Pharmacokinetics is the study of how the body affects drugs. It involves absorption, distribution, metabolism, and excretion of drugs. Absorption is how drugs enter the bloodstream and distribution is how drugs spread to tissues. Metabolism converts drugs to inactive forms through phase I (oxidation) and phase II (conjugation) reactions. Excretion eliminates drugs from the body. Together, these processes determine the effects of drugs over time.
suspension therapy in details with the principles, indications, benefits, advantages and disadvantages, materials required for performing activities using suspension techniques.
suspension therapy in details with the principles, indications, benefits, advantages and disadvantages, materials required for performing activities using suspension techniques.
In physics, a force is any interaction that, when unopposed, will change the motion of an object. A force can cause an object with mass to change its velocity, i.e., to accelerate. Force can also be described intuitively as a push or a pull. A force has both magnitude and direction, making it a vector quantity.
Watch other topics in http://bit.ly/2PIOIQM
Gait control theory of pain given by Melzack & Wall in 1965. This is very much helpful for those medical/paramedical professionals who deal with subjects having pain.
A chronicle on muscle strengthening:
MMT is a procedure for the evaluation of strength of individual
muscle or muscles group, based upon the effective performance of a movement in relation to the forces of gravity or manual resistance through the available ROM.
Joint mobilization refers to a technique of manual therapy by which a therapist applies a brief stretch of 30s or less through traction and gliding along a joint surface.
Principles of surgical and antimicrobial infection managemen/ dental crown & ...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
In physics, a force is any interaction that, when unopposed, will change the motion of an object. A force can cause an object with mass to change its velocity, i.e., to accelerate. Force can also be described intuitively as a push or a pull. A force has both magnitude and direction, making it a vector quantity.
Watch other topics in http://bit.ly/2PIOIQM
Gait control theory of pain given by Melzack & Wall in 1965. This is very much helpful for those medical/paramedical professionals who deal with subjects having pain.
A chronicle on muscle strengthening:
MMT is a procedure for the evaluation of strength of individual
muscle or muscles group, based upon the effective performance of a movement in relation to the forces of gravity or manual resistance through the available ROM.
Joint mobilization refers to a technique of manual therapy by which a therapist applies a brief stretch of 30s or less through traction and gliding along a joint surface.
Principles of surgical and antimicrobial infection managemen/ dental crown & ...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
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.
Pharmacokinetics is the study of the movement of drug molecules in the body. It includes absorption, distribution, metabolism, and excretion of drugs. Pharmacokinetics is the study of what happens to drugs once they enter the body (the movement of the drugs into, within, and out of the body). For a drug to produce its specific response, it should be present in adequate concentrations at the site of action. This depends on various factors apart from the dose.
Four pharmacokinetic properties determine the onset, intensity, and the duration of drug action (Figure 1.6.1):
• Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma.
• Distribution: Second, the drug may then reversibly leave the bloodstream and distribute it into the interstitial and intracellular fluids.
• Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues.
• Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces.
In short, pharmacokinetics means what the body does to the drug.
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.
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.
Similar to General Pharmacology for BPT Students (20)
Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
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Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
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The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
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Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
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2. What is Pharmacokinetics
how the human body act on the drugs?
Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body. Intensity of
effect is related to concentration of the drug at the site
of action, which depends on its pharmacokinetic
properties
Pharmacokinetic properties of particular drug is
important to determine the route of administration,
dose, onset of action, peak action time, duration of
action and frequency of dosing
3. Relationship – Dynamics and Kinetics
Absorption
Distribution
Metabolism
Excretion
Dosage Regimen
Concentration in
Plasma
Concentration at the
site of action
Pharmacokinetics
Pharmacodynamics
Effect
6. Drug Transportation
Drug molecules can cross cell membrane by:
Passive Diffusion
Protein – mediated transport (carrier mediated)
Facilitated Transport
Active trnsport
Primary
Secondary
7. Passive transport
(down hill movement)
Most important Mechanism for most of the Drugs
Majority of drugs diffuses across the membrane in the direction of
concentration gradient
No active role of the membrane
The rate of the transport being Proportional to lipid : water partition
coefficient
Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane
A more lipid solid drug attains higher concentration in the membrane
and diffuses quickly.
