This document provides information about biotransformation and elimination of drugs. It defines biotransformation as enzyme-catalyzed reactions that metabolize drugs within the body. The major sites of biotransformation are the liver, kidneys, lungs, intestine, adrenal cortex, placenta, and skin. Biotransformation can produce inactive, active, or toxic metabolites. It also describes first-pass metabolism in the liver and factors that influence it. The document outlines the three phases of biotransformation - phase I and II reactions catalyzed by drug-metabolizing enzymes, and phase III transport of metabolites. It discusses drug-metabolizing enzymes like CYPs and factors like induction and inhibition that affect their activity.
A brief presentation about the transport of drugs across the cell membrane including the many mechanisms and various transporters and a brief overview of the ABC and SLC superfamily of transporters.
Pharmacokinetics (PK) is the study of how the body interacts with administered substances for the entire duration of exposure (medications for the sake of this article). This is closely related to but distinctly different from pharmacodynamics, which examines the drug's effect on the body more closely.
Ace Your NAPLEX Exam: Master Kinetics, DDI, and Pharmacogenomics in Lecture 2!Jackson Wang
https://youtu.be/C1Rb4BFugzo
Attention all NAPLEX students! Are you ready to take your studying to the next level? In this video, we dive deep into the world of Kinetics, DDI, and Pharmacogenomics. With other pharmacy students that seeks to inspire, this lecture provides insight on how to approach your NAPLEX studies with a fresh perspective. But, we want to know, what's been your biggest challenge so far while memorizing this vital information? Leave your thoughts below and let's engage in a discussion that will motivate us all. Remember, don't just study harder, study smarter. Join the conversation and elevate your NAPLEX studying game.
https://youtu.be/C1Rb4BFugzo
A brief presentation about the transport of drugs across the cell membrane including the many mechanisms and various transporters and a brief overview of the ABC and SLC superfamily of transporters.
Pharmacokinetics (PK) is the study of how the body interacts with administered substances for the entire duration of exposure (medications for the sake of this article). This is closely related to but distinctly different from pharmacodynamics, which examines the drug's effect on the body more closely.
Ace Your NAPLEX Exam: Master Kinetics, DDI, and Pharmacogenomics in Lecture 2!Jackson Wang
https://youtu.be/C1Rb4BFugzo
Attention all NAPLEX students! Are you ready to take your studying to the next level? In this video, we dive deep into the world of Kinetics, DDI, and Pharmacogenomics. With other pharmacy students that seeks to inspire, this lecture provides insight on how to approach your NAPLEX studies with a fresh perspective. But, we want to know, what's been your biggest challenge so far while memorizing this vital information? Leave your thoughts below and let's engage in a discussion that will motivate us all. Remember, don't just study harder, study smarter. Join the conversation and elevate your NAPLEX studying game.
https://youtu.be/C1Rb4BFugzo
This ppt describes the anti-arrhythmic drugs pharmacology and the treatment of various arrhythmias. Novel drugs in clinical trials and older drugs with repurposed formulations also have been included. Useful for MD Pharmacology residents as well as MBBS students.
Malignant hyperthermia is a potentially fatal hyperdynamic response due to pharmacogenetic abnormalities. This ppt gives a brief description of pathology and pharmacotherapy of malignant hyperthermia.
The ppt is made for undergraduate students to have a basic understanding on Corticosteroids and its role in all feilds of medicine. This is also useful to Postgraduate students
Gout is a type of inflammatory arthritis that causes permanent disability if left untreated. This presentation focuses on the important salient points we need to remember in Gout in all aspects - diagnosis, managment (both non-pharmacological and pharmacological approaches).
