General Pharmacology PDF

General pharmacology By Omran Attir Dec 2023 1  Introduction  Pharmacology is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function....

General pharmacology By Omran Attir Dec 2023 1  Introduction  Pharmacology is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.  Drug is a chemical substance that is used to treat, diagnose or prevent (prophylaxis) a disease.  Pharmacology as a chemical science is practiced by pharmacologists. Sub- divided into  Clinical pharmacology : medication effects on humans  Neuro- and psychopharmacology : effects of medication on behavior and nervous system functioning.  Pharmacogenetics : clinical testing of genetic for therapeutic purposes  Pharmacogenomics: application of genomic technologies to new drug discovery  Pharmacoepidemiology study of effects of drugs in large numbers of people 2  Introduction  Toxicology: study of the harmful effects of drugs that involves the study of the adverse effects and the practice of diagnosing and treating exposures to toxins and toxicants.  Also Pharmacology can be subdivided into : Pharmacokinetics Pharmacodynamics  Pharmacokinetics it is what the body does to the drug it deals with ADME (absorption, distribution, metabolism and excretion)  Pharmacodynamics it is what the drug does to the body it deals with pharmacological actions of the drugs and its mechanism by which theses actions performed Routes of drug administration  Different routs of administration can be determined by:  The properties of the drug (such as water or lipid solubility, ionization, etc.) 3  Routes of drug administration  The therapeutic objectives (for example, the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site). A. Enteral , it is divided into : 1. Oral:  it is most common used rout.  Most drugs absorbed from the gastrointestinal (GI) tract enter the portal circulation and encounter the liver before they are distributed in the general circulation.  First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. e.g. more than 90% of nitroglycerin is cleared during a single passage through the liver.  Some drugs can be destroyed by gastric acid and enzymes because the presence of food so it becomes unavailable for absorption such as insulin and penicillin. Unconscious, emergency and vomiting patients limited the use of this pathway 4 Routes of drug administration 2. Sublingual:  Placement under the tongue allows the drug to diffuse into the capillary network and therefore to enter the systemic circulation directly.  Administration of an agent by this route has the advantage that the drug bypasses the intestine and liver and is not inactivated by metabolism. 3. Rectal:  50% of the drainage of the rectal region bypasses the portal circulation; thus, the biotransformation of drugs by the liver is minimized.  Both the sublingual and the rectal routes of administration have the additional advantage that they prevent the destruction of the drug by intestinal enzymes or by low pH in the stomach.  The rectal route also is commonly used to administer antiemetic agents 5 Routes of drug administration B. Parentral  Parenteral administration is used for drugs that are poorly absorbed from the gastrointestinal (GI) tract, and for agents such as insulin that are unstable in the GI tract.  Parenteral administration is also used for treatment of unconscious patients and under circumstances that require a rapid onset of action.  Parenteral administration provides the most control over the actual dose of drug delivered to the body.  The three major parenteral routes are according to the site of injection that give different rates of absorption : 1. Intravascular: Intravenous (IV) #Advantages: - Avoid first-pass metabolism - Avoid gastric secretions - High drug conc. In blood - Rapid onset of action 6 Routes of drug administration #Disadvantages: - Contamination - Pain 2. Intramuscular (IM):  Injection of drug in muscle.  Absorption of drugs in aqueous solution is fast.  Whereas that from depot preparations is slow. 3. Subcutaneous (SC):  SC injection minimizes the risks associated with intravascular injection.  Little amounts of epinephrine are sometimes combined with a drug to restrict its area of action.  Epinephrine acts as a local vasoconstrictor and decreases removal of a drug. 7 Routes of drug administration  E.g some drugs or programmable mechanical pumps that can be implanted to deliver insulin in some diabetics. 4. Intradermal (I.D):  Not common  An injection of very small volume (0.1 ml)  Site between the dermis and epidermis  E.g BCG vaccination 5. Intraarticular inj  The injection of the drug in the joints 6. Intracardiac inj  Such as injection of adrenaline in cardiac muscle in treatment of cardiac arrest 8 Routes of drug administration C. Other 1. Inhalation:  The drug is absorbed through the lung  Because of the large surface area of the lung, drugs are absorbed as rapidly as by intravenous injection which pass directly to systemic circulation.  This route of administration is used for drugs that are gases (for example, some anesthetics, and bronchodilators in treatment of asthma and other respiratory disorders). 2. Intranasal:  Desmopressin is administered intranasally in the treatment of diabetes insipidus; is available as a nasal spray. The abused drug, cocaine, is generally taken by sniffing. 9  Routes of drug administration 3. Intrathecal/lntraventricular:  It is sometimes necessary to introduce drugs directly into the cerebrospinal fluid (CSF), such as methotrexate in acute lymphocytic leukemia. 4. Topical  Topical application is used when a local effect of the drug is desired.  For example, clotrimazole is applied as a cream directly to the skin in the treatment of dermatophytosis, and atropine is instilled directly into the eye to dilate the pupil and permit measurement of refractive errors. 5. Transdermal  This route of administration achieves systemic effects by application of drugs to the skin, usually via a trans-dermal patch.  