Excretion

Question 1

What is the most important route of drug elimination?

Answer 1

Kidney most important route of elimination for both parent drug (esp water soluble) and metabolites

Question 2

What host factors determine renal excretion ability?

Answer 2

• Renal blood flow (glomerular filtration)
  • Active tubular secretion
  • Tubular (generally passive) reabsorption

Question 3

What is the formula that determines total renal excretion of a drug?

Answer 3

Total renal excretion of a drug = Rate of filtration + Secretion - reabsorption

Question 4

What is glomerular filtration? How do drugs enter the glomerulus? What occurs when drugs are protein bound or they are too large?

Answer 4

• glomerular filtration is passive. Drugs enter glomerulus via bulk flow. Drugs that are too large are excluded, + cant be filtered here.

Question 5

What is the process that allows for active tubular secretion? Is it a long process? What is it susceptible to? What is important to note about this method of secretion?

Answer 5

• Active transport of drugs in the proximal tubules is a very efficient and rapid process.
• It is susceptible to competition between drugs
◦ It is not limited by protein binding

Question 6

How does the transport system work across tubule cells?

Answer 6

The transport systems across tubule cells involves two separate pairs of transport proteins. One set is located in the brush border and the other is located in the basolateral membrane fl

Question 7

Fill in the blanks: Active tubular secretion is ___________ to competition between drugs. Separate active transport systems exist for ____, _____, and _________. (p-glycoprotein, OATPs, POTs).

Answer 7

It is susceptible to competition between drugs. Separate active transport systems exist for acid, basic, and neutral drugs (p-glycoprotein, OATPs, POTs).

Question 8

What are the two pathways in the later sections of proximal renal tubule? What are they for? What is the primary orientation of this system?

Answer 8

There are two distinct secretory pathways in the later sections of the proximal renal tubule: one for acidic (organic anion transporter, OAT) and one for basic compounds (organic cation transporter, OCT)
• The primary orientation of this system is from blood to tubular filtrate, removing drugs and/or metabolite conjugates from the blood

Question 9

In active tubular secretionWhat causes drug interactions? How is this work with weak acids?

Answer 9

• Many drugs compete for the same tubular transport sites, leading to drug interactions.
◦ This interaction has been studied with the organic acid transport system
◦ Weak acids such as probenecid or phenylbutazone will inhibit secretion of the weak acid penicillin, thereby prolonging the blood concentration of penicillin.

Question 10

What slows renal excretion? What does drug reabsorption depend on?
When are weakly acidic drugs more likely be reabsorbed? How is this prevented?

Answer 10

• Reabsorption of drugs from renal tubules into peritubular capillaries slows renal excretion
• The drug reabsorption depends on its lipid solubility and its ionization
• Weakly acidic drugs are more likely to be reabsorbed in acidic urine but are trapped and excreted in alkaline urine
◦ A brisk, alkaline diuresis is induce to decrease salicylate reabsorption into the blood and accelerate excretion into the urine

Question 11

What animals have more acidic urine?

Answer 11

Carnivores

Question 12

What animals will have higher renal excretion of weakly acidic drugs?

Answer 12

Herbivores

Question 13

What animals will have higher renal excretion of weakly basic drugs?

Answer 13

Carnivores

Question 14

Do small changes in urinary pH or flow alter drug clearance in healthy animals?

Answer 14

No

Question 15

How can changing urine pH help patients?

Answer 15

• Urinary pH can be therapeutically altered such that the renal excretion rate of a drug can be modified (overdose or toxicity)

Question 16

What is the benefit of alkaline urine and phenobarbital?

Answer 16

• Because phenobarbital is acidic, alkalinizing the urine increases clearance about five fold

Question 17

Where do drugs go that are excreted in urine but dont go through passive reabsorption?

Answer 17

• Drugs excreted in the urine that do not undergo passive reabsorption will be progressively concentrated in the renal tubule

Question 18

Why do tubular cells have an increased risk of nephrotoxicity?

Answer 18

Tubular cells may be exposed to higher concentrations of drugs, which may increase the risk of nephrotoxicity

Question 19

In what scenario would it be beneficial to have high drug concentrations in the urine?

Answer 19

Drug concentration in the urine can be of therapeutic benefit in some situations such bacterial cystitis

Question 20

How does low urine flow rate affect diffusion from distal tubular fluid? What facilitates this diffusion?

Answer 20

At low urine flow rates, there is greater opportunity for diffusion of drug from the distal tubular fluid back into the blood
• Diffusion is facilitated by the high concentration of drug in the tubular fluid

Question 21

What compounds are not reabsorbed in tubular passive reabsorption?

Answer 21

• Polar compounds having low lipid solubility (such as many drug metabolites) are not reabsorbed since they cannot cross the lipid membrane

Question 22

Active tubular resorption acts on what drugs? What is their usual role in the body?

