The slides describe concept of distribution, Volume of distribution, factors affecting volume of distribution and the barriers to distribution. Blood brain barrier and placental barrier.
The slides describe concept of distribution, Volume of distribution, factors affecting volume of distribution and the barriers to distribution. Blood brain barrier and placental barrier.
“ Bioavailability-
means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action."
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.
“ Bioavailability-
means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action."
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.
General pharmacology Diploma in pharmacy second year YogeshShelake
The General pharmacology ,Toxicology & Pharmacotherapeutics
To Undastanding the general pharmacology & Definitions of PHARMACODYNAMECIS ,PHARMACOKINITICS (Absorbation,Distribution,Metabolism,Excreation )Pharmacology ,Toxicology ,Pharmacotherapeutic ,
Advantages of Routs of Administration & Their Disadvantages
Factors affecting of absorpation ,excreation of drug,factor modifing deug action
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.
Therapeutic Drug Monitoring (TDM)
Discuss the logic for therapeutic drug monitoring, which refer to as (TDM)
List various classes of drugs that require TDM
General description of this therapeutic drag TD
Discuss the proper sample timing and method for TDM
And Discuss analytical methods available for TDM
List various drugs that not require TDM
Steady state
Therapeutic Drug Groups
Digoxin, quinidine, procainamide, disopyramide.
- Aminoglycosides (amikacin, gentamicin, kanamycin, tobramycin) - vancomycin
leucovorin rescue ?
First-pass metabolism
HPLC methods
- Routes of administration
- First pass metabolism, bioavailablilty, drug distribution,
- Drug interactions with proteins, Drug metabolism, elimination, Half-life
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
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
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
1. General Principles of Drug Therapy
Pharmacokinetics I:
ADME
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Integrated Scientific and
Clinical Pharmacology
2. General Principles of Drug Therapy
Topics Outline
2
ABSORPTION
Ionization
Molecular Weight
Dosage Form
Routes of Administration
DISTRIBUTION
Plasma Protein Binding
Selective Distribution
METABOLISM
Rates of Metabolism
Microsomal P450 Isoenzymes
Enzyme Induction and Inhibition
ELIMINATION
Pharmacokinetic Changes with Aging
3. General Principles of Drug Therapy
Pharmacokinetics (PK) study of ADME
3
Absorption
Distribution
Metabolism
Excretion
Movement of drug molecules through various
physiologic compartments drug deposition
Processes that determine drug delivery to (in)
and removal from (out) molecular targets
Drug concentration-Time relationship
drug in
drug out = Elimination
4. General Principles of Drug Therapy
Pharmacokinetics Overview
Understanding PK
parameters, enable
design of optimal drug
regimens, including :
route of
administration
(RoA),
dosage,
dosing interval, and
duration of Tx
PK what the body
does to a drug
Modified from: Lippincott Illustrated
Reviews: Pharmacology. 6e. (2014)
5. General Principles of Drug Therapy
Pharmacokinetics Overview (2)
5
Interrelationship of absorption, distribution,
binding, metabolism, and excretion of a drug and
its concentration at its sites of action
Goodman and Gilman's The Pharmacological Basis of Therapeutics 12e, (2011)
6. General Principles of Drug Therapy
Chemical properties
acid or base
degree of ionization
polarity
molecular weight
lipid solubility
or...partition coefficient
Physiologic variables:
gastric motility
pH at the absorption site
area of absorbing surface
blood flow
presystemic elimination
ingestion w/wo food
6
Important Properties Affecting
Drug Absorption
7. General Principles of Drug Therapy
Routes of Drug Administration (RofA)
Lippincott Illustrated Reviews,
Pharmacology. 6e. (2015)
Absorption is how the patient’s body
takes in (absorbs) the drug in question
RofA:
Enteral, meaning absorbed
through intestines: oral and rectal
Parenteral, meaning absorbed
without intestines: intravenous
(IV), intramuscular (IM),
subcutaneous (SQ ), inhaled,
topical, or transdermal
9. General Principles of Drug Therapy
Bioavailability (F)
9
F is how much of what is ingested makes it into the systemic
circulation
Drugs administered intravenously bypass absorption, thus
have a bioavailability of 1 (100%)
Oral drugs have < 100% bioavailability (< 1) because:
1) not everything is absorbed (incomplete
tablet breakdown, barriers to absorption across gut mucosa,
gastric acid or enzymatic destruction)
2) after absorption through intestines into portal vein, drug
first passes through liver, where some of drug is
metabolized before reaching systemic circulation-termed
first pass metabolism
10. General Principles of Drug Therapy
First-pass metabolism
10
Any substance absorbed through
the intestinal mucosa
(except at end of the rectum)
will drain into the portal system
and be processed by the
liver before reaching the
systemic circulation
From Brenner GM, Stevens CW. Pharmacology.