Also greater the difference in the concentration of the drug on the two
sides of the membrane, faster its diffusion.
8. Passive transport
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment
such as: fluid of body
fluid in cell
blood, urine
9. REMEMBER
The drugs which are Unionized, low polarity and
higher lipid solubility are easy to permeate
membrane.
The drugs which are ionized, high polarity and
lower lipid solubility are difficult to permeate
membrane.
10. pH Effect
Most of drugs are weak acids or weak
bases.
The ionization of drugs may markedly
reduce their ability to permeate
membranes.
The degree of ionization of drugs is
determined by the surrounding pH and
their pKa.
12. Implications
Acidic drugs re absorbed are largely unionized in stomach and
absorbed faster while basic drugs are absorbed faster in intestines
Ion trapping
Acidic drugs are excreted faster in alkaline urine – urinary
alkalizers
Basic drugs are excreted faster in acidic urine – urinary acidifiers
13. Filtration
Passage of Drugs through aqueous pores in
membrane or through Para cellular space
Lipid insoluble drugs can cross – if the molecular
size is small
Majority of intestinal mucosa and RBCs have small
pores and drugs cannot cross
But, capillaries have large paracellular space and
most drugs can filter through this
15. Carrier Mediated Transport
Involve specific membrane transport proteins know as drug
transporters or carriers – specific for the substrate
Drug molecules bind to the transporter, translocated across
the membrane, and then released on the on other side of
the membrane.
Specific, saturable and inhibitable
Depending on Energy requirement - Can be either
Facilitated (passive) or Active Transport
16. Facilitative transporters
Move substrate of a
single class (uniporters)
down a concentration
gradient
No energy dependent
Similar to entry of
glucose into muscle
(GLUT 4)
17. Active Transport – energy
dependent
Active (concentrative) transporters
can move solutes against a concentration gradient
energy dependent
Primary active transporters - generate energy
themselves (e.g. ATP hydrolysis)
Secondary transporters - utilize energy stored in
voltage and ion gradients generated by a primary
active transporter (e.g. Na+/K+-ATPase)
Symporters (Co-transporters)
Antiporters (Exchangers)
18. Major Drug
Transporters• ATP-Binding Cassette Transporters (ABC) Super family –
Primary active transport
• P-glycoprotein (P-gp encoded by MDR1)
• Intestinal mucosa, renal tubules and blood brain barrier etc.
• Mediate only efflux of solute from cytoplasm - detoxification
Solute Carrier (SLC) transporters – Secondary active transport
Organic anion transporting polypeptides (OATPs)
Organic cation transporters (OCTs)
Expressed in liver and renal tubules – metabolism and excretion of
drugs
19. It involves the invagination of a part of the cell
membrane and trapping within the cell of a small
vesicle containing extra cellular constituents. The
vesicle contents can than be released within the cell,
or extruded from the other side of the cell.
Pinocytosis is important for the transport of some
macromolecules (e.g. insulin through BBB).
Pinocytosis
20. 1. Absorption of Drugs
Absorption is the transfer
of a drug from its site of
administration to the blood
stream
Most of drugs are
absorbed by the way of
passive transport
Intravenous
administration has no
absorption
Fraction of administered
dose and rate of absorption
are important
21. Factors affecting absorption
Drug properties:
lipid solubility, molecular weight, and polarity etc
Blood flow to the absorption site
Total surface area available for absorption
Contact time at the absorption surface
Affinity with special tissue
Routes of Administration (important):
22. Route of administration:
Topical:
Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used
therapeutically
Examples – Hyoscine, Fentanyl, Nicotine, testosterone and
estradiol
Organophosphorous compounds – systemic toxicity
Abraded skin (burnt skin ): tannic acid – hepatic necrosis
Cornea permeable to lipid soluble drugs (absorbed from
nasolacrimal duct) e.g. timolol may produce bradycardia
and pricipitate asthma.
Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs
23. Route of administration:
Subcutaneous and Intramuscular:
Drugs directly reach the vicinity of capillaries –
passes capillary endothelium and reach
circulation.
Capillaries having large paracellular spaces do
not abstract absorption of large lipid insoluble
molecules or ions.
Very large molecules are absorbed through
lymphatics.
Passes through the large paracellular pores
Faster and more predictable than oral absorption
24. Route of administration: Oral Route
Physical properties – Physical state, lipid or water
solubility
Dosage forms:
Particle size
Disintegration time and Dissolution Rate
Formulation – Biopharmaceutics
Physiological factors:
Ionization, pH effect
Presence of Food
Presence of Other agents
25. Oral Administration – 1st
pass metabolism
Before the drug reaches the
systemic circulation, the
drug can be metabolized in
the liver or intestine. As a
Result, the concentration of
drug in the systemic
circulation will be reduced.
26. Absorption – contd.
Intravenous administration has no absorption phase
According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramuscular→sub
cutaneous→oral→transdermal
Example – Nitroglycerine:
IV effect – immediate, SL – 1 to 3 min and per rectal
– 40 to 60 minute
27. Bioavailability
Bioavailability refers to the rate and extent of absorption of a drug
from dosage form as determined by its concentration-time curve in
blood or by its excretion in urine. It is a measure of the fraction (F) of
administered dose of a drug that reaches the systemic circulation in the
unchanged form
Bioavailability of drug injected i.v. is 100%, but is frequently lower
after oral ingestion, because:
The drug may be incompletely absorbed
The absorbed drug may undergo first pass metabolism in intestinal wall
and/or liver or be excreted in bile.
Practical Significance – low safety margin drugs
29. BIOEQUVALENCE
Oral formulation of a drug from different manufactures
or different batches from the same mfr may have the
same amount of the drug (chemically equvalent) but
may not yield the same blood levels- biologically
inequivalent .
Before a drug administered orally in solid dosage form
can be absorbed,it must break into individual particle of
the active drug (disintegration) .Tablets and capsules
contains-diluents,stabilizing agents ,binders ,lubricants
etc.
30. Manufacture process – force used in compressing the
tablet may affect disintegration.
The rate of dissolution – solubility, particle size, crystal
form,and other physical properties of the drug.
Differences in bioavilability- may arise due to variation in
Disintegration and dissolution rates.
Reduction in particle size↑es the rate of absorption of
asprin(micrifine tablet)
31. 2. Distribution of Drugs
It is the passage of drug from the circulation to the
tissue and site of its action.
The extent of distribution of drug depends on its
lipid solubility, ionization at physiological pH
(dependent on pKa), extent of binding to plasma and
tissue proteins and differences in regional blood
flow,
Movement of drug - until equilibration between
unbound drug in plasma and tissue fluids
32. Volume of Distribution (V)
Definition: Apparent Volume of distribution is defined as
the volume that would accommodate all the drugs in the
body, if the concentration was the same as in plasma
Expressed as: in Liters
V =
Dose administered IV
Plasma concentration
34. Volume of Distribution (V)
Chloroquin – 13000 liters, Digoxin – 420 L,
Morphine – 250 L and Propranolol – 280 L
Streptomycin and Gentamicin – 18 L
35. Factors influencing Vd
Lipid solubility (lipid : water partition
coefficient)
pKa of the drug
Affinity for different tissues
Blood flow – Brain Vs Fat
Disease states
Plasma protein Binding
37. later ,less vascular but more bulky tissues take up the
drug –plasma concentration falls and the drug is
withdrawn from the sites.
Redistribution results in termination of the drug action.
Greater lipid solubility of a drug ,faster is its
redistribution.
Aneathetic action of thiopentone terminated in few min
due to redistribution.
38. Blood brain barrier (BBB): includes the capillary endothelial cells
(which have tight junctions and lack large intracellular pores) and an
investment of glial tissue, over the capillaries.
