Therapeutics Drug Interactions PDF

Preview

Summary

Drug Interaction Documents...

Description

Therapeutics: Introduction to Drug Interactions Important Thoughts  CDC: 82% of American adults take at least one medication and 29% take five or more  Adverse drug reactions (ADR) are the 4th – 6th leading cause of death in the US o Drug interactions (DI) may account for up to 15% of ADRs o DIs are a major source of medical errors o As pharmacist we should be the people impacting this  Physician recognition is generally poor  Computer databases/detection software systems are limited  Pharmacists are vitally important in detection, prevention, and treatment  Consequences of ADRs and DIs o Worsened Morbidity and Mortality o Interruption of therapy o New drug therapy o Clinic visits o Hospitalizations o Increased length of hospital stay o Increased healthcare costs o Loss of wages o Could lead to patient death Types of Drug Interaction  Drug-Drug**  Drug-Food**  Drug-Nutrient  Drug-Herb Drug Disease  More than one can occur at the same time Risk Factors (MUST KNOW**)  Polypharmacy – use of 4 or more regular medications o The more drugs they’re on, the more likely they are to have interactions  Multiple Prescribers o Each prescriber has no idea what the other has given you o The pharmacy should have that list!! o Sometimes can’t work around –if there is a specialist  Multiple Pharmacies o Lack of prescription drug coverage o Not all pharmacies have the capability to see everything that a patient is taking o Suggest to stick to one pharmacy  Patient Specific o Acute Medical Conditions  Started on medications that they have never been on  May or may not continue home medications  Some organs may not be working as well o Age extremes - very young and elderly  Have to be very careful – minor interaction for an adult could be deadly for a child  Different body surface area and metabolism (for children) o Decreased renal/hepatic function o HIV patients  Tend to have a lot of medications and tend to be highly interactive  Tend to cause other problems –ex: develop diabetes from meds o Female sex  Women’s bodies tend to metabolize drugs differently o Metabolic or endocrine condition - obesity, thyroid dz, etc o Pharmacogenetics  Drugs with Narrow Therapeutic Indexes o Examples: Digoxin, Warfarin, Lithium, Levothyroxine

o

If there was a drug interaction that increased the drug slightly then could have a major toxic effect

High Risk Disease States  Cardiovascular Disease  Neurologic Disease  Gastrointestinal Disease  Hepatic Disease  Kidney Disease  Psychiatric Disease  Respiratory Disease  Thyroid Disease  Infectious Disease Drug-Drug Interactions Mechanisms of Drug Interactions Pharmacodynamic  Effect the drug has on the body (what it’s doing to you)  A drug modulates the pharmacologic effect of another drug at the receptor site level or in similar physiological systems to enhance or antagonize the effects of another drug. o Additive o Synergistic o Antagonistic

 

Pharmacokinetic Effect the body has on the drug (what your body does to the drug) A drug modulates the effect of another drug by altering its concentration (increase or decrease) via: o Absorption o Distribution o Metabolism o Elimination

PharmacoDYNAMIC—Additive Drug Interaction (1+1 = 2)  Two drugs have the same/similar effect on a patient and have an additive effect o Both can cause an effect – add it together = double the effect  This is NOT related to an increase in drug concentration, work in a similar fashion and its additive o Both affect the same receptor, and it is amplified  Examples: o Two drugs that both cause sedation are prescribed to a patient leading to said patient being extremely sleepy.  Lorazepam (for anxiety) and Diphenydramine (for allergy) o Two drugs that both increase the risk QTc prolongation and fatal ventricular arrhythmias are prescribed to a patient and the patient dies from sudden cardiac death.  Erythromycin (for infection) and Haloperidol (for agitation) PharmacoDYNAMIC –Synergy Drug Interaction (1+1=4)  Two drugs have the same/similar effect on a patients when given alone, but when given together they have a magnified effect (more than additive)  Less predictable*** o So much more magnified, you know it’s going to be worse but don’t know how bad it’s going to be  This is NOT related to an increase in drug concentration  Examples: o Two drugs that both cause sedation taken by a patient lead to said patient being obtunded.  CNS depressant and EtOH o Not additive –insane amounts of synergy  something out of the ordinary PharmacoDYNAMIC –Antagonistic Drug Interaction  One drug decreases or blocks the effect of another drug  This is NOT related to a decrease in drug concentration o Ex: alcohol and caffeine (to counter tiredness)  Example: o One drug decreases inotropy of the heart and the other increases inotopropy  Metoprolol (Beta-antagonist) and Dobutamine (Beta-agonist)  Many interactions are due to effects on receptors in the body.  Both drugs are agonists of the same receptor leading to more of the same effect.