3rd ed. Philadelphia: Elsevier; 2009.
11. General Principles of Drug Therapy
• Governed by:
surface area for absorption, blood flow, physical
state of drug, concentration
occurs via passive process
In theory: weak acids optimally absorbed in
stomach, weak bases in intestine
In reality: overall rate of absorption of drugs is
always greater in intestine (surface area, organ
function)
11
Oral Ingestion
12. General Principles of Drug Therapy
Forms of Oral Drugs
12
Fastest
Slowest
liquids: syrups, elixirs
Suspensions
Powders
pills: capsules, tablets
13. General Principles of Drug Therapy
Rate of Appearance in Blood
13
Dependent on rate of dissolution
Rate of absorption from GI tract
For example:
Timed release capsules
dissolve at different rates
Enteric coating pills
dissolve in alkaline fluid
14. General Principles of Drug Therapy
Ingestion of a solid dosage form with a glass of cold
water will accelerate gastric emptying
accelerated presentation of drug to upper intestine
significantly increases absorption
Ingestion with a fatty meal, acidic drink, or with
another drug with anticholinergic properties, will
retard gastric emptying
Sympathetic output (as in stress) also slows
emptying
14
Effect of Changing
Rate of Gastric Emptying
15. General Principles of Drug Therapy
Sublingual (SL) Administration
Absorption from oral mucosa has special significance
for certain drugs despite small surface area
Nitroglycerin (SL-NTG) - nonionic, very lipid soluble
Due to venous drainage into superior vena cava, this
route “protects” from first-pass liver metabolism
15
16. General Principles of Drug Therapy
16
Rectal Administration
Advantages:
Useful when oral administration is precluded by
vomiting or when patient is unconscious
Approx. 50% of drug absorbed from rectum will
bypass liver, thus reducing influence of first-pass
hepatic metabolism
Disadvantages:
Irregular and incomplete absorption
Irritation
Patient aversion
18. General Principles of Drug Therapy
Subcutaneous
Slow and constant absorption
Slow-release pellet may be implanted
Drug must not be irritating
18
19. General Principles of Drug Therapy
Intramuscular
Rapid rate of absorption from aqueous solution,
depending on the muscle
Perfusion of particular muscle influences rate of
absorption: gluteus vs. deltoid
Slow & constant absorption of drug when injected in
an oil solution or suspension
19
20. General Principles of Drug Therapy
Occasionally a drug is injected directly into an
artery to localize its effect to a particular
organ, e.g., for liver tumors, head/neck
cancers
Requires great care and should be reserved
for those with experience
20
Intra-arterial administration
21. General Principles of Drug Therapy
21
Intrathecal administration
Necessary RofA if the blood-brain barrier
and blood-CSF barrier impede entrance into
CNS
Injection into spinal subarachnoid space:
used for local or rapid effects of drugs on
the meninges or cerebrospinal axis, as in
spinal anesthesia or acute CNS infections
22. General Principles of Drug Therapy
Peritoneal cavity offers a large absorbing
surface area from which drug may enter
the circulation rapidly
Seldom used clinically
Infection is always a concern
22
Intraperitoneal administration
23. General Principles of Drug Therapy
23
Pulmonary Absorption
Inhaled gaseous and volatile drugs are
absorbed by the pulmonary
epithelium and mucous membranes
of respiratory tract
almost instantaneous absorption
avoids first-pass metabolism
local application
24. General Principles of Drug Therapy
24
Topical Application
Mucous membranes
Drugs are applied to mucous membranes of
conjunctiva, nasopharynx, vagina, colon,
urethra, and bladder for local effects
Systemic absorption may occur (e.g.
