Dr. Brown Pharmacology Ch 3
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Study of how the drug produces its effects on the body
Study of how a drug moves into, through, and out of the body
The ideal range of drug concentration in the body
Top end of the therapeutic range, above that=toxicity
Maximum effective concentration
Bottom end of the normal therapeutic range, below that=subtherapeutic
Minimum effective concentration
What is the goal of drug therapy?
To maintain the drug within the therapeutic range
What 2 things effect the rate at which a drug leaves the body?
Metabolism and excretion
3 things that affect the concentration of a drug in the body
- 1) Route of administration
- 2) Dose
- 3) Dosage interval
Routes of administration
- 1) Intravenous (IV)
- 2) Intramuscular (IM)
- 3) Subcutaneous (SC or SQ)
- 4) Oral (Per OS)
- Others: Intra-articular, intraocular and per rectum, intra-peritoneal
Amount of drug administered at one
Expressed in units of mass: mg, g, gr
Raises the drug concentration in the body more quickly into the therapeutic range, initial drug dose.
Dose needed to maintain the level of drug at the middle of the threshold range
Time between doses
Accidental injection of IV drug outside the veins
Why do we give injections into the veins and not into arteries?
- By the time an IV drug passes through the heart and lungs and returns to the tissues, it has been well diluted in the blood.
- An intraarterial injection results in the entire drug being delivered in high concentrations directly to the tissues supplied by that artery
Drug administered in an inhaled gas or mist and is absorbed within the lung airways
Random movement of molecules from an area of high concentration through a semi-permeable membrane. Drug must dissolve in the membrane and doesn't require energy.
Passive transport that requires a carrier molecule and energy
Like a pump, moves molecules across the membrane using a specialized carrier and can move against the concentration gradient (low to high). Expends energy either to move the drug molecule or to “reset” the carrier molecule
Cell drinking. Requires cellular energy, the cell membrane physically engulfs the molecule and brings it into the cell
If it requires a carrier molecule and all of the molecules are occupied, the transport system is called ____. The system is operating at its _________.
- Transport maximum (t-max)
Cell eating, requires cellular energyand the cell membrane physically engulfs the molecule and brings it into the cell
Passive diffusion rates are related to....
- The concentration gradient
- Drug molecule size
- Nature of the drug- reflects its ability to dissolve in the phospholipid cell membrane
- Temperature of the environment
- Thickness of the membrane
Factors for faster diffusion...
- Large concentration gradient
- Small, lipophilic molecule
- If the temperature at the cell membrane is increased
- The membrane is thin
- Water loving, also known as lipophobic (fat-fearing)
- Usually polarized (contain charges at the end of the molecule) or ionized (the molecule has a net positive or negative drug
Fat loving, nonpolarized or non-ionized
Where is a lipophilic drug most likely to be found?
Acidic environment of the stomach
Where is a hydrophilic drug most likely to be found?
Alkaline environment of the intestines
4 steps in drug movement
- 1) Absorption
- 2) Distribution
- 3) Metabolism
- 4) Excretion
What alters 4 steps in drug movement?
Disease or physiologic conditions
Movement of drug molecules from the site of administration to the systemic circulation
Drugs not designed to be totally absorbed
- Local anesthetics
- Topical insecticides (flea powder)
- Topical antibiotics
- Drugs that are intended to work within the lumen of the intestine
Degree to which an administered drug is absorbed.
Represented by the letter F
IM and SQ drugs need to dissolve in the extracellular fluid to reach the capillaries, which drug form will be absorbed best?
Hydrophilic form will be absorbed best. Some are purposely made lipophilic to delay absorption over several days after injection
Routes of administration and their bioavailability fastest to slowest
PO drugs need to pass through the cell membranes of the intestinal tract, which drug form will be best absorbed?
