Excretion of drugs

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Excretion of drugs:

Excretion of drugs Dr.S.P.Dhanya Assistant Professor Department of Pharmacology Govt TDMC Alappuzha

Revision:

Revision The onset of pharmacological response: Drug absorption Drug distribution The duration and intensity of action : Tissue redistribution of drug and The rate of elimination

Drug Elimination :

Drug Elimination Termination of drug effect Metabolism Excretion

What is excretion?:

What is excretion? Passage out of systemically absorbed drugs defined as “ the process whereby the drugs and/or their metabolites are irreversibly transferred from internal to external environment.”

What are the routes of elimination?:

What are the routes of elimination?

Renal excretion of drugs :

Renal excretion of drugs

PowerPoint Presentation:

Agents that are excreted in urine are- Water soluble Non-volatile Small molecular size Metabolized slowly. 7

Renal Excretion :

Renal Excretion Glomerular filtration Tubular secretion Tubular reabsorption Rate of Excretion= (Rate of Filtration + Rate of Secretion) –(Rate of Reabsorption) Net renal excretion = (GF + TS) – TR

Glomerular filtration::

Glomerular filtration: Non-selective Unidirectional Ionized or unionized are filtered Plasma protein binding – decrease renal excretion Driving force - hydrostatic pressure of the blood flowing in the capillaries . Renal blood flow – increase excretion

Active tubular secretion::

Active tubular secretion: Most efficient In proximal tubule of nephron . Carrier mediated-capacity limited- Saturable . Requires energy Bidirectional Unaffected by pH & protein binding. Dependent on renal blood flow.

Active tubular secretion::

Active tubular secretion: OAT- secretion of organic acids/anions: e.g. penicillin, probenecid,salicylates , indomethacin , nitofurantoin,methotrexate & endogenous substances like Uric acid. OCT-organic bases or cations : e.g.Thiazide,Amiloride,Furosemide,Procainamide,Quinine,Cimetidine

Active tubular secretion:

Active tubular secretion Competition Similar structure Similar ionic charge Same carrier A drug with greater rate of clearance will retard the excretion of other drug with which it competes 12

Therapeutic advantages :

Therapeutic advantages Probenecid acts as a uricosuric agent in treatment of gout Competitively inhibits OATP. Suppresses reabsorption of endogenous metabolite uric acid. Probenicid inhibits active tubular secretion of organic acids e.g. Penicillin- increases their plasma conc. 2 fold. 13

PowerPoint Presentation:

OATP Uric acid Penicillin Probenecid X X Uricosuric Increase plasma conc

PowerPoint Presentation:

OATP Uric acid Nitrofurantoin Probenecid X X Decrease urinary conc Therapeutic disadvantages

Other competitions:

Other competitions Salicylates block uricosuric action of probenecid Probenecid and Salicylates impair tubular secretion of methotrexate Sulfinpyrazne inhibit excretion of tolbutamide

Tubular Reabsorption:

Tubular Reabsorption Passive diffusion All along renal tubule. Increases half-life of a drug. Lipid solubility: Lipid soluble- 99% reabsorbed Ionisation : - Ionised drugs can’t undergo reabsorption - Acidic drugs excreted in alkaline urine - Basic drugs excreted in acidic urine

PowerPoint Presentation:

pH of urine: 4.5-7.5 pKa - 5-8 18

Alteration of urine pH:

Alteration of urine pH Acidification of urine: by ammonium chloride, methionine and ascorbic acid  enhances excretion of basic drugs. e.g. morphine, Amphetamine. Alkanisation of urine : by citrates, tartarates , bicarbonates and carbonic anhydrase inhibitors  enhances excretion of acidic drugs e.g. barbiturates, salicylates . Prevention of crystalluria caused by precipitation of sulphonamides in the renal tubules. 19

Factors Affecting Renal Excretion:

Factors Affecting Renal Excretion Physicochemical properties of the drug Plasma concentration of the drug Distribution and binding of the drug Urine pH Blood flows to the kidneys Biological factors Drug interactions Disease states. 20

PowerPoint Presentation:

Hydrophilic 21 Mol. Wt. Excretion pattern < 300 Daltons Urine, < 5% in bile >500 Daltons Bile, <5% in urine 300-500 Both urine and bile

Biological factors:

Biological factors Renal excretion is 10% lower in females . Newborns : 30-40% less (attains maturity between 2.5-5 months of age) Old age : GFR decreased, excretion decreased, increased t 1/2 . 22

Non-renal Routes Of Drug Administration:

Non-renal Routes Of Drug Administration 23

Faecal elimination:

Faecal elimination Orally ingested drugs which are not absorbed from the gut e.g : Mg SO4, Neomycin Drugs excreted directly in colon e.g.Anthracine Purgative, Heavy Metals Drugs which are excreted through bile but not reabsorbed from the intestine

Faeces:

Faeces Drugs transferred from liver through bile - Erythromycin - Ampicillin - Rifampicin - Tetracycline - OCP - Phenolphthalein

Enterohepatic Cycling / Enterohepatic Circulation Of Drugs: :

Enterohepatic Cycling / Enterohepatic Circulation Of Drugs:

Enterohepatic Cycling:

Enterohepatic Cycling “The phenomenon of drug cycling between the intestine and the liver.” e.g. rifampicin,ampicillin,OCP Increased t 1/2 e.g oral contraceptives Prolongation of drug action : e.g. Rifampicin

Pulmonary Excretion:

Pulmonary Excretion

Pulmonary Excretion:

Pulmonary Excretion Gaseous and volatile substances Depends on partial pressure of drugs e.g.general anaesthetics - halothane, nitrous oxide etc. paraldehyde alcohol – excreted slowly through lungs.

Salivary Excretion:

Salivary Excretion pH of saliva- 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. Basic drugs secreted more than acidic drugs Li, KI,Rifampicin 31

Mammary excretion:

Mammary excretion Lipid soluble Less protein bound drugs Basic drugs excreted more

Mammary excretion:

Mammary excretion Drug Effect Chloramphenicol Bone marrow depression Diazepam Accumulation and sedation Heroin Prolonged neonatal dependence Methadone Possible withdrawal symptoms if breast feeding is stopped suddenly Propylthiouracil Suppression of thyroid function

PowerPoint Presentation:

Drug Effect Tetracycline Permanent staining on teeth Sulphonamides Kernicterus Penicillin Allergy Ampicillin Diarrhea Dapsone Hemolytic anemia Phenindione Bleeding Phenobarbitone Drowsiness Phenytoin Methemoglobinemia Theophylline Restlessness

Skin excretion (Sweat) :

Skin excretion (Sweat)

Skin excretion(Sweat):

Skin excretion(Sweat) keratin precursor cells: Griseofulvin Hair follicles : Arsenic , Mercury, Iodides Sweat: urea derivatives,heavy metals Benzoic acid , Salicylic acid , Alcohol.

KINETICS OF ELIMINATION:

Basis for devising rational dosage regimen Modify the regimen according to individual needs KINETICS OF ELIMINATION

Clearance::

Theoretical volume of plasma from which the drug is completely removed in unit time CL = Rate of elimination C Clearance:

t1/2:

t1/2 The time duration in which the plasma concentration of the drug falls by 50% of the earlier value Biological t ½=Time duration in which the principal pharmacological effect of drug declines by 1/2

Calculation of t ½ :

Calculation of t ½ t ½ = ln2 = 0.693 K K K= Cl V So t ½ = 0.693 x V Cl

PowerPoint Presentation:

Log Plasma Conc. Time  IV Drug  phase (Distribution)  phase (elimination)

First order kinetics:

First order kinetics Constant fraction of drug eliminated at a constant interval of time (F-F) Rate of elimination  Drug Conc. CL constant t½ constant 50% 50% 100g 50g 25g 2hr 2hr 50% 50% 200g 100g 50g 2hr 2hr

PowerPoint Presentation:

Plasma Conc. 200 100 50 25 2 4 6 0 Time

PowerPoint Presentation:

1 t ½ - 50% Drug eliminated 2 t ½ - 75% 3 t½ - 87.5% 4 t½ - 93.75% 5 t½ - 97% Complete drug elimination occurs in 4-5 half life

