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Part 3. ABSORPTION OF DRUGS A. ABSORPTION FROM THE GASTROINTESTINAL TRACT I. MECHANISMS 1. Diffusion 2. Carrier-mediated transport (by secondary and tertiary active transporters) 3. Receptor-mediated endocytosis II. INFLUENCING FACTORS 1. Motility of the GI tract: gastric emptying, intestinal propulsive motility 2. Luminal pH 3. Luminal content – quantity 4. Luminal content – quality acidity in the stomach; intake of fat, protein, fruit juice, vegetarian diet, Ca2+, non-absorbable resins III. ORAL BIOAVAILABILITY (F) 1. Definition of F 2. Determination of F = AUCpo : AUCiv 3. Potential causes of incomplete oral bioavailability: a. Incomplete release of the drug from the formulation b. Degradation of the drug molecule in the GI lumen c. Poor solubility of the drug in the GI juices (e.g., phenytoin, itraconazole) d. Poor diffusibility of the drug molecule across the GI mucosa (strong acids, strong bases) e. Presystemic elimination (PSE) of the drug = first pass elimination – intestinal PSE (by biotransformation, and/or export back to the lumen) and hepatic PSE (by biotransformation) B. ABSORPTION FROM THE ORAL, NASAL AND RECTAL MUCOSA I. COMMON FEATURES A. ABSORPTION FROM THE GI TRACT I. MECHANISMS 1. Diffusion: probably important for most drugs, at least partly 2. Carrier-mediated transport: important for several drugs, at least partly Secondary active transport: - Concentrative nucleoside transporter (CNT, Na+-coupled): ribavirin, acyclovir - Phosphate transporter (NPT2b; Na+-coupled): foscarnet - Sodium-dependent glucose transporter 1 (SGLT1, Na+-coupled): glucose Tertiary active transport: - Monocarboxylate transporter (MCT, H+-coupled): aspirin, valproate, pravastatin - Peptide transporter (PEPT, H+-coupled, see Fig. in Part B): -lactam antibiotics, e.g. ceftibuten; ACE inhibitors, e.g. captopril, lisinopril; valacyclovir (the antiviral acyclovir coupled to valine) - Divalent metal transporter (DMT, H+-coupled): Fe2+ (Cd2+) - Organic anion-transporting polypeptide (OATP): fexofenadine, montelukast, atenolol, aliskiren - Large neutral amino acid transporter 1 (LAT1): L-DOPA, -methyldopa, gabapentin Intestinal lumen Blood side 2K+ 11 HOOC O N HN H2N N N H valacyclovir C N O O O ADP 3Na Na NH2 N C C. ABSORPTION FROM THE SKIN S H + 2 H+ O ceftibuten H2N ATP COOH N O II. DRUGS SUITED FOR ABSORPTION FROM THE ORAL, NASAL AND RECTAL MUCOSA I. FEATURES NH2 lisinopril (ACEI) C C N H CH2 S 3 N H+ COOH O COOH X- II. INFLUENCING FACTORS 1. Chemical factors a. Lipid solubility b. Concentration 3. Receptor-mediated endocytosis: vitamin B12-IF complex; folates and methotrexate 2. Biological factors a. The thickness of stratum corneum b. Dermal circulation II. INFLUENCING FACTORS 3. The size of the exposed area D. ABSORPTION FROM THE LUNG I. FEATURES 1. Chemicals suited for pulmonary absorption 2. Mechanism and factors promoting pulmonary absorption II. OBJECTIVES FOR DRUG ADMINISTRATION BY INHALATION 1. Systemic effect 2. Local effect E. APPENDIX: More complete oral absorption and slower elimination of penicillin in neonates by folate receptor 1, FOLR1 (and also by transporters: RFTC1 and PCFT – see Part 2). Consider: The proximal small intestine (SI) has a vast absorptive surface compared to the stomach, owing to the villi on the mucosa and the microvilli of enterocytes. 1. Motility of the GI tract: gastric emptying (GE), intestinal propulsive motility (PM) Gastric emptying: determines how soon the drug reaches the proximal SI - Delayed GE caused by a fatty meal, drugs (e.g. anticholinergics), or disease (e.g. migraine) delays the onset of drug absorption. - Fastened GE caused by fasting state, intake of large volume of water, drugs (e.g. prokinetics) promotes the onset of drug absorption. Intestinal PM: determines how long the drug resides in the SI (normally for 3-4 hrs) - Sluggish motility improves the absorption of incompletely absorbed drugs (e.g. furosemide, ciprofloxacin, bisphosphonates, acyclovir, metformin, captopril, L-dopa, gabapentin) - Diarrhea may compromise the absorption of drugs, thus it may cause contraceptive failure despite taking an oral contraceptive. 