Pharmacokinetics. What the body does with the drug
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1 Pharmaclgy 203 Windward Cmmunity Cllege Pharmackinetics What the bdy des with the drug Ever wndered why different peple have different reactins t the same drug? Hw des genetics play int therapeutics? What are the variables? In this fact sheet, we will discuss these issues and mre S, what des yur bdy d with the drugs yu take? Kinetics Terms It treats them just like any ther chemical it encunters, just like fd, in fact. In general, the drug is: A Absrptin requires the drug t crss cell membranes. Absrbed Distributed thrughut the bdy Metablized, in an attempt t use the drug r parts f the drug fr energy r building blcks and then, T get rid f the drug, the bdy excretes it and any metablites prduced. All f this is accmplished using existing pathways and mechanisms, prcesses we call kinetics. D Distributin is the rle f the bld and lymph. M E Metablism is the prcess f altering the drug. Excretin is hw the bdy gets rid f the drug & metablites. Fr metablism, tw basic types f pathways are utilized using existing enzymes that carry ut redx and cnjugatin reactins. The vast majrity f metablism ccurs in the liver, but ther tissues are highly metablic as well. (Cntinued n page 4). We use kinetics t determine the best rute f administratin, dsage and frequency, frm & frmulatin
2 Lrem Pharmaclgy Ipsum Dlr 203 Windward Cmmunity Spring Cllege 2016 Variables affecting kinetics A number f variables affect kinetics. Variables related t the PATIENT Age (sensitive ppulatins are very yung r ld) Size and Weight Genetic factrs, including race and sex Pregnancy status (a sensitive ppulatin) Pre-existing disease (especially liver, kidney, diabetes mellitus type 2 and heart disease) Diet and envirnmental chemical expsures including alchl and tbacc Cmpliance with dsing prtcl Variables related t the DRUG Frmulatin and frm, including slubility & size Interactins with ther drugs/fds/hst prteins Effects f Metablism Metablism can result in many utcmes, including cmbinatins f the fllwing: Inactive prducts Active daughters (metablites) Similar, but different daughters Daughters that are mre active Daughters with a new actin Txic metablites Susceptibility t breakdwn Sme drug interactins are txic! These drugs are ptentially TOXIC when cmbined with a CYP3A4 inhibitr. CYP3A4 inhibitrs include: Antifungals like ketcnazle Macrlide antibitics like erythrmycin GRAPEFRUIT JUICE!!!! Benzdiazepines (alprazlam, midazlam ) Sterids (budesnide, dexamethasne ) Erectile dysfunctin drugs (sildenafil.) Statins (Lvastatin, simvastatin ) Ergt drugs (Brmcriptine), AEDs (carbamazepine), anti neplastics (vinblastine, vincristine ), anti arrhythmics (dispyramide, quinidine ). See the lecture ntes. 2
3 Pharmaclgy Lrem Ipsum 203 Dlr Windward Cmmunity Spring Cllege 2016 Yes, genetics makes a big difference! The enzymes respnsible fr metablizing drugs are what are called plymrphic. All that means is, they cme in many shapes. Remember back in bilgy and zlgy, they talked abut alleles? These are slightly different versins f the same gene and allw fr plymrphism. Plymrphic genes result in varius frms f a specific prtein, in this case, f metablic enzymes. 1. CYP3A4 a. The mst imprtant Phase 1 enzyme fr drug metablism, but it is NOT plymrphic i. Metablizes Calcium Channel blckers, benzdiazepines, HIV prtease inhibitrs, statins, cyclsprine, nn-sedating antihistamines. b. Its activity varies 50 fld in the general ppulatin!! 2. CYP2D6 i. This may be explained by having multiple cpies f the gene. a. Metablizes cdeine, hydrcdne, beta blckers, TCAs (many f the current cardivascular and neurlgic drugs) b. Inhibited by Fluxetine, Halperidl, Parxetine, Quinidine c. Absent in 7% f Caucasians; 1-2% f nn- Caucasians d. Hyperactive in 30% f East Africans (multiple cpies f the gene) 3. CYP2C9 a. Absent in 1% f Caucasians & African- Americans b. Metablizes NSAIDs, Warfarin, Phenytin c. Almst all inter-patient variability n warfarin can be explained by the activity level f this enzyme. 4. CYP2C19 a. Absent in 20-30% f Asians; 3-5% f Caucasians b. Metablizes Diazepam, Phenytin, Omeprazle (which als inhibits it!) 5. CYP1A2 a. Induced by smking! b. Metablizes Thephylline, Imipramine, Prpranll, Clzapine 6. N-acetyl Transferase, a Phase 2 enzyme a. 70% f Middle Easterners; 50% f Caucasians; 5-25% Asians are slw acetylatrs leading t INH txicity 3
