Pharmacokinetics and Pharmacodynamics

Question 1

Define liberation

Answer 1

Liberation is the first step of absorption.

Liberation is the separation of a drug from its vehicle.

Question 2

Why does atropine cross the BBB while glycopyrolate does not?

Answer 2

Atropine is neutral

Glycopyrolate is + charged and thus can’t cross the BBB

Question 3

Compare and contrast intrathecal morphine vs. fentanyl

Answer 3

Morphine = hydrophilic –> persists in circulation

Fentanyl = hydrophobic –> binds quickly to surrounding fat and protein affecting nearby nerve roots

Question 4

Compare and contrast the alpha and beta phases of elimination

Answer 4

Alpha - distribution phase of a drug from central circulation to the periphery right after a bolus

Beta - elimination, metabolism + excretion

Question 5

Define volume of distribution of a drug

Answer 5

Volume = dose (mg) /concentration (ml)

Volume of distribution exceeds total body volume in fat soluble or highly protein bound drugs

Children have larger volumes d/t larger intravascular and extracellular volumes

Dec protein in elderly, anemia and hypoalbuminemia = lower volume

Question 6

What is the Law of Mass Action?

And why rocuronium has a quicker onset than equipotent vecuronium?

Answer 6

Larger dose = faster onset

= use a greater quantity of a less potent drug

Question 7

How many half lives of an oral drug to reach steady-state?

Answer 7

4-5

Question 8

Explain 1st order elimination

Answer 8

Rate of elimination is proportional to the concentration of the drug. A constant proportion of the drug is eliminated

Exponential decay process:
8-4-2-1

Question 9

How does an antagonist effect the dose response curve?

Answer 9

Shift curve to the right

• Antagonist – block other drugs but cause no activity
 Competitive – physically displace agonist w/o blocking
 Non-competitive – irreversibly bind to receptor

Question 10

How does a noncompetitive antagonist effect the dose response curve?

Answer 10

Shift to right and reduce max efficacy

Non-competitive – irreversibly bind to receptor

Question 11

How does a partial agonist effect the dose response curve?

Answer 11

Sub maximal response

• Partial agonist – partially activate even at [high]

Question 12

What is therapeutic index?

Answer 12

TD50 / ED50

Question 13

GABA receptor belong to what receptor type?

Answer 13

Ligand-gated ion channel

Question 14

Drug potency is determined by what factors?

Answer 14

Affinity to the receptor
And receptor response to drug binding

Higher potency = lower ED50

Question 15

What type of agonist/antagonist decreases receptor response to a level below baseline response observed?

Answer 15

Inverse agonist

Question 16

What type of ligand effect does buprenorphine exhibit?

Answer 16

Partial mu agonist

Question 17

What type of drug will decrease efficacy of an agonist w/o affecting its potency?

Answer 17

Noncompetitive antagonist

Question 18

Explain 0 order elimination

Answer 18

Cleared at a constant rate, irrespective of the plasma concentration.

Ex: alcohol

Question 19

Explain context-sensitive half-life

Answer 19

Fat soluble drugs accumulate over time –> Half-life increases over time.

A continuous infusion has to be dialed back in long cases to prevent overdoses.

However other drugs like remifentanil don’t.

Question 20

What are the two major plasma proteins that affect drug protein binding?

Answer 20

1. Albumin

2. alpha-1 acid glycoprotein (acute phase reactant)

Question 21

Which plasma protein binds acidic drugs and basic drugs most readily?

Answer 21

Acidic = Albumin

Basic = (alpha-1)(narcotics, amines)

Question 22

Would a weak acid or a weak base more readily cross the cell membrane?

Answer 22

Weak acid

• it donates H+ becoming non-ionized and can easily cross

Question 23

What is the pKa of a drug?

Answer 23

The pH at which half the drug is in its ionized form and half in its non-ionized form.

• The lower the pH relative to the pKa, the greater the fraction of drug in the ionized form.
• Local anesthetics are weak bases, infected tissue is acidic –> LA becoming ionized and unable to penetrate the membrane to exert their action

Question 24

Compare the solubility of high blood: gas coefficient gases to low blood: gas coefficient gases

Answer 24

High blood: gas = more soluble = passes easily from air to blood

Question 25

What factors make a molecule transfer across cell membrane more quickly?

Answer 25

low degree of ionization low molecular weight high lipid solubility high concentration gradient

Question 26

What causes the initial decline in drug concentration of a lipophilic drug and what is it dependent on?

Answer 26

Redistribution Dependent on cardiac output - high CO tissues = faster equilibrium CO is based on LEAN body mass

Question 27

What drugs are metabolized by CYP3A4?

Answer 27

Tylenol, dexamethasone, lidocaine, midazolam, methadone, fentanyl, alfentanil, sufentanil, little bit of propofol

Question 28

Name inhibitors of CYP3A4

Answer 28

``` grapefruit juice anti-fungals protease inhibitors “mycins” SSRIs ```

Question 29

Name inducers of CYP3A4

Answer 29

``` Rifampin rifabutin tamoxifen glucocorticoids carbamazepine barbiturates St. John’s Wort ```

Question 30

What drugs are metabolized by CYP2B6?

Answer 30

Propofol, codeine, oxycodone, hydrocodone

Question 31

What class of drugs inhibits CYP2B6?

Answer 31

SSRIs

Question 32

What drugs are metabolized by plasma esterases?

Answer 32

Remifentanil, succinylcholine, esmolol Succinylcholine – pseudocholinsterase or butylcholinesterase can be cleared slowly with genetic defect

Question 33

What drugs are extensively really cleared?

Answer 33

Steroidal muscle relaxants 85% pancuroniu 20-30% vecuronium 10-20% rocuronium

Question 34

What is the formula for calculating CrCl?

Answer 34

Cockroft-Gault (140-age) x weight (kg) / 72 x serum Cr (mg%) Women are this x 85% Old people with normal Cr STILL have lower clearance

Question 35

What drugs utilize the Ligand-gated type receptor?

Answer 35

``` Propofol midazolam thiopental ketamine muscle relaxants ```

Question 36

Define tolerance

Answer 36

reduction in the pharmacologic response to a drug following exposure to the drug or a similar drug Inc amounts to produce same effect

Question 37

What are the types of drug tolerance?

Answer 37

1. Innate - genetic predisposition that renders one less sensitive to a drug = Opioid receptor gene polymorphisms 2. Acquired - increased metabolism as a result of liver enzyme induction (barbiturate and ketamine), receptor down-regulation (opioids) or desensitization (a reduction in the efficacy of a receptor-bound drug to produce its effect).

Question 38

What are the mechanisms for tolerance?

Answer 38

1. receptor down-regulation 2. desensitization 3. enzyme induction

Question 39

What is tissue tolerance?

Answer 39

increasing quantities of opioids are required to produce analgesia, euphoria, and respiratory depression, but tolerance to miosis and constipation does not develop

Question 40

What is tachyphylaxis?

Answer 40

Acute tolerance

Question 41

What is one mechanism for the development of tachyphylaxis?

Answer 41

depletion of neurotransmitter stores

Question 42

Name 5 drugs associated with tolerance and tachyphylaxis besides opioids.

Answer 42

ephedrine (depletion of norepinephrine stores) nitrates (depletion of sulfhydryl groups) succinylcholine (prolonged ion channel opening) desmopressin (depletion of both Factor VIII and vWF) Epidural lidocaine