antidiuretic hormone via nasal mucosa)
25. General Principles of Drug Therapy
25
Topical Application (2)
Skin
Few drugs readily penetrate skin
Absorption is proportional to surface area
More rapid through abraded, burned or denuded skin
Inflammation increases cutaneous blood flow and,
therefore, absorption
Enhanced by suspension in oily vehicle and rubbing into
skin
26. General Principles of Drug Therapy
26
Topical Application (3)
Eye
topically applied ophthalmic drugs are used
mainly for their local effects
systemic absorption that results from drainage
through nasolacrimal canal is usually undesirable
not subject to first-pass hepatic metabolism
27. General Principles of Drug Therapy
27
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES
Oral • Variable; affected by many
factors
• Safest and most common,
convenient, and economical RofA
• Limited absorption of some drugs
• Food may affect absorption
• Patient compliance is necessary
• Drugs may be metabolized before
systemic absorption
Intravenous • Absorption not required • Can have immediate effects
• Ideal if dosed in large volumes
• Suitable for irritating substances
and complex mixtures
• Valuable in emergency situations
• Dosage titration permissible
• Ideal for high molecular weight
proteins and peptide drugs
• Unsuitable for oily substances
• Bolus injection may result in adverse
effects
• Most substances must be slowly
injected
• Strict aseptic techniques needed
Subcutaneous • Depends on drug diluents:
Aqueous solution: prompt
Depot preparations: slow and
sustained
• Suitable for slow-release drugs
• Ideal for some poorly soluble
suspensions
• Pain or necrosis if drug is irritating
• Unsuitable for drugs administered in large
volumes
Intramuscular • Depends on drug diluents:
Aqueous solution: prompt
Depot preparations: slow and
sustained
• Suitable if drug volume is moderate
• Suitable for oily vehicles and certain
irritating substances
• Preferable to intravenous if patient
must self-administer
• Affects certain lab tests (creatine
kinase)
• Can be painful
• Can cause intramuscular
hemorrhage (precluded during
anticoagulation therapy)
Routes of Administration Summary Table (1)
28. General Principles of Drug Therapy
28
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES
Transdermal
(patch)
• Slow and sustained • Bypasses the first-pass effect
• Convenient and painless
• Ideal for drugs that are lipophilic and
have poor oral bioavailability
• Ideal for drugs that are quickly
eliminated from the body
• Some patients are allergic to
patches, which can cause irritation
• Drug must be highly lipophilic
• May cause delayed delivery of drug
to pharmacological site of action
• Limited to drugs that can be
taken in small daily doses
Rectal • Erratic and variable • Partially bypasses first-pass effect
• Bypasses destruction by stomach acid
• Ideal if drug causes vomiting
• Ideal in patients who are vomiting, or
comatose
• Drugs may irritate the rectal
mucosa
• Not a well-accepted route
Inhalation • Systemic absorption may
occur; this is not always
desirable
• Absorption is rapid; can have
immediate effects, Ideal for gases
• Effective for patients with respiratory
Problems, Dose can be titrated
• Localized effect to target lungs: lower
doses used compared to that with
oral or parenteral administration
• Fewer systemic side effects
• Most addictive route (drug can
enter the brain quickly)
• Patient may have difficulty
regulating dose
• Some patients may have
difficulty using inhalers
Sublingual • Depends on the drug: Few
drugs (for example,
nitroglycerin) have rapid
direct systemic absorption
Most drugs erratically or
incompletely absorbed
• Bypasses first-pass effect
• Bypasses destruction by stomach acid
• Drug stability maintained because
the pH of saliva relatively neutral
• May cause immediate pharmacological
effects
• Limited to certain types of drugs
• Limited to drugs that can be
taken in small doses
• May lose part of the drug dose if
swallowed
Routes of Administration Summary Table (2)
29. General Principles of Drug Therapy
Cell Membranes
Passive Properties
Carrier-Mediated Transport
29
Physicochemical Factors In Transfer of
Drugs Across Membranes
30. General Principles of Drug Therapy
30
“ADME of a drug all involve its passage across cell
membranes”
Drugs generally pass through cells rather than
between them
Thus, the plasma membrane is the common
barrier
Passive diffusion depends on movement down a
concentration gradient
Facts...