Lipophilic will be absorbed better. Hydrophilic drugs are poorly absorbed from the gut and remain in the intestinal tract to be expelled with the feces
Aspirin example in regards to pH ratio
- In the stomach, acidic, pH2
- Aspirin exists as a 1:10 ratio, 1 hydrophilic (ionized) molecule per 10 lipophilic (nonionized) molecules
In the duodenum, pH 6 Aspirin shifts to its hydrophilic form with 1000 hydrophilic molecules per 1 lipophilic molecule
Since lipophilic molecules are required to diffuse across cell membranes, aspirin is more readily absorbed in the stomach than the small intestine
The pH where the drug has an equal ratio (1:1) of ionized to nonionized molecules
For any acid drug with a pKa of 7, the ratio of ionized to nonionized molecules is 1:1 at a pH of 7
Movement of a drug molecule into a compartment where it changes from a lipophilic state to a hydrophilic state and remains in that compartment
pH of the stomach, duodenum and body fluids
- Stomach 1-3
- Duodenum 6-7
- Within cells and most body fluids, fairly constant 7.4
Aspirin example in regards to ion trapping
- Aspirin taken by mouth
- Acidic environment of stomach, it is nonionized and crosses cell membranes
- Inside the cells, it shifts to ionized form and is trapped within the cell
- Aspirin molecules can accumulate within the cells in the lining of the stomach and result in a slower absorption of the drug
Benefits of ion trapping in regards to the kidneys
- Used to remove excessive drugs through the kidneys
- Drug molecules are filtered out of the blood by the kidneys, but in their lipophilic state, they can be reabsorbed back into the systemic circulation
Benefits of on trapping in regards to urine
- If the pH of the urine can be changed, the drug or toxin molecule can be changed to its ionized form (hydrophilic)
- These hydrophilic molecules cannot diffuse across the renal tubulular cell membranes to be reabsorbed back into the body
- The change in urine pH by urinary acidifiers or alkalizers can trap the molecule within the lumen of the renal tubule and allow it to be safely excreted form the body
Dissolving of drugs from their tablet from into smaller particles and allow them to be absorbed
Stomach contractions that mix stomach contents and move them to the small intestine
The mixing and propulsive contractions of the small intestine
How does decreased and increased gastric motility affect drug absorption
- Decreased gastric motility can delay onset of orally administered drugs
- Increased gastric motility can allow the drug to reach the small intestine sooner
How can diarrhea and constipation affect drug absorption
Hypermotile diarrhea- the drug is moved past the small intestine before it is full absorbed and it is passed in the feces
Constipation or anti-diarrheal drugs may result in complete absorption of a drug that is not meant to be full absorbed
The phenomenon by which the liver removes so much of the drug that little reaches the systemic circulation
First pass effect
What does the hepatic portal system do in regards to drugs?
Blood from the intestines must pass through the liver where potential toxins are removed
The extent to which a tissue is supplied with blood
Which has better tissue perfusion, muscle or SQ?
What can effect tissue perfusion?
- Changes in temperature
- Vasoconstriction of skin when its cold
- Vasodilation of muscles with fight or flight
The movement of drugs from the systemic circulation into tissues
Distribution of drugs occurs through small gaps in capillary walls called _______.
Barriers to drug distribution
- Blood brain barrier
- Globe of the eye
Well perfused tissues
- Exercised skeletal muscle
Poor perfused tissues
- Inactive skeletal muscle
The movement of drug from the blood, to the first tissue, back to the blood and into a second tissue
Plasma contains _____ and ____ and other proteins that bind to specific hormones and compounds in the body
Only the ____ of the drug molecule is small enough to distribute through the capillary fenestrations
Take the amount of drug given and the resulting concentration in the body and you can calculate what?
Volume of distribution
A _____ volume of distribution means the more tissues that the drug is able to penetrate
What cellular changes can occur when a drug molecule binds with a receptor?
- Producing secretions
- Contracting muscle cells
- Depolarizing neurons
A drug that binds to the receptor and produces an effect on the cell
Reverses the effects of an agonist
Physically combine with ions or other compounds to produce their effect
What combines with lead in the body and facilitates the excretion of the combined product in the urine
What combines with calcium in a blood sample and prevents the clotting mechanism from turning the blood sample into a clot
What combines with the strong hydrochloric acid in the stomach to form a much weaker acid thereby reducing stomach irritation
The process by which drugs are altered by the enzymes and chemical reactions in the body before they are eliminated (drug metabolism)
Altered drug molecule is called what
The majority of enzymes involved in biotransformation are in which organ?
Other places biotranformation can occur besides the liver...
