Pharmacokinetic and Principles of Pharmacology Flashcards
(104 cards)
1
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Pharmacology
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Study of how drugs work
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Pharmacokinetics
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Study of how drugs move into, through, and out of the body
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Pharmacodynamics
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Study of how a drug actually produces its effect on the body (how does it change the animal’s physiology)
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Four Phases of Pharmacokinetics - ADME
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Absorption
Distribution
Metabolism
Elimination
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Q
Absorption
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The movement of drug from WHERE it is administered (GI tract, SQ tissue, skeletal muscle) TO the systemic circulation (blood stream to the whole body)
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Distribution
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The movement of drug FROM systemic circulation TO the target tissue (lungs, liver, skin, brain, etc.)
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Metabolism
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The breakdown of the drug into metabolites (usually inactive metabolites) - occurs primarily in the liver
8
Q
Elimination
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The movement of drug OUT of the body - occurs primarily via the liver and the kidney
9
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Therapeutic goal
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To use just enough drug to achieve the intended beneficial effect with the minimum adverse side effects
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Therapeutic range/window
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The drug concentrations in the body that provide benefit with minimum adverse effects (the window between the minimum and maximum effective concentration)
- -To keep concentrations within this window, the amount of drug administered (dose) must be balanced with how quickly the drug leaves (taking into account the altered physiology of the patient caused by disease)
- -Exceeding maximum would result in toxicity
- -Missing the minimum would be subtherapeutic
11
Q
Balancing In-flow with Out-go
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In-flow = the dose given and amount of drug absorbed Out-go = drug metabolism and elimination
12
Q
Adding water faster
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- More water = greater dose
- Exceeding max dose would exceed maximum of therapeutic range and result in toxicity
13
Q
Adding water slower
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- Less water = lower dose
- Missing min would be subtherapeutic
14
Q
Holes in bucket got smaller
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- Smaller holes = kidney disease or liver disease
- Need to adjust dose based on physiology of the patient (doses are still guesses)
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Q
Dosage regimen
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- Mass of drug to be given
- Dose interval (frequency)
- Route of administration
- Duration (if given more than once)
- -Altering any part of the regimen can cause a different drug concentration being achieved within the body –> concentrations may be outside of therapeutic range
- -Dosage may be altered if physiology is altered by disease, but may need to be altered for other reasons such as loading dose v. maintenance dose
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Q
Loading dose
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=A larger than normal dose designed to “load” the body with drug or initially fill the bucket to the desired level
–Helps to achieve therapeutic range faster
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Q
Maintenance dose
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–Keeps the water at the appropriate level
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Q
Multiple doses
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The reason for multiple doses, routes, and dose intervals is to get concentrations into the therapeutic range and keep it there
–Drug accumulates until the rate of absorption = rate of elimination (=steady state)
19
Q
Steady state
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After 5 half-lives, when peak concentrations and trough concentrations are stable
- -There is a lag time between when the drug is started until concentrations are consistently in the therapeutic range at steady state
- -When faced with a long lag time to steady state, use a loading dose to achieve therapeutic concentrations, then keep it there with the maintenance dose
20
Q
Routes of administration
A
PO = by mouth
—Parenterally (anything NOT going through the GI tract)
SQ (SC) = subcutaneous (under the skin)
ID = intradermal (into the skin)
IM = intramuscular (into the belly or thick part of the skeletal muscle)
IV = intravenous (bolus or infusion into the vein)
—Type of infusion administered at a constant drip rate = Constant Rate of Infusion (CRI)
EV = extravascular or perivascular (area surrounding a blood vessel, typically a vein - if an IV injection misses the vein, this is where it went)
Intra-arterial = within the artery (not common)
IP = intraperitoneal (within the peritoneal cavity of the abdominal artery; used mostly in small exotics)