31. General Principles of Drug Therapy
31
1. Molecular Size
In general, smaller molecules diffuse more readily across
membranes than larger ones because the diffusion
coefficient is inversely related to the sq. root of the MW
This applies to passive diffusion but NOT to specialized
transport mechanisms (active transport, pinocytosis)
tight junction: MW <200
diffusion through large fenestrations in capillaries: MW 20K-
30K
32. General Principles of Drug Therapy
The greater the partition coefficient, the higher the
lipid-solubility of the drug, and the greater its diffusion
across membranes
A non-ionizable compound (or the non-ionized form of
an acid or a base) will reach an equilibrium across the
membrane that is proportional to its concentration
gradient
32
2. Lipid-Solubility
Oil:Water Partition Coefficient
33. General Principles of Drug Therapy
Absorbed from stomach in 1 hour (% of dose)
1
52
580
barbital
(pKa 7.8)
secobarbital
(pKa 7.9)
thiopental
(pKa 7.6)
0
10
20
30
40
50
Other things (MW, pKa) being equal,
absorption of these drugs is
proportional to lipid solubility
33
34. General Principles of Drug Therapy
3. Ionization
• Most drugs are small (MW < 1000) weak electrolytes
(acids/bases)
• This influences passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much more permeable to
the non-ionized forms of drugs
The fraction of drug that is non-ionized depends on its
chemical nature, its pKa, and the local biophase pH...
34
35. General Principles of Drug Therapy
Ionization (2)
You can think of properties this way:
ionized = polar = water-soluble
non-ionized = less polar = more lipid-soluble
Think of an acid as having a carboxyl: COOH / COO_
Think of a base as having an amino: NH3+ / NH2
*For both acids and bases, pKa = acid dissociation constant, the pH at
which 50% of the molecules are ionized.
Example:
weak acid = aspirin (pKa 3.5)
weak base = morphine (pKa 8.0)
35
36. General Principles of Drug Therapy
Weak acid Weak base
H+
HA A-
HA
H+
A-
B BH+
H+
H+
B BH+
* The pH on each side of the membrane determines the equilibrium on each side
extracellular
pH
intracellular
pH
36
37. General Principles of Drug Therapy
A Useful Concept...
Drugs tend to exist in the ionized form
when exposed to their “pH-opposite”
chemical environment.
Acids are increasingly ionized with
increasing pH (basic environment),
whereas…
Bases are increasingly ionized with
decreasing pH (acidic environment).
37
38. General Principles of Drug Therapy
pH
2
4
6
7.4
8
10
acid
cromolyn sodium (2.0)
furosemide (3.9)
sulfamethoxazole (6.0)
phenobarbital (7.4)
phenytoin (8.3)
chlorthalidone (9.4)
base
diazepam (3.3)
chlordiazepaxide (4.8)
triamterene (6.1)
cimetidine (6.8)
morphine (8.0)
amantadine (10.1)
A
-
HA HB
+
B
38
39. General Principles of Drug Therapy
log = pKa - pH
39
[unprotonated]
[protonated]
Henderson-Hasselbalch Eqn.
