7.5 (9.1) Principles of drug therapy Flashcards
How is efficacy different from effectiveness? What is cost effectiveness?
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)
What are two statistical parameters that can be examined when determining the risk:benefit ratio of using a drug?
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
Define pharmacokinetics and pharmacodynamics
pharmacokinetics - what the body does to a drug
pharmacodynamics - the drug does to the body
What are four key elements of pharmacokinetics?
absorption
distribution
metabolism
excretion
ADME
List 4 factors that can affect the pharmacokinetics of a drug
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
Define bioavailability
the percentage of administered drug that can gains access unchanged to the systemic CIRCULATION
define volume of distribution
What does it determine?
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)
How does the volume of distribution of a drug differ based on its lipophilicity
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.
What 3 factors influence onset of action for opioids
(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
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
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
List two reactions in phase one metabolism.
- oxidation*
- reduction
- hydrolysis
- hydration*
- dethioacetylation
- isomerization
- oxidation rxns catalyzed by p450
List two reactions of phase two metabolism.
- conjugation
- glucuronidation*
- glycosylation
- sulphation
- methylation*
- acetylation
- conjugation with glutathione/certain amino acids
What two factors influence the difference between the peak and the trough blood level of a drug?
drug elimination t1/2 and frequency of administration
list four opioids metabolized by CYP 2D6
codeine tramadol meperidine oxycodone methadone
TOM-C
List four opioids metabolized by CYP3A4
tramadol buprenorphine meperidine oxycodone methadone fentanyl alfentanil
TOM-F
List three types of opioid receptors and their endogenous ligands
mu - beta endorphan, encephalins, endomorphins
delta - encephalins, beta endorphan
kappa - dynorphans
List 6 factors that affect clinical utility of a drug (ie balance between analgesic and side effects)*
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
List eight side effects from opioids
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
List 3 examples of CYP 2D6 inhibitors and 3 examples of substrates (from PC)
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
List 3 inhibitors of CYP 3A4, substrates, inducers
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
List two situations where caution is needed with transdermal formulations of drugs
wide variability in absorption in cachexic or pyrexial patients
also skin permeability of infants increased so increased absorption of transdermal drugs (ie. topical lidocaine)
List four factors that can increase drug adherence in a patient
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
What is the definition of an opioid receptor agonist and name THREE.
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
What is the definition of an opioid receptor ANTAgonist and name TWO.
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
What is the defintion of an opioid partial agonist and name ONE
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
