Problem 2_Pharmacology.pdf

This week’s problems… from outside anything given an source is a drug. Problem one (infant) : excess output Problem two (man) : reduced input both treated by...

This week’s problems… from outside anything given an source is a drug. Problem one (infant) : excess output Problem two (man) : reduced input both treated by : IV fluid that contains glucose 1 Pharmacokinetic principles Prof. Kannan Sridharan Department of Pharmacology & Therapeutics CMHS, AGU. 2  AlME/movement EffECI effect observed drug - movement in the body in the -now distributed body following the drug is administration of in the body the drug Two effects I wanted therapeutic. unwanted 2 (side effects) Pharmacokinetics is the branch of pharmacology (study of medicine) that deals with how drugs move through the body. If we split the term pharmacokinetics. In Greek, “Pharmakon” means drug (or medicine), and “kinetics” implies movement. In other words, pharmacokinetics is simply a movement of medicine in the body. Pharmacodynamics on the other hand refers to the power of the drug – meaning the effect produced by the administered drug. 3  Routes of drug administration Topical route Most common route most common route - orally 4 absorption metabolism - bution etcretion Unit V Unit V Pharmacokinetics include ADME – absorption, distribution, metabolism, and excretion. In this unit, we will be discussing only the absorption and distribution. stays in the stomach drug horrs for about 4 5  Drug concentration (blood) versus time curve time drug takes to T reach concentration Tmax Cmax maximum concentration acheived with close a single of drug Plasma drug concentration increases with extent of absorption; the maximum (peak) plasma concentration is reached when drug elimination rate equals absorption rate. absorption Plasma concentration Peak : drugelimination = drug concentration increase with extent of absorption 6  20 mg/ml 20 Drug 15 Concentration (µg/ml) 10 Shus 5 0 2 4 6 8 10 Time (h) 7 Arc : curve more Auc , more exposure area under the Area under the plasma drug concentration- time curve (AUC) The area under the plasma drug concentration-time curve (AUC) reflects the extent of body exposure to drug after administration of a dose of the drug. to what extent is the body getting exposed to the drug 8  A B 5 mg 10 mg smallest Auc The AUC is directly proportional to the dose. C 20 mg biggest Auz The AUC is directly proportional to the dose. more Auc more dose 9  same close but to two different individuals 20 A 20 B Steep mg/L Predominent mg/L Predominent elimentation absorption very fast very slow 0 0 5 mg dose of a drug 5 mg dose of the same drug The AUC is inversely proportional to the elimination. A smaller Auc B. Bigger AVC for Patient A we will increase close and for B we will decrease 10  20 concentration (mg/L) A Plasma drug 0 2 4 6 8 10 Time (h) B - Shorter T max concentration (mg/L) higher - 2 max - smaller Arc 10 Plasma drug - faster elimination 0 2 4 6 8 10 12 14 16 18 Time (h) slowly getting absorbed 11  Drug concentration (blood) versus time curve following bolus intravenous administration No element of drug absorption Following IV bolus administration, there is no absorption element of drugs. When given drug Intravenously : once I. bolus entire dose given like administering drug in bag (takes time 2. Infusion - bolus : Immediate (max 12  Factors determining oral drug absorption Drug-related Individual-related Drug formulation oral in drugs mostly tablets form Absorptive surface area & pH of Molecular size gut Lipid solubility Food intake Ionization status To be absorbed, a drug given orally must survive encounters with low pH and numerous gastrointestinal (GI) secretions, including potentially degrading enzymes. Peptide drugs (eg, insulin) are particularly susceptible to degradation and are not given orally. Absorption of oral drugs involves transport across membranes of the epithelial cells in the GI tract. Absorption is affected by Differences in luminal pH along the GI tract Surface area per luminal volume Blood perfusion The stomach is normally the first organ in which intense contact between a drug given orally and GI fluids occurs (for review, see [ 1]). Although the stomach has a relatively large epithelial surface, its thick mucous layer and short transit time limit drug absorption. These properties of the stomach can influence drug formulation and behavior. Because most absorption occurs in the small intestine, gastric emptying is often the rate-limiting step. Food, especially fatty food, slows gastric emptying (and rate