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. The four main parameters generally examined by this field include absorption, distribution, metabolism, and excretion (ADME). Wielding an understanding of these processes allows practitioners the flexibility to prescribe and administer medications that will provide the greatest benefit at the lowest risk and allow them to make adjustments as necessary, given the varied physiology and lifestyles of patients.
When a provider prescribes medication, it is with the ultimate goal of a therapeutic outcome while minimizing adverse reactions. A thorough understanding of pharmacokinetics is essential in building treatment plans involving medications. Pharmacokinetics, as a field, attempts to summarize the movement of drugs throughout the body and the actions of the body on the drug. By using the above terms, theories, and equations, practitioners can better estimate the locations and concentrations of a drug in different areas of the body.
The appropriate concentration needed to obtain the desired effect and the amount needed for a higher chance of adverse reactions is determined through laboratory testing. Using the equations given above, a clinician can easily estimate safe medication dosing over a period of time and how long it will take for a medication to leave a patient’s system. These are, however, statistically-based estimations, influenced by differences in the drug dosage form and patient pathophysiology. This is why a deep understanding of these concepts is essential in medical practice so that improvisation is possible when the clinical situation requires it.
ADME is the abbreviation for Absorption, Distribution, Metabolism and Excretion. ADME studies are designed to investigate how a chemical (e.g. a drug compound) is processed by a living organism. Toxicology tests are often a part of this process, yielding the acronym ADMET.
ADME is the abbreviation for Absorption, Distribution, Metabolism and Excretion. ADME studies are designed to investigate how a chemical (e.g. a drug compound) is processed by a living organism. Toxicology tests are often a part of this process, yielding the acronym ADMET.
Pharmacokinetics and Pharmacodynamic- General Pharmacology Ravinandan A PRavinandan A P
Pharmacokinetics and Pharmacodynamic- General Pharmacology Ravinandan A P - 2. Delivered a guest lecturer on “Pharmacokinetics and Pharmacodynamics” in Continuing Medical Education (CME) program, organized by Taluk Doctor’s Association Chalkere Taluk, Chitradurga District, Karnataka on 28th Sep 2010.
Pharmacokinetics of Drug_Pharmacology Course_Muhammad Kamal Hossain.pptxMuhammad Kamal Hossain
Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism and excretion (ADME) and their relationship with the pharmacological, therapeutic or toxicological response in man and animals.
GIT ABSORPTION FOR ORAL Administered DrugAli Mashwani
In this Lecture I have covered how the Drug is absorbed when it is administered orally, what is BCS classification system, Role of BCS and Importance of Biopharmaceutics Classification System. I have discussed how the Pharmakinetics process occur, what is Absorption, Distribution, Metabolism and Excretion.
Pharmacokinetics - drug absorption, drug distribution, drug metabolism, drug ...http://neigrihms.gov.in/
A power point presentation on general aspects of Pharmacokinetics suitable for undergraduate medical students beginning to study Pharmacology. Also suitable for Post Graduate students of Pharmacology and Pharmaceutical Sciences.
Implants- B.Pharm SEM 7- Novel Drug Delivery Systemvedanshu malviya
Implantable drug delivery device classification is not a straightforward task as there are a number of complex implants that will fall into hybrid categories. Nevertheless, implantable drug delivery devices can be broadly classified in two main groups: passive implants and active implants. The first group includes two main types of implants: biodegradable and non-biodegradable implants. On the other hand, active systems rely on energy dependent methods that provide the driving force to control drug release. The second group includes devices such as osmotic pressure gradients and electromechanical drives.
Enzyme Immobilization- Biotechnology- B.Pharm SEM 5vedanshu malviya
Immobilization is a technical process in which enzymes are fixed to or within solid supports, creating a heterogeneous immobilized enzyme system. Immobilized form of enzymes mimic their natural mode in living cells, where most of them are attached to cellular cytoskeleton, membrane, and organelle structures.
