7.5 (9.1) Principles of drug therapy

Question 1

How is efficacy different from effectiveness? What is cost effectiveness?

Answer 1

efficacy = the maximum response that can be achieved with a drug (performance under ideal and controlled circumstances)

effectiveness = benefits and burdens of a drug in a wider context - at a population level as part of everyday practice (performance under ‘real-world’ conditions)

cost effectiveness = comparison of effectiveness for a target indication against cost (ie ratio of effectiveness to cost)

Question 2

What are two statistical parameters that can be examined when determining the risk:benefit ratio of using a drug?

Answer 2

NNT - estimates the number of patients that would need to be treated for one of them to achieve clinical benefit

NNH - estimates the number of patients that would need to be treated for one them to have a harmful event

Question 3

Define pharmacokinetics and pharmacodynamics

Answer 3

pharmacokinetics - what the body does to a drug

pharmacodynamics - the drug does to the body

Question 4

What are four key elements of pharmacokinetics?

Answer 4

absorption
distribution
metabolism
excretion

ADME

Question 5

List 4 factors that can affect the pharmacokinetics of a drug

Answer 5

Age

• metabolism is often reduced in elderly -> increased in free drug concentration in plasma
• volume of distribution for hydrophilic drug decreases (decrease of body water) and increases for lipophilic drugs (increase in body fat)
• Hepatic blood flow decreases with age -> reduced clearance of opioids
• increased CNS sensitivity to opioids

Hepatic disease

• increased sensitivity to medications (unpredictable)
• reduced plasma protein concentration - increased free drug concentration in plasma

Renal failure

• metabolite accumulation for renally cleared drugs
• pharmcodynamic changes - drug effects compound uremic state

Obesity

• larger volume of distribution
• prolonged elimination

Hypothermia, hyperthermia, hypotension, hypovolemia may also cause variable absorption, distribution, and metabolism of opioids

Question 6

Define bioavailability

Answer 6

the percentage of administered drug that can gains access unchanged to the systemic CIRCULATION

Question 7

define volume of distribution

What does it determine?

Answer 7

Theoretical volume in which the total amount of drug would need to be uniformly distributed to achieve the blood concentration; a determinant of half life

ie. for very lipophilic drugs (fentanyl) that are taken up into fat stores the volume of distribution may be many times the body size

Another explanation: volume of plasma that would be necessary to account for the total amount of drug in the patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma

FS: ratio of ingested drug dose (mg) to plasma concentration of the drug (mg/L)

Question 8

How does the volume of distribution of a drug differ based on its lipophilicity

Answer 8

volume of distribution increases for very lipophilic drugs that are taken up into fat stores

Lipophilic molecules are more likely to pass through lipid bilayers and more likely to leave the bloodstream and distribute to areas with high lipid density (adipose) and therefore have a higher Vd.

Question 9

What 3 factors influence onset of action for opioids

Answer 9

(1) lipid solubility - highly lipid solubility facilitates diffusion across blood brain barrier = more rapid onset of action

(2) diffusable fraction (ie proportion of drug that is unionized and unbound - which will diffuse to site of action) - higher diffusable fraction (typically more acidic opioids) = higher unbound proportion = more rapid onset

(3) concentration gradient

Question 10

A patient presents with untreated MM and is in pain. Why might fentanyl (a more basic opioid) be a poor choice for pain control based on pharmacokinetic principles

Answer 10

in MM patients have high levels of serum proteins -> more opioids bound - less diffusible fraction

opioid molecules which are unbound and unionized are capable of diffusing to the site of action (diffusible fraction). The concentration of the diffusible and other factors such a lipid solubility determine the speed of onset of the drug.

The diffusible fraction may change with hypoalbuminemia associated with advanced illness -> opposite of MM

FS: fentanyl is a weaker base than other opioids = more bound to plasma protein = lower diffusable fraction

Question 11

List two reactions in phase one metabolism.

Answer 11

• oxidation*
• reduction
• hydrolysis
• hydration*
• dethioacetylation
• isomerization
• oxidation rxns catalyzed by p450

Question 12

List two reactions of phase two metabolism.