2. Luminal pH Consider: Ionization, and in turn the lipid solubility and diffusibility across the lipid bilayer, of weak (but not strong) organic acids and bases depends on pH. Example: Using the Henderson-Hasselbalch equation (see Part 2), the ratio of nonionized [NI] and ionized [I] molecules of acetylsalicylic acid (aspirin, a weak acid) and amphetamine (a weak base) is calculated at the pH of the stomach, the intestine and the plasma, knowing the pKa values of these drugs and the pH at these sites. Acetylsalicylic acid, pKa = 3.5 COOH COO O C CH 3 H + O C O Amphetamine, pKa = 9.5 _ O CH 3 CH2 CH CH3 H+ NH2 [NI]/[I] = 10 pKa – pH CH2 CH CH3 + NH3 [NI]/[I] = 10 pH – pKa Remember: the non-ionized molecules are relatively lipid soluble and diffusible across the lipid bilayer of the membrane, whereas the ionized molecules are not. NON-IONIZED MOLECULES / IONIZED MOLECULES Stomach, pH = 2 Intestine, pH = 6 Plasma, pH = 7.4 Acetylsalicylic acid, pKa=3.5 32 (32:1) 0.0032 (32:10,000) 0.00012 (12:100,000) Amphetamine, pKa=9.5 0.000000032 (32:1,000,000,000) 0.00032 (32:100,000) 0.0080 (80:10,000) Implications of the calculated ratios: Absorption of weak organic acids (e.g. aspirin) may start from the stomach (because of the favorable [NI]/[I] ratio there), but is likely to be completed in the proximal SI (because of the large surface area there). Absorption of weak organic bases (e.g. amphetamine) can not start from the stomach (because of the highly unfavorable [NI]/[I] ratio there), but they are absorbed from the proximal SI (because of the large surface area there). Do not forget that [NI] and [I] molecules are in equilibrium: when NI molecules are absorbed some I molecules become NI molecules to maintain the equilibrium. As the table indicates, there is a concentration gradient for the non-ionized amphetamine between the plasma and the stomach. Therefore, amphetamine diffuses from the plasma into the stomach, where it becomes protonated, and in the cationic form it cannot diffuse back into the blood: pH entrapment. To remove amphetamine from the stomach of the amphetamine-intoxicated patient, the gastric juice is aspirated continuously. The street drug phencyclidine (PCP) behaves similarly. NOTE: Ambenonium is a long-acting cholinesterase inhibitor without CNS effects for treatment of myasthenia gravis. This disease requires prolonged therapy, therefore parenteral ambenonium is impractical. Therefore a compromise is made: the multiple of the parenteral dose of ambenonium is given orally (to compensate for its very poor GI absorption) to reach therapeutic concentration at the neuromuscular junction, where it blocks the hydrolysis of acetylcholine and improves transmission. Absorption of some drugs (e.g. erythromycin) is significantly delayed by food. This necessitates administration of erythromycin on empty stomach (or rather, its substitution with congeners that are better absorbed, e.g. clarithromycin, azithromycin). 