The rate of absorption can vary markedly depending upon the physical characteristics of the skin at the site of application.  This route is most often used for the sustained delivery of drugs, such as the antianginal drug, nitroglycerin. 10  Absorption of drugs Absorption of drugs  Absorption is the transfer of a drug from its site of administration to the blood stream. Depends on: A. Transport of drug from the GI tract: drugs may be absorbed from the GI tract by either passive diffusion or active transport (Depending on their chemical properties). 1. Passive diffusion: The driving force for passive absorption of a drug is the concentration gradient. The drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier. 2. Active transport: This mode of drug entry involves specific carrier proteins that span the membrane. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, that is, from a region of low drug concentration to one of higher drug concentration. 11 Absorption of drugs B. Effect of pH on drug absorption  Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form:  Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B).  A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot. For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. 12 Absorption of drugs  Therefore, to determine the effective and permeable form of each drug at its absorption site, you have to know the relative concentrations of the charged and uncharged forms.  The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa.  Thus, The pKa is a measure of the strength of the interaction of a compound with a proton {Or the pH at which a drug is 50% protonated and 50% nonprotonated (ratio 1:1)}. The lower the pKa of a drug, the stronger the acid.  Why do we care about the pka? C. Physical factors influencing absorption:  Blood flow to the absorption site: 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. 13 Bioavailability  Total surface area available for absorption: Because the intestine has a surface rich in microvilli, it has a surface area about 1,000 times that of the stomach; thus, absorption of the drug across the intestine is more efficient.  Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as in severe diarrhea, it is not well absorbed. Also, the presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly. Bioavailability  Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug is administered orally and 70 mg of this drug is absorbed unchanged, the bioavailability is 70%. 14  Bioavailability A. 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 the entire agent enters the circulation. The Determination of the bioavailability of a drug by using (AUC = area under curve.) see the following figure (Determination of the bioavailability of a drug). B. Factors that influence bioavailability 1. 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. 15  Bioavailability  Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver. 2. Solubility of drug: Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes.  Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in the aqueous body fluids and, therefore, cannot gain access to the surface of cells. 3. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, may be destroyed in the GI tract by degradative enzymes. 4. 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, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 16 Bioavailability C. Bioequivalence: Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent. D. Therapeutic equivalence: Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety. [Note: Clinical effectiveness often depends both on maximum serum drug concentrations and the time after administration required to reach peak concentration. Therefore, therapeutic equivalence requires that drug products are bioequivalent and pharmaceutically equivalent. {two drugs that are bioequivalent may not be therapeutically equivalent.} 17  Drug distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues (drug from the plasma to the interstitium). Factors influencing distribution: A. Blood flow: The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles, whereas adipose tissue has a still lower rate of blood flow. B. Capillary permeability: Capillary permeability is determined by capillary structure and by the chemical nature of the drug.  Capillary structure: Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit (tight) junctions between endothelial cells. In the brain, the capillary structure is continuous, and there are no slit junctions. 18  Drug distribution Blood-brain barrier: In order to enter the brain, drugs must pass through the endothelial cells of the capillaries of the central nervous system (CNS) or be actively transported. Lipid-soluble drugs readily penetrate into the CNS, since they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS, since they are unable to pass through the endothelial cells of the CNS, which have no slit junctions.  Drug structure: The chemical nature of the drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily move across most biological membranes. C. Binding of drugs to proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Binding is relatively non-selective as to chemical structure and takes place at sites on the protein to which endogenous compounds such as bilirubin, normally attach. 19 Volume of distribution Plasma albumin is the major drug binding protein and may act as a drug reservoir, for example, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. Volume of distribution  The volume of distribution (Vd) is a hypothetical volume of fluid into which the drug is disseminated. Although the volume of distribution has no physiological or physical basis, it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body.  It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0). 