pharmacokinetics.pptx

PHARMACOKINETICS Department of pharmacology and toxicology, Faculty of pharmacy, Minya university  pharmacology pharmacokineti pharmacodyna cs mics Pharmacokinet ics: Absorption: Movement of drug from site of adm. to reach systemic circulati...

PHARMACOKINETICS Department of pharmacology and toxicology, Faculty of pharmacy, Minya university  pharmacology pharmacokineti pharmacodyna cs mics Pharmacokinet ics: Absorption: Movement of drug from site of adm. to reach systemic circulation. Factors affecting absorption: 1. Physical properties of drug, 2. Conc. of drug: 3. Surface area of site of absorption: 4. Blood flow to site of adm. Routes of drug administration.:  Onset of action Duration of action Time from taking the drug till Time from first appearance the appearance of the effect. till disappearance of drug effect.  Enteral route: Oral : Adv: easily used, convenient, economic. Disadv: 1. First pass metabolism: 2. Drug can be affected by GIT problems degradation in stomach (penicillin) 3. Not used in coma, nausea, vomiting, emergency  Enteral route: Sublingual &buccal: Adv: 1. Avoidance of first pass metabolism. 2. High blood flow, so rapidly absorbed. Disadv: 1. Bad taste 2. Drinking, eating & smoking easily affect drug absorption. Ex: sublingual (dinitra® ), buccal (fentora® ):fentanyl opioid analgesic.  Enteral route: Rectal: Adv: 1. Mostly used for infants. 2. very small amount lost by first pass metabolism. 3. Used when oral route is not available (nausea, vomiting). Disadv: 1-Not convenient 2-Irritation 3-Patient can’t take it by himself. Parenteral route:  Parenteral route: I.V: Adv: 1. Directly to systemic circulation(no absorption). 2. Useful in emergency cases. 3. Shortest onset of action 4. bioavailability=1 5. Ideal if dosed in large volumes.(IV infusion) Disadv: Not safe.  Parenteral route: I.M: Adv: 1. No first pass metabolism. 2. Suitable for oily preparations (unlike I.V) 3. High blood flow , rapid absorption. Disadv: 4. Painful 5. Patient can’t take by himself.  Parenteral route: Intraperitoneal(I.P): Adv: 1. No first pass metabolism. 2. High blood flow , rapid absorption. Disadv: High risk of infection.  Common route of adm. in experimental animal.  Parenteral route: Subcutaneous(S.C): Injected in adipose tissue layer(below epidermis &dermis) 45° Ex: heparin &insulin Adv: May provide constant, slow, and sustained effects. Disadv: Painful, atrophy.  Parenteral route: Intrathecal: Injected directly into CSF. Ex: nalbuphine (opioid analgesic). Intra-articular: Injected into joint. Intradermal: Injected in dermis layer (just below epidermis)15°. Ex: vaccines.  Other : Inhalation: Adv: provide big surface area for absorption Less systemic adverse effects Ex: aerosol in asthma. Topical: Ex: cream, ointment, eye drops. Give local effect. Rarely reach systemic circulation. Transdermal: achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. Ex: contraceptives, anti-anginal Exp1: -give the same drug to 3 mice by different routes(I.V ,I.M ,S.C) -measure onset of action. -result: Onset I.V THEN I.M THEN S.C Exp2: Administer MgSO4 oral and I.P. Observe the pharmacological actions. MgSO4 orally by stomach tube produce diarrhea (not absorbed→ hyperosmolarity and diarrhea). MgSO4 I.P: Block Calcium channels→ sedation(loss of righting reflex)  Parameters of absorption Bioavailability(F): Fraction of administered dose that reach systemic circulation. X100 FOR IV adm. For oral adm. Bioequivalent: Therapeutic equivalent: Drugs have same bioavailability But Drugs have same pharmacological different pharmacological effect effect but different bioavailability Ex: antibiotic &antihypertensive Ex: two antihypertensive drugs have same F & same rate of have different F & different rate absorption of absorption,  Distribution Movement of drug from systemic circulation to site of action. Factors affecting distribution: 1. Plasma protein binding(PPB) Albumin----------- acidic drug. Glycoprotein-------weakly basic drug. -Number of binding sites. -Disease: ex: malnutrition, liver disease Factors affecting distribution: 2.Tissue binding: Ex: garamycin®(gentamycin) has high affinity to kidney so its accumulation may cause nephrotoxicity. 