PCL102H1 Lecture 5: Pharmakokinetics for Drug Development

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7 Mar 2017

School

UTSG

Department

Pharmacology and Toxicology

Course

PCL102H1

Professor

Rebecca Laposa

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Document Summary

Pill?: physiological and genetic characteristics of the individual (body composition, liver/kidney function, genetic variability in metabolic enzymes, other medications taken at the same time, coffee/tea. Likes fat and has the ability to cross the membrane. Likes (cid:449)ater a(cid:374)d is(cid:374)(cid:859)t a(cid:271)le to (cid:272)ross the lipid bilayer. P-glycoprotein action: uses atp energy to export the drug out of the cell, the atp binding causes a shape-change of the p-glycoprotein pump, the shape change allows the drug to leave, not specific to a single drug. Chemical features of p-glycoprotein substrates: molecular weight: 250 to 1850, shape: aromatic, non-aromatic, linear/circular, chemistry: basic, acidic, zwitterionic (combination of both) or uncharged, water/oil solubility: hydrophobic, hydrophilic, amphipathic (combination of both) Strategy to prevent drugs from being pumped out of cells: block (inhibit) p-glycoprotein, this is a general strategy for preventing drug efflux, not just the drug you are interested in for the drug development pipeline.

Related Questions

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.

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

Exercise Pharmacology

Chapter 1

1. Distinguish between pharmacokinetics, pharmacodynamics, and pharmacology.

2. How would you determine a drugâs doseâresponse curve?

3. What is meant by drug efï¬cacy? Potency?

4. How would you determine equipotent doses for two drugs of the same class?

5. What features of a drugâs action may make its pharmacokinetic properties more sensitive to exercise?

6. How might a drugâs volume of distribution be altered in the case of a person who is obese? A person who is elderly?

7. How might you explain an antagonist with partial agonist activity?

8. What are some of the ways that taking a second drug can affect the activity of the ï¬rst drugâor either drug?

Chapter 2

1. Bill is 60 years old and in reasonable shape. Working out on an elliptical machine, Bill sees that his heart rate is 135 bpm. Can you determine his ap-proximate exercise intensity without hooking him to a metabolic cart? What is he primarily burning for energy?

2. Your mother asks your advice about starting an exercise program. She is in pretty good health, but wants to drop some weight besides improving her cardiovascular health. What kind of exercise plan would you recommend to get her started? How would you explain to her the beneï¬ts of such a plan? After the initial couple of weeks, would you recommend any changes that might help her with her long-term ï¬tness goals?

3. Compare and contrast the three major muscle ï¬ber types in terms of their metabolism and fuel preference.

4. You are a graduate student working in an exercise physiology lab. You see a claim in a bodybuilding magazine about a supplement that rapidly increases power, strength, and muscle mass. How would you set up an experiment to test whether these claims are true?

5. Obesity is now considered by some to be reaching epidemic proportions. What is contributing to this trend, and what can be done?

Chapter 3

1. Compare and contrast the sympathetic and parasympathetic nervous systems.

2. What is meant by allostatic load, and how does it differ from stressing over a single test?

3. Explain three ways drugs can affect the signals transmitted by nerve cells.

4. How might exercise lessen the effects of stress?

5. Describe some of the theories that attempt to explain the bodyâs paradoxical response to exercise.

6. What are the key physiological changes that occur during the ï¬ght or ï¬ight response? How do they help in survival?

Chapter 4

1. What is meant by âbeta-blockers with ISAâ? What advantages might these drugs have? Disadvantages?

2. What property makes some beta-blockers cardio selective?

3. What are the effects of beta-blockers on exercise physiology?

4. A serious walker (5 miles/day) notices that she has stopped losing weight since starting her new prescription of propranolol (non-cardio selective, without ISA). She also fatigues more quickly than she used to. What can you offer her as an explanation?

5. The NCAA and USOC have banned beta-blockers from many types of com-petition. Why?

Chapter 5

1. Bill, a deconditioned, recently divorced 50-something exec driving that new BMW, wants to drop some weight and look good. He has high blood pressure. What kind of exercise regime would you recommend?

2. Why do calcium channel blockers mostly affect smooth muscle, with little effect on skeletal muscle?

3. How do calcium channel blockers reduce blood pressure?

4. Mary enjoys running and likes to compete in 10K races and half marathons. She also is diagnosed with high blood pressure. What are her options for regulating her blood pressure while maintaining a training schedule and remaining competitive?

5. How do ACE inhibitors affect blood pressure?

6. How do ARBs affect blood pressure?

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PCL102H1 Lecture 5: Pharmakokinetics for Drug Development

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