4. Luminal content – quality Consider: Only molecules in solution can be absorbed from the GI tract, solid particles cannot! There are drugs whose dissolution requires acid (e.g. itraconazole), whereas the dissolution of others (e.g. phenytoin) is facilitated by lipids. Low acidity in the stomach. This impairs the dissolution of itraconazole, and in turn, its absorption, whereas the absorption of itraconazole is improved by taking it with an acidic beverage, such as Coca-Cola. High-fat meal. This promotes the dissolution of hydrophobic lipidsoluble drugs, such as phenytoin, cyclosporine, sirolimus, probucol, griseofulvin and ticlopidine, and in turn their absorption (see figure). However, high fat meal also decreases gastric emptying and thus may slow absorption of some drugs (e.g. zidovudine). High-protein meal. This results in 3. Luminal content – quantity Drugs are typically better absorbed from empty stomach. This is especially true for highly ionized drugs, such as the bisquaterner (di-cationic) ambenonium (see fig.) and the bisphosphonate ibandronate, which are barely absorbed from the gut, as they lack lipid solubility. Yet, their absorption is improved when these drugs are taken in the fasted state (as recommended), as compared to the non-fasted condition. NOTE: In figures on ambenonium, phenytoin and fexofenadine (see the next two pages), the plasma concentrations of drugs versus time are shown after oral dosing. For these drugs, the area under the plasma concentration vs. time after per os administration (AUCpo) is proportional to their intestinal absorption. Thus, decreased AUCpo in these figures indicates decreased intestinal absorption. high concentration of amino acids and dipeptides in the intestinal lumen, which competitively inhibit the absorption of drugs, such as - L-DOPA by the L-type amino acid transporter 1 (LAT1), and - Captopril by the peptide transporter (PEPT). High intake of fruit juices. This decreases the absorption of fexofenadine via OATP in enterocytes because bergamottin, a furocumarin in fruits and juices like grapefruit juice (GFJ), orange juice (OJ) and apple juice (AJ), inhibits OATP (see figure). Administration of non-absorbable ion-exchange resins or adsorbents: To decrease the GI absorption of some endogenous compounds (e.g. bile acids), inorganic ions and drugs may be a therapeutic objective. - Non-absorbable ion-exchange resins are used to decrease the absorption of: > Bile acids by cholestyramine, an anion-exchange resin with quaternary N atoms, which is used in hypercholesterolemia and pseudomembranous colitis. NOTE: As anion-exchange resins can bind not only the anionic bile acids but anionic drugs as well, their simultaneous administration with such drugs should be avoided. > Phosphate by sevelamer, an anion-exchange resin with -NH2 groups, which is used in renal failure to prevent hyperphosphatemia. > K+ by polystyrene sulfonate, a cation-exchange resin with sulfonate groups, which is used in hyperkalemia to lower K+ absorption. FIGURE: Plasma fexofenadine concentration-time profiles in persons (n=10) orally administered fexofenadine (120 mg) with 300 ml water, 25% grapefruit juice (25% GFJ), grapefruit juice (GFJ), orange juice (OJ), or apple juice (AJ) followed by 150 ml of the same fluid every 0.5 hr for 3 hrs. CHOLESTYRAMINE (an anion-exchange resin) decreases hypercholesterolemia by binding bile acids in the intestine CH3 CH2 CH CH2 N + H3C Cholic Acid OH O CH3 CH3 decreases the absorption of Fe2+ because these anions form insoluble salts with Fe2+. CH2 CH CH2 S _ O O n COO n _ K + CH3 CH3 High intake of Ca2+ (milk, yoghurt): Absorption of tetracyclines, fluoroquinolones (see figure) and mycophenolate mofetil is decreased by Ca2+ because these drugs form nonabsorbable chelates with Ca2+ in dairy products. The intake of Ca2+, Mg2+, Al3+, Fe2+, Bi3+ found in drugs (e.g. antacids and supplements) causes similar effects. Dietary or therapeutic calcium also impairs the absorption of strontium ranelate (used for osteoporosis) because Ca 2+ at high concentration displaces Sr2+ from its complex with ranelic acid, thus reducing its absorption. CH CH2 CH CH2 CH CH2 CH CH2 NOTES: (1) The AUCpo of some other drugs absorbed from the gut through OATP (e.g. atenolol and aliskiren) is also decreased by fruit juices. (2) As opposed to