolites (Alkylating agents etc) **Bind to many proteins, DNA ** Example: acetaminophen, ethylene glycol

Question 28

# Lecture 8: Toxicity Be able to describe excitotoxicity and acetaminophen toxicities.

Answer 28

Excitotoxicity refers to an excessive activation of neuronal amino acid receptors. The specific type of excitotoxicity triggered by the amino acid glutamate is the key mechanism implicated in the mediation of neuronal death in many disorders. AT: Does not depend on receptor-mediated inhibition of cyclooxygenase (COX)

Question 29

# Lecture 8: Toxicity Be able to contrast pharmacology and toxicology.

Answer 29

Pharmacology Compound not damaging Study of “Potions” (L.: Potio, to drink) Compound given intentionally Receptor mediated effects (usually) Effects end when compound is gone (No permanent damage?) Toxicology Compound damaging Study of “Poisons” (L.: Potio, to drink) Compound often given unintentionally (detective work) Receptor & non-receptor mediated effects Changes/damage often persist after the toxin is gone (Study organ damage)

Question 30

# Lecture 9&10: Special Populations Be able to describe qualitatively the most accurate way to adjust drug dosage for differences in animal size. Predict whether large/small animals are under/overdosed if drug doses are calculated using the weight of the animal.

Answer 30

If you give a drug based on weight of animal you can: Underdose small animals Overdose large animals Double the size can mean... Mass increases by 8 (2h X 2w X 2l) Metabolic rate increases by 4 Surface area increases by 4 Beware of species differences in metabolism!!

Question 31

# Lecture 9&10: Special Populations Be able to describe how liver disease may alter drug levels through changes in: metabolic rate, blood protein binding, secretion of drug in bile… At what level does liver damage cause clinically significant changes in drug levels?

Answer 31

* Liver a major site of metabolism: Less drug metabolism in liver disease * Liver produces albumin and other proteins that bind drugs: Less drug binding in liver disease * Some drugs are secreted in bile: Less bile secretion in liver disease * Liver disease often decreases drug metabolism (decreased CL) Rule of thumb: Need extreme liver damage (> 80%) to overwhelm liver metabolism of drugs. But no routine test is available to test liver metabolism of drugs.

Question 32

# Lecture 9&10: Special Populations Be able to describe how renal disease may alter drug elimination. What clinical test(s) give you a good estimate of renal function?

Answer 32

Less blood “filtered” (↓GFR) → less drug in urine : Increased half-life of drug in body How can you measure GFR, i.e. clearance of drug from blood? Renal clearance: amount of blood “cleared” in a period of time. Can use clearance of creatinine as an estimate. Can use blood levels of creatinine as an estimate of clearance (GFR) (except birds) Renal failure can increase the half life of a drug. only 20% of renal function, 5 fold increase 10%, 10 fold increase. half of kidney, doubling of blood levels. renal failure can include leaking which could make protein level lower

Question 33

# Lecture 9&10: Special Populations Be able to describe how drug levels and responses may be altered in neonates and old animals.

Answer 33

In old animlas: Drug metabolism decreases in old age, Decreased oral uptake of drug Often ↓lean body mass, ↑fat (Longer half-life for lipid soluble drugs), Diseases of old age may affect half-life of drug (Renal disease in old cats usually slows metabolism/elimination), Old animals often given multiple drugs (Drug interactions may occur) In neonates: Few drugs approved, Receptors may not be expressed (Drugs may not work) Decreased barriers (Skin → ↑ topical absorption, Blood-brain barrier → ↑CNS toxicity), ↓Biotransformation, renal excretion, ↑Water, ↓fat

Question 34

# Lecture 11: Exotic Animal Pharmacology Be able to describe specific pharmacologic concerns of exotic animals including: lack of pharmacokinetic data, renal venous portal system, changes in temperature of exotherms

Answer 34

* lack of pharmacokinetic data: Most doses are empirically derived or extrapolated from other species an there is a general lack of approved drugs. * renal venous portal system: Kidneys of nonmammalian animals have a venous portal system that can pass venous blood from the caudal half of the animal through the kidneys for excretion/secretion. * changes in temperature of exotherms: POTZ preferred optimal temperature zone. Drug absorption, metabolism, distribution, and excretion vary with ambient temperature. Uptake and elimination increases with increasing temperature.

Question 35

# Lecture 11: Exotic Animal Pharmacology Be able to compare differences between drug delivery in mammals and selected exotics including: jugular intravenous injections, intraosseous injection, Baths, Skin, intraperitoneal injections vs intracoelomic injections Intraperitoneal, Intracoelomic

Answer 35

jugular intravenous injections: in birds and some reptiles the right jugular vein is bigger than the other and is preferred intraosseous injection: reptiles and birds Baths: amphibians, fish Skin: amphibians intraperitoneal injections vs intracoelomic injections Intraperitoneal: Intracoelomic: fish