Pharmacology 3620 Lecture Notes - Lecture 3: Common Bile Duct, Distal Convoluted Tubule, Proximal Tubule

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Lecture 003: Drug Elimination and Dosage Regimens

Objectives

● Describe the major mechanisms and organs of drug elimination.

● Define first order drug elimination.

● Define the pharmacokinetic parameter, clearance, and describe how a drug’s clearance

is measured.

● Define a drug’s half life in the body.

● Describe how volume of distribution and clearance affects the half-life of drugs.

● Describe the effect of repeated dosing on drug concentrations.

● Define what is the pharmacokinetic steady-state.

● Describe what affects the time to steady-state and the steady- state plasma drug

concentration.

● Describe the effect of changing dosing interval on plasma drug concentrations.

Drug Elimination

● Ways to eliminate drugs in our body

○ Metabolize

■ Convert it into another chemical

■ Occurs in the liver

○ Urinary Excretion

■ Get rid of the drugs and into the urine

■ By the kidneys

○ Biliary Excretion

■ Liver pump drugs into the bile

● Main organs responsible for drug elimination are the liver and kidney.

○ Liver and kidneys are very important!

Drug Elimination by Metabolism

● Lipophilic drugs absorbed by passive diffusion easy enter the tissue

○ Need to be convert into to hydrophilic metabolic for the body to get rid of

● Phases of Metabolism

○ Phase I

■ Conversion of the drug into its oxidized form

○ Phase II

■ Adding something very hydrophilic or ionized to the drug

● Like a sugar

■ To make a conjugated metabolite (very hydrophilic)

● Many drug do not have to go through phase 1 systems but can be directly conjugated to

phase 2 systems

● Also a drug can be formed into a conjugated by phase 2 system then metabolized by

phase one enzymes

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Drug Elimination by the Kidneys

● 10% of renal blood flow is filtered

● Nepheron

○ Functional unit of the kidney

○ Blood flows in from the top

○ Bowman’s capsule at the top

■ A cellular sive, free (unbound)

drug in plasma is filtered here

● Allow solutes from the

blood to pass into the

proximal tubules

● Plasma protein binding

affects the drug filtration

rate

○ Solutes move from the proximal tubule,

the loop of henle, the distal tubule, and

eventually into the bladder for excretion

● Alside from the filtration that occurs at the

Bowman’s capsule drugs can also enter the

urinary excretion pathway via another process

called active secretion

○ The movement of the drug from the

bloodstream from one side of the tubule

into the tubular space via the actions of

the drug membrane transporters

● 99% of the water is reabsorbed in the distal

tubules to prevent dehydration

○ This means the the solute

concentration in the tubule increases dramatically

○ Thus a concentration gradient is established

○ High solute concentration in the tubule compared to the blood

○ If a drug is lipophilic enough (can cross the cell membrane) the concentration

gradient will drive it from the tubule and back into the blood

■ Passive reabsorption (via passive diffusion)

■ This is why we metabolized drugs to hydrophilic molecules

■ Need drugs to be kept hydrophilic for efficient elimination and prevent

lipophilic passive reabsorption

Drug Elimination by Biliary Excretion

● Liver produce bile

● Bile

○ digests lipids in our diets

○ Made of bile salt

○ Is stored in the gallbladder

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● Gallbladder release bile after a meal

● Liver

○ Hepatocytes form sheets called lobules

○ Bathed by the bloodstream

■ Sinusoid is the the capillary space

■ Blood comes from the small intestine via the portal vein -> small portal

venous

■ Blood also comes from the hepatic artery

○ For a drug to be excreted into the bile

■ First it must be in the sinusoid

■ The drug then passes through the endothelial cells to get to the

hepatocytes

■ In the hepatocytes

● The drug is metabolized

● Or secreted into the bile-canaliculi -> bile ducts -> right/left hepatic

bile duct -> common bile duct

Elimination phase is very obvious when the

concentration is monitored

● After an IV dose of a drug, the elimination phase

of the drug concentration vs time curve shows an

exponential decline

● Exponential decline or first-order decline

○ Not constant

○ A curve

○ Dependent on the concentration of the

drug in the body at that time

■ the rate of drug elimination at a

given time is directly proportional to

the amount of drug in the body at

that time

○ Ex. rate of drug elimination is higher at 1 hr

than 4 hr

Why is Drug Elimination a First-Order Process?