Topical = administration of a drug onto the surface of the skin (lotions, liniments, ointments)
Aerosol or nebulization = drug administered as a gas or mist and is inhaled into the lungs
21
Q
Intra-arterial
A
- Drug delivered as a high concentration to the specific tissue or organ supplied by the artery
- Can happen accidentally when an IV drug misses the vein and goes into the adjacent artery
- High concentrations achieved at the target organ can produce local toxicity (for drug injected into the carotid, can produce seizures)
- Blood samples taken for measuring blood concentrations of oxygen or carbon dioxide are taken intra-arterially
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Q
Intraperitoneal
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- Used when IV routes are impractical (ex: small laboratory animals)
- Used when large volumes of fluid or liquid drug need to be administered rapidly (if large volumes are given IV, the increased blood volume would increase blood pressure and cause fluid to leak out of the capillaries into the tissue producing swelling and pulmonary edema)
23
Q
Total daily dose (TDD)
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=Total amount of drug given in a 24 hour time period
- -Less frequent dosing can be more convenient for the client (increases client compliance)
- -When giving larger amounts (greater dose) less frequently, need to consider potential to fill above the therapeutic range and give a toxic dose
- -Smaller dose given more frequently helps keep the dose within therapeutic range (lowering the risk of giving a toxic dose)
24
Q
Therapeutic index
A
=The relationship between the maximum effective concentration and the minimum effective concentration
- -Wide therapeutic index = Cmax - Cmin is very great; drugs with a wide therapeutic index may tolerate higher doses/less frequency; tolerates wide swings without producing toxic effect
- -Narrow therapeutic index = narrow therapeutic range; toxic concentrations are close to subtherapeutic concentrations; wide swings of peak and trough concentrations fall outside the therapeutic range; ex: many cardiovascular and cancer drugs
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Four mechanisms by which drugs move to target tissues
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis/phagocytosis
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Passive Diffusion
- Through liquids
- Drug molecules are driven by random molecular motion
- No cellular energy is expended to move the drug
- Drug molecules always move from an area of higher concentration to an area of lower concentration (move down the concentration gradient) until equilibrium is achieved
- Drugs can move across a cellular membrane (as long as they are in the right form)
- -A drug must be able to dissolve into a cell membrane to be able to passively diffuse through to the other side
- -Lipophilic (fat loving) - can then move through the cell membrane
- -If a drug molecule is hydrophilic, will not readily diffuse through membranes
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Lipophilic
=Molecule that is neither polarized nor ionized
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Hydrophilic
=Molecule that is polarized OR ionized
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Polarized
=Having both a positive and a negative charge on either end that do not cancel each other out
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Ionized
=Having a net positive or net negative charge
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Facilitated diffusion
- Move by using a carrier molecule (usually a protein)
- Still driven by random molecular motion
- No cellular energy is expended to move the drug molecule (a "passive" process)
- Drug molecule must be able to combine with a receptor to be transported across the membrane (has to fit like a lock and key)
- Can also be helped across by a "porin" (a channel through the membrane that admits the molecule)
- Always moves down the concentration gradient (from high to low concentration) until equilibrium is achieved
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Active transport
- Uses a carrier
- Cell expends energy to pump drug molecules in ONE direction, AGAINST the concentration gradient
- Equilibrium is NOT attained and the pump will continue to move drug molecules across the membrane as long as there are drug molecules available to move
- Drug can accumulate large disproportionate amounts on one side of the membrane
- Large accumulations can produce toxicity in the concentrated area - or this can be used to move drugs to needed sites
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Pinocytosis
="Cell drinking"
- Engulfs drug molecules by a cell
- Less common means of drug transport across the cell membrane
- Relatively slow
- Requires cellular energy
- Moves molecules against the concentration gradient
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Phagocytosis
="Cell eating"
- Engulfs drug molecules by a cell
- Less common means of drug transport across the cell membrane
- Relatively slow
- Requires cellular energy
- Moves molecules against the concentration gradient
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Absorption
- Most drugs are useless until they are absorbed
- Exceptions: local anesthetics, topical insecticides, topical antibiotics, locally administered antiparasitic drugs
- Different routes of administration have different success rates for absorption of drugs
- Different bioavailability
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Bioavailability