This presentation is useful to both MBBS and Postgraduate students of Pharmacology.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
1. Dr. Arun.S
First year Post Graduate
Department of Pharmacology
Government Medical College
Ananthapuramu
2. SPECIFIC LEARNING OBJECTIVES - AT THE END OF THE
SEMINAR THE LEARNER WILL BE ABLE TO
1. Define and Describe Biotransformation of drugs
and Factors affecting it
2. Describe first pass metabolism
3. Describe the drug metabolizing enzymes
2. Describe Enzyme induction and inhibition
3. Describe the process of elimination of drugs
3. DEFINITION
• Pharmacokinetics deals with Absorption, Distribution, Metabolism an
Excretion of the drugs.
• Pharmacon - drug
• kinesis - movement
• It is a branch which deals with “what the body does to the drug”.
• It is also called ADME study.
4.
5. BIOTRANSFORMATION OF DRUGS
• Enzyme catalysed biochemical transformation of drugs within the living
organism.
• Lipid soluble to lipid insoluble - Not reabsorbed in kidney.
• Sites:
Liver (m.c)
Kidney
Lungs
Intestine (small & large)
Adrenal cortex
Placenta
Skin
6. 4 CONSEQUENCES OF BIOTRANSFORMATION
1. Inactive metabolite from active drug:
Eg - Paracetamol, propranolol, phenobarbitone, morphine, etc
2. Active metabolite from inactive (prodrug) or a less active drug:
/
Eg - L-Dopa Dopamine (in basal ganglia)
Prednisone Prednisolone
Enalapril Enalaprilat
Dipivefrine Epinephrine
7. 3. Active metabolite from an equally active drug:
Eg - Digitoxin Digoxin
Morphine Morphine - 6 - glucuronide
Allopurinol Alloxanthine
4. Formation of toxic metabolite:
Eg:
Paracetamol N-acetyl-p-benzoquinoneimine (NAPQI)
Cyclophosphamide Acrolein
13. Attributes of drugs with high first pass metabolism:
(a) Oral dose >> sublingual or parenteral dose.
(b) Marked individual variation in the oral dose due to differences in the extent of first
pass metabolism.
(c) Oral bioavailability is apparently increased in patients with severe liver disease.
(d) Oral bioavailability of a drug is increased if another drug competing with it in first pass
metabolism is given concurrently, e.g. chlorpromazine and propranolol.
17. PHASE - 1 REACTIONS
• Degradative reactions
• Metabolite formed - active / inactive
• Mostly CYP mediated.
• Introduction of a new group - smaller non-polar / polar
18.
19.
20.
21. PHASE - 2 REACTIONS
• Conjugation reactions
• Catalysed by Microsomal, mitochondrial or cytoplasmic enzymes
• Metabolite - polar, water soluble - inactive
36. CYP 450 SYSTEM
• Superfamily of heme containing sozymes located primarily in the smooth endoplasmic
reticulum of liver and GI tract.
• Metabolism of
1. Endogenous compounds (steroids and lipids)
2. Exogenous compounds - drugs, carcinogens, and environmental pollutants
• Metabolize only lipid soluble drugs
• Phase 1 (oxi, red, hyd) and phase 2 (glucuronyl conj)
47. ENZYME INDUCTION
• Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of
microsomal enzyme protein, especially cytochrome P-450 and UGTs.
48.
49. CLINICAL SIGNIFICANCE OF ENZYME INDUCTION:
1. Decreased intensity and/or duration of action of drugs. e.g. Unwanted pregnancy -
failure of contraception with oral contraceptives, Phenytoin - ↑ metabolism of Vit D -
Osteomalacia
2. Increases intensity of drug action - Acute paracetamol toxicity in alcoholics
3. Tolerance - due to autoinduction - increase dose after 2 weeks. Eg - Carbamazepine,
rifampin, nevirapine
4. Faster metabolism of endogenous substrates.
5. Interference with chronic toxicity testing
50. USES OF ENZYME INDUCTION
1. Congenital nonhaemolytic jaundice: deficient glucuronidation of bilirubin -
phenobarbitone hastens clearance of jaundice.
2. Cushing’s syndrome: phenytoin - enhances degradation of adrenal steroids.
3. Chronic poisonings: by faster metabolism of the accumulated poisonous substance.
51.