Brain and CSF Penetration
39. Brain and CSF Penetration –
contd
BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cell (also in intestinal mucosal, renal
tubular, hepatic canicular, placental and testicular cells)
extrude drugs that enter brain by other processes
brain increases permeability of BBB)
Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.
40. Placental Transfer
Only lipid soluble Drugs can penetrate –
limitation of hydrophillic drugs
Placental P-gp serves as limiting factor
But, REMEMBER, its an incomplete barrier –
some influx transporters operate
Thalidomide
41. Plasma Protein Binding
Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic drugs
bind to plasma albumin and basic drugs to α1-glycoprotein
Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively saturate
the binding sites
The clinical significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between PPB fraction of drug and
free molecules of drug.
42. Plasma Protein Binding – contd.
d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs(e.g. acenocoumarol, warfarin) or
endogenous compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting,
because bound fraction is not available for metabolism,
unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer
to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
44. What is Biotransformation?
Chemical alteration of the drug in the body
Aim: to convert non-polar lipid soluble
compounds to polar lipid insoluble compounds to
avoid reabsorption in renal tubules
Most hydrophilic drugs are less biotransformed
and excreted unchanged – streptomycin,
neostigmine and pancuronium etc.
Biotransformation is required for protection of
body from toxic metabolites
45. Results of Biotransformation
1. Active drug and its metabolite to inactive metabolites
– most drugs (ibuprofen, paracetamol, chlormphenicol
etc.)
2. Active drug to active product (phenacetin –
acetminophen or paracetamol, morphine to Morphine-
6-glucoronide, digitoxin to digoxin etc.)
3. Inactive drug to active/enhanced activity (prodrug) –
levodopa - carbidopa, prednisone – prednisolone and
enlpril – enlprilat)
4. No toxic or less toxic drug to toxic metabolites
(Isonizide to Acetyl isoniazide)
(teratogenicity, carcinogenicity, hepatotoxicity)
46. Biotransformation - Classification
2 (two) Phases of
Biotransformation:
• Phase I or Non-synthetic
– metabolite may be
active or inactive
• Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6
glucoronide is exception)
47. Phase I - Oxidation
Most important drug metabolizing reaction –
addition of oxygen or (–ve) charged radical or
removal of hydrogen or (+ve) charged radical
Various oxidation reactions are – oxygenation
or hydroxylation of C-, N- or S-atoms; N or 0-
dealkylation
Examples – Barbiturates, phenothiazines,
paracetamol and steroids
48. Phase I - Oxidation
Involve – cytochrome P-450 monooxygenases (CYP),
NADPH and Oxygen
More than 100 cytochrome P-450 isoenzymes are
identified and grouped into more than 20 families – 1, 2
and 3 …
Sub-families are identified as A, B, and C etc.
In human - only 3 isoenzyme families important –
CYP1, CYP2 and CYP3
CYP 3A4/5 carry out biotransformation of largest
number (30–50%) of drugs. In addition to liver, this
isoforms are expressed in intestine (responsible for first
pass metabolism at this site) and kidney too
49. Inhibition of CYP 3A4 by erythromycin,
clarithromycin, ketoconzole, itraconazole,
verapamil, diltiazem and a constituent of grape
fruit juice is responsible for unwanted interaction
with terfenadine and astemizole
Rifampicin, phenytoin, carbmazepine,
phenobarbital are inducers of the CYP 3A4
50. Nonmicrosomal Enzyme
Oxidation
Some Drugs are oxidized by non-microsomal
enzymes (mitochondrial and cytoplsmic) –
Alcohol, Adrenaline, Mercaptopurine
Alcohol – Dehydrogenase
Adrenaline – MAO and COMT(catechol –o-methyl
transferase)
Mercaptopurine – Xanthine oxidase
51. Phase I - Reduction
This reaction is conversed of oxidation and involves
CYP 450 enzymes working in the opposite direction.