=The percentage of drug given that actually makes it into systemic circulation
- Represented by an F and the %
- Ex: IV administration is always F=1.0
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Different routes have different absorption patterns
- IV bolus puts all of the drug dose into the blood immediately - high peak concentration
- -Used when a drug is needed stat
- -High peak may produce toxicity for short period of time - seen with IV anesthetics that produce temporary apnea (cessation of breathing)
- IM is almost as fast IF put into active muscle (inactive muscle slowly absorbs drug)
- -If given in comatose or anesthetized patients, absorption is slower (inactive muscle)
- SQ has to diffuse long distances to find open capillaries
- -Bioavailability >>> 1.0
- -Slower absorption spreads out the curve longer, but at lower concentrations
- PO has multiple barriers to overcome (which takes time)
- -Bioavailability >>> 1.0
- -Slower absorption spreads out the curve longer, but at lower concentrations
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Absorption via oral route
Challenges:
- Drug swallowed needs to get to the part of the GI tract to be absorbed
- Drug particles need to be small enough (dissolve)
- Drug molecules need to be able to get across the GI tract wall (lipophilic)
- Drug molecules need to be able to get past the liver and into systemic circulation
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Effect of GI motility on absorption
Intestinal motility effects the amount of drug absorbed
- Peristalsis: wave of intestinal smooth muscle contraction that propels food along the GI tract
- -An increase moves the drug quickly and the drug may not be able to dissolve sufficiently while in the small intestine to be absorbed (decreased amount of drug absorbed - more lost into the excreted feces)
- Segmental contractions: provide resistance to flow and slow the propulsion of food along the GI tract, mixes the intestinal contents
- -An increase causes an increase in contact time and the drug remains in the small intestine and can increase the amount of drug absorbed
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Effect of dissolution on absorption
Dissolution/dissolving = the process by which a solid dosage form breaks down into particles small enough that they can pass across the GI tract wall (take time)
- Liquid dosage forms either have the drug particles small enough to pass (i.e. liquid solution) or the drug particles are already very small (i.e. liquid suspension)
- Liquids move from the stomach to duodenum faster than solid dosage forms
- Liquid dosage forms typically attain therapeutic concentrations faster than solid dosage forms
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Sustained/Extended release tablets
Dissolve very slowly over hours
- Slow dissolving = slow absorption
- Not as predictable
- If tablets pass beyond small intestine before completely dissolving, they won't be absorbed very well
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Oral drugs need to be lipophilic to get across GI tract wall
- Drug molecules mostly pass across the GI tract cell membrane via passive diffusion
- Tight junctions fuse cells together and form a continuous cell membrane barrier
- Membranes composed of phospholipid bilayer
- To dissolve in the cell membrane, drug molecules need to be in a lipophilic (non-ionized) form
- -Hydrophilic molecules are not well absorbed
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Lipophilic v. hydrophilic
- When any drug dissolves in any liquid environment (tissue fluid between cells, acidic liquid in the stomach, urine in the bladder), some of the molecules become ionized, some become non-ionized
- Depending on the liquid environment and the chemical nature of the drug, the majority of the drug molecules will be in mostly one state or the other
- Regardless, some molecules will always exist in both of the states
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State of drug is dependent upon three things
1. The acid or base chemical nature of the drug
2. The pH of the environment in which they are immersed
- -Different parts of the body have different pH so a drug can change from mostly lipophilic to hydrophilic as the drug moves from one compartment to another
3. The pKa chemical characteristic of the drug
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The acid or base chemical nature of the drug
Acid
-When acid drugs give up an H+ ion, they become ionized (hydrophilic)
-When acid drugs gain an H+ ion, they become non-ionized (lipophilic)
Base
-When base drugs give up an H+ ion, they become non-ionized (lipophilic)
-When base drugs gain an H+ ion, they become ionized (hydrophilic)
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The pH of the environment
Stomach pH = 2
Duodenum pH = 6
Tissue fluid between cells pH = 7.4
-When a drug molecule goes from one pH to another and is exposed to more free H+ (more acidic environment) or less free H+ (more alkaline environment), they acquire or lose a H+ from the drug molecule and change their charge according to whether the drug is considered to be an acid drug or a base drug
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Acid drug in acid environment
Acquire H+ ion and become non-ionized
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Acid drug in base environment
Lose H+ ion and become ionized
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Base drug in base environment
Lose H+ ion and become non-ionized
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Base drug in acid environment
Acquire H+ ion and become ionized
