Pharmacology Introduction PDF

Pharmacology Basic principles of pharmacology 2nd lecture 30 /9 /2024 Dr: Orass Saad Basic principles of Pharmacology ARE::::: PK, PD which its combine of the effects pharmacokinetic ( its effect o...

Pharmacology Basic principles of pharmacology 2nd lecture 30 /9 /2024 Dr: Orass Saad Basic principles of Pharmacology ARE::::: PK, PD which its combine of the effects pharmacokinetic ( its effect of the body on the drug) and pharmacodynamics (PKPD): (its effect of the drug on the body). ………………………………………… Basic principles of Pharmacology are: 1)) pharmacokinetic 2)) pharmacodynamics ………………………………………………………………. 1)) pharmacokinetic: means effect of the body on the drug (i.e. movement of the drug into the body), which includes (or also called pharmacokinetic parameters): Absorption, Distribution, Metabolism and Excretion (ADME). Absorption Absorption: means movement of the drug from the site of administration to the blood stream (blood means drug car). The rate and efficiency of absorption depend on the route of administration. ‫ جميع طرق اعطاء الدواء يحدث فيها امتصاص عدا طريقه واحد ال يحدث فيها امتصاصه فما هي هذي الطريقة؟ ولماذا ال‬:‫سؤال‬ ‫يحدث فيها امتصاص؟؟؟؟؟؟‬ Q// absorption occur in all routes of administration, except one route, what is these route? And why absorption not occur in it????????????????? ………………………………………………………………………………… Transmission of the drug across cell membrane Cell membranes are biologic barriers that selectively inhibit passage of drug molecules. The membranes are composed primarily of a bimolecular lipid matrix, which determines membrane permeability characteristics. Unless drugs that given IV, a drug must cross several semipermeable cell membranes before it reaches the systemic circulation. 1 Drugs may cross or passage cell membranes by 1- Active absorption: is the movement of molecules across a cell membrane from a region of their lower concentration to a region of their higher concentration and required energy ATP and carrier. 2- Passive absorption or simple diffusion: the drug should be lipid solubility, small size, non-polar (no water soluble) 3- Facilitated diffusion is a type of diffusion in which the molecules move from the region of higher concentration to the region of lower concentration assisted by a carrier protein that undergo conformational change to allow passage of drugs into the cell. This type of diffusion for large molecules. This route is inhibited when taken two drugs at same time that compete on the same carrier protein............................................................. 4- through aqueous pores 5- Pinocytosis= means engulf the large drug molecules by cell and stored into vesicle and then released through exocytosis. E.G: 1- storage of Vit B12 transport cross gut wall (endocytosis) 2- storage of adrenaline, noradrenaline and release it by (exocytosis). 2 The factors that effect on the rate of absorption are: A- Factors related with the patient 1-Route of administration: IV> IM > SC > oral. 2- Blood flow: increase blood flow in intestine more than stomach, lead to increase absorption in intestine. 3- Surface area: in the intestine the rate of absorption is increased than in the stomach, due to large surface area in the intestine. 4- Presence of GIT diseases like diarrhea, vomiting or other problems. 5- Presence of other drugs. 6- Presence of food. B- Factors related with the drug 1-Dosage form: solution > suspension > tablet. 2- Solubility: lipid solubility > water solubility. 3- Drug nature: small molecule > large molecule. ………………………………………………………. Distribution Means transfer of drug between blood, extra-vascular fluids and tissues (like muscle, fat, and brain tissue). The systemic circulation distributes drugs to various body tissues in addition to the target sites. Volume of Distribution Factors that effect on the distribution of drugs 1) Blood flow 2) Capillary permeability: increase capillary permeability cause increase rate of distribution. Example increase capillary permeability in liver and spleen more than in brain. 3) Binding of the drug with plasma protein (see figures below) 3 The distribution of a drug in the body also depends on the drug binds to proteins and tissues in the body. Only drugs that are unbound to proteins and other components in the blood are free to diffuse across the cell membranes into the tissues of the body. The most important proteins in the blood that can affect the distribution of a drug include the plasma protein albumin, the alpha-1 acid glycoprotein, and lipoproteins. It is observed that albumin binds acidic drugs, in general, while more basic drugs bind to the lipoproteins and acid glycoprotein. As only the unbound drug can be utilized in extravascular and tissue sites, it is important to establish or estimate the unbound drug fraction in the blood. Factors affecting on the plasma protein: a) Displacement of one drug by another drug. b) Decrease in plasma protein due to liver disease which lead to increase free active drug. …………………………………………………. 4) Binding of the drug with the tissues..‫بعض األنسجة لها القدرة على تخزين الدواء وهذا التخزين قد يسبب سميه للجسم بسبب تجمع كميات كبيره من الدواء في الجسم‬ 5) Solubility: lipid soluble is rapid distributed more than water soluble................................................................... Metabolism Metabolism, also called biotransformation, is the process by which a drug is converted by the liver enzymes to another form, it may convert to inactive form, or converted it to different form to easily excretion. 4 This process occurs through a series of chemical reactions include: oxidation, reduction, hydrolysis, hydration, conjugation, condensation, and isomerization. Factors affecting on the metabolism 1- Age. 2- Genetic factor. 