Pharmacokinetics and Pharmacodynamic- General Pharmacology Ravinandan A PRavinandan A P
Pharmacokinetics and Pharmacodynamic- General Pharmacology Ravinandan A P - 2. Delivered a guest lecturer on “Pharmacokinetics and Pharmacodynamics” in Continuing Medical Education (CME) program, organized by Taluk Doctor’s Association Chalkere Taluk, Chitradurga District, Karnataka on 28th Sep 2010.
Pharmacokinetics of Drug_Pharmacology Course_Muhammad Kamal Hossain.pptxMuhammad Kamal Hossain
Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism and excretion (ADME) and their relationship with the pharmacological, therapeutic or toxicological response in man and animals.
GIT ABSORPTION FOR ORAL Administered DrugAli Mashwani
In this Lecture I have covered how the Drug is absorbed when it is administered orally, what is BCS classification system, Role of BCS and Importance of Biopharmaceutics Classification System. I have discussed how the Pharmakinetics process occur, what is Absorption, Distribution, Metabolism and Excretion.
Pharmacokinetics - drug absorption, drug distribution, drug metabolism, drug ...http://neigrihms.gov.in/
A power point presentation on general aspects of Pharmacokinetics suitable for undergraduate medical students beginning to study Pharmacology. Also suitable for Post Graduate students of Pharmacology and Pharmaceutical Sciences.
Implants- B.Pharm SEM 7- Novel Drug Delivery Systemvedanshu malviya
Implantable drug delivery device classification is not a straightforward task as there are a number of complex implants that will fall into hybrid categories. Nevertheless, implantable drug delivery devices can be broadly classified in two main groups: passive implants and active implants. The first group includes two main types of implants: biodegradable and non-biodegradable implants. On the other hand, active systems rely on energy dependent methods that provide the driving force to control drug release. The second group includes devices such as osmotic pressure gradients and electromechanical drives.
Enzyme Immobilization- Biotechnology- B.Pharm SEM 5vedanshu malviya
Immobilization is a technical process in which enzymes are fixed to or within solid supports, creating a heterogeneous immobilized enzyme system. Immobilized form of enzymes mimic their natural mode in living cells, where most of them are attached to cellular cytoskeleton, membrane, and organelle structures.
Concept of Health and Diseases- B.Pharm Semester 7vedanshu malviya
health is a state of bodily equilibrium while disease is a state of homeostatic failure. But the process of human growth as Boorse observed is itself leading to homeostatic disequilibrium . Value: disease is undesirable while health is desirable. Health is thus a social value in human society.
Microencapsulation in Novel Drug Delivery Systemvedanshu malviya
Microencapsulation is a process in which tiny particles or droplets are surrounded by a coating to give small capsules, with useful properties. In general, it is used to incorporate food ingredients, enzymes, cells or other materials on a micro metric scale.
Pharmaceutical film coating is considered a key part in the production of solid pharmaceutical dosage forms since it gives superior organoleptic properties products. In addition, it can improve the physical and chemical stability of dosage forms, and modify the release characteristics of the drug. Several troubleshooting problems such as twinning mottling, chipping, etc., may arise during or after or even during the shelf life of the film coated dosage forms. These troubleshooting problems may be due to tablet core faults, coating formulation faults and/or coating process faults. These problems must be overcome to avoid unnecessary product problems. Film coating as well as other parts of the pharmaceutical technology is subjecting to continuous innovation. The innovation may be at different levels including pharmaceutical excipients, processes, software, guidelines and equipment. In fact, of particular note is the growing interest in process analytical technology, quality by design, continuous coating processing and the inclusion of new ready for use coating formulations. In this review, we tried to explore and discuss the status of pharmaceutical film coating, the challenges that face this manufacturing process and the latest technological advances in this important manufacturing process.
The most common tablet manufacturing process techniques are wet granulation, dry granulation, and direct compression.
Your active pharmaceutical ingredients’ (APIs) physical and chemical stability influences manufacturing.