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The pKa chemical characteristic of the drug
- Drugs exist in ratios of ionized to non-ionized drug molecules at different pHs (there are always some of both forms present at every pH)
- The acid/base nature of the drug determines which molecule form dominates at the ends of the pH scale
- Between the two extremes, there is a pH where the ratio of ionized to non-ionized molecules is 1:1 (=pKa)
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Depending if a molecule is ionized or not determines if it can pass through a cell membrane like the GI tract
1. Whether the drug is an acid or a base
2. The pKa of the drug
3. pH into which the drug is going to be placed
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P-glycoprotein pump
- Even if a molecule is lipophilic, it may be kicked out of the GI tract wall and into the lumen, or destroyed, before it reaches the bloodstream
- This pump is located in the GI tract wall and can pump drug molecules out of the GI tract cell and back into the lumen
- This pump is found in endothelial cells of the blood-brain-barrier, GI epithelial cells, liver, and kidney
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Certain herding breeds have decreased # of P-gps
- Have a genetic defect that prevents formation of functional P-gp molecules
- Cannot exclude these drugs as much as normal dogs, therefore more of the drug enters their system
- They are at risk for toxicity from too much of a "normal" dose
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Cytochrome P450 (CYP 3A)
- Also found in GI tract wall where it is designed to destroy poisons entering from the GI tract
- Many drugs are viewed as poisons and attacked by this enzyme
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P-gps and CYP 3A
Dosages of drugs are based upon the anticipated "loss" incurred by CYP 3A and/or P-gp
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Drug molecules need to be able to get past the liver and into systemic circulation
- Hepatic portal system: shunts blood from the GI tract to the liver
- -All molecules that are successfully absorbed across the GI tract wall and make it to the GI capillaries are then shunted by the hepatic portal system blood supply directly to the liver
- -Liver screens things coming into the body from the GI tract and removes poisons before they can enter the main systemic circulation and distribute to the rest of the body
- -Liver removes poisons and xenobiotics (=anything foreign entering the body)
- -Liver can efficiently remove some drugs, allowing only a small portion of the drug dose to reach systemic circulation and rest of the body
- -First pass effect
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First pass effect
=Removal of large percentage of drug before it can reach circulation
- -Exception: drugs given per rectum
- --Enters systemic circulation without being screened by the liver
- --More drug will be absorbed than reported
- --Ex: Diazepam suppositories owners to use at home for epileptic seizures
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Parenteral absorption
=Not via the GI tract
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Parenteral absorption depends on:
1. How much of the drug is in an ionized, hydrophilic form
2. The amount of blood supply to the tissue into which the drug has been injected (tissue perfusion)
3. How quickly the drug form injected into the site dissolves into small enough molecules to get into the capillaries
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Molecules must be in the ionized (hydrophilic) form
- Drug molecules must be able to dissolve in the tissue fluid between cells - lipophilic molecules won't dissolve in water
- Hydrophilic molecules move by random passive diffusion until they enter a capillary and are absorbed
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Entry through capillary cell membrane
- Body capillaries have fenestrations (windows) through which water, electrolytes, and drug molecules can pass without going through the membrane
- Note the brain and CNS have continuous capillaries without fenestrations so drugs entering the brain/CNS must pass through cell membranes
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Tissue perfusion
=The amount of blood supply going to a tissue
- Determines the rate at which a drug is absorbed
- Well perfused tissues have many open capillaries near the site of injection
- Drugs injected into well perfused tissues do not have to diffuse very far to enter a capillary and be absorbed, and they are absorbed faster
- -Ex: IM dose into active muscle v. dose into inactive muscle or fat
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SQ injection in warm v. cold cow
- On a cold day, superficial blood vessels under the skin constrict to shunt blood to deeper tissues and avoid loss of by heat through superficial blood vessels
- SQ injected drugs have to diffuse farther to find an open capillary when superficial vessels are constricted
- It takes longer for the drug to reach the capillary and be absorbed in the cold cow
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Epinephrine in lidocaine
- The epinephrine causes a local vasoconstriction where the lidocaine was injected
- This decreases the perfusion in this area and requires the lidocaine to diffuse farther to find an open capillary
- By delaying lidocaine's absorption, the epinephrine increases the anesthetic duration of action
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Drug molecules have to dissolve into small enough particles to be able to passively diffuse to open capillaries