Answer 22

Active reabsorption systems are also present that act on a drug already present in the filtered load
• These systems are generally present to recover essential nutrients (e.g., glucose)

Question 23

How can active tubular reabsorption benefit some drugs? What is an example of this and how does it occur?

Answer 23

• Some drugs reach their target sites by this mechanism making their TFC more important for predicting activity than their blood concentration.
• Example: the diuretic furosemide
◦ Furosemide is first secreted by the tubules into tubular fluid and than is actively reabsorbed back into tubular cells to gain access to its receptors for activity

Question 24

What factors are important in active tubular secretion?

Answer 24

◦ Renal blood flow
◦ Drug pKa (weak base, weak acid, or neutral carrier proteins)

Question 25

What factors are important in glomerular filtration ?

Answer 25

◦ Molecular weight
◦ Protein binding
◦ Renal blood flow

Question 26

What factors are important in passive reabsorption ?

Answer 26

◦ Drug concentration
◦ Molecular weight
◦ Lipid solubility
◦ Drug pKa
◦ Urine pH

Question 27

Are the biotransformation phases that occur in the liver present anywhere else in the body?

Answer 27

• Most of the Phase I and Phase II enzymatic systems present in the liver also exist in the kidney

Question 28

Where do oxidative processes occur more frequently?

Answer 28

Oxidative processes generally occur within the proximal tubule cells

Question 29

What are the 2 scenarios regarding renal drug biotransformation?

Answer 29

◦ A drug is solely metabolized by the kidney and not the liver
◦ The kidney metabolizes a drug already biotransformed by the liver, relay metabolism

Question 30

What are two mentioned drugs that are metabolized by the kidneys.

Answer 30

• Morphine and acetaminophen are also metabolized by the kidney

Question 31

What is the ultimate route of drug elimination? What are the other routes? Are they important?

Answer 31

The ultimate route for drug elimination from the body is the kidney
• Drugs can also be eliminated in bile, milk, saliva, expired air, feces, sweat, and tears
• However for most therapeutic drugs these routes are generally not quantitatively important for reducing total body burden of drug.

Question 32

What factors determines biliary excretion? What is important to note about biliary excretion?

Answer 32

• Biliary excretion is very slow and much less clinically important
• Chemical structure, polarity, and MW of drugs (drugs > 600 MW in size) determine this excretion
• Drugs excreted in the bile are in big contact with the intestine and its flora

Question 33

What is more likely to cause adverse reactions in the gi tract?

Answer 33

• The contact with intestine is more likely to cause adverse reactions in the GI-tract

Question 34

What is enterohepatic circulation? What form of drugs is excreted here? How is the intestinal flora involved?

Answer 34

Enterohepatic circulation refers to the process whereby a drug or a metastable metabolite thereof in the liver is secreted into the bile, stored in the gall bladder, and subsequently released into the small intestine, where the drug can be reabsorbed back into circulation and subsequently returned to the liver.

Conjugated (Phase II) drugs excreted by this route may undergo enterohepatic circulation

• Intestinal bacteria unconjugate the drug or metabolite, allowing intestinal absorption to occur

Question 35

Fill in the blanks: Enterohepatic circulation can _______ the ________ _____-____ of a drug.

Answer 35

Enterohepatic circulation can prolong the elimination half-life of a drug

Question 36

After oral or parenteral administration, what happens to a drug that undergoes enterohepatic circulation

Answer 36

• After oral or parenteral administration the drug is conjugated in the liver and eliminated in the bile
• Degradation results in deconjugation of drug, which can then be reabsorbed in the small intestine.

Question 37

How do drugs enter the saliva? What animals is this important to remember in? What issues can it cause?

Answer 37

◦ Drugs enter the saliva by passive diffusion from the blood
◦ Important in herbivores receiving parenteral antimicrobial drugs
◦ Copious salivation by cattle and sheep and the swallowing of antimicrobial-drug-laden saliva may upset the digestive process in the rumen

Question 38

What drugs are excreted via expired air?

Answer 38

◦ This route of excretion is primarily important for volatile drugs: gas anesthetic drugs

Question 39

Is excretion into milk a common route for drug excretion? Why is it not? What other routes are minor routes? Do weakly acidic or weakly basic drugs diffuse into milk?

Answer 39

◦ This is not a major route for drug excretion
◦ It is important if the milk is to be used for human consumption (requiring a withdrawal period)
◦ Weakly acidic drugs will tend not to distribute into the milk after systemic distribution (e.g., penicillin), while weakly basic drugs will (e.g., erythromycin)
- Tears and sweat are minor routes of excretion

Question 40

What is the pH of milk? Plasma? Which is more alkaline?

Answer 40

‣ Plasma pH = 7.4; Milk pH = 6.5-6.8
Plasma is more alkaline

Question 41

What routes of drug absorption are excreted in feces?