of drug absorption), explaining why taking some drugs on an empty stomach speeds absorption. Drugs that affect gastric emptying (eg, parasympatholytic drugs) affect the absorption rate of other drugs. Food 13 may enhance the extent of absorption for poorly soluble drugs (eg, griseofulvin), reduce it for drugs degraded in the stomach (eg, penicillin G), or have little or no effect. The small intestine has the largest surface area for drug absorption in the GI tract, and its membranes are more permeable than those in the stomach. For these reasons, most drugs are absorbed primarily in the small intestine, and acids, despite their ability as un-ionized drugs to readily cross membranes, are absorbed faster in the intestine than in the stomach (for review, see [ 1]). The intraluminal pH is 4 to 5 in the duodenum but becomes progressively more alkaline, approaching 8 in the lower ileum. GI microflora may reduce absorption. Decreased blood flow (eg, in shock) may lower the concentration gradient across the intestinal mucosa and reduce absorption by passive diffusion. Intestinal transit time can influence drug absorption, particularly for drugs that are absorbed by active transport (eg, B vitamins), that dissolve slowly (eg, griseofulvin), or that are polar (ie, with low lipid solubility; eg, many antibiotics). To maximize adherence, clinicians should prescribe oral suspensions and chewable tablets for children < 8 years of age. In adolescents and adults, most drugs are given orally as tablets or capsules primarily for convenience, economy, stability, and patient acceptance. Because solid drug forms must dissolve before absorption can occur, dissolution rate determines availability of the drug for absorption. Dissolution, if slower than absorption, becomes the rate-limiting step. Manipulating the formulation (ie, the drug’s form as salt, crystal, or hydrate) can change the dissolution rate and thus control overall absorption. 13  Oral drug formulations Solid dosage formulations Liquid dosage formulation Tablets, capsules are referred to as solid dosage formulations while syrups are liquid dosage formulations. Tables are inexpensive, simple, and may be split when partial doses are required. Capsules have drug covered by hard shells to protect the drug from getting degraded in the stomach acid. Liquid dosage preparations contain the drug in solution and are easy to be administered in children. Capsules are covered so stomach acd doesn't degrade It. ORS : Oral rehydration solution , contains electrolytes lost 14  Disintegration & Dissolution of oral drugs Dosage formulations (eg, tablets, capsules, solutions), consisting of the drug plus other ingredients, are formulated to be given by various routes. Regardless of the route of administration, drugs must be in solution to be absorbed. Thus, solid forms (eg, tablets) must be able to disintegrate and dissolute. If drug administered solid , slower to reach systemic circulation Syrup faster absorbed than tablets 15  Factors affecting oral drug absorption Drug-related Individual-related Drug formulation Absorptive surface area & pH of Molecular size gut Lipid solubility Food intake Ionization status Molecular size of the drug is inversely proportional to the drug absorption. Hence, smaller the size, better is the absorption. 16 Peptide molecules such as insulin are destroyed by digestive enzymes and so extremely challenging to be administered orally. 17  Factors affecting oral drug absorption Drug-related Individual-related Drug formulation Absorptive surface area & pH of Molecular size gut Lipid solubility Food intake Ionization status Lipid solubility of a drug is directly proportional to drug absorption. absorption the more soluble , the better 18  More the lipid solubility, better is the drug absorption Drugs have to cross the cell membranes for absorption. Hence, as the cell Phospholipid bilayer membranes consist of phospholipid bilayer, drugs have to cross this layer for entering the cells and hence they have to be lipid soluble for better absorption. If drug is hydrophilic , never given orally because It will be hard to pass 19 Factors affecting oral drug absorption Drug-related Individual-related Drug formulation Absorptive surface area & pH of Molecular size gut Lipid solubility Food intake Ionization status 20  Lesser the ionization of drug, better the lipid solubility and hence, better is the absorption The proportion of the un-ionized form present (and thus the drug’s ability to cross a membrane) is determined by the environmental pH and the drug’s pKa (acid dissociation