1st trim-pharmacology lec2.pdf

UOFCM 2024-2025 1st trimester Pharmacology course Lec 1  Lec 2 Pharmacokinetics BIOAVAILABILITY Oral plasma concentration-time curve BIOAVAILABILITY The bioavailability of a drug is the fraction (F) of the administered dose that reaches the systemic circulation. B...

UOFCM 2024-2025 1st trimester Pharmacology course Lec 1  Lec 2 Pharmacokinetics BIOAVAILABILITY Oral plasma concentration-time curve BIOAVAILABILITY The bioavailability of a drug is the fraction (F) of the administered dose that reaches the systemic circulation. Bioavailability is defined as unity (or 100%) in the case of intravenous administration. After administration by other routes. FACTORS DETERMINES BIOAVAILIBILITY OF A DRUG Biological factors GIT degradation food and other drugs Absorption First pass metabolism Entero-hepatic circulation Pharmaceutical factors Particle size. disintegration agents type of excipient. DISTRIBUTION Volume of Distribution Vd = Volume of distribution. Cp = estimated plasma concentration per liters at the time of plasma tissue equilibrium after i.v. injection. DISTRIBUTION Blood- brain and CSF barriers water soluble drugs cannot filter in CSF or brain. Crossing occur either by diffusion or carrier mediated transport. Placental barrier Plasma protein- binding.  METABOLISM : ( Biotransformation) Metabolic processes convert lipid soluble drugs into water soluble products which are easily eliminated either in the urine or through the bile There are 2 types of chemical reactions : 1. Phase I reaction 2. Phase II reaction METABOLISM : ( Biotransformation) Phase I reaction: non synthetic ; occur by microsomal enzymes, (a) Oxidation: alcohol, Barbiturates, diazepam, morphine (b) Reduction: chloramphenicol, naloxone, prednisone (c) Hydrolysis: succinyl-choline, procaine METABOLISM : ( Biotransformation) Phase II reaction: Synthetic involving addition of an endogenous water soluble group (conjugation) by transferases enzymes a. Glucuronidation : salicylates, digoxin, morphine. b. Acetylation: Sulhonamide, isoniazid, dapsone c. methylation : catecholamines, histamine. d. Glutathione : Ethacrynic acid. e. Glycine: nicotinic acid. f. sulphation : Estrogens, acetaminophen. g. glutamine : paraaminosalicylate. METABOLISM : ( Biotransformation) First pass effect: pre-systemic elimination ; oral administration only Include 2 parts: A. Intestinal first pass effect Intestinal lumen ; intestinal wall B. Hepatic first pass effect: Portal circulation ; microsomal enzymes Hepatic diseases decreases the first pass effect. Hepatic enzyme induction increases the first pass effect. Hepatic enzyme inhibition decreases the effect. Iv. Saturation of metabolizing enzymes decreases the effect. METABOLISM : ( Biotransformation) Enzyme induction: microsomal metabolizing enzymes. - Drug efficacy and plasma half- life will be significantly reduced. Enzyme inducer drug affected Cigarettes Benzodiazepines, paracetamol (benzpyrene) propoxyphine, theophyline. Ethanol Ethanol, barbiturates, phenytoin. Barbiturates Barbiturates, Phenytoin, warfarin (phenobarbitone) corticosteroids, oesterdiol, doxycycline,digitoxin Carbamazepine corticosteroids, oesterdiol, doxycycline Phenytoin Digtoxin, quinidine, hydrocortisone, theophylline Rifampine Oral contraceptives, corticosteroids, Digtoxin Griseofulvin Warfarin METABOLISM : ( Biotransformation) Enzyme Inhibition. Enzyme Enzyme inducer drug affected Hepatic microsomal cimetidine diazepam, phenytoin, antidepressants theophylline, lidocaine, propranalo Erythromycin theophylline, warfarin, cyclosporine Sod. Valproate Phenytoin, Phenobarbital Quinolone Theophylline Chloromphenicol Phenytoin, tolbutamise, warfarin Angiotensin Captopril Angiotensin I , bradykinin Mono aminoxidase MAO inhibitors Pithidine, tricyclic antidepressants Cholinesterase Echothiophate Suxamethonium, procain, propanidid METABOLISM : ( Biotransformation) Factors affecting metabolism A. Age and sex. B. Diseases. C. Drugs. D. Genetic factors. METABOLISM : ( Biotransformation) The metabolic products usually: Biologically active -------Biologically inactive Or active drug ----- active metabolite Diazepam --------- Oxazepam, Desmethyldiazepam. pro-drug (inactive)------- active metabolite Prednisone -------------------- Prednisolone Metabolic product is toxic. Sulphonamides acetyl derivative Drug elimination without metabolism e.g. Lithium ELIMINATION 1. Rout of excretion 2. Clearance 3. Half - life ( t ½ ) ELIMINATION Rout of excretion A. Renal B. Liver C. Lungs D. Gastro- intestinal tract (GIT) E. Breast milk F. Miscellaneous ELIMINATION Rout of excretion A. Renal Glomerular