Pharmacology 2060A/B Lecture Notes - Lecture 6: Pharmacokinetics, Bioavailability, Circulatory System

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15 May 2018

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Module 6 – Pharmacokinetics – Time Course of Drug Action

6.1 - Clinical pharmacokinetics

- The underlying principle of clinical pharmacokinetics is that a relationship exists between the

effects of a drug and the concentration of drug in the body

o Higher the concentration = greater effect

- In clinical pharmacokinetics we try to provide:

o 1) a quantitative relationship between drug dose (concentration) and effect

o 2) a framework to interpret measurements of drug concentrations in biological fluids to

benefit patient drug therapy

The most important parameters determining drug disposition (response) in humans are:

- 1) Clearance – the od’s efficiency in drug elimination

- 2) Volume of Distribution – the apparent space in the body available to contain the drug

o (Not a physical or anatomical space)

- 3) Elimination Half Life (T1/2) – a measure of the rate of removal of the drug from the body

- 4) Bioavailability – the fraction of drug that reaches the systemic circulation unchanged.

6.2 - Plasma drug concentrations

Measuring Drug Concentrations

- Ideally drug concentrations would be measured from the site of action

o This would be the most important place to know how much drug is there

o In reality, this is not feasible

- Let’s take the eaple of drugs used to treat shizophreia (CNS disorder)

o These drugs act in the brain to treat the condition

o Clearl takig a saple fro a patiet’s rai to easure drug oetratios is iasie

and would likely do more harm than good

- In reality drug concentrations are usually measured in plasma

- Plasma is a good site to measure drug concentrations because:

o 1) It is relatively non-invasive

▪ Can take a blood sample fairly easily from a patient by a phlebotomy

▪ Centrifuge the blood sample to obtain plasma (non-cellular component)

o 2) For most drugs there is a good correlation between plasma concentration of the drug

and therapeutic and toxic drug effects

- Can take a blood sample to determine how much is there

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Free vs. total plasma drug concentration

- Drugs in plasma exist as bound to plasma proteins or free state

- It is only free drug that is able to get to target to elicit a pharmacological response

- In theory, measuring free drug concentration would be ideal to guide drug dosing

- In reality, measuring free drug concentration is difficult and tedious so total (free + protein

bound) concentration is usually measured

- For most drugs, measuring total plasma concentration provides enough information to guide

drug dosing

6.3 - Drug concentration time curves

Oral administration

- When a drug is administered orally it must be absorbed into the blood

- At the beginning of a drug dose:

o Rate of drug absorption is greater than the rate of drug elimination so plasma drug

concentrations increase over time

- At a later time (the peak of the curve):

o Concentration is at a maximum (C max)

o Rate of absorption equals the rate of elimination (no net change)

o This is the peak of the concentration time curve and is called the Cmax

- After the Cmax

o Plasma concentrations of the drug begin to decrease over time

o Rate of elimination is greater than the rate of absorption so the plasma concentration

begins to decline

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Characteristics of plasma concentration time curves

- Plasma drug concentrations must be high enough to have a therapeutic effect but not so high as

to induce toxicity

- Minimum Effective Concentration (MEC)

o The minimum concentration required to have a therapeutic effect

o Drug concentrations below this level do not have a therapeutic effect at all

o Drug concentrations above this level will have a therapeutic or potentially toxic effect

- Duration of action

o Length of time the drug concentration is above the MEC

o Determines time frame that a drug is actually effective for

- Toxic Concentration

o If plasma drug concentrations are too high, toxic side effects will occur

o If toxic concentrations are above where plasma concentrations levels are, they are not

likely to experience toxicity

- Therapeutic Range

o Drug concentrations above the MEC but below toxic concentrations

o The goal of pharmacotherapy is to attain plasma concentrations in the therapeutic

range → producing therapeutic effects and not toxic reactions

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Document Summary

Module 6 pharmacokinetics time course of drug action. The underlying principle of clinical pharmacokinetics is that a relationship exists between the effects of a drug and the concentration of drug in the body: higher the concentration = greater effect. In clinical pharmacokinetics we try to provide: 1) a quantitative relationship between drug dose (concentration) and effect, 2) a framework to interpret measurements of drug concentrations in biological fluids to benefit patient drug therapy. Ideally drug concentrations would be measured from the site of action: this would be the most important place to know how much drug is there. In reality drug concentrations are usually measured in plasma. Can take a blood sample to determine how much is there. Drugs in plasma exist as bound to plasma proteins or free state. It is only free drug that is able to get to target to elicit a pharmacological response. In theory, measuring free drug concentration would be ideal to guide drug dosing.