Answer 41

◦ Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestine or into bile are excreted in the feces

Question 42

Fill in the blank: The combined effects of __________ and ______ and ________ excretion, as well as other routes of elimination _________ clear the drug from the body

Answer 42

• The combined effects of hepatic metabolism and renal and biliary excretion, as well as other routes of elimination irreversibly clear the drug from the body

Question 43

At what age is an animal considered a neonate?

Answer 43

• Neonatal : 0-2 weeks

Question 44

At what age is an animal considered a infant?

Answer 44

• Infant: > 2 weeks- 6 weeks

Question 45

At what age is an animal considered a Pediatric?

Answer 45

• Infant: > 2 weeks- 6 weeks
• Pediatric: > 6 weeks to 12 weeks

Question 46

What are 3 important reasons neonate physiology affects ADME?

Answer 46

◦ decreased hepatic metabolic capacity
◦ immature biliary function
◦ decreased GFR with renal clearance

Question 47

What are some ways neonate physiology affects ADME?

Answer 47

◦ Increased gastric ph
◦ decreased gastric emptying
◦ milk diet
◦ thicker unstirred water layer
◦ decreased hepatic metabolic capacity
◦ immature biliary function
◦ decreased GFR with renal clearance
◦ large water to fat ratio
◦ decreased serum albumin
◦ increased skin hydration
◦ immature SNS
◦ increased blood flow to heart/ brain
◦ more BBB permeability.
◦ Poor thermoregulation
◦ increased intestinal permeability.
◦ Irregular intestinal peristalsis
◦ Intestinal microflora differences.

Question 48

In neonatal or pediatric patients what is wrong with their metabolic capacity for drugs?

Answer 48

• Drug elimination, including both hepatic metabolism and renal excretion is limited in neonatal and pediatric patients

Question 49

What are drugs given to young animals characterized by? When does this change?

Answer 49

• Many drugs administered to the young animal are characterized by decreased renal clearance (until 2 to 3 months), and longer half-life.

Question 50

When are renal tubular function values reach adult level in young animals?

Answer 50

Although glomerular filtration and renal tubular function progressively increase, adult values may not be reached until approximately 2.5 months of age

Question 51

What is needed for renal tubular reabsorption in puppies so that it can be similar to adults?

Answer 51

• Renal tubular reabsorption in puppies appears to be similar to that in adults as long as body fluids and electrolytes are maintained.

Question 52

what can cause a decrease in absorption of many drugs?

Answer 52

Increased gastric pH may decrease the absorption of many drugs. Specifically drugs that require disintegration and dissolution

Question 53

Absorption from what mucosa is rapid?

Answer 53

Rectal mucosa

Question 54

What is the benefit of using rectal administration of drugs in pediatric patients?

Answer 54

◦ venous catheterization is rough.
◦ Reduce complications associated with IV administration. ( eg. Sedation, anesthesia).
◦ When oral administration is undesirable ( antiemetics)
◦ Several pediatric drugs intended for systemic affects are available as rectal suppositories.

Question 55

Fill in the blank: • Absorption of drugs administered _______ to pediatric animals also varies from adults.
• The rate of absorption after ____ administration changes with age as muscle ______ and _________ increase.
• Because muscle mass is small, _____ administration is frequently preferred.

Answer 55

• Absorption of drugs administered parenterally to pediatric animals also varies from adults.
• The rate of absorption after IM administration changes with age as muscle mass and blood flow increase.
• Because muscle mass is small, SC administration is frequently preferred.

Question 56

How does temperature affect SC absorption?

Answer 56

• Environmental temperature probably influences SC absorption. Cold environments are more likely to reduce SC drug absorption if the neonate is not ket warm. The same is true for patients in hypothermia.

Question 57

What is the benefit to intraperitoneal administration? What fluids are rapidly absorbed?

Answer 57

• Intraperitoneal administration can be lifesaving route of blood and fluid administration, particularly for the newborn with inaccessible central veins.
Isotonic fluids are rapidly absorbed.

Question 58

What percent of RBC are absorbed when a transfusion is given to a neonate and over how much time?

Answer 58

Up to 70 % of red blood cells are absorbed in 48 to 72 hours.

Question 59

What factor influences absorption of volatile anesthetics in pediatric patients? Why? What is the consequence of this?

Answer 59

• Absorption of volatile anesthetics from pediatric respiratory tract is rapid because minute ventilation is greater. They are more sensitive to the effects of gas anesthetic.
- Neonatal animals breath faster so minute ventilation is higher.

Question 60

What is minute ventilation? What is tidal volume? What is respiratory frequency? What is the formula for minute ventilation?

Answer 60

Minute ventilation ( VE) is the total volume of breathed air per minute.
Tidal volume(VT): is the sum of the air volume that enters the perfused alveoli and the volume that remains in the physiologic dead space ( anatomic + alveolar dead spaces)
Respiratory frequency( F): breaths per minute
VE = VT x f