Answer 12

• conjugation
• glucuronidation*
• glycosylation
• sulphation
• methylation*
• acetylation
• conjugation with glutathione/certain amino acids

Question 13

What two factors influence the difference between the peak and the trough blood level of a drug?

Answer 13

drug elimination t1/2 and frequency of administration

Question 14

list four opioids metabolized by CYP 2D6

Answer 14

codeine
tramadol
meperidine
oxycodone
methadone

TOM-C

Question 15

List four opioids metabolized by CYP3A4

Answer 15

tramadol
buprenorphine
meperidine
oxycodone
methadone
fentanyl
alfentanil

TOM-F

Question 16

List three types of opioid receptors and their endogenous ligands

Answer 16

mu - beta endorphan, encephalins, endomorphins

delta - encephalins, beta endorphan

kappa - dynorphans

Question 17

List 6 factors that affect clinical utility of a drug (ie balance between analgesic and side effects)*

Answer 17

intensity of pain
prior opioid exposure in terms of drug, duration, dose (and degree of cross tolerance that this confers)
age
route of administration
LOC
metabolic abnormalities
genetic polymorphism in terms of relevant receptors, enzymes

Question 18

List eight side effects from opioids

Answer 18

GI - nausea, constipation, dry mouth, vomiting, ileus

Nervous system - somnolence, confusion, myoclonus, abnormal dreams, hallucinations, hyperalgesia

GU - urinary retention

resp - cough decreased, resp depression

skin - hyperhidrosis, pruritus

endocrine - hypogonadism, immunosuppression

5th Ed. Box 9.1.3

Question 19

List 3 examples of CYP 2D6 inhibitors and 3 examples of substrates (from PC)

Answer 19

Inhibitors - amiodarone, celecoxib, duloxetine, fluoxetine, haloperidol, levomepromazine, methadone, paroxetine, quinine, sertraline

Substrates - amitriptyline, codeine, oxycodone, duloxetine, fluoxetine, haloperidol, methadone, methylphenidate, metoclopramide, mirtazapine, omeprazole, ondansetron, paroxetine, promethazine, risperidone, sertraline, tamoxifen, tramadol, trazodone, venlafaxine

FS:
Inhibitor - antidepressant, antipsychotic

Question 20

List 3 inhibitors of CYP 3A4, substrates, inducers

Answer 20

Inhibitors (see 9.1.4) - amiodarone, clarithromycin, diclofenac, diltiazam, haldol, grapefruit juice (others)

substrates (many) - carbamezapine, dex, clonazepam, fentanyl, oxycodone etc

inducers - carbamazepine, dex, phenobarbital, rifampicin

FS:

Inhibitor - antibiotic, antifungal, antiviral, grapefruit

Inducer - Dex, phenobarb, St. John wort

Question 21

List two situations where caution is needed with transdermal formulations of drugs

Answer 21

wide variability in absorption in cachexic or pyrexial patients

also skin permeability of infants increased so increased absorption of transdermal drugs (ie. topical lidocaine)

Question 22

List four factors that can increase drug adherence in a patient

Answer 22

explain principles and goals of therapy

plan for follow up*

simple regimen*

low frequency of administration*

small amount of meds*

proactive management and/or prevention of side effects

address concerns re addiction tolerance, side effects or fear that tx implies end stage illness

Question 23

What is the definition of an opioid receptor agonist and name THREE.

Answer 23

Drug that has affinity for and binds to cell receptors to induce changes in the cell that stimulate physiological activity
Ex:
- fentanyl
- morphine
- codeine
- oxycondone
- hydromorphone

Table 7.5.1

Question 24

What is the definition of an opioid receptor ANTAgonist and name TWO.

Answer 24

Antagonist have no intrinsic pharmacological action but can interfere with the action of an agonist.

Competitive antagonist bind to the same receptor and compete for receptor sites.

Non-competitive antagonist block effects of the agonist in some other way

Ex
- naloxone
- naltrexone

Table 7.5.1

Question 25

What is the defintion of an opioid partial agonist and name ONE

Answer 25

A partial agonist has low intrinsic activity (efficacy) so that its dose-response curve exhibits a ceiling effect at less than the max effect produced by a full agonist.

Ex
- buprenorphine