Jan 25, 2007

Jan 25, 2007  Adverse Drug Reactions o Any substance has potential to cause deleterious effect  Biggest reason why people turn to CAM o Thalidomide  Used in pregnant women  Sudden outbreak of birth defects, traced back to moms who had taken thalidomide  First formal study of adverse drug reactions  ADR: Definition o Unintentended  Eliminates cases of overdose  Definition…2 o Drug is the same whether I take it or you take it o Pharmacokinetic responses are the same but one person has a reaction and the other one doesn’t  ADR Classification According to Severity  Predictable ADRs: (Dose-Related) o Those that are predictable – Dose Related o Those that are unpredictable o Look at table at end of discussion – important to understand differences o Predictable usually seen o Can be prevented by doing certain things upfront  Unpredictable ADRs: (Not Dose-Related_ o Important – Unrelated to therapeutic effects o Due to inherent changes within the person o Isoniazind  Used to treat TB  There are slow metabolizers and fast metabolizers  Don’t know who those populations are  Therefore, unpredictable reaction o Can get better idea of reaction if genetic screening done o Allergic type reactions are included in this group  Adverse Drug Reactions: Summary of Characteristics o Important to know table  Terminology  Type 1 Allergic Reactions o Memorize all the different types o Anaphylactic  Peanut reaction, penicillin reaction, bee sting reaction…  Interaction with IgE antibody  Excess IgE related to genetic predisposition  Commonly see clusters of reactions with children

IgE is the instigator and the effector cells are the mediators (eg. Histamine)  ASA • Asthmatic patients may respond to ASA b/c of IgE levels Type 2 Allergic Reaction o Cytotoxic  IgG or IgM mediated  Methyldopa is almost an extinct drug, except in the treatment of HTN in pregnant women Type 3 Allergic Reaction o Immune-Complex Mediated  As a consequence see serum sickness  Second one where we see complement involved Type 4 Allergic Reaction o Cell-mediated  TB test is an example of Type 4 • Checks for previous exposure • Sensitized lymphocytes • If have exposure and have sensitized lymphocytes then the serum is injected interdermally • Causes an inflammatory response Predisposing Factors o Memorize o Age  If take no drugs, will not have drug reaction  If taking drugs, have a higher change for a drug reaction o In allergic rhinitis will see a familial pattern o Genetic alterations in metabolism  G6PD • Required for the elimination of specific drug • One of the few that can be screened for Assessment of Suspected Adverse Drug Reaction o Manifestation of ADR may not be unique  Two agents may cause a reaction  Might be hard to separate or tease out reactions o If therapy stopped, does the patient improve? o If rechallenge, do you see the reaction again?  If give small amounts over time can desensitize them  Done in a very controlled environment Reporting ADRs o Can report ADR for NDs on health Canada website o Reporting go Adverse Reactions for Naturopathic Doctors o Also have some forms that should be used to report adverse reactions 













o Health Canada wants those that are newer in the market to be reported  Differentiating between predictable and unpredictable dose reactions o Predictable  Common  Dose related  Related to therapeutic profile of the drug  More in patients with impaired elimination  More concerned about adverse reaction in a 70 year old male than an 18 year old male  Drug Interactions o Why do we care about this?  Many of our patients are on more than one agent (pharmacological drug, supplement…)  In a hospital ward patients can be on up to 10 medications  The more complex the regiment the higher chance for drug interaction  Need to be cognizant of drugs and herbs, foods, food additives  When a patient can only take a certain brand of a certain drug • The chemical entity is the same, but they may have a reaction to the dyes, preservatives or certain fillers  Polypharmacy • Prevalent in our population • Particularly in elderly • Each of the practitioners don’t necessarily talk to each other and thus don’t know what they are doing  Can be the cause of adverse drug interactions resulting in death • Results in removal from the market  Consequences of Drug Interactions o May sometimes be used to our benefit o Levodopa and carbidopa  Both marketed together as Sinement for Parkinson Disease  Levodopa converted to dopamine which helps in movement • On its own it’s metabolized before it reaches the brain  Carbidopa preventing the breakdown of levodopa such that we are allowing more dopamine levels to get into the brain • Drug interaction used to our advantgage  Cyclosporine • Immunosuppressant used in amutation patients • Very expensive • Give drug that inhibits P450 system that allows cyclosporine to be in the body longer  Opiates