Examples - Chloramphenicol, levodopa, halothane
and warfarin
Levodopa (DOPA) Dopamine
DOPA-decarboxylase
52. Phase I - Hydrolysis
This is cleavage of drug molecule by taking up of a molecule of water. Similarly
amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis
occurs in liver, intestines, plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Ester + H20 Acid + Alcohol
Esterase
53. Phase I – contd.
Cyclization: is formation of ring structure
from a straight chain compound, e.g.
proguanil.
Decyclization: is opening up of ring
structure of the cyclic molecule, e.g.
phenytoin, barbiturates
54. Phase II metabolism
Conjugation of the drug or its phase I metabolite with an endogenous
substrate - polar highly ionized organic acid to be excreted in urine or
bile - high energy requirements
Glucoronide conjugation - most important synthetic reaction
Compounds with hydroxyl or carboxylic acid group are easily
conjugated with glucoronic acid - derived from glucose
Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin,
thyroxine
Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by
bacteria, producing beta-glucoronidase - liberated drug is reabsorbed
and undergoes the same fate - enterohepatic recirculation (e.g.
chloramphenicol, phenolphthalein, oral contraceptives) and prolongs
their action
55. Phase II metabolism – contd.
Acetylation: Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA,
e.g.sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators)
Sulfate conjugation: The phenolic compounds and
steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal and sex steroids
56. Factors affecting
Biotransformation
Factors affecting biotransformation
Concurrent use of drugs: Induction and inhibition
Genetic polymorphism
Pollutant exposure from environment or industry
Pathological status
Age
57. Enzyme Inhibition
One drug can inhibit metabolism of other – if utilizes
same enzyme
However not common because different drugs are
substrate of different CYPs
A drug may inhibit one isoenzyme while being
substrate of other isoenzyme – quinidine
Some enzyme inhibitors – Omeprazole, metronidazole,
isoniazide, ciprofloxacin and sulfonamides
58. Microsomal Enzyme
Induction
CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and
glucocorticoide
CYP2E1 - isoniazid, acetone, chronic use of alcohol
Other inducers – cigarette smoking, charcoal broiled meat, industrial
pollutants – CYP1A
Consequences of Induction:
Decreased intensity or duration of action of drugs – Failure of OCPs
Increased intensity – Paracetamol poisoning
Tolerance – Carbmazepine (if the drug induce its own metabolism)
Some endogenous substrates are metabolized faster – steroids, bilirubin
60. Organs of Excretion
Excretion is a transport procedure which the
prototype drug (or parent drug) or other metabolic
products are excreted through excretion organ or
secretion organ
Hydrophilic compounds can be easily excreted.
Routes of drug excretion
Kidney
Biliary excretion
Sweat and saliva
Milk
Pulmonary
61. Hepatic Excretion
Drugs can be excreted in
bile, especially when the are
conjugated with – glucuronic
Acid
• Drug is absorbed → glucuronidated or
sulfatated in the liver and secreted
through the bile → glucuronic
acid/sulfate is cleaved off by bacteria in
GI tract → drug is reabsorbed (steroid
hormones, rifampicin, amoxycillin,
contraceptives)
• Anthraquinone, heavy metals – directly
excreted in colon
Portal
vein
Bile duct
Intestines
63. Glomerular Filtration
Normal GFR – 120 ml/min
Glomerular capillaries have pores larger than usual
The kidney is responsible for excreting of all water soluble
substances
All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered
Glomerular filtration of drugs depends on their plasma
protein binding and renal blood flow - Protein bound drugs
are not filtered !
Renal failure and aged persons
64. Tubular Re-absorption
Back diffusion of Drugs (99%) – lipid soluble drugs
Depends on pH of urine, ionization etc.
Lipid insoluble ionized drugs excreted as it is – aminoglycoside (amikacin,
gentamicin, tobramycin)
Changes in urinary pH can change the excretion pattern of drugs
Weak bases ionize more and are less reabsorbed in acidic urine.
Weak acids ionized more and are less reabsorbed in alkaline urine
Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
Acidified urine – atropine and morphine etc.
