Pharmacology For The Third Year Dental Students 2024-2025 PDF

Pharmacology For The Third Year Dental students Sphinx University BY Assoc. Prof. Mohamed Mostafa Elbadr 2024-2025  Introduction What is Pharmacology ? -Pharmacology is the drug science. -It is the major...

Pharmacology For The Third Year Dental students Sphinx University BY Assoc. Prof. Mohamed Mostafa Elbadr 2024-2025  Introduction What is Pharmacology ? -Pharmacology is the drug science. -It is the major body of information about drugs. -This information includes knowledge about the mechanism of action, pharmacological effects, therapeutic uses, adverse effects and any other information about the drug. What is the drug? Drug is a chemical substance used for prevention, diagnosis and treatment of diseases What is general pharmacology? -General pharmacology include pharmacokinetics and pharmacodynamics -Pharmacokinetics -Pharmacokinetics deals with the processes that undergo to the drug following its administration. -These processes include: absorption of the drug, its distribution as well as its elimination (biotransformation and excretion) -Pharmacodynamics -It deals with the relationship between the concentration of drugs at the site of action and the magnitude of the obtained effects. -Pharmacodynamics includes the mechanism of action of drug and its pharmacological effects. A. Drug absorption -Drug absorption occurs by one of the following mechanisms: 1-Passive or lipid diffusion. -It occurs with the lipid soluble drugs. -The most important one -The drug penetrates from high to low concentration after their solubility in lipid membrane -Passive process, so not need energy -It depends on lipid solubility, ionization of the drug and the concentration difference across the membrane -Facilitated diffusion is a special type of passive diffusion that is facilitated by a carrier 2-Filtration or aqueous diffusion: -It occurs with water soluble drugs, where drugs pass through aqueous channels or pores between the cells. -These pores are absent in the blood brain barrier (BBB) and placental barrier so any water soluble drug cannot cross BBB and placental barrier 3-Active transport: -It needs energy and carrier, so there are selectivity, saturability and competition. 4-Pinocytosis (endocytosis): -It occurs with high molecular weight drugs as iron, hormones and vit.B12.  Factors affecting drug absorption (a) Factors related to the drug: -Lipid solubility -Ionization -Molecular weight -Dosage form -Concentration  (b) Factors related to the patient: -Route of administration -Blood supply -Healthy state -GIT motility -Presence of other drugs -Presence of food B. Drug distribution  The drugs are first rapidly distributed to blood rich organs (heart, liver, kidney, brain) then to the muscles, fat and skin which have poor blood supply. If the drug is unionized, high lipid soluble and less bound to plasma protein; it is highly distributed to different areas as it easily passes to interstitial and cellular compartment.  Some drugs have selective accumulation in certain tissue as: -Iodides in thyroid tissue. -Tetracyclines in bone. Some areas in the body are protected from drugs by a special barrier as, for example, the blood brain barrier through which drugs pass to the brain.  Factors affecting drug distribution 1- Lipid solubility 2-Ionization 3-Plasma protein binding 4-Tissue protein binding 5-Blood supply 6-Healthy state 7-Age and sex C. Drug Biotransformation (Drug metabolism) Definition: - Drug biotransformation is the chemical transformation which occurs to the drug inside the body in order to decrease its lipid solubility and increase its water solubility to be excreted by the kidney. Types of alteration of biological activity of drugs: a) An active drug changes to inactive metabolite (as in most of drugs). b) An active drug changes to another active metabolite, e.g. codeine is metabolized to morphine c) An inactive drug (prodrug) changes to an active metabolite as enalapril is metabolized to enalaprilat. Organs responsible for biotransformation include: 1- Liver (main site of biotransformation). 2- Others: kidney, gut mucosa, lung and skin.  The most important enzymes responsible for metabolism are mixed functional oxidases (MFOs) and they form large family of isozymes and called also cytochrome P450. (N.B) cytochrome P45o- 3A4 is most important enzyme and responsible for metabolism of more than 60% of drugs. Types of metabolic reactions (Phases): (1) Phase I (Non- synthetic reaction) Here; the drug is changed to a more polar form and is prepared to undergo phase II. In certain cases; the drug may be still active. Phase I includes: oxidation, reduction or hydrolysis reaction. Oxidation is the most important one (2) Phase II (Synthetic or conjugation reactions) Drugs released from phase 1 are coupled with an endogenous substance. The coupled drugs are more polar and water soluble and, thus, easily excreted by kidney. However, some drugs are excreted in bile. Decoupling may occur by gut bacteria, so reabsorption of the uncoupled drug can occur and this is called enterohepatic circulation as with estrogen. Factors affecting drug biotransformation: (1) Genetic polymorphism: -In some individuals, there is rapid biotransformation (fast metabolizers). In others there is slow biotransformation (slow metabolizers).  In fast metabolizers, the therapeutic effective blood levels may not be reached due to rapid metabolism of the drug. In slow metabolizers, toxicity may occur from the usual doses due to accumulation of the drug.  