- Depot drugs, or repositol drugs, are drugs that chemically combine with other molecules to form crystals that slowly dissolve
- The slow dissolving ability releases the drug over hours to days
- Does NOT include IV drugs
- Ex: Benzathine is added to pen-G antibiotic molecules to form a crystal that slows absorption of the drug for up to five days
- Ex: Depo-Medrol is a depot glucocorticoid anti-inflammatory injectable that provides slow drug absorption for up to a month
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Barriers to distribution
- Fenestrations are present in capillaries in most parts of the body
- -The brain and spinal cord (CNS) have continuous capillaries without fenestrations/openings
- Water, electrolytes, and drug molecules can pass without going through the membrane - there is no real barrier to distribution of drug molecules here
- Larger molecules, like proteins and RBCs, are too big to pass through openings and remain within the capillaries
- Drug molecules attached to proteins or RBCs do not distribute to the tissues
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Brain and CNS
- Continuous capillaries (no fenestrations/openings)
- Drugs entering the brain/CNS must pass through capillary cell membrane
- Supporting cells also surround the capillary and constitute additional membrane barriers drugs must pass through
- Drugs can only get into the brain if they are lipophilic
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P-glycoprotein pump
- Located in the capillary cell membranes that (like in the GI tract) moves drug molecules FROM the CNS tissue BACK into the blood after they have moved across the membrane
- ATP dependent (energy dependent) process so P-gp can continuously pump lipophilic drugs and poisons that get across the membrane back into the blood
- The combination of continuous capillary + P-gp = the blood brain barrier
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Other organs with barriers
- Similar capillary barriers (but not P-gp) exist for the:
- -Eyeball
- -Prostate gland
- -Testicular gland
- -Synovial tissue surrounding joints
- Limits the distribution of drugs into these locations
- Presents a therapeutic challenge for fighting infections with antibiotics since many of those are hydrophilic
- Drugs may have to be injected directly into these locations to be successfully delivered (distributed)
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Placenta
- Often thought of as "protective"
- Capillaries have fenestrations that allow most drugs to readily pass from maternal circulation to fetal circulation
- There is a P-gp pump in the placenta that will move some drug molecules back into the maternal circulation
- Important to remember that drugs given to the mother will distribute to the fetus
- Some drugs can disrupt normal fetal development resulting in fetal malformation - must be aware of this in pregnant animals (check the drug insert or other information for warnings)
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Effect of tissue perfusion on drug distribution
- Perfusion = flow of blood or degree of blood supply to tissues
- Poorly perfused tissues = fat, inactive skeletal muscle
- -Drugs are slowly absorbed FROM these locations if injected into these tissues
- -Drugs are likewise slowly distributed TO these tissues because of low perfusion
- Highly perfused tissues = brain, kidney, liver, active skeletal muscle (have extra components present to help with perfusion
- -Drugs rapidly distribute to those tissues (distribution to the brain is dependent upon the drug being lipophilic and being able to get around the P-gp pumps)
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Redistribution
- Tissue perfusion affects drugs like injectable propofol anesthetic or ultrashort acting barbiturate injectable anesthetics
- When propofol is injected as an IV bolus, the drug distributes quickest to the well perfused tissues (i.e. provides immediate anesthesia)
- Brain is well perfused, therefore propofol (lipophilic) rapidly achieves high concentrations, resulting in immediate anesthesia
- Fat tissues are poorly perfused, therefore propofol enters the fat tissues from systemic circulation over several minutes (propofol has no effect on fat cells)
- The animal starts to wake up shortly after IV bolus is given due to the concept of redistribution
- When propofol is given IV, it passes through systemic circulation in high concentrations, enters the brain, provides anesthesia
- As blood concentration drops below the brain concentration, propofol redistributes from the brain (down the concentration gradient) back into circulation and redistributes to the fat (therefore increased in obese animals)
- -The drug is trying to reach equilibrium within the systemic circulation
- As the drug concentration drops in the brain, anesthesia is reduced, resulting in the animal waking up
- -The concept of redistribution results in this rapid recovery from the anesthetic (too quick to be a result of metabolism or elimination of the drug)
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Obese patients
- Redistribution is most noticeable in these patients
- The "whole body weight worth" of the drug is going to the brain first --> initial overdose (get apnea with anesthetics like propofol)
- -Give lower initial dose based upon the estimated "lean" body weight (which will include well perfused tissues like the brain - but not fat)
- -Give a second, smaller, dose when redistribution causes the animal to get light --> replenishes the drug in the brain as the drug continues to move slowly into the large volumes of fat tissue