65. Tubular Secretion
Energy dependent active transport – reduces the free
concentration of drugs – further, more drug dissociation from
plasma binding – again more secretion (protein binding is
facilitatory for excretion for some drugs)
OATP – organic acid transport
OCT – organic base transport
P-gp
Bidirectional transport – Blood Vs tubular fluid
Utilized clinically – penicillin Vs probenecid, probenecid Vs uric
acid (salicylate)
• Quinidine decreases renal and biliary clearance of digoxin by
inhibiting efflux carrier P-gp
67. Kinetics of Elimination
Pharmacokinetics - F, V and CL
Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is
completely removed in unit time
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml and RoE is 100
mcg/min
CL = 100/20 = 5 ml /min
68. Kinetics of Elimination
First Order Kinetics (exponential): Rate of elimination
is directly proportional to drug concentration, CL
remaining constant
Constant fraction of drug is eliminated per unit time
Zero Order kinetics (linear): The rate of elimination
remains constant irrespective of drug concentration
CL decreases with increase in concentration
Alcohol, theophyline, tolbutmide etc.
69. Plasma half-life
Defined as time taken for its plasma concentration to be
reduced to half of its original value – 2 phases rapid declining
and slow declining
t1/2 = In2/k
In2 = natural logarithm of 2 (0.693)
k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
CL = RoE/C
V = dose IV/C
71. Excretion - The Platue Principle
Repeated dosing:
• When constant dose of a drug is repeated
before the expiry of 4 half-life – peak
concentration is achieved after certain
interval
• Balances between dose administered and
dose interval
72. Repeated Dosing
At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL/F
In zero order kinetics: follow Michaelis Menten
kinetics
RoE = (Vmax) (C) / Km + C
Vmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
CL = Roe/C
73. Target Level Strategy
Low safety margin drugs (anticonvulsants, antidepressants,
Lithium, Theophylline etc. – maintained at certain concentration
within therapeutic range
Drugs with short half-life (2-3 Hrs) – drugs are administered at
conventional intervals (6-12 Hrs) – fluctuations are therapeutically
acceptable
Long acting drugs:
Loading dose: Single dose or repeated dose in quick succession – to
attain target conc. Quickly
Loading dose = target Cp X V/F
Maintenance dose: dose to be repeated at specific intervals
74. Monitoring of Plasma
concentration
Useful in
Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc
Large individual variation – lithium and antidepressants
Renal failure cases
Poisoning cases
Not useful in
Response mesurable drugs – antihypertensives, diuretics
etc
Drugs activated in body – levodopa
Hit and run drugs – Reseprpine, MAO inhibitors
Irreversible action drugs – Orgnophosphorous compounds
75. Summary – Must Know
Definition of Pharmacokinetics
Transport of Drugs across Biological Membrane – different processes
with example
Factors affecting absorption of drugs
Concept of Bioavailability
Distribution of Drugs – Vd and its concept
Biotransformation Mechanisms with examples
Enzyme induction and inhibition concept and important examples
Routes of excretion of drugs
Orders of Kinetics
Definition and concept of drug clearance
Definition of half life and platue principle
76. Prolongation of Drug action
By prolonging absorption from the site of
action – Oral and parenteral
By increasing plasma protein binding
By retarding rate of metabolism
By retarding renal excretion
Editor's Notes
Faeces: Liver actively transport drugs and its metabolites into bile (Glucoronides). OATP – orgnic acids and OCT – organic bases. Other lipophillic drugs – by P-gp. Most lucoronides are deconjugated by bacteria and reabsorbed in intestine – enterohepatic circulation. Drugs – erythromycin, rifmpicin and tetracycline etc. Ultimate excretion occurs in urine
Milk – not importnt for mother but for fetus. Basic drugs can pass to milk as it has slightly lower pH Drugs –
Saliva – Lithium, KI, heavy metals and rifampicin
Although Cpss cn be calculated, its real value actually varies with individuls – deviation from averge ptients