Pharmacology Exam 1 - How to do Drugs

The study of the relationship between drug concentration and physiological response is ...

Pharmacodynamics

ex. anti-inflammatory

The study of the time course of drug absorption, distribution, metabolism, and excretion is called:

Pharmacokinetics

The use of drugs in the treatment of disease is:

Pharmacotherapy

Pharmacology founded on observation of patient treatment is ...

Clinical pharmacology

What are the drug nomenclature names?

Chemical name (7-chloro-1,3-dihyrdo-1-...)

Nonproprietary (generic) name (Diazepam)

Proprietary (brand) name (Valium)

Drugs achieve a pharmacological response, the magnitude of which is determined by ...

The number of receptors

Drug ___ and ___ determine plasma/tissue concentrations, while biotransformation ____ and ____ terminate drug actrion

Absorption

Distribution

Metabolism

Excretion

Drugs pass across membranes via ___ and ___ transport processes

Passive and active

The most important mechanism of drug transfer is ...

Passive diffusion

Any molecule with sufficient ____ can cross via passive diffusion

lipid solubility

What factors are directly proportional to the rate of drug transport?

What factors are inversely related?

Direct: Concentration gradient, lipophilicity

Inverse: Molecular weight, membrane thickness, polarity

Does carrier mediated transport require energy?

Depends

Facilitated diffusion - no energy

Active transport - energy

Carrier mediated transport is saturable, meaning ...

At a certain point, adding more into the blood will not affect it if there are no more carriers for the higher concentration, meaning it is competitive

Physiochemical factors are site dependent, and for drugs crossing the skin, ___ is of great importance

Lipid solubility (as opposed to drugs outside of capillary beds, since they are very good for passive diffusion)

Most drugs are weak acids or bases and are present as nonionized or ionized, meaning ...

Nonionized: lipid soluble, diffuse across cell membrane

Ionized: Low lipid solubility, can't cross lipid membrane

What is the formulas for percent ionization?

100/(1 + antilog(x))

x = pKa - pH if weak acid

x = pH - pKa if weak base

How do you calculate an antilog?

An antilog counts the number of places that a decimal is moved from the number one.

antilog(0) = 1 (moved 0 decimal places)

antilog(3) = 1000 (moved 3 decimal places right)

antilog(5) = 100000 (moved 5 decimal places right)

antilog(-3) = 0.001 (moved 3 decimal places left)

Calculate the percent ionization of a weak acid with pKa = 4 in a pH = 3

What about a weak base with pKa = 8 in a pH = 3?

antilog(4 - 3) = antilog(1) = 10

100/(1 + 10) = 9.1% ionized

antilog(3 - 8) = antilog(-5) = 0.00001

100/(1 + 0.00001) = 99.999% ionized

Weak bases are more ionized in ___ environments, and vice versa

acidic

An acidic drug will accumulate on the more (acidic/basic) side of the membrane

Basic, because that will ionize it and it won't pass the membrane easily

If pKa and pH differ by 1, the ratio of U:I varies by ___ fold

10

What is the rate limiting step of release of an orally administered drug?

Dissolution (salts dissolute faster)

What is micronization for?

To enhance absorption by decreasing particle size

What is Griseofluvin for?

Fungal infection of skin, hair, and claws in dogs/cats/horses

Microsize absorption: 25 - 70%

Ultramicrosize: 100%

Generally, food (prevents/enhances) absorption

However, if a drug is ____, this affect is swapped

Prevents, due to dilution and blocking surface area. Lipophilic drugs

What are the major factors affecting the small intestine's drug absorption?

pH

Epithelial surface/surface area

Motility

Efflux proteins (P-glycoprotein)

- Fights against drug absorption

If a drug somehow escapes the GI tract, it then encounters the evil ...

Liver! May be removed entirely with the "first pass effect"

So dosages take into account that 90% of the drug may be metabolized by the liver

The rate/extent a drug will enter systemic circulation is ...