52. ENZYME INHIBITION
• Rapid process, usually reversible
• Irreversible - secobarbital (antoinhibition of its own metabolism) - overdose
• Enzymes involved - Hepatic Microsomal mixed function oxidase (MFO), MAO,
Xanthine oxidase, etc.
55. THERAPEUTICALLY BENEFICIAL CONSEQUENCES:
• ↑ L-dopa in brain when given with Carbidopa
• Alcohol deaddiction with disulfiram
• d-tubocurarine induced skeletal muscle paralysis - reversed by neostigmine
56.
57. DRUG CLEARANCE THROUGH METABOLISM
• Drug enters the body - elimination begins (Elimination - Biotransformation + excretion)
• 3 major pathways:
hepatic metabolism,
biliary elimination,
urinary excretion.
Clearance (CL) estimates the volume of blood from which the drug is cleared per unit of
time.
Total CL - reflects all mechanisms of drug elimination
CL = Rate of elimination / plasma conc.
CL = 0.693 × Vd / t1/2
58. RATE OF ELIMINATION (R) OF PARTICULAR ORGAN
R = Amount of drug entering the organ per unit time -- Amount of drug leaving the organ per
unit time
R = Q.CA – Q.CV
Q is Rate of blood flow to that organ
CA is Concentration of drug in arteries entering that organ
CV is Concentration of drug in veins leaving that organ
Thus, R = Q. (CA – CV)
Since, CL = Rate of elimination / plasma conc.
CL = Q. (CA – CV) = Q. = Q x Extraction ratio.
Q. CA
Extraction ratio = CL / Q
59. HEPATIC EXTRATION RATIO
• Fraction of the absorbed drug prevented by the liver from reaching systemic circulation.
• Both presystemic metabolism as well as direct excretion into bile determine ERLiver,
• Orally given drugs - active metabolites reach the blood
• Parenterally give drug - directly reaches the blood
• So if active metabolites cause more ADR than the parent drug, Oral is less safe than
parenteral route.
60. EXCRETION OF DRUGS
Major routes
1. Renal
2. Biliary
3. Faecal
4. Alveolar
Minor routes
1. Breast milk
2. Skin
3. Hair
4. Sweat
5. Saliva
65. RENAL EXCRETION
TUBULAR REABSORPTION
• Passive diffusion - lipid solubility, pH of urine and pKa of the drug.
• Acidic drugs are more reabsorbed - urinary pH - acidic
Significance:
• In poisonings,
1. Acidification of urine by Ammonium chloride / Ascorbic acid / Acetazolamide
2. Alkalinization of urine by Sodium bicarbonate / sodium citrate
66.
67. BILIARY EXCRETION AND ENTEROHEPATIC CIRCULATION
Drugs > 500 Da weight are secreted in bile
Conjugation with glucuronic acid increases the molecular weight of the substrate by almost 200 Da,
so bile is an important route for eliminating glucuronide conjugates.
Drugs eliminated via bile into feces:
• Quinine
• colchicine
• d-tubocurarine
• corticosteroids
• erythromycin
Biliary Clearance = Biliary excretion rate
Plasma drug conc.
68. ENTEROHEPATIC CIRCULATION
• A drug can be recycled between the gut lumen,
hepatic portal vein, liver, bile and back to the gut
lumen;
• This is described as enterohepatic circulation.
• Some of the reabsorbed drug may escape hepatic
extraction and proceed into the hepatic vein,
maintaining the drug concentrations in the general
circulation.
69.
70. FAECAL ELIMINATION
• Orally ingested drugs - not absorbed throughout the gut
• Examples
1. Magnesium sulfate
2. Streptomycin
3. Neomycin
4. Bacitracin
5. Cholestyramine
6. Laxatives
71. ALVEOLAR EXCRETION
• Gases and volatile liquids - breath
• Excretion depends on partial pressure of the gaseous drug in the blood, not on lipid
solubility
• Essential oils - eucalyptus oil and garlic oil - via cough / mucous expectoration.