fexofenadine, the plasma concentrations of several drugs (e.g. buspirone and simvastatin) were markedly increased when taken with GFJ (their AUCpo was increased several fold – see Part 6 for more detail). This is attributed to the fact that these drugs are eliminated by CYP3A4-catalyzed biotransformation and that bergamottin and naringenin (constituents of the GFJ) are not only OATP inhibitors but also inhibitors of CYP3A4, the major form of CYP in the GI mucosa and the liver (see Part 6 for more detail). In contrast, fexofenadine is not biotransformed in the body but is excreted into bile largely unchanged. High intake of phytate, tannate, oxalate, or phosphate (vegetarian diet): POLYSTYRENE SULFONATE (a cation-exchange resin) decreases hyperkalemia by binding K+ in the intestine HO OH - Adsorbents (e.g. charcoal) are used to decrease the absorption of drugs after oral overdose. NOTE: Adsorbents (e.g. charcoal) may also be used to increase the elimination of some drugs that are sufficiently lipophilic to diffuse from the blood across the layer of intestinal epithelial cells into the gut, such as phenobarbital, carbamazepine, theophylline. Charcoal in the gut lumen can bind such a drug, thus maintaining the concentration gradient for the drug and promoting its diffusion from the capillaries into the intestine. Indeed, charcoal is given per os for days to patients intoxicated with the above-mentioned drugs in order to enhance their elimination from the body. Experimental evidence indicates that charcoal can indeed enhance the elimination of phenobarbital. In volunteers receiving i.v. phenobarbital, the elimination halflife of phenobarbital decreased from 110 hrs in control subjects to 45 hrs in subjects given charcoal repeatedly for 3 days. III. ORAL BIOAVAILABILITY (F) The major sites of presystemic elimination (with examples): 1. Definition: Oral bioavailability is the fraction (F) of the orally administered dose The intestinal mucosa; intestinal presystemic elimination may occur by: that reaches the SYSTEMIC circulation. 2. Determination of F: To determine F, in an ideal case, human subjects are given the drug in the same dose once i.v. and – and after the drug had been eliminated – once p. os. After dosing, the concentration of the drug in the plasma is repeatedly measured and plotted against time. F is calculated as shown from the areas under the plasma conc. vs. time curves (AUC). The highest value of F is 1. This indicates that the oral bioavailability of the drug is complete, i.e. 100% of the oral dose reaches the systemic circulation. If F is < 1, the oral bioavailability of the drug is incomplete. - Biotransformation catalyzed by: > CYP3A4 (the most abundant CYP in human enterocytes): cyclosporine (F = 0.3), midazolam (F = 0.4), fluticasone (F < 0.01), ergotamine (F < 0.01) > MAO-A: tyramine (For this reason, irreversible MAO-A inhibitors cause the cheese reaction.) sumatriptan (F = 0.2), zolmitriptan (F = 0.4), rizatriptan (F = 0.4) > SULT: terbutaline (F = 0.1), isoprenaline > UGT: morphine (F = 0.2), labetalol (F = 0.2) - Export from the enterocytes back into the gut via transporters, typically Pgp/MDR1 (or MRP2 and/or BCRP). Drugs exported by Pgp and their F values: F = AUCp.o. : AUCi.v. vinca alkaloids loperamide doxorubicin dabigatran 0.02 0.03 0.05 0.07 paclitaxel verapamil cyclosporine digoxin 0.07 0.2 0.3 0.6 The liver (hepatic presystemic elimination) by uptake + biotransformation: 3. Potential causes of incomplete oral bioavailability: a. Incomplete release of the drug from the tablet or capsule, as the tablet or capsule incompletely disintegrates – a problem caused by poor drug formulation. b. Degradation of the drug in the lumen (by digestive enzymes or acid) - by hydrolysis – e.g. peptides (insulin) by peptidases, esters (Ach, procaine) by