For successful tablet manufacturing, you need granulators, mixing equipment, drying machinery, and coating systems.
Even if you’re using the right equipment to manufacture your product, there is a wide range of common tablet defects that can occur that affect quality.
There are several goals to aim for during the tablet manufacturing process:
Develop tablets that are strong and hard enough to hold up against mechanical shock during manufacturing, packaging, shipping, and dispensing
Formulate tablets that are uniform in weight and drug content
Manufacture bioavailable products according to indication requirements
Create chemically and physically stable tablets that last over long periods
Formulate products that are free of defects and have an elegant finish
Pharmacovigilance supports safe and appropriate use of drugs. Spontaneous reporting of adverse drug reactions (ADRs) is an essential component of pharmacovigilance. However, there is significant underreporting of ADRs. Adverse drug reactions have become a major problem in developing countries. Knowledge of pharmacovigilance could form the basis for interventions aimed at improving reporting rates and decreasing ADRs.
Biopharmaceutics is a scientific discipline that examines the interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption.
Ayurveda, the knowledge of life, immortalized in the form of elegant Sanskrit stanzas in the samhitas describe diagnosis and therapy of disease as well as ways to maintain positive health. Although the technical term “Pharmacovigilance” does not feature in ayurvedic texts, the spirit of pharmacovigilance is vibrant and is emphasized repeatedly in all major texts. The major goals of pharmacovigilance, namely to improve patient care and safety in relation to drug use, and thus promote rational drug use are recurrent themes of ayurvedic pharmacology (dravyaguna vigyan) and therapeutics (chikitsa).
Mixing is a general term that includes stirring, beating, blending, binding, creaming, whipping, and folding. In mixing, two or more ingredients are evenly dispersed in one another until they become one product.
The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States.
What is ICH Q8 guidelines?
Image result for ICH Pharmaceutical development guideline-Q8
The ICH Q8 guideline is intended to provide guidance on the contents of Section 3.2. P. 2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH topic M4).
ICH Q7A means the good manufacturing practice guidance for active pharmaceutical ingredients developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
Tablet defects can come from any of the unit operations upstream and from the tablet press. The raw materials may be of poor quality or do not meet specifications, causing excessive fines that lead to a host of defects. The formulation may be the source of defects if the material does not compress well or the processing step specified within the formulation fail to produce a powder with a good flow, compressibility, and ejection properties. The processing and granulation of powder are often the sources of the defect.
Every product behaves differently on a tablet press, even if it‘s the same product run on a different day. The variation often
stems from changes in the properties of the raw materials—active ingredients and excipients- from batch to batch. Naturally,
the goal is to minimize these changes. Tablet press operators, however, don‘t have any control over formulation and
granulation. Tablet specifications are tight, and the list of possible defects is long: Variable weight, sticking, picking, capping, lamination, variable hardness, among others. This article focuses on these variations. It pinpoints the possible causes of these defects and offers advice on preventing and fixing the source of the problems.
The main principle involved in the FBP is the air suspension in which the material to be coated is suspended in the coating material with the help of an air stream. A fluid bed processor (fbp) is a popular material processing technique in different field industries.
The suspension dosage form has long been used for poorly soluble active ingredients for various therapeutic indications. Development of stable suspensions over the shelf life of the drug product continues to be a challenge on many fronts.
Distillation, or classical distillation, is the process of separating the components or substances from a liquid mixture by using selective boiling and condensation. Dry distillation is the heating of solid materials to produce gaseous products. Early evidence of distillation was found on Akkadian tablets dated c. 1200 BCE describing perfumery operations. The tablets provided textual evidence that an early primitive form of distillation was known to the Babylonians of ancient Mesopotamia.[8] Early evidence of distillation was also found related to alchemists working in Alexandria in Roman Egypt in the 1st century CE.