Bioavailability

Take 2 grams, 0.3 enters circulation, only 15% bioavailable

Bioavailability is described by three aspects of the function:

Peak plasma concentration (Cmax)

Time to reach Cmax

Area under the curve (AUC)

The major reason for species differences in doses is ...

Bioavailability

What is firocoxib for?

Pain/inflammation associated with osteoarthritis in dogs (Previcox) and horses (Equioxx)

0.1 mg/kg in horses and 5 mg/kg in dogs due to bioavailability

Administering drugs _____ will give 100% bioavailability

intravenously

Bioavailability is calculated using the formula:

F = (Oral AUC)/(IV AUC)

So it is the fraction of the area of the curves of oral over IV

What factors may negatively affect bioavailability?

Poor dissolution

Instability, inactivation

Poor passage

First pass metabolism

What is buprenorphine for?

Low/high first pass?

Administration?

Pain management in in cats

Oral, with extensive first pass metabolism

Giving transmucosally (pKA = 8.24, saliva = 8-9)

What are the factors affecting drug distribution?

Physiochemical properties of the drug

- pKa

- Lipid solubility

- Molecular weight

Conc. Grad. between blood and tissue

Ratio of blood flow to tissue mass

Affinity of drug to tissue constituents

How do insoluble drugs travel in the blood?

On plasma proteins (albumin)

They are inactive when bound

What are some potential setbacks when dealing with drugs that are highly protein bound?

Administering 2 drugs will yield competition, leading to a higher free drug concentration

An injured dog with an unknown but lower protein count will need a different dosage than usual to avoid overdose

What proteins do acidic and basic drugs bind to?

Acid: Albumin (50% - 55%)

Base: alpha - 1- acid glycoproteins and lipoproteins

Ivermectin toxicity is due to a gene mutation that leads to decreased production of ...

P-glycoprotein, meaning the blood brain barrier was easier to cross

The theoretical volume required for a set drug dosage to create a specific plasma concentration is ...

Volume of distribution

25 mg/L plasma conc. desired

Have 500 mg of a drug

Vd = 20 liters (since 500/20 = 25)

What areas of the body are the following drugs limited/allowed to?

Protein-bound

Water soluble

Lipid spluble

Protein: Limited to plasma since proteins don't pass

Water: Can pass to the extracellular fluid, as well as plasma

Lipid: Distributed to plasma, ECF, and ICF, equivalent to total body water

To determine the dose of a drug, the equation is ...

Dose = Volume of Distribution (Vd) * Target conc.

500 mg = (20 L) * (25 mg/L)

A drug with a very large volume of distribution implies ...

The drug is trapped

(500 mg)/(2000 L) = 0.25 mg/L

=> small plasma conc.

=> large tissue conc.

=> trapped in tissues

Drug metabolism typically involves the enzymatic alteration to make it (more/less) lipid soluble and (more/less) polar

Less lipid soluble and more polar so it doesn't travel through cells and stays in the blood to reach organs of excretion

General metabolism is biphasic. Those two phases involve:

Phase 1: Add a polar group (-OH or -COOH)

Phase 2: Conjugation to endogenous compounds, typically water soluble

Note: Not necessarily sequential (Either or both phases can be absent)

Cytochrome P450 is a major phase (1/2) metabolic enzyme

Phase 1

It is key in producing an "active oxygen complex" which will oxidize drugs

What are the 3 effects of phase 1 metabolic reactions?

1) Active drug --> inactive metabolite

2) Active drug --> active metabolite

3) Inactive drug (pro-drug) --> active drug

4)

Note: active drug --> toxic metabolite

Phase II reactions are synthetic reactions that combine a ____ with a natural compound to form a readily excreted polar metabolite

Drug or phase I metabolite

The most common conjugating agent is ....

Glucuronic acid

Why would you give a cat a drug less often than a dog?