constant). The pKa is the pH at which concentrations of ionized and un-ionized forms are equal. Ionized charged drugs given orally either I. weakly acidic 2. weakly basic smore lipid Solubility un-ionized or uncharged easily cross phospholipid drugs bilayer 21 When the pH is lower than the pKa (more acidic environment), the un- ionized form of a weak acid predominates, but the ionized form of a weak base predominates. Vice versa happens with the weakly basic drugs. not understood 22  Acidic drugs tend to remain unionized in stomach Basic drugs tend to remain unionized in intestines Therefore, when a weak acid is given orally, most of the drug in the stomach is un-ionized, favoring diffusion through the gastric mucosa. For a weak base, the outcome is reversed; most of the drug in the stomach is ionized. Theoretically, weakly acidic drugs (eg, aspirin) are more readily absorbed from an acid medium (stomach) than are weakly basic drugs (eg, quinidine). However, whether a drug is acidic or basic, most absorption occurs in the small intestine because the surface area is larger and membranes are more permeable. weal acid absorbed better in stomach weak base absorbed better in small intestine 23  Factors affecting oral drug absorption Drug-related Individual-related Drug formulation Absorptive surface area & pH of Molecular size gut Lipid solubility Food intake Ionization status To be absorbed, a drug given orally must survive encounters with low pH and numerous gastrointestinal (GI) secretions, including potentially degrading enzymes. Peptide drugs (eg, insulin) are particularly susceptible to degradation and are not given orally. Absorption of oral drugs involves transport across membranes of the epithelial cells in the GI tract. Absorption is affected by Differences in luminal pH along the GI tract Surface area per luminal volume Blood perfusion 24  Surface area for absorption is larger (several-folds) in small intestines compared to stomach. Both the weakly acidic and weakly basic drugs get absorbed better from small intestines. The stomach is normally the first organ in which intense contact between a drug given orally and GI fluids occurs. Although the stomach has a relatively large epithelial surface, its thick mucous layer, relatively less blood flow, and a short transit time that limits drug absorption. However, due to villi that increases the surface area of the intestines, and more blood flow, and more permeability of the mucosa, drugs get better absorbed from the small intestines. small intestine : Villi increases surface area in intestine. major site of drug absorption drugs absorbed mostly in small Intestines not stomach because of villi 25  Factors affecting oral drug absorption Drug-related Individual-related Drug formulation Absorptive surface area & pH of Molecular size gut Lipid water solubility Food intake Ionization status Food, especially fatty food, slows gastric emptying (and rate of drug absorption), explaining why taking some drugs on an empty stomach speeds absorption. Food may enhance the extent of absorption for poorly soluble drugs (eg, griseofulvin), reduce it for drugs degraded in the stomach (eg, penicillin G), or have little or no effect. ↓ some drugs better absorbed when theres no Intake food z some drugs better absorbed. when given a fatty food ↳ peanut butter before accutane thesedrugsare reada fat 26  All the administered drug reaches systemic circulation following the intravenous route. Incomplete absorption is noted in all other routes. Bioavailability = Quantity of drug absorbed/Quantity of drug administered Drug absorption following IV administration is rapid and almost 100%. In other routes, some time is taken and only a certain fraction gets absorbed into the systemic circulation. bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. 27  Calculate the bioavailability of this drug Dose administered: 100 mg Dose absorbed: 50 mg When long is administered and only 50 my is absorbed Bioavailability = Quantity of the bloavailability is 50 % drug absorbed/Quantity of 100 + 50 = 0. 5x100 = 50 % drug administered. = 50/100 = 0.5 or 50% 28 Drug bioavailability: Clinical relevance Better bioavailability = Better therapeutic effect. Drugs with poor bioavailability Needs to be administered at higher doses Or Administered through other routes (parenteral/rectal). 29 Drug absorption Definition Drug-plasma concentration versus time curve Routes of drug administration - Oral Factors affecting oral drug absorption – Drug formulations, Molecular size, Lipophilicity, surface area & pH of GIT Bioavailability 30