3.Barriers : Ex: blood brain barrier, placental barrier, mammary gland barrier. Parameter of distribution: Volume of distribution(Vd) (apparent volume of distribution) the volume of fluid that would be required to contain the amount of drug in the body if it were uniformly distributed at a concentration equal to that in the plasma. Ex: dose(100mg), plasma conc(0.1mg/l) Then Vd= ??? As Vd increases, drug is highly distributed in extravascular tissue Ex: digoxin(500L), tolbutamide(7L) (Hemodialysis) Significance of Vd: Calculation of loading dose  Loading dose(LD): initial dose given at the beginning of treatment to achieve the target conc.  For I.V: LD=Vd (mg/L) For others: LD=(Vd) (desired steady state plasma conc)/F Steady State= Rate of adm=rate of elimination Time to reach steady state=4-5 t For drugs with long half life it requires long time to reach steady state so we give LD to achieve target conc.  Maintenance Dose: Dosing rate (mg/h)= {𝑡𝑎𝑟𝑔𝑒𝑡 𝑐𝑜𝑛𝑐. (mg/L) 𝑥 𝐶𝑙 (L/hr)}/ F%  Cases 1- 45-year-old, 65 kg female, is to be started on intravenous phenobarbital sodium, its volume of distribution is 0.6 L/Kg. Calculate a loading dose (LD) to yield a phenobarbital concentration of 20 mg/L. LD=Vd× 𝑡𝑎𝑟𝑔𝑒𝑡 𝑐𝑜𝑛𝑐 =0.6*65*20 =780mg If the seizure attack is relieved, the clinician might want to maintain this plasma level using oral dosage form, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. F oral is 0.96, CL is 2.8 L/h/65kg. When the dosing interval is 12 hours, the size of each maintenance dose would be??? MD= TC *CL/F = (20 mg/L* 2.8 L/h)/.96 = 58mg/h=700 mg/12hr 2-A drug with a half-life of 12 hours is administered by continuous IV infusion. How long will it take for the drug to reach ninety percent of its final steady-state level?  3.Metabolism Biotransformation of lipophilic drug into hydrophilic metabolite to be easily excreted.  3.Metabolism Biotransformation of lipophilic drug into hydrophilic metabolite to be easily excreted. 1.Active form→ inactive form (for most of drugs) 2.Inactive form→ active form (prodrug) Ex: enalapril→ enalaprilate 3. Active form→ active metabolite Ex: diazepam convert to oxazepam. Site of metabolism: Liver is the major site of metabolism by liver microsomal enzymes(LME)CYP450. It also occur in kidney, lung, GIT, skin Phases of metabolism: Phase I :  Non-synthetic reaction, functionalization.  Introducing or unmasking a polar functional group to convert the drug from lipophilic form to hydrophilic form  Involve reduction, oxidation, or hydrolysis  By CYP450 Phase II:  synthetic reaction, conjugation  Includes: methylation, acetylation, sulfation, glucuronidation, glycine conjugation, glutathione conjugation. Factors affecting metabolism: 1.Genetic polymorphism: For example, INH rapid acetylators (therapeutic failure), need higher doses. INH slow acetylators, accumulate (neuritis), need smaller doses.  Succinyl choline is used as skeletal muscle relaxant, pseudo choline esterase metabolize Succinyl choline Some people have deficiency of this enzyme so this cause relaxation of the diaphragm resulting in succinyl choline apnea. ttt: fresh plasma transfusion(contains pseudo choline esterase ). 2.diseases: Cardiac diseases decrease blood flow to liver so decrease metabolism Liver diseases decrease metabolism. 3.diet:  Malnutrition(starvation):LME inhibitor ↓protein content→↓synthesis of enzymes  Grapefruit juice: LME inhibitor.  Smoking: LME inducer. 