Basic Pharmacology Lecture 2 PDF

ABSORPTION Absorption is the transfer of a drug from its site of administration to the blood stream.  PHARMACOKINETICS Transport of drug from the GIT Depending on their chemical properties, drugs may be absorbed from the GI tract by either passive diffusion or active transport....

ABSORPTION Absorption is the transfer of a drug from its site of administration to the blood stream.  PHARMACOKINETICS Transport of drug from the GIT Depending on their chemical properties, drugs may be absorbed from the GI tract by either passive diffusion or active transport. 1- Passive diffusion: The drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier. Most of drugs are absorbed by this mechanism.  Types of passive diffusion Aqueous diffusion: low molecular weight and water soluble drugs can diffuse through aqueous channels or pores in cell membrane (filtration). Lipid diffusion: low molecular weight and lipid soluble drugs are absorbed via diffusion through lipid cell membrane itself. 2- Facilitated diffusion: In facilitated diffusion a carrier facilitates the passage of the drug through the membrane. Passage of the drug continues until its concentration is equal on both sides of the membrane. No energy is required. 3- Active transport: Drug entry involves specific carrier proteins that span the membrane. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate (ATP). Drug is moved against concentration gradient (i.e. From a region of low drug concentration to one of higher drug concentration). 4- Endocytosis and exocytosis: This type of drug delivery transports drugs of exceptionally large size across the cell membrane Endocytosis : Uptake of membrane-bound particles. involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. # For example, vitamin B12 is transported across the gut wall by endocytosis. Exocytosis : expulsion of membrane-bound particles It is the reverse of endocytosis and is used by cells to secrete many substances by a similar vesicle formation process. # For example: Certain neurotransmitters (for example, norepinephrine) are stored in membrane-bound vesicles in the nerve terminal and are released by exocytosis  Remember Mechanisms of drug Absorption The transport of drugs across cell membrane occurs through one or more of the following processes: 1. Simple diffusion = passive diffusion. 2. Active transport. 3. Facilitated diffusion. 4. Pinocytosis (Endocytosis).  PH effect and Passive diffusion Most drugs are weak acids or weak bases. Drugs can exist in two forms ionized (water soluble) & unionized forms (lipid soluble) in equilibrium. Only unionized form is absorbable. Ionization of drugs reduce passage of drugs across cell membranes. The degree of ionization of drugs is determined by their pKa and pH of the surrounding.  Pka of the drug (Dissociation or ionization constant): pH at which Half of the substance is ionized & half is unionized  Weak acids such as acetylsalicylic acid ( Aspirin) are readily absorbed from acid medium because they are less ionized in this medium. On the other hand, weak acids are difficultly absorbed from alkaline medium because they are more ionized in alkaline medium. Weak bases such as amphetamine or morphine are readily absorbed from alkaline medium because they are less ionized in this medium. On the other hand, weak bases are less readily absorbed from acid medium because they are more ionized in this medium. Strongly ionized drugs such as streptomycin and hexamethonium are poorly absorbed. N.B. Usually drugs are absorbed from GI tract by passive diffusion with few exceptions.  FACTORS AFFECTING ABSORPTION: 1.- Blood flow to the absorption site:: absorption is less in shock and CHF. [Note: shock severely reduces blood flow to cutaneous tissues, thus minimizing the absorption from SC administration.] Blood flow to the intestine is much greater than the flow to the stomach; thus, absorption from the intestine is favored over that from the stomach. 2- Total surface area available for absorption: Absorption is more efficient from intestine than from stomach. Because, the intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach; thus, absorption of the drug across the intestine is more efficient. 3- Gastric emptying and Contact time at the absorption surface: If a drug moves through the GIT tract very quickly, as in severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: parasympathetic input increases the rate of gastric emptying, whereas sympathetic input ( by exercise or stressful emotions), as well as anticholinergics (for example, atropine), prolongs the onset time of the drug ( decrease the rate of)  Gastric Emptying Time Anatomically, a swallowed drug rapidly reaches the stomach. Eventually, the stomach empties its content in the small intestine. Because the duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach the duodenum will slow the rate of drug absorption, thereby prolonging the onset time for the drug. Some drugs, such as penicillin are unstable in acid and decompose if stomach emptying is delayed (prolonged contact with stomach). Other drugs, such as aspirin, may irritate the gastric mucosa during prolonged contact. 4- Ingestion of drugs with food: - The presence of food in the stomach delays gastric emptying, so ✓drugs that are destroyed by acid (for example, penicillin) become unavailable for absorption ✓ Other drugs Taken with a meal are generally absorbed more slowly. Note: enteric coating of a drug 1. protects it from the acidic environment; 2. The coating may prevent gastric Irritation 3. The release of the drug may be prolonged, producing a sustained release effect. 5- Solubility of the drug and degree of ionization: Very hydrophilic (Lipophobic) drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Thus, Non-ionized, lipophilic drugs are readily absorbed. Ionized drugs cannot cross lipid membranes drugs that are extremely Lipophilic (hydrophobic) are also poorly absorbed, because they are totally insoluble in aqueous body fluids. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin. Fentanyl more lipophilic than morphine Fentanyl is a synthetic opioid with higher lipophilicity compared to morphine. This higher lipid solubility allows fentanyl to cross the blood–cerebrospinal fluid barrier (BBB) more rapidly and produce analgesic effects more quickly than morphine. 6- first-pass hepatic metabolism: when a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. if the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation.  More than 90% of oral nitro glycerin is exposed to first pass effect in the liver, which is the primary reason why this agent is administered via the sublingual route]. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration.  Remember First pass effect Also known as PRESYSTEMIC METABOLISM, refers to the metabolism of drugs or chemicals in liver prior to their reaching the systemic circulation. FIRST PASS METABOLISM RESULTS IN: Low bioavailability (low conc. of drug in blood). Short duration of action (t ½). drugs with high first pass effect should not be given orally but parenterally. 7- Chemical instability: Some drugs, such as penicillin G, are unstable in the PH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. 8- Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, increase the rate of absorption.  Bioavailability bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged (Active) form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. NB: Bioavailability express the extent of absorption  Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection in which all of the agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug. [Note: by definition, this is 100 % for drugs delivered IV.]  REMEMBER Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for iv injection 1. Plasma conc-time graph for the drug after oral and iv administration is plotted. 2. The area under the curve (auc) is measured. Bioavailability = auc (oral) x 100 auc (iv)  Bioequivalence ❖Two related drugs are bioequivalent if they show comparable bioavailability. ❖Two related drugs with a significant difference in bioavailability are said to be bioinequivalent ❖ Usually a difference in AUCs more than 20% results in bioinequivalence.  Therapeutic equivalence ❑ Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.  BIOAVAILABILITY STUDIES IMPORTANCE: ◼ Bioavailabilitystudies provide an estimate of the fraction of the orally administered dose that is absorbed into the systemic circulation when compared to the bioavailability for an intravenous dosage form that is completely available ◼ Bioavailability studies provide other useful information that is important to establish dosage regimens. (The dosage regimen is the schedule of doses of a medicine, including the time between doses, the duration of treatment and the amount to be taken each time) ◼ Bioavailability studies provide indirect information regarding the presystemic and systemic metabolism of the drugs.  BIOAVAILABILITY STUDIES IMPORTANCE: ◼ Bioavailability studies designed to study the food effect on drug absorption ◼ Such studies when designed appropriately provide information on the linearity or nonlinearity in the pharmacokinetics of the drug and the dose proportionality ◼ Bioavailability studies provide information regarding the performance of the formulation and subsequently are a means to document product quality