ZERO ORDER KINETICS:

ZERO ORDER KINETICS Constant amount of drug is eliminated in unit time Rate of elimination constant t ½ increases with dose, eg : Ethyl alcohol 25g 25g 100g 75g 50g 1hr 1hr 25g 25g 25g 25g 200g 175g 150g 125 g 100 g 1hr 1hr 1hr 1hr

PowerPoint Presentation:

Plasma Conc. Time

MICHAELIS-MENTEN KINETICS (Mixed Order Kinetics):

MICHAELIS-MENTEN KINETICS (Mixed Order Kinetics) Dose dependent kinetics Smaller doses handled by first order kinetics As plasma conc.  elimination -- zero order Saturation of metabolising enzymes-high conc Eg : phenytoin , digoxin , warfarin , tolbutamide

PowerPoint Presentation:

Plasma Conc. 200 100 50 25 2 4 6 0 Time Zero Order I order

Clinical significance of t ½ :

Clinical significance of t ½ For a single dose of drug 97% of drug gets eliminated after 5 t ½ If a fixed dose of drug is administered every t ½ - 5 t ½ s would be needed for its steady state level because @ 5 t ½ rate of absorption-rate of elimination If dose of drug is doubled its duration of action is prolonged by more than one half life

Dosing schedules:

Dosing schedules Very short t ½ = constant iv infusion e.g. Norepinephrine 1-2 min, Dobutamine-2 min Oxytocin 3-5 min t ½ 30mts-2h=6-8hrly e.g.Paracetamol-2h, Cephalexin-1 h t ½ 4-12h= every half life t ½ very long due to increased V d Digoxin-40h,Chloroquine -40h

TARGET LEVEL STRATEGY:

TARGET LEVEL STRATEGY To achieve a certain plasma conc which has been defined to be in the therapeutic range. Loading Dose: Single or few quickly repeated doses given in the beginning to attain target conc. Rapidly. LD=desired plasma conc x V d eg Digoxin,Chloroquine,Lignocaine

MAINTENANCE DOSE:

MAINTENANCE DOSE This dose is one that is to be repeated at specified intervals after the attainment of target plasma conc so as to maintain the same by balancing elimination : Digoxin , Chloroquine , Doxycycline

:

Plasma Conc. Half lives 0 1 2 3 4 5 6 7 100 150 175 187.5 194 50 75 87.5 93.75 97

Steady state plasma concentration:

Steady state plasma concentration Drug is given @ relatively short intervals and in a repetitive fashion Input=elimination Cpss = dose rate Cl Dose rate= Cl x Target Cpss Dose rate= Cl x Target Cpss Fraction of oral drug

PowerPoint Presentation:

THERAPEUTIC DRUG MONITORING Drugs with low safety margin- Digoxin If individual variations large- Lithium Potentially toxic drugs used in the presence of renal failure- Aminoglycosides Poisoning Failure of response without any apparent reason – antimicrobials To check patient compliance

Timing of TDM:

Timing of TDM Dose adjustment Long acting-Trough-just prior to next dose Short acting-Immediate post absorptive Poisoning-Early and repeatedly Check compliance-random sampling

MONITORING OF PLASMA. CONC. IS OF NO VALUE:

MONITORING OF PLASMA. CONC. IS OF NO VALUE Drugs whose response is easily measurable. eg.antihypertensives, hypoglycaemics Drugs activated in the body – Levodopa Hit and run drugs – Reserpine, Omeprazole Drugs with irreversible action – Organophosphate

PROLONGATION OF DRUG ACTION:

PROLONGATION OF DRUG ACTION Frequency reduced Improving patient compliance Large fluctuations in plasma conc. avoided Drug effect could be maintained overnight without disturbing sleep.

PowerPoint Presentation:

Prolonging absorption from site Oral: Sustained release tables Controlled release tablets Parenteral : SC, IM, Injection of drug in insoluble form – Benzathine Penicillin Oily solution – Depot Progestin Pellet implantation Transdermal drug delivery system, eg : GTN 2. Increasing plasma protein binding 3. Retarding rate of metabolism 4. Retarding renal excretion

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