Polymorphism is the ability of solid materials to exist in two or more crystalline forms with different arrangements or conformations of the constituents in the crystal lattice. ... More than 50% of active pharmaceutical ingredients (APIs) are estimated to have more than one polymorphic form
Conductometry is a measurement of electrolytic conductivity to monitor the progress of the chemical reactions. Conductometry has notable application in analytical chemistry, where conductometric titration is a standard technique.
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
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
3. Pharmacokinetics (PK)
The study of the disposition of a drug
The disposition of a drug includes the processes of
ADME
Absorption
Distribution
Metabolism
Excretion
Toxicity
Elimination
5. DRUG R&D
Drug discovery and development
•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million – 1 billion dollars (US)
7. Importance of PK studies
Patients may suffer:
Toxic drugs may accumulate
Useful drugs may have no benefit because doses are
too small to establish therapy
A drug can be rapidly metabolized.
9. Absorption
The process by which drug proceeds from the site of
administration to the site of measurement (blood stream) within
the body.
Necessary for the production of a therapeutic effect.
Most drugs undergo gastrointestinal absorption. This is extent to
which drug is absorbed from gut lumen into portal circulation
Exception: IV drug administration
10. IV vs Oral
I.V Drug Oral Drug
Immediately Delayed
completely incomplete
11. Absorption relies on
Passage through membranes to reach the blood
passive diffusion of lipid soluble species.
The Process
12. The Rule of Five - formulation
There are more than 5 H-bond donors.
The molecular weight is over 500.
The LogP is over 5.
There are more than 10 H-bond acceptors.
Poor absorption or permeation are
more likely when:
14. First Pass Metabolism
Bioavailability: the fraction of the administered dose reaching the systemic
circulation
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
15. Determination of bioavailability
A drug given by the intravenous route will
have an absolute bioavailability of 1 (F=1
or 100% bioavavailable)
While drugs given by other routes usually
have an absolute bioavailability of less
than one.
The absolute bioavailability is the area
under curve (AUC) non-intravenous
divided by AUC intravenous .
16. Toxicity
The therapeutic index is the
degree of separation
between toxic and
therapeutic doses.
Relationship Between Dose,
Therapeutic Effect and
Toxic Effect. The
Therapeutic Index is Narrow
for Most Cancer Drugs
100× 10×
18. DISTRIBUTION
Determined by:
• partitioning across various membranes
•binding to tissue components
•binding to blood components (RBC, plasma protein)
•physiological volumes
19. DISTRIBUTION
All of the fluid in the body (referred to as the total body water), in which a drug
can be dissolved, can be roughly divided into three compartments:
intravascular (blood plasma found within blood vessels)
interstitial/tissue (fluid surrounding cells)
intracellular (fluid within cells, i.e. cytosol)
The distribution of a drug into these compartments is dictated by it's physical
and chemical properties
21. Distribution
Apparent volume of distribution (Vd) =
Amt of drug in body/plasma drug conc
VOLUME OF DISTRIBUTION FOR SOME DRUGS
DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000
22. Factors affecting drugs Vd
Blood flow: rate varies widely as function of tissue
Muscle = slow
Organs = fast
Capillary structure:
•Most capillaries are “leaky” and do not impede diffusion of drugs
•Blood-brain barrier formed by high level of tight junctions between cells
•BBB is impermeable to most water-soluble drugs
23. Blood Brain Barrier
•Disruption by osmotic means
•Use of endogenous transport
systems
•Blocking of active efflux
transporters
• Intracerebral implantation
•Etc
24. Plasma Protein Binding
Many drugs bind to plasma proteins in the blood
steam
Plasma protein binding limits distribution.
A drug that binds plasma protein diffuses less
efficiently, than a drug that doesn’t.
25. Physiochemical properties-
Po/w
The Partition coefficient (Po/w) and can be used to determine
where a drug likes to go in the body
Any drug with a Po/w greater than 1(diffuse through cell
membranes easily) is likely be found throughout all three fluid
compartments
Drugs with low Po/w values (meaning that they are fairly water-
soluble) are often unable to cross and require more time to
distribute throughout the rest of the body
26. Physiochemical Properties-
Size of drug
•The size of a drug also dictates where it can go in the body.