The cause of this condition is due to a genetic difference in affinity of the enzyme to the drug or difference in the amount of the enzymes especially cytochrome P450. Examples: 1-Acetylation of isoniazid: In slow acetylator drug accumulation may occur causing peripheral neuropathy 2- Succinylcholine apnea due to genetic deficiency of the pseudocholinesterase enzyme  (2) Age and sex: Young age especially newborn are slow metabolizers due to immaturity of the enzyme system, as enzymes of phase 1 need several months and enzymes of phase II need 2-3 years to be as in adult enzymes. -Males may be rapid metabolizers than females due to androgen hormone. (3) Environmental factors: Cigarette smokers, persons exposed to pesticides are rapid metabolizers due to enzyme induction. Charcoal –broiled foods, cruciferous vegetables induce P450-1A while grapefruit juice inhibits P450-3A (4) Pathological factors: Liver, heart and lung diseases as well as malnutrition decrease drug metabolism by reducing the amount and activity of enzymes. (5) Drug- drug interaction (enzyme inducers and inhibitors): Enzyme inducers: -They induce liver enzymes by increasing the amount or activity of these enzymes. -There is rapid metabolism of the drugs which are metabolized by the induced enzymes, so the effect of these drugs is decreased. -Examples: as phenobarbitone, phenytoin, rifampicin and carbamazepine Enzyme inhibitors: -They inhibit metabolism of other drugs, so potentiate their effects. -Cimetidine and erythromycin are the most important enzyme inhibitors. D. Drug Excretion  Drugs are excreted either unchanged or in the form of metabolic products. Drugs to be excreted must be water soluble (ionized). Lipid soluble drugs are not excreted (due to their passive tubular reabsorption) until their metabolism. Sites of excretion: -Kidney (main site) -Bile -Lung (more with inhalational anesthesia). -Saliva - Milk, sweat, skin, and hair are minor routes. Factors affecting renal excretion: 1-Lipid solubility and ionization of the drug -Increase in lipid solubility and in unionization decrease drug excretion 2-Plasma protein binding of the drug - Increase in binding leads to decrease in free form so decreasing excretion 3-Presence of other drugs - As competition between drugs with the same transport mechanism may occur Probenecid inhibits active tubular section of penicillins due to competition for the same carrier system - Some drugs may cause acidification of alkalinization of urine, so may increase or decrease ionization of other drugs so may increase or decrease excretion of these drugs Examples: A- Na HCO3 and acetazolamide cause alkalinization of urine -They increase ionization of weak acidic drugs as aspirin and barbiturates, so they decrease passive tubular reabsorption causing increase in their excretion So used to treat toxicity of acidic drugs -They decrease ionization of weak basic drugs as atropine, morphine, benzodiazepines, so they increase passive tubular reabsorption causing decrease in their excretion B- NH4Cl and ascorbic acid (vitamin C) cause acidification of urine -They decrease ionization of weak acidic drugs as aspirin and barbiturates, so they increase passive tubular reabsorption causing decrease in their excretion -They increase ionization of weak basic drugs as atropine, morphine, benzodiazepines, so they decrease passive tubular reabsorption causing increase in their excretion So used to treat toxicity of basic drugs 4-Molecular weight of the drug -increase in molecular weight of the drug causes decrease in drug excretion 5-Renal blood flow 6-Healthy state of the kidney Pharmacokinetic variables (Parameters)  They are variables which differ from one individual to other according to certain physiological factors (as age, sex,....), or pathological factors (as liver, kidney diseases......) and so need adjustment of the dose. They include: a) Bioavailability (F) b) Volume of distribution (Vd) c) Clearance (Cl) d) Biological half- life (t 1/2). (a) Bioavailability (F) - It is the fraction of a given dose that reaches systemic circulation - Bioavailability = Plasma or systemic concentration dose given - It ranges from 0-1, in cases of I.V. injection equal to1 (or 100%). If no drug reach systemic circulation equal to 0 - Causes of low oral bioavailability (factors affecting it). (a) Poor absorption as aminoglycosides which are not absorbed at all. (b) Extensive first pass- metabolism (metabolism which occurs before the drug reach systemic circulation , may occur in GIT or the liver as in cases of insulin, lidocaine and epinephrine ) - Drugs with low oral bioavailability can be given I.V., I.M., sublingual (b) Clearance (CI) - Clearance of a drug is the rate of elimination by all routes relative to the concentration of drug in any biologic fluid. -Clearance of the drug from the body may involve process occurring in the liver, kidney, lung or other organs. -Clearance may be constant or variable -In cases of renal failure, we use drugs that do not depend on the kidney for their clearance -In cases of hepatic failure, we use drugs that do not depend on the liver for their clearance (c) Biological half- life (t ½ ) -The half-life is the time needed for the plasma concentration or the amount of drug in the body to be reduced by 50%. -Measurement of the t ½: So t ½ = Vd ×0.693 / Cl -The half-life depends on the clearance and volume of distribution, so it affected by factors affect both. - The half-life is important in the selection of dosage interval for maintenance therapy - Drugs reach to Css (steady state concentration) after 4-5 t ½ -In cases of drugs with long t ½ , we may use the loading dose (very high dose used at the start of the therapy) to reach to Css rapidly. Maintenance dose (dosing rate) Definition: Dose that is needed to maintain Css Calculation: Maintenance dose = Cl × Css It depends on the clearance Loading dose Definition: Dose that is used to reach Css It is large dose that is given at the onset of therapy to reach the Css rapidly Calculation: Loading dose = Vd× Css It depends on Vd Indication: Loading dose is needed when the time required to reach Css (target concentration) is long relative to the condition which is treated