- Intestinal tract
Phase 1 of biotransformation
- Chemical process of reduction, oxidation, or hydrolysis
- Sometimes phase I does not diminish the activity of a drug
- Drugs that require biotransformation to become active are “prodrugs”
- Example: prednisone is biotransformed by liver enzymes to its active anti-inflammatory metabolite form, prednisolone
Phase 2 of biotransformation
- The metabolite is combined with another molecule such as glucuronic acid, sulfate, or glycine
- The conjugated molecule is usually more water soluble (hydrophilic) and more easily excreted into the urine
Repeated exposure of a drug results in an increased biotransformation of these dugs “induced metabolism” and other drugs that use that system
Mixed function oxidase system
The seemingly shorter duration of effect of the drug after it’s metabolism has been induced from repeated exposure
What can decrease the chances of a drug undergoing biotransformation
- Young animals
- Old animals
Movement of drug molecules out of the body
2 major routes of drug elimination
- Kidneys out in the urine
- Liver into bile and out in feces
Other ways drugs are eliminated from the body
- Filtration through glomerulus
- Active secretion through the proximal convoluted tubule
- Possible reabsorption, some molecules may move back into circulation from the loop of Henle
- Must be in lipophilic form
Things that effect renal excretion
- Hypoalbuminemia or hypoproteinemia
- Lowered blood pressure
- Blood loss
- Increased sympathetic tone
- IV fluids
- Drugs move by passive diffusion into the hepatocytes then are secreted directly into the bile or are metabolized and then secreted into bile
- If secreted in lipophilic form, the drug can be reabsorbed across the intestinal wall transported back to the liver by the hepatic portal system. This is called “enterohepatic circulation”
The time it takes for the drug concentration to be reduced by 50%
When a drug is given repeatedly, it accumulates to a point at which the highest and lowest concentrations are the same
The time from the beginning of therapy to reach steady state is equal to __ times the half life
The time after drug administration during which the animal cannot be sent to market for slaughter and the milk and eggs must be discarded, based on the elimination half-life of the drug
Drug withdrawal time
In a dosage regimen, the instructions "b.i.d" would be what component?
Form of a drug molecule that cannot readily penetrate a cell membrane
Hydrophilic or ionized
Type of drug (not drug molecule form) that becomes more ionized as the environmental pH becomes more acidic
Alkaline or basic drug
Movement of a drug from the blood into the brain would be an examaple of this movement of drugs in pharmacokinetics
Movement of drug from the intestinal tract, to the liver, to the blood and tissue, back to the liver, to the intestinal tract, and then reabsorbed back from the GI tract to the liver
Route of administration in which a drug is injected into the layers of the skin
A. 100 mg of drug administered, bioavailability 0.7
B. 150 mg of drug administered, BA 0.5
C. 200 mg of drug administered, BA 0.4
D. 250 mg of drug administered, BA 0.2
Which drugs is absorbed in the greatest amount?
Drug A is an acidic drug, is it more likely to be in lipophilic or hydrophilic form when placed in an acidic environment?
With acid drugs if the pKa is lower than the pH of the liquid its in then its in which form?
With acid drugs if the pKa is higher than the pH of the liquid its in then its in which form?
With alkaline drugs is the pKa is lower than the pH of the liquid its in then its in which form?
With alkaline drugs is the pKa is higher than the pH of the liquid its in then its in which form?
Rank the following drugs in order from 1 to 4, with 1 being the most rapidly absorbed and 4 being the slowest to be absorbed from a SQ tissue site with a pH of 7.4
- Basic drug, pKa of 5.4 (4)
- Acid drug, pKa of 8.4 (3)
- Acid drug, pKa of 6.4 (2)
- Basic drug, pKa of 9.4 (1)
If the half life for a drug is extended should you increase or decrease the dose?
If the metabolism of a drug has been accelerated by exposure to phenobarbital should the dose be increased or decreased
A hypoproteinemic animal is given a drug that is normally highly protein bound should the dose be increased or decreased?
The volume of distribution for a drug is decreased should the dose be increased or decreased
TRUE OR FALSE. If the metabolism of a drug has been induced, the dose of the drug should be decreased to compensate?
TRUE OR FALSE. Excretion of a drug by the liver is called biliary excretion
TRUE OR FALSE. The neutralization of stomach acid by tums or rolaids is a non-receptor mediated action
TRUE OR FALSE. An agonist would typically have little or no intrinsic activity on a receptor to which it binds
TRUE OR FALSE. If the Vd of a drug increases the concentration of the drug decreases
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