5. drug interactions, adverse effects, specific populations

patient-related factors (ex: diet, genetics..)

administration - related factors (ex: route, dosage, order...)

beneficial if therapeutic effects increase and toxicity or cost decrease

harmful if opposite

potentiation: drug B increases drug A

additive: total effect = drug A + B -> alcohol & anxiolytics (harmful)

synergistic: total effect > drugs A + B -> codeine + NSAIDs (beneficial)

antagonistic: drug B decreases drug A -> naloxone decreases heroin (beneficial)

unique: effect unrelated to A or B

most common when drugs pre-combined in IV -> frequently form precipitate

most likely antagonist

risk of chemical interactions in body decreases cuz of body water dilution

no precipitate DOES NOT MEAN no interaction

response alteration via changes in bioavailability

absorption: gastric pH alterations, GI transit alterations, P-glycoprotein affinity/concentration

distribution: extracellular pH alterations, plasma protein affinity

metabolism: hepatic enzyme induction/inhibition

excretion: GF alterations, urine pH alterations, P-glycoprotein, tubular secretion transporters competition

clozapine, methadone

tobacco, carbamazepine

acyclovir, oral contraceptives

warfarin, diazepam

carbamazepine, st-john's worth

azaleas, isoniazid

clopidogrel, phenytoin

st-john's worth, phenytoin

cimetidine, isoniazid

codeine

not inducible

ritonavir, propanolol

immunosuppressants, anti-cancer, antibiotics...

carbamazepine, st john's worth

ritonavir, cyclosporine, grapefruit

response alteration via changes in effective concentration -> amount of drug molecule contributing to physiological effects?

1. receptor interactions

a. antagonism ex: warfarin + vitamin K

b. regulation/tolerance ex: alcohol abuse decreases GABA receptors

2.physiological interactions

ex: alcohol + cocaine = opposite physiological effect

clinically significant but poorly researched

decreased drug response

metabolic interactions

absorption interactions

grapefruit juice -> inhibition of CYP3A4 -> increase drug bioavailability

1. notice situations w/higher risk of interactions

2. minimize adverse effects of interactions (complete history, reduce Rx)

3. watch for timing of meal + drug intake (empty stomach is 1 hour before meal or 2 hours after)

lower drug response

higher drug response

adverse drug reactions: noxious, unintended, undesired effect occuring at normal dose

Augmented -> dose dependent predicted from known pharmacology of drug -> hypoglycaemia insulin (most common)

Bizarre -> unpredictable, dose independent, rare, fatal -> anaphylaxis to penicillin (most common)

Chronic -> prolong treatment

Delayed -> after years of treatment

End of use -> withdrawal effect

SJS and TEN

an acute or chronic liver injury secondary to drugs or herbal compounds.

liver enzymes convert drugs into toxic metabolites

frequent cause of acute liver failure

statins, anti seizure, antifungals, antimicrobials, acetaminophen

frequent LFT -> look for increases AST or ALT (liver enzymes)

monitor liver injury Sx (jaundice)

educate patient

they prolong QT interval time, female risk > cuz already long QT

QT>470 sec -> increased dysrhythmias -> increased V fib

antidysrhythmic, antipsychotics, antidepressants, antimicrobials..

Nearly unavoidable secondary drug effectsat therapeutic dosage• Usually Type A (Predictable & Dose-dependent)• Ex.: Gastric irritation from Aspirin• Ex.: Constipation from opioid analgesics

Uncommon DR resulting from GeneticVariation• Usually Type B (Dose independent & Unrelated)• Ex.: G6PD Deficiency + Aspirin → RBC Hemolysis

Detrimental physiologic effects caused byexcessive drug dosage• Definines ANY SEVERE ADR regardless of dosage• Ex.: Coma from Morphine overdose• Ex.:Neutropenia from anticancer therapeutic dose

Aberrant and harmful immune responsetriggered by a drug• Example of idiosyncratic effect• Most severe AR caused by Penicillins

Physiological adaptation to long-term drug effects• Ex.: Nasal congestion after using sprays• Ex.: Insomnia without sleeping pills

Ability of a drug to induce mutations leading to cancer development• Usually undocumented until many years post-marketing

Addiction = Physical + Psychological Dependence

Intense motivational cravings to consume a drug• Ex.: Opioids; Nicotine dependence

Ability of a drug to induce birth defects (Thalidomide!!)• Scrutinized and tested during new drug development

1. identifying ADRs

2. Minimizing ADRs

3. Patient advocacy + education

any preventable event that may cause inappropriate medication use or patient harm, while medication is in control of HCP

major cause of morbidity + mortality -> injures 1.5 M + kills 7000/year

wrong patient/drug/route/time/dose...

human factors: stress, knowledge deficit, drug preparation error

communication mistakes: illegible handwriting, oral order confusion

name confusion: Celebrex vs celexa / rifampin vs rifaximin

packaging mistakes

nurses = last line of defence -> no one can catch nurse mistake

minimize them

report them

pregnancy physiological changes = increased BP -> increased GFR -> increased excretion

increased GI transit time -> increased absorption

no, there are windows of variability that vary per organ/drug/defect/fetus

minor cause of birth defects <1%

fast-acting = easier to detect

slow acting = harder to detect

behavioural = impossible

alcohol, ACE inhibitors, sex hormones, anti seizure drugs, anticancer, thalidomide

all drugs of abuse

anticancer/immunosuppressants

radioactive compounds

atenolol

lithium

analgesia

anticoagulants

antidepressants

beta-blockers

glucocorticoids

administer immediately after or even during it

avoid Rx w/long T1/2 or sustained release formulations

kids NOT mini adults

organ immaturity -> infant drug sensitivity > adults

absorption

protein binding

permeable BBB

hepatic metabolism

renal excretion

interference w/developmental process

ex: androgens, aspirin, chloramphenicol, glucocorticoids, promethazine, fluoroquinolone...

dosage

adherence promotion

essentially everything decreases except body fat + gastric pH

kinetics similar to neonates

lipid soluble = more diluted

water soluble = more concentrated

minimize ADR

avoid these drugs: ibuprofen + aspirin, proton-pump inhibitors, benzodiazepines barbiturates, alpha-blockers

remember adherence promotion