esterases, amides (penicillin by gastric acid – see Appendix): lack of acid in the neonatal stomach results in high oral bioavailability of penicillin in newborn babies. - by oxidation – e.g. catecholamines (are spontaneously oxidized to quinones) c. Poor solubility of the drug in the intestinal fluids. Poor dissolution can limit the absorption of some drugs (e.g. phenytoin and itraconazole), as mentioned above. d. Poor diffusibility of the drug across the mucosa (highly ionized drugs) - Strong acids: bisphosphonates, cromoglycate, suramin, deferoxamine, EDTA - Strong bases: aminoglycosides (cont. protonated NH2 groups), tubocurarine (quat. N) NOTE: Because these drugs are very poorly absorbed from the GI tract, their oral dose must be increased several fold over their i.v. dose in order to reach therapeutic blood levels after per os administration. For example: - Neostigmine (cholinesterase inhibitor): i.v.: 0.5 mg, per os: 30 mg - Pyridostigmine (cholinesterase inhibitor): i.v.: 1 mg, per os: 60 mg - Ibandronate (bisphosphonate, for osteoporosis): i.v.: 3 mg once in every 3 months per os: 150 mg once a month e. Presystemic elimination of the drug (= first pass elimination) Consider: Before reaching the systemic circulation, an orally administered drug passes through the intestinal mucosal epithelial cell layer (to reach the portal blood), then the liver (to reach the inferior v. cava), and finally the lung. At each of these sites drug molecules may be eliminated even before reaching the systemic circulation which carries most drugs to the site of their pharmacologic action. Most typically, such presystemic elimination takes place in the enterocytes and the liver. - verapamil: lidocaine: propranolol: nitroglycerin: by CYP, via N-demethylation (F = 0.2; i.v. dose 5 mg, p.o. 40-80 mg) by CYP, via N-deethylation (F = 0.3) by CYP, via aromatic hydroxylation and N-dealkylation (F = 0.3) by organic nitrate reductase, aldehyde dehydrogenase (?) (F < 0.01) Both the intestinal mucosa and the liver, e.g.: - morphine: by glucuronidation in both the enterocytes and liver (F = 0.2) - buspirone: by CYP3A4-catalyzed N-dealkyl. in enterocytes and liver (F = 0.05) - cyclosporine: by Pgp-mediated export from the enterocytes and CYP3A4-catalyzed hydroxylation in enterocytes and liver (F = 0.3) - ergotamine: by Pgp-mediated export from the enterocytes and CYP3A4-catalyzed oxidation in enterocytes and liver (F < 0.01) 4. Consequences of low oral bioavailability: Low F is unfavorable for drugs that reach their site of action by the systemic circulation (i.e. for most drugs). Some of these drugs (e.g. vinblastine, doxorubicin, paclitaxel) must be used only parenterally. Others can still be given orally (e.g. nitroglycerin, verapamil, dabigatran), however, at a dose much higher than the dose that would be effective if the F value were close to 1. Low F may be favorable for drugs whose target site is presystemic. Examples: - High presystemic elimination by hepatic uptake via OATP1B1 is favorable for HMG-CoA reductase inhibitors (e.g. simvastatin, pravastatin) for two reasons: (1) it directs statins into the liver, their major site of therapeutic action, and (2) it diverts statins from the skeletal muscles, the site of their myotoxic action. - Poor GI absorption and export by Pgp from the enterocytes back to the gut may contribute to maintenance of high intestinal (and low systemic) drug concentration. This may be beneficial for drugs that act on/in the GI tract (e.g. the GI spasmolytic pinaverium bromide and methylhomatropine, the anti-inflammatory mesalazine, the obstipant loperamide, the anthelminthic ivermectin, and the antibiotic vancomycin for pseudomembranous colitis). Pgp (MDR1) works as an exporter at multiple sites: e.g. vincristine and vinblastine (can be given only parenterally) B. ABSORPTION