41. General Principles of Drug Therapy
Problem: What percentage of phenobarbital (weak acid, pKa = 7.4)
exists in the ionized form in urine at pH 6.4?
pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio
between non-ionized (HA) and
ionized (A-) forms of the drug:antilog of 1 = 10
if pH = pKa then HA = A-
if pH < pKa, acid form (HA) will always predominate
if pH > pKa, the basic form (A-) will always predominate
Ratio of HA/A- = 10/1
% ionized = A- / A- + HA X 100 = 1 / (1 + 10) X 100 = 9% ionized
41
42. General Principles of Drug Therapy
Problem: What percentage of cocaine (weak base, pKa =8 .5)
exists in the non-ionized form in the stomach at pH 2.5?
pKa - pH = 8.5 - 2.5 = 6
take antilog of 6 to get the ratio
between ionized (BH+) and non-ionized
(B) Forms of the drug:antilog of 6 = 1,000,000
if pH = pKa then BH+ = B
if pH < pKa, acid form (BH+) will always predominate
if pH > pKa, the basic form (B) will always predominate
Ratio of BH+/B = 1,000,000/1
% non-ionized = B / (B + BH+) X 100 = 1 X 10-4 % non-ionized or 0.0001%
42
43. General Principles of Drug Therapy
43
In a Suspected Overdose...
The most appropriate site for sampling to identify the
drug depends on the drug’s chemical nature
Acidic drugs concentrate in plasma, whereas the
stomach is a reasonable site for sampling basic drugs
Diffusion of basic drugs into the stomach results in
almost complete ionization in that low-pH environment
44. General Principles of Drug Therapy
naproxen (weak acid, pKa 5.0)
plasma
pH 7.4
HA = 1.0
+
A-
= 251
total
HA + A- = 252
small intestine
pH 5.3
HB+
= 501
+
B = 1.0
total
HB+
+ B = 502
plasma
pH 7.4
HB+
= 4
+
B = 1.0
total
HB+
+ B = 5
morphine (weak base, pKa 8.0)
gastric juice
pH 2.0
HA = 1.0
+
A-
= 0.001
total
HA + A-
= 1.001
44
45. General Principles of Drug Therapy
amphetamine (weak base, pKa 10)
its actions can be prolonged by ingesting bicarbonate to
alkalinize the urine...
this will increase the fraction of amphetamine in non-ionized
form, which is readily reabsorbed across the luminal surface of
the kidney nephron...
in overdose, you may acidify the urine to increase kidney
clearance of amphetamine
45
Other aspects….
46. General Principles of Drug Therapy
Certain compounds may exist as strong electrolytes
This means they are ionized at all body pH values
They are poorly lipid soluble
Examples:
strong acid = glucuronic acid derivatives of drugs.
strong base = quaternary ammonium compounds such as
acetylcholine
46
Other aspects….
47. General Principles of Drug Therapy
47
ATP
ADP-Pi
passive
diffusion
carrier-mediated endocytosis
active passive
Membrane Transfer
48. General Principles of Drug Therapy
This is a carrier-mediated process that does NOT
require energy
Movement of substance can NOT be against its
concentration gradient
Necessary for transport of endogenous
compounds whose rate of movement across
membranes by simple diffusion would be too slow
Example: Insulin
48
Facilitated Diffusion
49. General Principles of Drug Therapy
Special carriers
49
Substances that are important for cell function
and too large or too insoluble in lipid to diffuse
passively through membranes
eg, peptides, amino acids, glucose.
These kind of transport, unlike passive diffusion,
is saturable and inhabitable
Active transport - requirement of energy
Facilitated diffusion - needs no energy
50. General Principles of Drug Therapy
Special carriers (2)
50
Carrier-mediated transport is important
for some drugs that are chemically related
to endogenous substances
The transporter proteins also mediate
drug efflux
P-glycoprotein /MDR1
MRP transporters
Function as a barrier system to protect
cells
51. General Principles of Drug Therapy
MDR1/P-glycoprotein
51
P-glycoprotein: P-glycoprotein 1
(permeability glycoprotein, abbreviated
as P-gp or Pgp) also known as
multidrug resistance protein 1 (MDR1)
or ATP-binding cassette subfamily B
member 1 (ABCB1) is an important
protein of the cell membrane that
pumps many foreign substances out of
cells.