● Enzyme kinetic (or the rate of drug Elimination) can be described by the Michaelis-

Menten equation

● Michaelis-Menten Equation

○ Describes the rate of elimination or

the rate of metabolism

○ Vmax: maximum rate of metabolism

(mol/s or mol/min)

■ Reflects how much of the

enzyme is in the body

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Document Summary

Describe the major mechanisms and organs of drug elimination. Define the pharmacokinetic parameter, clearance, and describe how a drug"s clearance is measured. Define a drug"s half life in the body. Describe how volume of distribution and clearance affects the half-life of drugs. Describe the effect of repeated dosing on drug concentrations. Describe what affects the time to steady-state and the steady- state plasma drug concentration. Describe the effect of changing dosing interval on plasma drug concentrations. Ways to eliminate drugs in our body. Get rid of the drugs and into the urine. Main organs responsible for drug elimination are the liver and kidney. Lipophilic drugs absorbed by passive diffusion easy enter the tissue. Need to be convert into to hydrophilic metabolic for the body to get rid of. To make a conjugated metabolite (very hydrophilic) Many drug do not have to go through phase 1 systems but can be directly conjugated to phase 2 systems.

Related Questions

Multiple Choice questions 2 points each

1. Creatinine clearance is a commonly used estimate of:

A)Glomerular filtration rate (mL/min)

B)Tubular secretion (mL/min)

C)Total renal blood flow (mL/min)

D)Renal reabsorption (cc/min)

E)Steady state muscle breakdown rate (mcg/min)

2. Which of the following is not a measure of exposure?

a) Peak concentration

b) Time of maximum concentration

c) Area under the concentration time curve

d) Concentration measured 2 hours after dose administration

3. A clinically impactful drug interaction based upon inhibition of cytochrome P450 is most likely when:

a)The drug is metabolized by multiple enzymes

b)The drug has a narrow therapeutic index

c)There is limited variation in interindividual enzyme activity in the involved enzyme

d)The drug is a substrate of P-glycoprotein

e)All of the above

2. Why are dose-response (or concentration-response) analyses recommended for drug approval by a regulatory agency?

a) To increase the potential for adverse reactions in clinical trials in order to fully characterize the safety profile

b) To prolong the length of time it takes for drug approval

c) To maximize the likelihood that optimal drug dose will be prescribed after approval

d) To reduce the costs of clinical trials

e) To explore all possible disease state indications at time of initial approval

5. Which of the following is true of inhaled delivery of an aerosolized drug suspension?

a)An ideal drug would have low first pass hepatic metabolism to maximize systemic absorption

b)In contrast to milled powders, drugs in suspension are dosed in partial pressures

c)Efficiency of drug delivery by multi-dose inhalers is highly dependent upon patient technique

d)Typical multi-dose inhalers produce a very homogenous particle size of drug

e)Nebulized delivery of drug by face mask is not appropriate for children, demented or obtunded patients

6. The apparent volume of distribution (Vd):

a)Does not represent an actual physiologic volume

b)Can never be higher than total body water volume

c)Can be determined using only the half life of a drug

d)Will be large in a drug that is highly bound to serum proteins

e)Is usually small in drugs that require a loading dose

7. Which of the following characteristics of a drug make it most amenable to removal by hemodialysis?

a)Large volume of distribution

b)Large molecular weight

c)Strong protein binding

d)Good water solubility

8. Which is the best predictor of need for dosage adjustment in hepatic disease?

Child Pugh score

Portal splanchnic pressure (as measured by peripheral heart rate)

Degree of fibrosis and shunt on ultrasound

Levels of liver function tests

There is no single marker of hepatic dysfunction

9. Fexofenadine is not metabolized but is a P-glycoprotein (Pgp) substrate. How does St. Johnâs Wort cause decreased serum fexofenadine levels?

Inhibition of gut Pgp

Induction of gut PgP

Induction of CNS Pgp

Inhibition of biliary Pgp

None of the above

10. Which of the following is the best measure of renal function?

a)age

b)random urine creatinine concentration

c)spot plasma creatinine concentration

d)estimated creatinine clearance (Cockroft Gault)