4.Age &sex:  Metabolismin males higher than females as androgens are LME inducer  Geriatrics usually have liver dysfunction, slow metabolic rate, need smaller doses. Infants have immature liver, slow metabolic rate, need smaller doses. Ex: chloramphenicol due to lack of glucuronidation cause Grey baby syndrome. (UDP-glucuronyl transferase) 5.Drug interaction: LME inducers LME inhibitors Increase met. Of other drugs so higher doses Decrease met. Of other drugs so smaller are required. doses are needed Ex: Ex: Phenytoin Erythromycin Phenobarbital Oral contraceptives rifampicin Ketoconazole Exp 3: (effect of hexobarbital as sedative) Mouse 1:starved 36 hr before drug adm. Mouse 2: given phenobarbital 50mg/kg daily for 10 days before drug adm. Mouse3:control Mouse1:starvation(LME inhibitor) Mouse2:phenobarbital (LME inducer) Mouse3:control Duration of action: mouse21  Excretion: Site: 1.Kidney(major site) 2.Biliary excretion 3.Other routes: Milk, tears, sweat, saliva, hair follicle. Hair follicle: arsenic ,mercury Milk: tetracycline, phenobarbital 2.Biliary excretion: Metabolite excreted in bile→ large intestine→ excreted in feces. Enterohepatic circulation: Drugs conjugated with glucuronide when reach large intestine & by glucuronidase enzyme they transform back to active form then reabsorbed and give their effect again and prolong the duration of action e.g contraceptives. Renal elimination of a drug: 1.Glomerular filtration: For small molecules (aa’, glucose) Free form can be filtered but not bound. 2.Tubular secretion: Active process, need energy, require carrier Ex; penicillin Excreted by tubular secretion and has short duration of action To elongate duration of action, give probencid that competes with penicillin for the same carrier  3.Tubular reabsorption : Reabsorption of water, sodium, inorganic ions. Ionized form →not reabsorbed Unionized form→ reabsorbed So change in PH can affect reabsorption. A. Alkalinization of urine by sod.bicarbonate→ ionize weak acidic drugs→ excreted not reabsorbed B. Acidification of urine by ammonium chloride→ ionize weak basic drugs→ excreted not reabsorbed  Parameters of Elimination Clearance (CL) estimates the amount of drug cleared from the body per unit of time. CL = 0.693 x Vd / t1/2 Half-life (t1⁄2) is the time required for drug conc. to fall to half its initial value. EX: After an intravenous bolus administration of a drug X (6.5 g), its half-life equal 8h Determine the total clearance (L/hour) of this drug if the apparent volume of distribution is reported to be 23 L CL = (0.693 x Vd )/ t1/2 =0.693*23/8 =1.99 L/h  Cases 1- A 40-year-old male patient (70 kg) was recently diagnosed with infection involving methicillin-resistant S. aureus. He received 2000 mg of vancomycin as an IV loading dose. The peak plasma concentration of vancomycin was reported to be 28.5 mg/L. Calculate the volume of distribution? 2- A drug with a half-life of 10 hours is administered by continuous intravenous infusion. Which of the following best approximates the time for the drug to reach steady state? A. 10 hours. B. 20 hours. C. 33 hours. D. 40 hours. E. 60 hours.  Cases 3- Ramy is a 40 kg teen who has been admitted to the hospital with a severe case of septicemia caused by a Gram-negative bacteria that has been determined to be sensitive to gentamicin. Gentamicin's Vd = 0.5 L/kg. What i.v. loading dose would you give Brian to rapidly achieve a therapeutic plasma level of 5 ug/ml? 4- After being given a loading dose, treatment of Ramy bacterial infection requires maintenance dosing with gentamicin for 48 hours. Gentamicin's elimination clearance is 5.0 L/hr. What i.v. maintenance dose should you give every 8 hours to maintain an average plasma level of 5 ug/ml?  Cases 5- A new immunosuppresant, Noreject, is being studied in the renal transplant clinic where you work. Based on previous studies, the following area under the serum concentration/time curves (AUC) were measured after single doses of 10 mg in renal transplant patients: intravenous bolus AUC = 1530 mg ⋅ h/L, oral capsule AUC = 1220 mg ⋅ h/L, oral liquid AUC = 1420 mg ⋅ h/L. What is the bioavailability of the oral capsule and oral liquid? What is the relative bioavailability of the oral capsule compared to the oral liquid? My e-mail: [email protected]