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

Need help with biology questions:

1. To increase the excretion of an acidic drug, what would you do to the urine?

	A.	Make it more basic
	B.	None of the above
	C.	Make it neutral
	D.	Make it more acidic

2. G-Protein coupled receptors directly act on which of the following secondary messenger molecules:

	A.	cAMP
	B.	ATP
	C.	ADP
	D.	GTP
	E.	None of the above or more than one of the above

3. Drug A and Drug B both produce the same level of biological/physiological response. Drug A produces this effect with 100 mg/kg dose. Drug B produces this effect with 50 mg/kg dose. Which of the following is true?:

	A.	Drug B is more efficacious than Drug A. Both drugs are equally potent.
	B.	Drug A is more efficacious than Drug B. Both drugs are equally potent.
	C.	Drug A and B are equally efficacious. Drug A is more potent than Drug B.
	D.	Drug A and B are equally efficacious. Drug B is more potent than Drug A.

4. The stomach has a ______ pH, whereas the small intestines have a _______ pH. The colon has an approximately ___________ pH.

	A.	High; low; neutral
	B.	Low; high; neutral
	C.	Low; neutral; neutral
	D.	None of the above

5. Which receptor is most likely to reduce norepinephrine levels when activated?

	A.	alpha 2 adrenergic
	B.	alpha 1 adrenergic
	C.	dopamine D1 receptors

6. Which of the following statements are FALSE?

	A.	If the Vd of a drug is between 60 and 80 L the drug has likely distributed to the total body water of a 200 kg man.
	B.	In the enterohepatic system the activity of bacteria to remove conjugates from a drug in the gut will decrease the clearance of the drug.
	C.	Lipid drugs are more likely to be reabsorbed by the kidney from the urine.
	D.	A weak basic drug (pKa = 6) will be mostly ionized in urine of a pH= 3 and only the non- ionized drug will be eliminated.
	E.	The major conjugate in Phase 2 metabolism is glucuronide.

7. Isoproterenol (Î²-agonist) is a vasodilator that increases HR. What happens to systolic and diastolic pressures upon IV administration of isoproterenol?

	A.	â systolic; â diastolic
	B.	â systolic; â diastolic
	C.	â systolic; â diastolic
	D.	â systolic; â diastolic
	E.	None of the above

8. If you want to increase the blood concentration of a drug A, you can perform which of the following procedures:

	A.	Inhibit Drug A metabolism with Drug B
	B.	Enhance Drug A reabsorption from renal proximal tubule by changing ionization of Drug A with Drug B
	C.	Allow competition of Drug B with Drug A for active renal secretion processes
	D.	Increase the binding of Drug A to serum albumin
	E.	All of the above

9. Which of the following describes Phase I metabolism?

	A.	Inactive products are always produced in this phase.
	B.	Large molecules such as glucuronic acid are conjugated to drugs in this phase.
	C.	This phase may produce active metabolites from prodrugs.
	D.	This phase only occurs in the liver.

10. Which of the following is NOT an enzyme involved in the biosynthesis of biogenic amines?

	A.	Phenylethanolamine N-methyl Transferase
	B.	Dopamine Î²-hydroxylase
	C.	Tyrosine dehydroxylase
	D.	DOPA decarboxylase
	E.	All of the above

11. Why would an antibiotic at the same concentration be more active against bacteria in water than in serum or plasma? (Activity is measured in a test tube)

	A.	activity of the antibiotic is increased in water.
	B.	due to drug-protein interaction in serum
	C.	the antibiotic is more stable in water
	D.	all of the above
	E.	none of the above

12. Ion channels are targets for drugs. Which drug class targets Na+ channels?

	A.	Benzodiazepines
	B.	Beta blockers
	C.	Local anesthetics
	D.	Antihypertensive drugs (cardiac and smooth muscle)
	E.	Glibenclimide (diabetic drug)

13. _________________ not metabolized by catechol-O-methyltransferase (COMT).

	A.	Dopamine
	B.	Epinephrine
	C.	Phenylephrine
	D.	Norepinephrine
	E.	All of the above are metabolized by COMT.

Pharmacology 2060A/B Lecture Notes - Lecture 6: Pharmacokinetics, Bioavailability, Circulatory System

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