3- Liver disease 4- Inhibit or induction of liver or microsomal enzymes. The kidneys, lungs, plasma, and intestinal mucosa also aid in the metabolism of drugs. Cytochrome P450 enzymes: ….…………… Is a family of enzymes that essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. ………………………………………………………………………. Excretion The elimination of drugs from the body is called excretion. only hydrophilic molecules are excreted effectively. After the liver renders drugs inactive, the kidney excretes the inactive compounds from the body. Also, some drugs are excreted unchanged by the kidney without liver involvement. Renal Excretion Renal excretion is quantitatively the most important route of excretion for most drugs and drug metabolites. Renal excretion involves three processes: glomerular filtration, tubular 5 secretion, and/or tubular reabsorption. The sum of these processes determines the extent of renal drug excretion. Patients with kidney disease may require a dosage reduction and careful monitoring of kidney function. Children have immature kidney function and may require dosage reduction and kidney function tests. Similarly, older adults have diminished kidney function and require careful monitoring and lower dosages. Other drugs are eliminated by sweat, breast milk, breath, or by the gastrointestinal tract in the feces. FACTORS AFFECTING RENAL EXCRETION 1. Physicochemical properties of drug 2. Molecular size 3. Biological factor: Age, sex 4. Drug interaction: increase or decrease 5. Disease state Urine pH: 6. Blood flow to the kidney Types of drugs elimination A) First-order elimination: The term first order elimination indicates that the rate of elimination is proportional to the concentration (i.e., the higher the concentration, the greater the amount of drug eliminated per unit time). The result is that the drug’s concentration in plasma highly decrease with time. Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concentration of such a drug in blood will decrease by 50% for every half-life. Most drugs in clinical use demonstrate first-order kinetics. B) Zero-order elimination: The term zero-order elimination implies that the rate of elimination is constant regardless of concentration. 6 Half-Life Half-life refers to the time required for the body to eliminate 50% of the drug. Knowledge of the half-life of a drug is important in planning the frequency of dosing. For example, drugs with a short half-life (2–4 hours) need to be administered frequently, whereas a drug with a long half-life (21–24 hours) requires less frequent dosing. Although half-life is fairly stable, patients with liver or kidney disease may have problems excreting a drug. Difficulty in excreting a drug increases the half-life and increases the risk of toxicity. For example, digoxin (Lanoxin) has a long half-life (36 hours) and requires once-daily dosing. However, aspirin has a short half-life and requires frequent dosing. Older patients or patients with impaired kidney or liver function require frequent diagnostic tests measuring renal or hepatic function. OR Half-life (t ½): is the time required to change the amount of drug in the body by one- half during elimination. half-life is constant for drugs that follow first-order kinetics..................................................................................................................................... 2))) PHARMACODYNAMIC Pharmacodynamics: means effect of the drug on the body Drug + Receptor/Effector = DR complex = Effect D+R = DR = Effector Molecule = Effect Receptor: a large group of molecules linked together found inside the body on the cell or inside the cell that attaches or binds to the drug molecule. This alters the abnormal function of the cell and produces the therapeutic response of the drug. Drug response is a result of chemical interactions between a drug and a binding site. The classification of drug receptors is based on tissue location, specificity of the drug, and the primary amino acid sequence. Majority (95%) of the total receptors are protein in nature. Not all proteins in the plasma membrane are receptors, some serves as transporters, enzymes or ion channels. 7 Major types of drugs can be seen in the figure. A) ligand-gated ion channel (found on the cell membrane): means binding of the drug with receptor result in open ion channel. E.G: cholinergic nicotinic receptor. B) G-protein coupled receptor GPCR (coupled of receptor with G-protein): E.G. alpha and beta adreno-receptor. C) Intracellular receptor (receptor found in the cytoplasm or cell): binding of drug with receptor result in produce protein. E.G. steroid receptor. D) Enzymatic linked receptor (receptor binding with enzyme): binding of drug with receptor result in activation of enzyme. Drug-receptor interaction (drug also called ligand) Drug or ligand: any substance binding with receptor. Type of drug or ligand: Agonist: a drug or ligand that binds and activates receptor. Antagonist: a drug or ligand that binds and not-activates receptor only occupy. 8 Types of agonist see figure: 1) Full agonist: when binding with receptor it produces maximum effect similar to effect of endogenous substance 2) Partial agonist: when binding with receptor it produces effect less to effect of endogenous substance, but partial agonist has high or less or equal to full agonist. ‫مامعنى هذا الكالم؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟؟‬ ‫معناه ان النوع الثاني يمكن ان تكون قابليته على االرتباط مع المستقبل اعلى او اقل او تساوي قابليه النوع االول لالرتباط مع‬.‫ وهذا يعني انه قد يعمل ضد النوع االول اذا تم اخذهم بنفس الوقت الن له قابليه اقوى لالرتباط مع المستقبل‬.