FROM THE ORAL, NASAL AND RECTAL MUCOSA I. COMMON FEATURES 1. Mechanism: diffusion 2. Small absorptive surface area 3. Drugs are not exposed to HCl and high concentration of digestive enzymes 4. Drugs avoid the intestinal mucosa and the liver, thus are not subjected to intestinal and hepatic presystemic elimination. II. FORMULATIONS AND DRUGS suited for absorption from the: ORAL CAVITY e.g. digoxin (excreted by renal tubular secretion) (can be given only parenterally Formulation: sublingual (buccal) tablet, spray Drugs given sublingually for systemic effect: relatively lipophilic compounds e.g.: - Nitroglycerine – for angina - Fentanyl – for pain in cancer patients - Prochlorperazine – to relieve nausea in migraine NASAL CAVITY Formulation: nasal spray Drugs given nasally for systemic effect: a. Oligopeptides (diffuse across the mucosa by the paracellular route): e.g.: - Desmopressin – an ADH analogue, for diabetes insipidus - Oxytocin – to promote lactation (milk ejection) - Calcitonin – in osteoporosis and hypercalcemia - Buserelin – an LH-RH analogue, for prostatic cancer e.g. loperamide (IMODIUM) (an opioid which cannot enter the brain but can act on the gut as an antidiarrheal drug) b. Non-peptide drugs: e.g.: - Butorphanol – an opioid; for analgesic effect - Sumatriptan – an 5HT1D receptor agonist, used in migraine attack - Estradiol – in menopause, osteoporosis - Cyanocobalamin – given when vitamin B12 is not absorbed from the gut RECTUM Formulations: rectal suppository, enema Drugs given rectally for systemic effect when: - oral administration is difficult (babies, vomiting), - exposure of the gastric mucosa or the liver to high concentrations of the drug is undesirable (gastric ulcer, liver disease), - oral dosing results in very high presystemic (first pass) elimination of the drug, e.g. ergotamine (see the figure on the next page). FIGURE: Ergotamine (used to relieve migraine) reaches 10 times higher blood levels after rectal administration than after oral dosing. C. ABSORPTION FROM THE SKIN ERGOTAMINE IN PLASMA (pg/ml) I. FEATURES 100 1. Operative for drugs that are applied to the skin in: a. Dusting powders, solutions, ointments – for topical effects b. Transdermal patches – for systemic effects 2. Mechanism: diffusion; the main barrier is stratum corneum 2 mg ergotamine rectally after cleansing enema II. INFLUENCING FACTORS 1. CHEMICAL FACTORS a. Lipid solubility Unlike hydrophilic anesthetics, e.g. procaine, lipid soluble local anesthetics, e.g. tetracaine, are useful for surface anesthesia because they more readily diffuse through the epidermis to reach the sensory nerve endings in the dermis. 10 1 2 mg ergotamine orally to fasted patients From: Sanders et al. Eur. J. Clin. Pharm. 30: 331, 1986. 0.1 0 2 4 6 8 10 12 14 16 18 20 22 O Procaine H2N C O CH2 CH2 C2H5 N 24 TIME AFTER ERGOTAMINE ADMINISTRATION (hrs) C2H5 H CH3 CH2 CH2 CH2 N NOTE: Poor oral bioavailability of ergotamine is thought to be due to its intestinal and hepatic presystemic elimination. This appears to originate from its (1) intestinal and hepatic biotransformation by CYP3A4 (the predominant form of CYP in both hepato- and enterocytes) and (2) export by P-glycoprotein (Pgp) from the enterocytes into the gut. Several drugs that are inhibitors of CYP3A4 or Pgp or both, such as erythromycin, verapamil and ritonavir (a HIV protease inhibitor), may cause ergotism in patients treated with these drugs and who also receive ergotamine. Ergotism is characterized by signs of peripheral ischemia (headache, intermittent claudication, muscle pain, numbness, coldness and pallor of the extremities; gangrene may occur). Ergotamine is a vasoconstrictor due to its 5HT1 and α1-adrenoceptor agonistic actions and it has a beneficial effect in migraine attack. O C O CH2 CH2 CH3 N CH3 Tetracaine is lipophilic