•Most drugs : 250 and 450 Da MW
•Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through cell
membranes
•Antibodies and other drugs range into the thousands of daltons
•Drugs >200 Da with low Po/w values cannot passively cross membranes- require specialized
protein-based transmembrane transport systems- slower distribution
•Drugs < thousand daltons with high Po/w values-simply diffuse between the lipid molecules that
make up membranes, while anything larger requires specialized transport.
27. Elimination
The irreversible removal of the parent drugs
from the body
Elimination
Drug Metabolism
(Biotransformation)
Excretion
28. Drug Metabolism
The chemical modification of drugs with the overall goal of
getting rid of the drug
Enzymes are typically involved in metabolism
Drug
Metabolism
More polar
(water soluble)
Drug
Excretion
29. •From 1898 through to 1910 heroin was marketed as a non-addictive morphine
substitute and cough medicine for children. Bayer marketed heroin as a cure for
morphine addiction
•Heroin is converted to morphine when metabolized in the liver
METABOLISM
30. Phases of Drug Metabolism
Phase I Reactions
Convert parent compound into a more polar (=hydrophilic) metabolite
by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH,
etc.) eg. oxidation
Often these metabolites are inactive
May be sufficiently polar to be excreted readily
31. Phases of metabolism
Phase II Reactions
Conjugation with endogenous substrate to further increase
aqueous solubility
Conjugation with glucoronide, sulfate, acetate, amino acid
32. Mostly occurs in the
liver because all of the
blood in the body
passes through the liver
33. The Most Important Enzymes
Microsomal cytochrome P450 monooxygenase family of
enzymes, which oxidize drugs
Act on structurally unrelated drugs
Metabolize the widest range of drugs.
34. • Found in liver, small intestine, lungs, kidneys, placenta
• Consists of > 50 isoforms
• Major source of catalytic activity for drug oxidation
• It’s been estimated that 90% or more of human drug oxidation can be attributed
to 6 main enzymes:
• CYP1A2 • CYP2D6
• CYP2C9 • CYP2E1
• CYP2C19 • CYP3A4
In different people and different populations, activity of CYP oxidases
differs.
CYP family of enzymes
35.
36. Inhibitors and inducers of microsomal
enzymes
Inhibitors: cimetidine prolongs action of drugs or inhibits action of
those biotransformed to active agents (pro-drugs)
Inducers: barbiturates, carbamazepine shorten action of drugs or
increase effects of those biotransformed to active agents
Blockers: acting on non-microsomal enzymes (MAOI,
anticholinesterase drugs)
37. Phase II
Main function of phase I reactions is to prepare chemicals
for phase II metabolism and subsequent excretion
Phase II is the true “detoxification” step in the metabolism
process.
38. Phase II reactions
Conjugation reactions
Glucuronidation (on -OH, -COOH, -NH2, -SH groups)
Sulfation (on -NH2, -SO2NH2, -OH groups)
Acetylation (on -NH2, -SO2NH2, -OH groups)
Amino acid conjugation (on -COOH groups)
Glutathione conjugation (to epoxides or organic halides)
Fatty acid conjugation (on -OH groups)
Condensation reactions
39. Glucuronidation
Conjugation to a-d-glucuronic acid
Quantitatively the most important phase II pathway for drugs and endogenous
compounds
Products are often excreted in the bile
40. Phase I and II - Summary
Products are generally more water soluble
These reactions products are ready for (renal) excretion
There are many complementary, sequential and competing pathways
Phase I and Phase II metabolism are a coupled interactive system interfacing with
endogenous metabolic pathways
41. Excretion
The main process that body eliminates "unwanted"
substances.
Most common route - biliary or renal
Other routes - lung (through exhalation), skin (through
perspiration) etc.
Lipophilic drugs may require several metabolism steps before
they are excreted