filtration Tubular secretion: The most effective mechanism of drug elimination by the kidney. Acidic : Penicillins, Cephaloridines Indomethacin, Salisylic acid Basic: Dopamine, Histamine, Morphine Pithidine, Quinidine. Passive tubular re -absorption: Weak acids, Weak bases ELIMINATION Rout of excretion A. Renal Rate and extent of renal excretion of drugs depends upon: Plasma protein- binding : decrease excretion. Lipid solubility: decrease excretion. Ionization in renal tubules : increase excretion. Kidney function: dysfunction decrease excretion. ELIMINATION Rout of excretion A. Renal B. Liver: Chief site of metabolism…( Bile excretion). Entero - hepatic circulation…(Intestinal micro flora) C. Lungs : Volatile gases, gaseous anaesthetics, few ethanol D. Gastro- intestinal tract (GIT) : Basic drugs ( Morphine poisoning ) E. Breast milk F. Miscellaneous sweat, saliva. Poisoning by heavy metals. Hair, nails , skin. ELIMINATION Clearance: The volume of plasma cleared of the drug in unit of time. Total clearance = Cl renal + Cl liver + Cl others A. Rate of clearance B. kinetics of clearance ELIMINATION Clearance: A. rate of clearance Drug excreted by glomerular filtration only Clearance < GFR (120 ml/min) e. g. aminoglycosides. Drugs removed totally by renal tubular secretion. Clearance < renal plasma flow (77 ml/min) e.g. penicillin Lipid soluble & diffusible drugs Clearance..from ( 1 ml/min) to ( 700 ml/min) ELIMINATION Clearance: B. kinetics of clearance I. First order kinetics non saturable. log plasma concentration - time curve is linear. drugs have constant t ½. after single dose, near complete (97 %) clearance is expected by the end of 5 t ½ intervals. e.g. most of the drugs. II. Zero order kinetics saturable ; dose dependent elimination. t ½ is not constant. e.g. alcohol, phenytoin, salicylates. ELIMINATION Half - life ( t ½ ) The time taken for the circulatory plasma concentration to fall by 50 %. The duration of t ½ is determined by : A. Rate of clearance: B. distribution and storage.highly distributed and sequestrated in tissue increased t ½ C. plasma protein- binding increase t ½ ELIMINATION Half - life ( t ½ ) Expectation of t ½ : t ½ is not indicative of duration of action and dosage schedule in the following cases: Active metabolites. e.g. diazepam, prednisone “Hit and run “ drugs.e.g. resrpin, anticancer drugs, organophosphorus compounds. Dose - dependant pharmacokinetics : e.g. Phenytoin; salicylates. Pathological conditions. e.g. Renal and /or hepatic dysfunctions Pharmacokinetic Models 1. Multi-compartment distribution: After absorption many drugs undergo an early distribution phase followed by a slower elimination phase. Mathematically, this behavior can be modeled by means of a “two compartment model” and each phase is associated with a characteristic t ½. 2. Single compartment distribution: A few drugs may behave as if they are distributed to only one compartment (e.g. if they are restricted to the vascular compartment). Other drugs may be distributed to more than two compartment. Single compartment 2 compartments STEADY STATE (SS) LEVEL When the intake of a drug is equal to it’s elimination, in most drugs( which follows first order kinetics) the SS level reached after 5 half-lives (t ½) , the following two points are of significance 1. The time to reach SS level is a function of t ½ ( 5 half-lives ) irrespective of the dose or dose - interval. 2. The SS level reached is a function of the dose and dose interval and not of t ½. DOSAGE REGIMEN Variables to be considered in dosage regimen: amount of single dose. the route of administration. the dose interval. total duration of therapy. Treatment could be by : 1. Single dose treatment. e.g. hypnotics, analgesics , purgatives. 2. multiple dosing : it is better to give smaller doses at shorter intervals There are variants in dosage schedule: (a) Drugs with short plasma t ½ e.g. dopamine. (b) Drugs with long plasma t ½ ( loading dose ; maintenance dose ) Loading dose = plasma concentration/ L X Vd in L PROLONGATION OF DRUG ACTION 1. Delay absorption. A. Oral administration: sustained release preparations. B. Parenteral administration Aqueous suspension or oily solutions e.g. procain penicillin, benzathin penicillin implants of pellets S.C. injection of drug along with vaso-constrictor. e.g.adrenaline with local anaesthetics. 2. Delay metabolism : Simultaneous administration of carbidopa inhibits peripheral de- carboxylation of 1- dopa carboxylase. 3. Plasma protein binding : e.g. long acting sulphonamides 4. Delay excretion : e.g. probencid competition with penicillin and ampicillin at tubular secretion. Thank you