They are poor glucuronic acidifiers, so they can't convert drugs to excretable metabolites very quickly

T/F: Cats get acetaminophen toxicity because normally, 42% of acetaminophen is turned into glucuronide, but since cats are bad at that, it is overwhelmed and instead turns to NAPQI, which is toxic

True, leads to cyanosis

GI microorganisms can mediate metabolic transformations, including:

Hydrolysis and reduction reactions

Renal excretion is the principle route for drugs that ...

have limited lipid solubility and are ionized at physiological pH

What are the three mechanisms of renal excretion?

1) Glomerular filtration

2) Carrier mediated excretion (polar)

3) Passive reabsorption

T/F: Biliary excretion involves the reversible transfer from plasma to bile

False, it is irreversible

What sort of compounds are conjugated by hepatocytes?

What is the conjugate?

High MW, polar compounds

Glucuronic acid

T/F: Once a drug glucuronide enters the intestines by the bile duct, it is always excreted

False, glucoronidase in the intestines will reactivate it, and it can be absorbed again (enterohepatic circulation)

Enterohepatic circulation, inhibited renal/biliary secretion, and drug competition will alter the drug's ...

Dosage

Parentral administration means ...

The GI tract is bypassed (IV, IM, SQ)

Doctors give local anesthetics with epinephrine because ...

It is a vasoconstrictor and keeps the anesthetic in the site of action longer

Drugs delivered across the skin (transdermal) are ...

Percutaneous absorbed

Must be lipophilic

Buccal, sublingual, intranasal, and rectal are all examples of ...

transmucosal administration

What is buprenorphine?

How is it administered

Opioid agonist used to treat mild/moderate pain in dogs/cats

Transdermal or buccal

The study of the time course of ADME principles is ...

Pharmacokinetics

The rate and extent a drug enters circulation is ...

Bioavailability (F)

Bioavailability is described by three factors:

Peak plasm concentration (Cmax)

Time to reach peak

Area under the curve (AUC)

The curve that graphically defines the time course, described in its entirety by the area under the curve, is the ...

Disposition curve

The bioavailability of an IV drug is ...

100%

Comparing an IV drug versus non-IV, it is called ...

Comparing two non-IV drugs is called ...

Absolute bioavailability

Relative bioavailability

What are the two phases associated with IV administration?

Alpha/Distribution phase: rapidly distribute to tissues

Beta/Elimination phase: removal of drug via biotransformation

The fraction of drug eliminated per unit of time is denoted as ___ and is determined by ...

Elimination rate (K_el)

Slope of beta phase

K_el = 0.1 implies __% of that drug is eliminated per minute

K_el = 0.3 implies __%

10%

30%

The time required for the body to eliminate 1/2 of the drug from the blood is called ...

Half-life

What is equation for half-life?

T(1/2) = 0.693/(K_el)

What are the two major determinants of half life?

Drug distribution and clearance

If a drug is administered to concentration A, falls to concentration B, and is re-administered to concentration A, this is called ...

Fluctuation (dosed after half-life)

If a drug is administered to concentration A, falls to concentration B, and is re-administered to a higher concentration C, this is called ...

Accumulation (dosed before half-life)

When the amount of drug eliminated is equivalent to the amount taken in, this is called ...

Steady-state

The volume of tissue that dilutes the drug or the volume to which a drug appears to distribute is the ...

Volume of distribution

The volume required to contain all drug in the body if it were at an equal concentration to plasma

Volume of distribution is calculated as:

Vd = Dose/(Target Conc.)

Increasing the volume of distribution will have what affect on plasma concentration and half-life?

lower plasma concentration

Increase half-life

The volume of plasma irreversibly emptied of the drug

Body clearance

The calculation for body clearance is:

CL = Vd * K_el

Units = mL/(minutes * kg)

In drugs with similar _________, the smaller the volume of distribution the shorter the half-life

body clearance values

Two drugs, A and B, have the same clearance rate of 4

Drug A has a half-life of 100 minutes

Drug B has a half-life of 1000 minutes

Calculate their volume of distribution

Vd = Cl/K_el

K_el = 0.693/T(1/2)

Drug A

Vd = 4/(0.693/100) = 577.2

Drug B

Vd = 4/(0.693/1000) = 5772.0

Forumulas

Yay