‫المستقبل‬ Examples of partial agonists include buprenorphine, butorphanol, and tramadol. 3) Inverse agonist: Some substances produce effects that are specifically opposed to those of the agonist. Example: The agonist action of benzodiazepines on the benzodiazepine receptor in the central nervous system produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances called β- carbolines, which also bind to this receptor, cause stimulation, anxiety, increased muscle tone and convulsions; they are inverse agonists. Both types of drug act by modulating the effects of the neurotransmitter γ-aminobutyric acid (GABA). Types of antagonist see figure: 1) Pharmacological antagonist: which has two types of antagonist a- Competitive antagonist: two drugs competition on the same receptor E.G.: atropine and ACH b- Non-competitive antagonist: which divided into reverse or non-reverse, two drugs acts on the same receptor but non-competition on it E.G.: Organ phosphorus and ACH 2) Physiological or functional antagonist: two drugs act on different receptors, different in mechanism of action E.G.: histamine acts on H1 in bronchus cause bronchoconstriction And adrenaline acts on Beta2 in bronchus cause bronchodilation 9  3) Chemical interaction: occur after chemical interaction between two drugs, lead to decrease absorption of each drug. E.G.: heparin and protamine sulphate............................................................................. What is dose? It is a single quantity of a substance that is given to achieve a desired effect. In pharmacology, the dose of a medication may be expressed in milligrams (mg) per kilogram (kg) of body weight. What is dosage? Dosage refers to the regimen or schedule of administering a substance, usually over a period of time. ‫ عادة على مدى فترة من‬،‫تشير الجرعة إلى النظام أو الجدول الزمني إلدارة مادة ما‬ ‫الزمن‬ It is the total amount of a substance given over a period, often expressed in terms of frequency and duration. For example, in clinical trials, a medication dosage may be administered once daily for a week. Types of dose: 1- Therapeutic dose: is the average dose that produce therapeutic effect 2- Maximum tolerated dose: large dose that can be taken safely. 3- First or initial dose: dose used as start of treatment. 4- Maintain dose: the dose that required to maintain the therapeutic effect. 5- Lethal dose: the dose that produce death. What is ED50? ED50 (Effective Dose 50): refers to the dose of a drug or substance that produces a desired effect in 50% of a population or sample under a given set of experimental conditions or in a group of test subjects. It is a quantitative measure used to evaluate the potency or efficacy of a drug in pharmacology and toxicology studies. ED50 can be used to compare the potency of different compounds within the same class of drugs. What is LD50? LD50 (Lethal Dose 50), or Toxic dose TD: which is the dose that causes death in 50% of a population. Drug with small LD50 mean more toxic than a drug with high LD50 drug. What is The therapeutic index (TI)? The therapeutic index (TI): which is the ratio of LD50 to ED50, is a commonly used safety indicator. a- If The larger the therapeutic index (TI), means the safer the drug is. b- If the TI is small, means the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity 10  For example, if the TD50 is 200 and the ED50 is 20 mg, the TI would be 10. A clinician would consider a drug safer if it had a TI of 10 than if it had a TI of 3 (Figure 1). ……………………………………………………………………. Stander margin of safety: is the ratio between LD that kill 1% and ED that effective in 99% of population. SMS= LD1/ED99 The higher SMS mean that drug is better and safe SMS like TI indicate on the safety of the drug. The factors affecting dosing and action of the drug 11 1-Age a- Elderly required small dose due to decrease renal excretion and decrease hepatic metabolism. b- Child required small dose due to immature kidney and liver and decrease plasma proteins. 2- sex: female should be given smaller dose than male, because: a- She has high fat i.e. slower rate of oxidation and decrease metabolism thus increase drug effect. b- Inhibitory effect of estrogen hormone on liver enzyme. c- Some drugs are contraindication in pregnant and lactation. 3- Routes of administration: IV ˃ IM ˃ SC ˃ Oral 4- time of administration a- Some drugs should be taken after meal to prevent irritant effects E.G: aspirin. b- CNS stimulants drugs should be not given at night; it may cause insomnia E.G: ephedrine. 5-genetic abnormality (idiosyncrasy: abnormal reaction occurs due to genetic factors) 6-Hypersensitivity = drug allergy: as an immunological dysfunction is defined as exaggerated or inappropriate response of the immune system, due to patient taken incorrect drug that has sensitive from it, this lead to histamine release and anaphylactic symptoms (hypotension, bronchoconstriction). ‫في هذا التفاعل او لكي ال يحدث هذا التفاعل يجب معرفة اذا‬ ‫كان المريض عنده حساسيه من بعض االدويه من خالل سؤاله ومن خالل اجراء فحص الحساسية له اذا لم يكم بحساسيته من‬ ‫بعض األدوية‬ 7-Hyper susceptibility= super sensitivity= drug intolerance: is an increased predisposition ‫استعداد‬of certain individuals to react to a chemical. Because of biological variability among humans, some individuals respond to a chemical at a dose too low to produce a similar effect in others. ‫وليس له عالقة بالجهاز المناعي هذا التفاعل يحدث بسبب وجود حاله مرضيه عند المريض‬ The pharmacodynamics of the drug includes: 1) Mechanism of action. 2) Clinical effect= clinical uses= therapeutic uses= uses= indication 3) Route of administration. 4) Side effect and Contraindication The end 12