72. EXCRETION THROUGH BREAST MILK
• pH partition principle
• Basic drugs - trapped in relatively acidic pH
of breast milk.
• Basc drugs secreted via breast milk:
1. Chloramphenicol
2. Tetracyclines
3. Morphine
4. Metronidazole
5. Cytotoxic drugs
6. Diazepam
7. Oral contraceptives
8. Anti-histamines
9. Purgatives
10. Carbimazole
• Non electrolytes:
Ethanol, urea - independent of milk pH.
• Acidic drugs secreted
1. Sulfonamides
2. Penicillins
3. Ampicillin
4. Dapsone
5. Phenobarbitone
6. Theophylline
76. TOTAL BODY CLEARANCE
• The total body (systemic) clearance, CLtotal, is the sum of all clearances from the drug-
metabolizing and drug-eliminating organs.
Care should be exercised while administering:
• renally excreted drugs;
• drugs with a narrow therapeutic index—digoxin;
• drugs which produce active metabolites
benzodiazepines (diazepam + chlordiazepoxide),
antipsychotics (risperidone, thioridazine), and
opioids (morphine, pethidine, dextropropoxyphene); and
• drugs that may further reduce renal function—NSAIDs.
77. FACTORS AFFECTING DRUG METABOLISM
1. Age
2. Sex
3. Species
4. Race
5. Genetic variation
6. Nutrition and diet
7. Pregnancy
8. Thyroid imbalance
9. Temporal factors
10. Diseases
11. Drug-Drug interactions - Enzyme induction / inhibition
78. FACTORS AFFECTING DRUG METABOLISM
1. AGE:
Neonates and infants - low microsomal enzymes and glucuronyl transferase.
The activity of CYP450 enzymes in neonates is <<< adult human
Grey baby syndrome - chloramphenicol
Floppy baby syndrome - Diazepam
Elderly age - ↓ Hepatic blood flow - slow metabolism of propranolol and pethidine - toxicity
2. SEX:
Males - ↑ BMR - efficient metabolism - salicylates, alcohol, propranolol and
benzodiazepines.
79.
80. FACTORS AFFECTING DRUG METABOLISM
3. SPECIES
Atropine metabolism - Rabbits > Man
4. RACE
Eskimos metabolize drugs faster than Asians.
Chinese - ↑ alcohol dehydrogenase, ↓ Aldehyde dehydrogenase - More aldehydes in blood
- more symptoms of headache, palpitation.
5. NUTRITION AND DIET:
Protein rich diet - ↑ Metabolism of drugs
Carb rich diet - ↓ Metabolism of drugs
Starvation - enzyme inhibition.
85. KINETICS OF METABOLISM
Terminologies:
• Plasma Half life (t1/2)
• Biological half life
• Biological effect half life
• Terminal half life
• Steady state concentration
• Plasma half life and Vd is very important to consider dosing schedule for any drug.
• 3 types of kinetics
First order
Zero order
Mixed order kinetics
86. PLASMA T1/2
• Significance of Plasma t½:
To know the,
The duration of action of the drug
The frequency of administration
The time needed for attainment of steady state concentration (SSC)—longer the t½,
longer is the time needed to attain SSC.
To calculate the loading and maintenance doses of the drug
88. STEADY STATE CONCENTRATION
• Repeated administration of drug at short intervals before complete elimination - Drug
accumulation in the body - rate of elimination equals rate of administration.
• It takes 4 - 5 half-lives for the plasma concentration to reach the plateau level.
92. FIRST ORDER KINETICS
• Drugs obey Michaelis–Menten kinetics, where Km is Michaelis constant (the substrate
concentration at half maximal velocity).
• In most clinical situations, Km >> [C]
• Rate of drug metabolism and elimination - directly proportional - concentration of free
drug.
• A constant fraction of drug is metabolized per unit of time (with each half-life, the
concentration decreases by 50%).