- -Anesthetic recovery in obese animals is longer because it takes longer for the drug to move from the fat into circulation
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Effect of plasma protein binding on distribution
- Plasma contains large proteins
- Drugs may bind to these proteins in circulation
- Proteins are too large to fit through the fenestrations, so they are trapped in the capillary
- Any drug bound to the proteins are also trapped in the capillary
- Only the free form of the drug molecule is small enough to distribute to the target tissue and produce its effect
- Protein bound drugs act as a reservoir of drug molecules to be distributed as the free drug molecules leave the capillary
- Drug doses take into account the amount of drug that will be protein bound and thus not readily available for distribution to the target tissues
- The ratio of bound to free drug molecules remains the same, so as one drug molecule leaves, one of the bound molecules becomes free to distribute
- "High protein bound" drugs are those that have 80% or greater of the drug bound to these blood proteins
- Anything that decreases blood protein increases drug distribution
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Hypoproteinemic blood
- More free drug molecules are left unbound, therefore more available to distribute and produce an effect
- Significant loss of protein from PLE, PLN, or severe liver disease (liver produces proteins) would require a decreased dose to avoid an overdose in the tissue
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Compartments
- Drugs do not just evenly distribute in the body; the body is divided into different compartments, separated by partitions, or membranes, that must be traversed by drugs
- Concentrations achieved in the blood may not necessarily equal the concentrations achieved by distribution in all compartments
- Each transition between compartments has its own challenges or barriers
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Volume of distribution (Vd)
=The pharmacokinetic value that provides an approximation of how well a drug distributes to all the compartments of your body (into how much liquid a drug distributes)
- A drug with a low Vd might not distribute to some compartments
- A drug with a high Vd would likely distribute to most compartments
- The higher the Vd, the more liquid the drug is diluted in --> the lower the concentration of the drug in the liquid
- A drug needs to achieve the therapeutic concentrations to work
- If the Vd of the drug increases (i.e. barriers are not as effective and the drug can penetrate more compartments than normal), this means the drug will be diluted more and concentrations will fall below the therapeutic range
- Usually changes in Vd are not significant enough to warrant a dosage change
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Xenobiotics
=Substances foreign to the body
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Role of metabolism of xenobiotics
- In order to survive, the body developed a means to rapidly eliminate xenobiotics to keep them from accumulating
- Animals must be able to metabolize toxins (poisons of biologic origin) found in plants in order to consume them
- -Many of the older drugs are plant poisons
- -Ex: Foxglove - digitalis glycoside heart medication, Willow tree - bark contains salicylic acid (aspirin)
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Biotransformation
=Metabolism specifically of xenobiotics
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Drug metabolism
=The conversion of a drug into another chemical form
- Primarily occurs in the liver (minor metabolism may occurs elsewhere - such as Cyp enzymes in the wall of the GI tract)
- The converted form of the original drug, or xenobiotic, is called a metabolite
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Metabolite
- Inactive, ionized, or polar drug molecule that has been processed through the liver
- Usually inactive (means it can no longer combine with the receptor site = no longer has affinity)
- If it cannot bind to the receptor site, then the drug can no longer produce an an effect (no longer has intrinsic activity)
- Ionized (can no longer penetrate the cell membranes)
- -Hydrophilic...but needs to be lipophilic to cross cell membrane
- -Decreased distribution across barriers
- -Decreased reabsorption across renal tubule walls, and more effective elimination
- -Therefore, metabolism stops drug action AND increases its excretion from the body (main goal of metabolism)
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Metabolism is completed by enzymes acting on the drug molecule
- Majority of liver enzymes are mixed function oxidase (MFO) enzymes
- -These enzymes are members of the Cytochrome P450 family of enzymes
- CYP 450 enzymes are the family of enzymes that metabolize drugs attempting to enter the body through the GI tract wall
- These cytochrome enzymes are inducible, meaning when they are exposed to the same drug or poison, they increase in number of enzymes and accelerate the metabolism of the drug
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Enzymatic metabolism
Phase 1:
-The drug molecule is chemically altered, and structurally transformed, by processes that add or remove oxygen, hydrogen, or other key molecules
-Usually less active at the end of this phase
-Exception: some drugs are converted to a more active metabolite
--The original drug molecule form is called a prodrug and the metabolite is referred to as the active form of the drug (ex: prednisone --> prednisolone)
--The prodrug is not active until it goes through the liver
Phase 2:
-The drug molecule is enzymatically fused with another molecule via a process called conjugation (=coming together)
-Most common conjugates are glucuronic acid ("glucuronidation"), sulfate, and glutathione
-Resulting conjugated molecule is usually hydrophilic and more readily excreted by the kidney
-Cats do not do this process very efficiently or effectively
-End goal is to make the drug more readily excretable
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Drug interactions with liver enzymes can affect biotransformation
- CYP enzymes in the liver are inducible, therefore the rate and efficiency of metabolism of these drug molecules by the enzymes is increased
- -The rate of drug inactivation is sped up and the metabolism is induced
- After metabolic induction, the dose of the drug must be increased to produce the same therapeutic effect, because of the more rapid metabolism
- -One of the major mechanisms by which DRUG TOLLERANCE occurs
- -Ex: Alcoholics must drink more to get drunk
- The metabolic induction affects any other drugs that use the same cytochrome P-450 enzymes for metabolism
- The dose for the other drugs would also have to be increased to produce the same therapeutic effect
- -Ex: Pheno for long-term control of epileptic seizures
- -Ex: Doses of phenylbutazone, glucocorticoids, and estrogen drugs must have their doses adjusted with long term pheno induction of metabolism
- Some drugs can inhibit the activity of CYP enzymes and slow the rate of metabolism of other drugs
- Net effect is slower metabolism of drugs that use the same CYP enzymes --> decreased elimination/excretion --> increased duration of action on the body
- Doses of some drugs may need to be decreased
- Ex inhibitors: antifungals, cimetidine (H2 blocker antacid), and macrolide antibiotics (erythromycin)
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Species differences in metabolism
- Metabolism in cats is always a concern
- Cats have low concentrations of glucuronyl transferase enzyme that causes conjugation in Phase 2 metabolism
- Drugs metabolized by glucuronyl transferase would have a very long active duration in the body of the cat
- -Aspirin half-lives:
- --Humans - 2 hours
- --Dogs - 8 hours
- --Cats - 36 hours
- Since cats conjugate poorly, and Tylenol is normally metabolized by glucuronyl transferase (which the have very little of), Tylenol is toxic due to the metabolite produced (the metabolite is toxic in all species, but ESPECIALLY the cat)
- -Normally the toxic metabolite is quickly converted to a non-toxic metabolite by the glutathione pathway - but the cat is deficient in this pathway also, so toxic metabolites produced by the liver accumulate and produce toxicosis
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Age differences in metabolism - Neonate
- Hepatic metabolism in neonates and pediatric animals is not developed
- Phase 1 metabolism is absent for the first few weeks of life - takes 3-4 months to reach full activity
- Phase 2 may be present, but not all pathways will be equally activated
- Rule: always check the drug info before giving a drug to a newborn or very young patient
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Age differences in metabolism - Senior
- Metabolism changes are often not considered in dosing the geriatric patient
- With age, the number of hepatocytes decreases, blood flow to the liver decreases, and CYP 450 enzymes decrease
- This can be worsened by older age degenerative changes in the liver that cause formation of scar tissue replacing functional liver tissue (cirrhosis of the liver)
- Rule: always check drug info before giving a drug to an older patient
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Routes of drug elimination
Major routes:
-Kidney = renal excretion into the urine
-Liver = biliary or hepatic excretion into the bile
--Bile moves into the small intestine
--Drugs are excreted into the feces
Minor routes:
-Lungs = route of elimination for anesthetic gas
-Mammary glands = excretion in the milk
--Concern about contamination from drugs
-Salivary gland = excretion into the saliva
-Sweat glands = excretion in sweat
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Two processes of renal elimination
1. Glomerular filtration
- Passive movement of drug molecules from capillaries of the glomerulus
- Driven by pressure in the glomerulus that pushes drugs and small molecules into the Bowman's capsule
2. Renal tubule active transport
- Active secretion FROM the peritubular capillaries next to the renal tubules INTO the urine
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Glomerular filtration
- Afferent arteriole carries blood INTO the glomerulus
- Efferent arteriole carries blood AWAY from the glomerulus to peritubular capillaries that parallel the renal tubules
- Constricting or relaxing afferent arteriolar smooth muscle regulates flow into the glomerulus --> pressure attained in the glomerulus --> amount of drug filtered into the Bowman's capsule
- Vasodilation --> increased flow and pressure
- Vasoconstriction --> decreased flow pressure
- Glomerular capillary has fenestrations with slits that allow small molecules to pass through into the Bowman's capsule
- Protein molecules are too large to pass, so they remain in the blood in the glomerulus
- -Highly protein bound drugs are not filtered out into the urine
- -In hypoproteinemia, there are fewer blood proteins --> more free drug molecules --> more drug molecules pass through the fenestrations into Bowman's capsule
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Changes in glomerular filtration
- Under conditions of low arterial blood pressure the afferent arteriole flow decreases --> filtration decreases --> decreases renal excretion