•



 





If have excess levels of opiates and have respiratory depression, will give a dose of naloxone • Shoots off the methadone from its receptor sites • Will see a sudden awakening from the patient • Will be alert! Classification of Drug Interactions o Pharmacodynamics  What the drug does to the patient o Pharmacokinetic  What does the body do to the drug  Liver metabolizing the drug o Object Drug  Morphine o Precipitant drug  Naloxone Pharmacodynamic Interactions o Common but not that significant for the most part Pharmacokinetic Interactions: Absorption o Chemical type interactions  Change in gastric pH  Activated charcoal • Used to mop up other drug in the GI system • Used in some forms of overdose o Changes in GI motility  The more SA it has, it might attract other medication o Happens when drug is being absorbed Pharmacokinetic Interaction: Distribution o Once its absorbed its distributed throughout the body o Plasma protein displacement  Some drugs are highly bound to protein  Rapid to occur  Worry if drug has narrow therapeutic window • Below certain level worry about efficacy • Above certain level worry about toxicity  If has narrow distribution • The consequence of increasing the free fraction is important  If drug is highly protein bound  If take 100 mg of that drug 5 mg will be free  If have plasma protein displacement  Go from 5mg to 7mg in the vasculature  Almost increase by double amount Pharmacokinetic Interaction:

o 3A4 family is the one that’s used the most for the elimination of drugs o Memorize  3A4 is not subject to genetic changes  Pharmacokinetic Interactions: Metabolism o Smoking induces 1A2  When in a smoking cessation clinic  One of the things considered, as they stop smoking, is there any effect on their enzymes?  Inducing too much/too little metabolism? o Enzyme induction  If we don’t account for enzyme induction might see therapeutic failure  Enzyme inhibition • Slows down (eg. 3A4) – now have a lot of the drug in the body • Grapefruit juice o Inhibitor – counseled not to take when on certain drugs o Will cause fluctuation in drug levels • Garlic o Also inhibitor of certain systems o Induction  Takes a little more time to start and end when offset with a participant drug o P-glycoprotein transporter  Limits absorption from the gut • Takes drug and pumps it back to lumen so that it can go back to the GI system to be absorbed • Less in blood stream • That’s why it’s known as eflux • Limits absorption into the body • Can be inhibited or induced • Big area of study in chemotherapy  Pharmacokinetic Interactions: Elimination o KI most important area to eliminate (besides LIV) o Time when we see enhanced elimination o Higher refraction o Will have altered tubular reabsorption  When processing drugs in the KI, ultimately that becomes urine  In the lumen of the nephron will become urine  At different points will have reabsorption of electrolytes  Reabsorption can be active/passive

Some drugs do better when reabsorbed in acidic/alkaline environment  That may effect whether a drug will be reabsorbed  Reabsorption occurs and can be changes in whether a drug is absorbed based on the pH o Secretion  Along the tubule there’s vaculature  Stuff that’s in the tubule can be added into the lumen and added to the secretion  Blood to urinesecretion  When penicillin first made it was partially eliminated through secretion • Serves to decrease blood circulation • Probenacin (sp?) inhibits secretion • Administer penicillin and probenaciin at the same time to get higher concentration of penicillin • Took advantage of drug at the level of drug secretion  Evaluation of Drug Interactions o When have a drug interactions ask whether it’s a drug interaction or a class interaction o Cimetidine  Potent inhibitor of the P450 and ranitidine is not o Time course of interaction  Important to understand o Clinical significance  If wide therapeutic window • Not so important  Dosage and route of administration  Interactions • May be more or less important to think about • Eldely vs. young patient  Case: Monascus Pupureus o When there is an elevated about of statins in the body get greater damage to the body  Rhabdomyolysis  Number one cause for stopping meds  