  

One drug may be an agonist and the other an antagonist of the same receptor leading to a decreased effect of the agonist. o Compete for the same receptor – receptor related Some interactions are related to physiologic changes that occur from a drug. One drug depletes the body of a substance necessary for another drug to work properly. o Example: Furosemide (diuretic) decreases K+ in the blood leading to Digoxin toxicity

Not changing the level of the drugs**** and how the drug affects you!! Agonist and Antagonist

PharmacoKINETIC Drug Interactions More common/serious**  PERPERTRATOR DRUG: Drug that cause the interaction  VICTIM DRUG: Drug that is affected by the interaction  One drug alters the rate or extent of absorption, distribution, metabolism or excretion of another drug o Drug level/efficacy can increase/decrease  Alters blood concentration of another drug which MAY result in changes of drug effects  Significance of the drug interaction is dependent upon: o Blood levels of the drug o Effects at the receptor o Therapeutic index of the drug  Effects on metabolism will change half-lives of drugs and affect steady state concentrations o Inhibition – T ½ of victim drug will increase and the [ ] will increase PharmacoKINETIC—ADME  Absorption – has to be absorbed in GIT (mostly intestine followed by stomach) o Chelation (bind out medication you’re taking) o GI transit time o pH  Distribution o Albumin/Protein o If another drug has a higher affinity –some of the drug not bound and increase levels in the blood/ chance of side effects  Metabolism o Cytochrome P-450 o p-glycoproteins/OATPs o Pro-drugs need to be metabolized to their active form  Elimination o Kidney o Liver PharmacoKINETIC Interactions: Absorption  Alterations in motility o Increase or decrease in GI motility MAY alter the efficacy of medication o Ex. Increased GI motility with metoclopramide reduces digoxin absorption  Alterations in pH o Some medications require a more acidic environment for proper absorption. (ex. ketoconazole) o Taking medications that increase stomach pH may alter the effectiveness of these medications



Chelation o Irreversible binding of a medication in the GI tract causing a reduced bioavailability o Ex. Cholestyramine binds to warfarin and reduces bioavailability

PharmacoKINETIC Interactions: Distribution General questions on the exam***  Drug interactions affecting distribution alter protein binding  Not typically a significant drug interaction  Only a major concern when a medication is highly plasma protein bound (>80%) o If we know it’s going to bind, want to make sure there is enough that is not bound so it will be effective  Examples include: o Phenytoin o Warfarin **PharmacoKINETIC Interactions: Metabolism**  Most common reason that drugs interact  Principle site of drug metabolism is the liver  Metabolism activity is classified as either nonsynthetic (Phase I) or synthetic (Phase II)  Phase I (oxidation, reduction, hydrolysis) o Typically occur in the hepatocytes via the Cytochrome P450 system (CYP450) o Heavily involved with drug interactions  Phase II (conjugation reactions) o Include: Glucuronidation, Acetylation and Sulfation o Less frequently involved with drug interactions If there is a question on the exam about two medications –will provide that section of the chart to figure out, will need to know substrate, inducer, inhibitor  If something is listed as BOTH an inhibitor and substrate or an inducer and substrate think of it as the inhibitor or the inducer and not the substrate Focus on CYP not Phase II** CYP450 System  CYP always means CYP450  CYP450 enzymes are responsible for the breakdown of many compounds in the body  CYP 450 enzymes found predominantly in the liver and are responsible for the metabolism of most drugs  Drug interactions involving these isoenzymes result from: o Enzyme inhibition OR o Enzyme induction Cytochrome P450 (CYP 450) – bolded = 90% of the main CYP metabolism  Known to be important in drug metabolism o CYP 1A1 o CYP 1A2 Most active CYP’s for drug metabolism are those o CYP 2A6 in the following families: o CYP 2B6  CYP 2C o CYP 2C8  CYP 2D o CYP 2C9  CYP 3A o CYP 2C19 o CYP 2D6 o CYP 2E1 o CYP 3A4 o CYP 3A5  CYP 3A4 –involved in the metabolism of >40% of medications  CYP 2C9 –involved in the metabolism of ~15-20% of medications  CYP 3D6 – involved in the metabolism of ~20% of medications