- When arterial blood pressure decreases --> sympathetic nervous system is activated --> norepinephrine release stimulates alpha receptors on afferent arteriole --> vasoconstriction --> reduces flow further --> decreases filtration pressure further --> decreases renal excretion
- IV fluids --> increases blood volume --> increases arterial blood pressure --> increases filtration --> accelerates renal excretion
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Bowman's capsule to proximal convoluted tubule
- Urine formed from glomerular filtrate passes into the proximal convoluted tubule (PCT)
- PCT has many active transport mechanisms
- -Glucose, some drug molecules, and other essential molecules are reabsorbed FROM the urine in the PCT back into the body tissues
- -Some drug molecules are actively secreted from the peritubular capillaries INTO the urine (Ex: penicillin antibiotics)
- -Even protein bound drug molecules can be actively secreted into the urine here
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Loop of Henle to distal convoluted tubule
- Drug molecules can be reabsorbed from the urine in the Loop of Henle and the distal convoluted tubule (DCT) by passive diffusion
- -The drug molecule mist passively diffuse through the renal tubule cell membrane - so only reabsorbed if in the lipophilic form
- -Hydrophilic drug molecules are "trapped" in the renal tubule and excreted into the urine
- -Urinary acidifiers or urinary alkalinizers can change the urine pH so the drug molecules are more in the ionized form, are not reabsorbed, and more readily excreted
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DCT to the collecting duct
- A few molecules continue to be passively reabsorbed from the urine of the DCT and collecting duct...
- ...But because its a pretty small amount, and at this point, the drug is considered to be "excreted"
- Urine passes into the renal pelvis --> ureter --> urinary bladder
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Total renal elimination
=Amount of drug filtered at glomerulus + amount of drug actively secreted into PCT - amount of drug reabsorbed by passive diffusion or by active transport (less common)
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Biliary excretion/elimination
- Biliary excretion from the liver refers to the bile duct that carries the liver bile to the small intestine
- A slower and less clinically significant route of elimination than the kidney
- Drug molecules may be metabolized by the liver prior to biliary excretion, or the drug molecule can be excreted in its original unmetabolized form
- If the drug molecule excreted into the intestine is still in the lipophilic form, it can be reabsorbed from the GI tract and re-enter the body
- -Drug circulates back to the liver --> GI --> body --> liver --> etc. (takes much longer to completely eliminate the drug)
- --Called enterohepatic circulation
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Rates of elimination
- Any compromise of kidney function, or reduced afferent arteriole blood flow, decreases the rate of renally excreted drugs
- Any liver disease can reduce the elimination of drugs that are excreted primarily by biliary excretion
- -Drugs with enterohepatic circulation are eliminated more slowly by biliary excretion than drugs that do not do this
- Rate at which the drug is eliminated from the body (regardless of route) is expressed as the drug's clearance, and is measured by the drug's half-life of elimination
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Clearance
=A measure of how much volume of blood is cleared of drug per unit of time
- May be described as "X liters of plasma cleared per hour"
- A drug that is "rapidly cleared" means it is eliminated quickly
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Half-life of elimination
=The amount of time it takes for the drug concentration in the plasma or blood to decrease by half (50%)
-Because concentrations drop by a fraction (50%) the concentrations do NOT drop in a straight line, but form a curve
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Rates of elimination
- If a drug is excreted by the kidney and the kidney function is decreased, the half life of elimination would increase (it will take a longer time for concentrations to drop by half)
- If a drug is excreted by the liver and the liver function is decreased, the half life of elimination would increase
- If a drug is excreted by the liver and the kidney function is decreased, the half life of elimination should be unchanged from normal because the drug is not dependent upon renal function to be eliminated
- The same is true for drugs primarily excreted by the kidney, and the liver function and biliary excretion is decreased --> the half-life would be unchanged
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Half-life and steady state
- Starting at any point on the elimination curve or the absorption curve, there will be a consistent time frame for the concentration to decrease by half (elimination curve) or increase by half (absorption curve)
- Steady state is achieved after five half-lives
- For multiple doses, steady state is achieved at the point where all peak concentrations and trough concentrations are the same
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Steady state
=Point where amount of drug absorbed during a dose interval exactly equals the amount of drug eliminated during a dose interval
-Because steady state is determined partially by the rate of drug elimination, the time to reach this steady state is still five times the half-life