4 Pharmaclgy Lrem Ipsum Dlr 203 Windward Cmmunity Spring Cllege 2016 Cntinued frm page 1 The tw basic pathways are called: Phase 1, which invlves membrane-bund enzymes called Cytchrme P450s. There are many CYP enzymes and they are plymrphic. This means there are many alleles f the genes fr these prteins. Think abut hw many eye clrs there are it s essentially the same thing: ne trait, many expressins. Phase 2, which uses a variety f transferase enzymes t cnjugate the drug with anther material t imprve either water slubility (fr excretin thrugh the kidneys and urine) r lipid slubility (fr excretin, alng with bile, thrugh the intestines in the feces). Once metablized, there are tw basic pathways fr excretin. The physilgically preferred rute is thrugh the kidney in urine. If a drug cannt easily be made plar, it will be cnjugated int a mre lipid sluble frm and stwed away with bile in the gall bladder until the bile is released (fllwing a meal). Then the drug cnjugate cmbinatin will be secreted int the small intestine. It is pssible fr GIT bacteria t cleave the cnjugate ff and reactivate the drug. In this case, the active drug can be enterhepatically cycled and reused. Otherwise, the cnjugated drug will cntinue ut f the bdy with the feces. Other rutes f excretin, including sweat, mther s milk, and exhaled air, are generally cmpletely insignificant. An imprtant exceptin wuld be the vlatile liquid anesthetics and gas anesthetics that are excreted in exhaled air. Absrptin Nt all drugs are absrbed. Sme are given rally with the full knwledge they wn't be absrbed. Fr instance, Chlestyramine, a resin used as a bile acid sequestrant, binds t bile acids and ther lipids in the GIT carrying them ut f the bdy in the feces and thus lwering chlesterl levels (bile acids are made frm chlesterl). If a drug is absrbed, it must crss many cellular membranes in mst cases t get t the target tissue. Drugs that are lipid sluble crss membranes mre easily, but the vast majrity f ral drugs are actually salts f weak bases, r weak acids (less cmmnly). The un-inized frm f the drug mre easily crsses cell membranes due t the nature f a phsphlipid bilayer. If it is a weak base, the slightly acidic ph f the cell interir can inize the drug, trapping it inside the cell. This is called in trapping and is discussed n lecture slides. Again, the mst cmmn frm fr drugs are rally administered weak bases, s they are uninized and absrbed alng with fd frm the small intestines. Small drugs mre easily crss membranes than large drugs, but smetimes there are active prcesses that pump the drug inside, r ut, regardless f its size. 4
5 Pharmaclgy Lrem Ipsum Dlr 203 Windward Cmmunity Spring Cllege 2016 (cntinued) Lets lk at sme f the ADME variables and hw they are impacted by age, sex and preexisting disease. First, age. In the very yung, we see a number f differences t the adult: 1. Surface area t vlume rati is different 2. Ttal bdy water is greater in the infant 3. The infant has limited metablic capability In the very ld, there are als a number f imprtant differences t the average adult: 1. Lss f muscle leads t altered vlumes f distributin (decreased bdy water) 2. Age-related lss f liver functin leading t reduced plasma prteins and metablic capability 3. Age-related lss f kidney functin leading t reduced ability t excrete drugs and metablites. 4. Cardivascular dysfunctin leads t perfusin issues. 5. Typically n multiple medicatins with increased risk f adverse effects and interactins. 6. Age-related memry prblems may lead t cmpliance issues. 7. See Beer s List fr drugs t avid in the elderly. Next, sex. Wmen have less bdy water than men and they may becme pregnant. Pregnancy leads t a number f issues including: 1. Susceptible fetus with lack f metablism 2. In trapping f weak bases in fetus 3. Altered metablism in the mther due t inductin f metablic enzymes may lead t increased prductin f txic metablites. Next, pre-existing disease 1. Liver a. Decreased prtein synthesis leads t altered distributin, absrptin, metablism & excretin 2. Kidney a. Decreased functin leads t altered metablism & excretin 3. Cardivascular a. Decreased functin leads t (mstly) decreased distributin, but als impacts absrptin, metablism & excretin. 4. Gastrintestinal (GI) a. Inflammatin/edema reduces absrptin b. Oral antibitics, reduce GIT flra, which alters absrptin/recycling 5. Other a. Diabetes mellitus affects vasculature. b. Thyrid dysfunctin affects metablism and distributin. 5
6 Pharmaclgy 203 Windward Cmmunity Cllege A gd medicatin histry helps AVOID Mistakes Allergies? Vitamins/herbs? Old drugs r OTCs (include current drugs)? Interactins? Dependence? Mendel (the genetics guy) is there a family histry f benefits r prblems with drugs? Pharmaclgy 203 Windward Cmmunity Cllege Hmewrk and Exercises 1. Read the START HERE annuncement in Laulima fr updates and instructins. 2. Read Chapter 4, Pharmackinetics in Adams & Urban. PHARMACOLOGY Cnnectins t Nursing Practice 3. Review the PwerPints and listen t the audi frm the face-t-face lecture. 4. Cmplete the SLO Practice set in Tasks, Tests and Surveys. 5. Cmplete the nline quiz in Laulima If yu have questins, me abeale@hawaii.edu
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