**Key Terms**  Substrate o A medication that is metabolized by a specific enzyme o Of note; medications can be a substrate for several isoenzymes  Enzyme inhibition (Inhibitor) o A medication can be an inhibitor of a specific CYP 450 enzyme and block the metabolism of other drugs metabolized by that enzyme  Enzyme Induction (Inducer) o A medication can be an inducer of a specific CYP 450 enzyme and increase the speed of metabolism of other drugs metabolized by that enzyme o Breaks things down faster! Enzyme INHIBITION  Drug-drug interactions resulting from inhibition may be seen after administration of the first dose of the perp o See a change in the victim drug right after the first dose  Inhibition interactions are classified as: o Reversible  Most common – majority  Compounds form weak bonds with CYP enzyme without permanently disabling them  Enzymes start working just as well when you clear the drug from the system o Irreversible (very rare)  Drug forms a covalent bond to an enzyme and permanently inactivates the enzyme  More serious interaction  Return to normal activity will be dependent on the half-life of drug and synthesis of new enzymes  Shut off metabolism –and doesn’t work again  “Inhibitors” will increase the half-lives of victim drugs, thereby causing an accumulation of unmetabolized drug in the blood stream o Makes the victim drug hang out longer in the body  Overall effect is an increased effect of the “victim drug”  Example: o Drug A is metabolized via CYP3A4 (substrate/victim) o Drug B is an inhibitor of CYP3A4 (perp) o Patient has been taking drug A regularly and Drug B is added to regimen o Patient experiences an increased effect from Drug A as more drug is available in the body due to Drug B “inhibiting” its metabolism  Can feel the side effects of drug A to a greater degree  Full effect is dependent on the half-life of inhibiting medication (the perp)  Onset can be noticed after the first dose and is maximal when the inhibiting drug reaches steady state (typically 4-5 half lives)  Upon discontinuation of the drug, the duration of inhibition will also depend on the half-life of the medication causing inhibition o Metabolism will go back to normal after T ½  When inhibiting metabolism – everything backs ups! o Ex: highway traffic Prodrug Inhibition  Prodrug: medication administered as an inactive form then converted to its active form via metabolism  Inhibition of a prodrug can therefore decrease the effect of the prodrug (victim drug) o Going to have the opposite effects on prodrugs!!  If it’s a straight drug, inhibiting =  the drug in the body o Less of the active metabolite will be activated by the enzyme  End result is a decreased effect from the prodrug Enzyme INDUCTION  Onset is typically gradual and depends on the half-life of the inducer  Inducers of metabolism can DECREASE the effect of the substrate drug o Less of an immediate concern due to delayed reaction o Leads to compromised therapeutic goals vs. therapeutic toxicity  Full effect on metabolism may not be seen for several days to several weeks  Drug leaves the body faster





Overall effects: o Half-life of “victim” drug is shortened o Blood levels are lowered o New steady state is reached more quickly o Interaction will be reversed upon discontinuation of drug causing induction, however time to normalization will depend on half-life of medication causing induction Introduction of a prodrug therefore increase the effect of the prodrug (victim drug) o  metabolism of a prodrug o More active drug is given faster

Effects of STOPPING Interacting Drugs  Interaction will be reversed depending on the half-life of the perpetrator and victim drugs  If you have made an adjustment in dose (either knowing or not knowing of the interaction) you may need to readjust dose on the basis of a change in steady state concentration  Long standing interactions may have been in “equilibrium” o Ex: smoking can  metabolism of meds if patient stops smoking = they can see the later effects of the drug after o Make adjustments – decrease the dose to prevent the increase Pharmacokinetic Interactions: Excretion  Drug A increases or reduces the excretion (usually renal) of Drug B.  Elimination half-life of Drug B increases or decreases changing blood levels  Most significant with drugs with narrow TI  Most Drug interactions occur via: o Tubular secretion o Tubular reabsorption Transport Protein Interactions – a general concept question, be familiar of what they do  P-glycoprotein (P-gp) o Efflux Transporter o Acts as a pump to transport drugs and toxins out of tissues  In the GIT if a toxin goes into a tissue it gets pumped out and eliminated in the feces  Protective mechanism – protect a tissue from a toxin o Can be induced (decrease drug effect) or inhibited (increase drug effect)  Inhibit = not pushing toxins out, so it will stay there and cause the effect o Think GI, Brain, Kidneys o Often overlaps w/CYP 3A4 – not all but often have the same kind of profile o Polymorphisms can occur  Organic Anion Transport Polypeptides (OATPs) o Transport drugs across cell membranes o Can be induced or inhibited o Think Intestine, Liver  Inhibition in intestine would decrease plasma concentration (decrease absorption)  Inhibition in liver would increase plasma concentration (decrease metabolism)  Opposite of the P-gp Drug-Food Interactions Lots of auxiliary labels associated with this! General Principles  Food may increase, decrease, or not affect the bioavailability of a medication  Types of interactions o Pharmacokinetic** (primarily where you see the food interactions)  Absorption–Chelation, Complexation, Adsorption, Binding  Metabolism–Inhibition, Induction o Pharmacodynamics  Alcohol (drug? Food?)  Caffeine