due to the 4 C-atom-long aliphatic chain linked to the p-amino group. Drugs that are both lipid soluble and potent enough can be administered in topical patches for systemic effects. Examples: nitroglycerin, scopolamine, nicotine, fentanyl, lidocaine, estradiol, testosterone, rotigotine. To make some acidic NSAIDs suitable for use in subdermal inflammations (e.g. tendinitis) in topical preparations, the –COOH group in such drug is esterified with an alcohol in order to make the drug more lipophilic and diffusible through the skin. Examples: - salicylic acid + methanol methylsalicylate - flufenamic acid + ethylene glycol etofenamate (may be used in a topical gel) Lipid soluble chemicals may cause intoxication upon dermal exposure. Examples: OP insecticides, hexane (a solvent), pentachlorophenol (a fungicide). b. Concentration (as the driving force for dermal absorption) A tragic example: Severe and fatal intoxications with encephalopathy resulted in the past in France when a 6%-hexachlorophene powder was accidentally manufactured and used on babies as dusting powder. (The antiseptic concentration of hexachlorophene is 0.5-1%; hexachlorophene is no longer used due to its unavoidable contamination with dioxin, also called TCDD.) 2. BIOLOGIC FACTORS a. The thickness of stratum corneum (as the main diffusion barrier) determines the degree of dermal absorption of drugs and other chemicals – see table: AREA RELATIVE ABSORPTION OF C14-CORTISOL sole palm arm back scalp armpit forehead submandibular area scrotum 1 6 7 12 25 26 43 93 300 Examples demonstrating the significance of the thickness of str. corneum: Scrotum cancer was prevalent in chimney sweeps, as described by Sir Percival Pott in 1775. The causative chemicals are polycyclic aromatic hydrocarbons, which diffuse into the keratocytes readily in the skin of the scrotum where, the str. corneum is lacking (table above). In infants (whose skin does not contain str. corneum) intoxications with chemicals have been caused through dermal exposure. Historical examples: - Pentachlorophenol (PCP): lethal intoxications by PCP-contaminated diapers St. Louis, MO, 1967: As a fungicide, PCP was added to the rinsing water of the diapers. - Warfarin: lethal intoxications by warfarin in baby dusting powder Saigon, 1981: 177 babies died of hemorrhages caused by a baby dusting powder which contained warfarin by mistake. b. Dermal circulation – increased by heating and rubbing Examples demonstrating the significance of dermal circulation: Taking sauna increases drug absorption from a topical patch. D. ABSORPTION FROM THE LUNG I. FEATURES 1. Chemicals suited for pulmonary absorption – inhalable substances: a. Gases (therapeutic: e.g. N2O, CO2; toxic: e.g. CO, HCN, H2S) b. Vapors of liquids (therapeutic: e.g. amyl nitrite, desflurane; toxic: e.g. organic solvents, metallic Hg) c. Vaporized solutions (e.g. terbutaline solution – although absorption is undesirable) d. Small particle-size powder (e.g. insulin) 2. Mechanism: diffusion, which is influenced by: a. Chemical factors: Inhaled concentration: Among others, the inhaled concentration determines the onset of anesthetic effect of an inhalation anesthetic (i.e. the speed of induction). Lipid solubility: The degree of lipid solubility determines (in part by influencing pulmonary absorption) the potency of inhalation anesthetics. b. Biological factors – the pulmonary absorption of compounds is promoted by: The huge absorptive surface area (the alveolar surface is ~100 m2) The small diffusion distance across the type-I pneumocytes (~0.5 m) The large pulmonary blood flow (= cardiac output) These extremely favorable biological factors permit sufficient transport even for large peptides, such as insulin (6 kDa), from the alveolar space into the pulmonary blood. Indeed, in 2014 US FDA approved Afrezza (rapid-acting insulin inhalation powder with particle size of 1 μm or less) for treatment of diabetes. II. OBJECTIVES of drug administration by inhalation In hot weather pesticide sprayers are more likely intoxicated than in mild weather. 