e)Child-Pugh

11. Which pharmacokinetic parameter is the best measure of total systematic drug exposure after an oral dose?

a)Cmax

b)Elimination half life

c)Absorption rate constant

d)Area under the curve

e)Clearance

12. Which of the following is a mechanism that would cause a drug to have zero order elimination in humans?

a)Ultra-metabolizer genotype

b)Enterohepatic recirculation

c)High serum protein binding

d)Saturation of the prime metabolic enzyme

e)Sustained release version of a drug

13. Phase II metabolic metabolism:

a)Involves the covalent binding of a polar side chain

B)Always follows phase 1 metabolism

c)Employs breaking of aromatic ring structures

d)Is not subject to pharmacogenetic variation

e)Occurs exclusively pre-systemically, in the gut lumen

14. Which is not a high profile FDA Initiative?

a)Orphan Disease Act

b)Childhood Vaccine Act

c)Rare Disease Act

d)Breakthrough Drug Designation

15 In explaining risk posed by pharmaceutical R&D, which is not a development risk:

a)Patient population

b)Clinical endpoint

c)Predictability of trials

d)Competitive advantage

16. The key pivotal trials undertaken as part of the IND are part of which phase of the clinical drug development process?

a)Phase I

b)Phase II

c)Phase III

d)Phase IV

17. Which is not an EU Regulatory Process

a)Centralized Procedure

b)Certificate of Pharmaceutical Product Procedure

c)De-Centralized Procedure

d)Mutual Recognition

18. The role of experimental medicine strategies is to

a)Explore disease and drug biology to support go/no go decisions

b)Generate and fully validate biomarkers for FDA approval

c)Primarily to co-develop diagnostic tests to be filed with the NDA (new drug application)

d)Harmonize FDA and EMA phase 1 requirements

e)Define the pharmacokinetics of exploratory drugs in healthy volunteers or selected patient populations

1) The neurotransmitters acetylcholine and norepinephrine are digested by enzymes that are located at the axon synapse or within the axon terminal of the neurons.

a)What are the names of these different types of enzymes?

b)Where are they located and what is the result of their enzymatic activity?

2) Explain how the Investigational New Drug process works as well as the four different phases of clinical trials. Why are some drugs still taken off the market after approval by the FDA?

3) A single IV injection of 100 mg drug with a half-life of 4 hours is administered to a young adult.

a) Plot drug concentration versus time on a graph making certain to clearly label.

b) How long will it take to eliminate > 95% of the drug?

c) If the volume of distribution is 4L, what is the clearance of the drug?

4) Many drugs are metabolized in the liver through the microsomal metabolizing system.

a) What specific enzymes are involved in this metabolism?

b) What are the main functions of these enzymes?

c) What are some factors that can contribute to individual drug metabolism variation? Explain.

5) Think of an emergency situation requiring immediate and intense physical exertion.

a) List as many body organs as you can and predict the desired level of activity [increased or decreased].

b) Which neurotransmitter would produce these effects and through what receptors?

6) It is interesting that a drug can produce a therapeutic effect and an undesired side effect in one situation, and that the same drug side effect may be considered a therapeutic effect in another situation. Explain this phenomenon using the drug promethazine as an example.

7) A patient brought into the emergency room is experiencing severe hypotension. Blood pressure reads 90/50.

a) What class of drugs is indicated for treatment and why?

b) What precautions should be observed when these drugs are administered?

c) What would be the first indication that too much drug has been administered?

8) Only certain drugs are capable of crossing the blood brain barrier.

a) How is the blood brain barrier different than barriers found in other areas of the body? Be specific.

b) What properties of drugs will make it more likely to cross the blood brain barrier? Explain your answers.

9) A 32-year-old, presents to the Emergency Department by ambulance with vomiting, confusion, salivation, and respiratory distress. The patient states that he was feeling fine until today when I started getting ill. He then vomits. During a physical exam you record the following information: Heart rate 45; Blood pressure 90/60; Respiratory rate 25; Temperature 36.6C; Pupils constricted. During your exam, 4 more ambulances arrive with patients with similar symptoms. You find out they were all riding in the same care on the Red Line when they began feeling ill.

a) What do you feel is happening and why?

b) Would you expect their symptoms to improve over time? Why or why not?

c) What drug would you prescribe to treat these patients and why?

10) Betty has diabetes and asthma. She also has developed high blood pressure, for which doctor just prescribed propranolol. One of your duties as a physicianâs assistant is to make sure patients are not prescribed drugs that are contraindicated because of other health problems.

a) What should you tell the doctor about Bettyâs prescription for propranolol and why?

b) Is there a more appropriate drug for Betty? Explain you answer.

Pharmacology 3620 Lecture Notes - Lecture 3: Common Bile Duct, Distal Convoluted Tubule, Proximal Tubule

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