Bioavailability  Definition: the fraction of an administered medication that reaches the systemic circulation unchanged o Drug via mouth –% able to utilize after going through GIT, compare to IV  Intravenous administration is always 100% bioavailable  Example: o When 100 mg of PO furosemide is administered, about 60 mg reaches the systemic circulation; thus, PO furosemide has a 60% oral bioavailability. Food and Bioavailability  FDA mandates all new or generic products be studied in human subjects to exam the effects of food on drug absorption and bioavailability o High Fat – High Calorie Test Meal o Want to see if bioavailability changes with empty stomach vs. high fat high calorie meal  Some foods may increase or decrease bioavailability o Ex: Xarelto taken with food (dinner) because better absorbed + concentration with food  Some foods may not change bioavailability, but may quicken or delay absorption  Some foods may do nothing at all Shows  [ ] of drugs show up if taken with food  Propranolol likes fat (lipophilic) Grape Fruit Juice ( villain)  Inhibits CYP 3A4 and P-gp in the small bowel o Does not impact IV medication  Only impacts someone taking medication orally o Impact can last up to 72 hours o Drugs with low bioavailability are most effected  If you have a drug that is 100% bioavailable –probably isn’t going to make a big difference  If 10% then it is going to make a huge deal o No one really knows how much you have to ingest to have a full blown effect on metabolism – avoid  Substrates o CCB, Atorvastatin, Lovastatin, Simvastatin, Warfarin, Cyclosporine, Tacrolimus  Inhibits intestinal OATP Vitamin K Rich Foods  WARFARIN – inhibits vitamin K dependent clotting factors II, VII, IX, X and proteins C and S  Vitamin K rich food decrease the effectiveness of Warfarin S  Sample of Vitamin K Rich Food o Green leafy vegetables o Brussel sprouts o Broccoli o Onions o Soy products  Also – multivitamins and supplement beverages o Supplemental beverages often have a lot of Vitamin K in them  Need to be consistent in diet– will keep INR more level Alcohol  Pharmacodynamic interactions  Additive/Synergistic Effects o Enhanced CNS depressant effects  Opiates, TCAs, Benzos, etc. o Increased gastric irritation/increased risk GI bleed  Aspirin, NSAIDs o Enhanced glucose lowering  Insulin – can have major effects!  Please consult your endocrinologist and have a plan on what to do  Disulfuram-like reaction o Metronidazole – make you very sick + puke your brains out o Very bad reaction with alcohol  Pharmacokinetic interactions – EtOH is metabolized via aldehyde dehydrogenase and CYP2E1; with chronic heavy use CYP2E1 is induced and its activity increases upwards of 10 fold

o

Acetaminophen NAPQI  Acute EtOH ingestion decreases production of toxic metabolite  Chronic EtOH ingestion increases production of toxic metabolite  Toxic metabolite will build up  liver failure

No Tylenol for alcohol** NEVER USE AS A HANGOVER CURE  More worried about heavy drinkers Acute ingestion of alcohol = competitive inhibition, Tylenol + alcohol trying to be metabolized at the same time  less NAPQI (not an issue but you’ll have extra APAP in the body) Caffeine  Pharmacodynamic Interactions o Additive/Synergistic Effect  Stimulants–risk of heart effects/HTN  Diuretics–risk of dehydration/electrolyte abnormalities o Antagonistic Effect  Adenosine–caffeine block effects needed for stress testing; must dc 24 hrs prior to test  Interact at the same sites because have similar structure  Doesn’t change the level  Pharmacokinetic Interactions o Caffeine is metabolized via CYP 1A2 o Cipro + caffeine = very bad reaction (very jittery)  Stay hydrated when drinking coffee  Never have coffee before a stress test Dairy  Pharmacokinetic interactions - Absorption o Decreases the absorption of some medications via Calcium-Chelation leading to a decreased effect  Antibiotics  Fluoroquinolones  Tetracyclines  Cefuroxime  Levothyroxine  Methotrexate  Alendronate o Separate by a minimum of 2-4 hours  Ideally take the medication first, 4 hours before Fiber  Pharmacokinetic interaction – Absorption o Binds to some drugs to prevent the proper absorption leading to a decreased effect (# of them have low TI)  Levothyroxine  Digoxin  Metformin  Carbamazepine  Lithium  TCAs Sample Online and Smart Phone Resources How do we find out if a drug interaction exists? Let’s practice! Patient Case #1  JT is a 66 year old female recently prescribed sertraline for recently diagnosed depression.  She presents to the local emergency department a few days after filling the prescription.  She is suffering from N/V, headache, agitation, jerky movements, sweating and a fast heart rate.  What is going on with JT??  What do we need to know?

Additional Information  PMH: Migraines, Depression, HTN, h...