1. SYSTEMIC EFFECT – alveolar absorption is desirable Rubbing, when decontaminating the skin, may increase the dermal absorption of a contaminant. So, do not rub the skin when decontaminating the skin of a sprayer! Examples: - Inhalation anesthetics (gases, e.g. N2O; vapors, e.g. sevoflurane) - Amyl nitrite for angina Inflammation: in addition to the higher dermal circulation other factors may also contribute to increased dermal absorption of drugs in dermatitis. 2. LOCAL EFFECT on the bronchial mucosa or smooth muscle In this case alveolar absorption of the drug is undesirable! 3. THE SIZE OF THE EXPOSED AREA Examples demonstrating the significance of the exposed area: Infants are susceptible for intoxications by dermal exposure (see above) not only because of the lack of str. corneum, but also because they have large body surface relative to their body weight. The size of topical patch (e.g. 20-30-40 cm2) determines the dose rate of a drug administered in a transdermal patch. By increasing or decreasing the size of the patch, one can increase or decrease the dose rate proportionately. Examples for inhaled solutions as antiasthmatics: Bronchodilator spray (e.g. terbutaline, fenoterol in combination with ipratropium) Glucocorticoid spray (e.g. beclomethasone, budenoside, fluticasone) The fluid droplet or particle size determines the site of deposition: >10 μm: deposition in the upper airways 1-5 μm: deposition in the bronchioles – desirable for asthmatic patients. <1 μm: passage to the alveolar space, from where the drug is readily absorbed and then causes systemic effect – undesirable for asthmatic patients. E. APPENDIX Penicillin is more completely absorbed and more slowly eliminated in neonates than in children On oral administration of penicillin G (benzylpenicillin; 22,000 units/kg) the AUC0-6hr was found to be 7-fold larger in neonates than in children (Huang and High, J. Pediatr. 42: 658-668, 1953; see the left figure). This is attributed to two pharmacokinetic alterations in the neonatal age. 1. In the newborn, the oral bioavailability of penicillin G is much higher than in children or adults. This is due to lacking hydrochloric acid secretion in the neonatal stomach. Benzylpenicillin is acidlabile, i.e. the amide bond in the four-membered -lactam ring undergoes hydrolysis in the gastric acid. In the absence of HCl from the newborn stomach, penicillin is not degraded, therefore it is orally bioavailable. When gastric acid secretion starts (a few days after birth) penicillin becomes degraded in the stomach, resulting in its low oral bioavailability. 2. In the newborn, the elimination of penicillin G is much slower than in children or adults. Benzylpenicillin is eliminated by renal excretion, i.e. glomerular filtration and tubular secretion. As an organic acid, penicillin is taken up into proximal convoluted tubular cells by OAT1 (a tertiary active transporter; see under Transport mechanisms), and exported across the luminal membrane (by the primary active MRP4 and/or the exchanger OAT4) into the tubular fluid. In the newborn, the renal excretory function is immature: both the GFR and the capacity of tubular secretion is low (the latter is due to diminished expression of transporters). The figure on the right indicates, that elimination of penicillin G (22,000 units/kg) after intramuscular injection is slower in neonates as compared to children, resulting in approximately 4-fold longer elimination half-life of penicillin in the babies than in children above 2 years of age (Huang and High, J. Pediatr. 42: 658-668, 1953).