20  Volume of distribution Water compartments in the body: Once a drug enters the body, from whatever route of administration, it has the potential to distribute into any one of three functionally distinct compartments of body water, or to become sequestered in some cellular site. 1. Plasma compartment: If a drug has a very large molecular weight or binds extensively to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and thus is effectively trapped within the plasma (vascular) compartment.  Is about 6% of the body weight or, in a 70-kg individual, about 4 L of body fluid.  Aminoglycoside antibiotics show this type of distribution. 2. Extracellular fluid: If the drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. 21  Volume of distribution  Hydrophilic drugs cannot move across the membranes of cells to enter the water phase inside the cell, Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid.  This is about 20% of the body weight, or about 14 L in a 70-kg individual. 3. Intracellular fluid: If the drug has a low molecular weight and is hydrophobic, it can not only move into the interstitium through the slit junctions, but can also move through the cell membranes into the intracellular fluid.  The drug therefore distributes into a volume of about 60% of body weight, or about 42 L in a 70-kg individual.  Determination of Vd: A. Distribution of drug in the absence of elimination:  The concentration within the vascular compartment is the total amount of drug administered divided by the volume into which it distributes, Vd: 22  Volume of distribution C = D/Vd or Vd = D/C C = Plasma concentration of drug D = Total amount of drug in the body  For example, if 25 mg of a drug (D = 25 mg) is administered, and the plasma concentration is 1.0 mg/L, then the Vd = 25 mg/1.0 mg/L = 25 L. B. Distribution of drug when elimination is present:  In reality, drugs are eliminated from the body, and a plot of plasma concentration versus time shows two phases.  The initial decrease in plasma concentration is due to a rapid distribution phase in which the drug is transferred from the plasma into the interstitium and the intracellular water.  This is followed by a slower elimination phase during which the drug leaves the plasma compartment and is lost from the body, for example, by renal or biliary elimination or hepatic biotransformation. 23 Volume of distribution Figure shows Drug concentrations in plasma after a single injection of drug at time = 0. 24  Volume of distribution Effect of a large Vd on the half-life of a drug:  A large Vd has an important influence on the half-life of a drug, since drug elimination depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time.  Therefore, any factor that increases the volume of distribution can lead to an increase in the half-life and extend the duration of action of the drug. Binding of drugs to plasma proteins  Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues and elicit a biological response. Thus, by binding to plasma proteins, drugs become "trapped" and, in effect, inactive. [Note: Hypoalbuminemia may alter the level of free drug.]  Binding capacity of albumin: The binding of drugs to albumin is reversible and may show low capacity (one drug molecule per albumin molecule) or high capacity (a number of drug molecules binding to a single albumin molecule). 25  Volume of distribution  Drugs can also bind with varying affinities. Albumin has the strongest affinity for anionic drugs (weak acids) and hydrophobic drugs. Most hydrophilic drugs and neutral drugs do not bind to albumin.  The tolbutamide is normally 95% bound, and only 5% is free. This means that most of the drug is sequestered on albumin and is inert in terms of exerting pharmacologic actions. 26 Drug metabolism (biotransformation) Drug metabolism  Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile.  The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues (intestine, lung ….etc). [Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms.]  Metabolism of drugs undergo two types of chemical reactions, phase l (oxidation, reduction and hydrolysis) and phase ll (conjucation with fuctional group in the body). 27 Drug metabolism Results of metabolic reactions  Change active drug to inactive metabolite (most drugs)  Change inactive drug to active metabolite (pro drug) e.g. enalpril, minoxidil  Change active drug to other active metabolite e.g. codeine to morphine. A. Kinetics of metabolism: 1. First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis- Menten kinetics.  Here, Vmax represents the maximum rate achieved by the system, happening at saturating substrate (drug) concentration for a given enzyme concentration. 28  Drug metabolism  In most clinical situations the concentration of the drug (substrate), [C], is numerically much less than the Michaelis constant, Km, and the Michaelis Menten equation reduces to:  The rate of drug metabolism is directly proportional to the concentration of free drug, and first order kinetics are observed. This means that a constant fraction of drug is metabolized per unit time. 29 Drug metabolism Figure: Effect of drug dose on the rate of metabolism. 30 Drug metabolism 2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol and phenytoin, the doses are very large, so the [C] is much greater than Km, and the velocity equation becomes:  The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time (independent of drug dose). This is called zero order kinetics (or sometimes referred to clinically as non-linear kinetics). A constant amount of drug is metabolized per unit time. 31  Drug metabolism B. Reactions of drug metabolism:  The kidney cannot efficiently excrete lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II Phase I  Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2.  Phase I reactions usually involve reduction, oxidation, or hydrolysis.  Phase I Metabolism may increase, decrease, or have no effect on pharmacologic activity.  Phase I reactions utilizing the P-450 system: The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P-450 system (also called microsomal mixed function oxidase). 32 Drug metabolism Figure: The bio-transformations of drugs. 