• Linear kinetics
94. ZERO ORDER KINETICS
• Here [C] >> Km
• Fixed amount of the drug is eliminated per unit time
• The rate of elimination is constant and does not depend on the drug concentration
• Non-linear kinetics
• Repeated drug administration over short intervals - lead to toxicity.
• The only way to speed the elimination process is to go for dialysis
• The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains
constant over time.
95. MIXED ORDER KINETICS OR
MICHAELIS MENTON KINETICS OR
SATURATION KINETICS
• Low dose - first order kinetics
• High doses - Zero order kinetics
• Eg - Aspirin, warfarin, digoxin, tolbutamide etc.
• Most of the drugs like phenytoin, undergo both first
and zero order kinetics at normal doses due to
saturation of enzymatic process
96. REFERENCES
1. Goodman and Gilman - The pharmacological basis of therapeutics - 14th edition
2. Lippincott’s Pharmacology - First South Asian edition
3. K.D.Tripathi - Medical Pharmacology - 8th edition
4. Padmaja Udaykumar - Medical Pharmacology - 7th edition
5. HL & KL Sharma - Principles of Pharmacology - 3rd edition
6. Review of Pharmacology - Gobind Rai Gag - 14th edition
7. Brenner and Steven’s Pharmacology - 6th edition
Editor's Notes
Metabolism of a drug can begin even before a drug is absorbed: Gut bacteria represent the first metabolic interface between orally administered drugs and the body.
Interindividual differences in composition of the gut flora could influence drug action and contribute to differences in drug response
Xenobiotic-metabolizing enzymes can produce electrophilic metabolites that react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. This can cause cell death and organ toxicity – Carcinogenesis.
This potential for carcinogenic activity makes testing the safety of drug candidates vitally important. Testing for cancer-causing potential is particularly critical for drugs that will be used for the treatment of chronic diseases.
Other organs that contain significant xenobiotic metabolizing enzymes include tissues of the nasal mucosa and lung, which play important roles in the metabolism of drugs that are administered through aerosol sprays. These tissues are also the first line of contact with hazardous substances that are airborne.
Prodrugs bioactivated by CYPs are the antitumor drug cyclophosphamide, which is bioactivated to a cell-killing electrophilic derivative.
Anti-thrombotic agent clopidogrel, which is activated to 2-oxo-clopidogrel and further metabolized to an irreversible inhibitor of platelet ADP P2Y12 receptors.
The liver is the major “metabolic clearinghouse” for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins) and xenobiotics.
The phase 1 enzymes lead to the introduction of functional groups, such as –OH, –COOH, –SH, –O–, or NH2.
The phase 1 oxidation reactions are carried out by CYPs, FMOs, and epoxide hydrolases (EHs). The CYPs and FMOs are composed of superfamilies and subfamilies encoded by multiple genes. The phase 2 enzymes include several superfamilies of conjugating enzymes. Among the more important are the glutathione-S-transferase (GSTs), UGTs, sulfotransferases (SULTs), N-acetyltransferases (NATs), and methyltransferases (MTs).
The conjugation reactions of the phase 2 enzymes usually require the substrate to have oxygen (hydroxyl or epoxide groups), nitrogen, or sulfur atoms that serve as acceptor sites for a hydrophilic moiety, such as glutathione, glucuronic acid, sulfate, or an acetyl group, that can be covalently conjugated to an acceptor site on the substrate.
Induction involves microsomal enzymes in liver as well as other organs and increases the rate of metabolism by 2–4 fold. Induction takes 4–14 days to reach its peak and is maintained till the inducing agent is being given. Thereafter the enzymes return to their original value over 1–3 weeks.
Plasma half-life (t½) is the time taken for the plasma concentration of a drug to be reduced to half its value
Biological half-life is the time required for total amount of drug in the body to be reduced to half.
Biological effect half-life is the time required for the biological effect of the drug to reduce to half.
Terminal half-life: On long-term use, certain drugs may remain in secondary compartments and they get gradually released into the circulation as the plasma concentration of drugs fall.