33  Drug metabolism  Phase I reactions not involving the P-450 system: These include amine oxidation (for example, oxidation of catecholamines or histamine, alcohol dehydrogenation (for example, ethanol oxidation), and hydrolysis (for example, of procainamide). Phase II  This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many metabolites are too lipophilic to be retained in the kidney tubules.  A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid or an amino acid results in polar, usually more water-soluble compounds that are most often therapeutically inactive. Glucuronidation is the most common and the most important conjugation reaction.  Neonates are deficient this conjugating system making them particularly vulnerable to drugs such as chloramphenicol. 34  Drug elimination  Reversal of order of the Phases: Not all drugs undergo Phase I and II reactions in that order. For example, isoniazid is first acetylated (a Phase II reaction) and then hydrolyzed to isonicotinic acid (a Phase I reaction). Drug elimination  Removal of a drug from the body may occur via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. A patient in renal failure may undergo extracorporeal dialysis, which will remove small molecules such as drugs. A. Renal elimination of a drug  A drug passes through several processes in the kidney before elimination: glomerular filtration, Proximal (active) tubular secretion, and passive tubular reabsorption. 35  Drug elimination 1. Glomerular filtration:  Glomerular filtration is the process by which the kidneys filter the blood, removing excess wastes and fluids. Glomerular filtration rate (GFR) is a calculation that determines how well the blood is filtered by the kidneys, which is one way to measure remaining kidney function.  Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into Bowman's space as part of the glomerular filtrate.  The glomerular filtration rate (GFR = 125 ml/min) is normally about 20% of the renal plasma flow (RPF = 600 ml/min). Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. 2. Proximal tubular secretion:  Drug that was not transferred into the glomerular filtrate leaves the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. 36  Drug elimination  Secretion primarily occurs in the proximal tubules by two energy- requiring active transport systems, one for anions (for example, deprotonated forms of weak acids) and one for cations (protonated forms of weak bases).  Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the blood. 3. Distal tubular reabsorption:  As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen back into the systemic circulation.  Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. Generally, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. 37  Drug elimination  This process is called “ion trapping.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If the drug is a weak base, acidification of the urine with NH4CI leads to protonation of the drug and an increase in its clearance. This process is called "ion trapping." B. Quantitative aspects of renal drug elimination  Plasma clearance (a volume per time) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration. for example, as ml/min. Clearance equals the amount of renal plasma flow multiplied by the extraction ratio, and since these are normally invariant over time, clearance is constant.  Extraction ratio: This ratio is the decline of drug concentration in the plasma from the arterial to the venous side of the kidney. The drugs enter the kidneys at concentration C1 and exit the kidneys at concentration C2. The extraction ratio = C2/C1 38  Drug elimination Figure: Drug elimination by the kidney. 39 Drug elimination  Excretion rate:  The elimination of a drug usually follows first order kinetics, and the concentration of drug in plasma drops exponentially with time. This may be used to determine the half-life of the drug (the time during which the concentration of the drug decreases from C to 1/2c). 40  Drug elimination C. Total body clearance  The total body (systemic) clearance (CLtotal) is the sum of the clearances from the various drug metabolizing and drug- eliminating organs. The kidney is often the major organ of excretion; however, the liver also contributes to drug loss through metabolism and/or excretion into the bile. A patient in renal failure may sometimes benefit from a drug that is excreted by this pathway into the intestine and feces, rather than through the kidney. Some drugs may also be reabsorbed through the enterohepatic circulation, thus prolonging their half-life. Total clearance can be calculated by using the following equation: 41  Drug elimination  It is not possible to measure and sum these individual clearances. However, total clearance can be derived from the steady state equation: Cltotal = Ke Vd ke = first-order rate constant for drug elimination from the total body D. Volume of distribution and the half-life of a drug  The half-life of a drug is inversely related to its clearance and directly proportional to its volume of distribution.  This equation shows that as the volume of distribution increases, the half-life of a drug becomes longer. The larger the volume of distribution, the more drug is outside the plasma compartment and is unavailable for excretion by the kidney or metabolism by the liver. 42  Drug elimination E. Clinical situations resulting in increased drug half-life  When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. It is important to be able to predict in which patients a drug is likely to have a longer half-life. The half- life of a drug is increased by: 1. Diminished renal plasma flow, for example, in cardiogenic shock, heart failure, or hemorrhage. 2. Addition of a second drug that displaces the first from albumin and, hence, increases the volume of distribution of the drug. 3. Decreased extraction ratio, for example, as seen in renal disease. 4. Decreased metabolism, for example, when another drug inhibits its biotransformation, or hepatic insufficiency as with cirrhosis. 43