Produced by the mdr-1 gene
(Characterization of the human MDR1 gene. 2005).
52. General Principles of Drug Therapy
52
Active Transport
Occurrence:
neuronal membranes, choroid plexus, renal tubule cells,
hepatocytes
Characteristics:
carrier-mediated
Selectivity
competitive inhibition by congeners
energy requirement *
Saturable
movement against concentration gradient *
*differences from facilitated diffusion
53. General Principles of Drug Therapy
53
Endocytosis (or pinocytosis): a portion of the plasma
membrane invaginates and then pinches off from the
surface to form an intracellular vesicle
Example:
This is the mechanism by which thyroid follicular cells, in
response to TSH, take up thyroglobulin (MW > 500,000).
Endocytosis, Exocytosis, Internalization
54. General Principles of Drug Therapy
54
Drug Absorption and Bioavailability (F)
Absorption describes the rate and extent at which a drug
leaves its site of administration
Bioavailability (F) is the extent to which a drug reaches its
site of action, or to a biological fluid (such as plasma) from
which the drug has access to its site of action
55. General Principles of Drug Therapy
Pharmacokinetics
Locus of
action
“receptors”
Bound Free
Tissue
reservoirs
Bound Free
Absorption Excretion
Biotransformation
Free drug
Systemic
circulation
Bound drug Metabolites
55
56. General Principles of Drug Therapy
AUC
injected i.v.
AUC
oral
time
plasmaconcentrationofdrug
Bioavailability =
AUC oral
AUC injected i.v.
X 100
AUC = area under the curve
56
57. General Principles of Drug Therapy
Factors Modifying Absorption
drug solubility (aqueous vs. lipid)
local conditions (pH)
local circulation (perfusion)
surface area
57
58. General Principles of Drug Therapy
Bioequivalence
Drugs are pharmaceutical equivalents if they contain the same
active ingredients and are identical in dose (quantity of drug),
dosage form (e.g., pill formulation), and route of
administration
Bioequivalence exists between two such products when the
rates and extent of bioavailability of their active ingredient are
not significantly different
58
59. General Principles of Drug Therapy
Distribution
Once a drug is absorbed into the bloodstream, it may be
distributed into interstitial and cellular fluids
The actual pattern of drug distribution reflects various
physiological factors and physicochemical properties of the
drug
59
60. General Principles of Drug Therapy
Phases of Distribution
first phase
reflects cardiac output and regional blood flow
Thus, heart, liver, kidney & brain receive most of the drug during
the first few minutes after absorption
next phase
delivery to muscle, most viscera, skin and adipose is slower,
and involves a far larger fraction of the body mass
60
61. General Principles of Drug Therapy
Drug Reservoirs
Body compartments where a drug can accumulate are reservoirs
Have dynamic effects on drug availability.
plasma proteins as reservoirs (bind drug)
cellular reservoirs
Adipose (lipophilic drugs)
Bone (crystal lattice)
Transcellular (ion trapping)
61
62. General Principles of Drug Therapy
Pharmacokinetics
Locus of
action
“receptors”
Bound Free
Tissue
reservoirs
Bound Free
Absorption Excretion
Biotransformation
Free drug
Systemic
circulation
Bound drug Metabolites
62
63. General Principles of Drug Therapy
Protein Binding
Passive movement of drugs across biological membranes
is influenced by protein binding
Binding may occur with plasma proteins or with non-
specific tissue proteins in addition to the drug’s receptors
***Only drug that is not bound to proteins (i.e., free or
unbound drug) can diffuse across membranes
63
64. General Principles of Drug Therapy
Plasma Proteins
albumin
- binds many acidic drugs
α1-acid glycoprotein
- binds basic drugs
The fraction of total drug in plasma that is bound is
determined by
1. its concentration
2. its binding affinity
3. the number of binding sites
At low concentration, binding is a function of Kd (dissociation
constant); at high concentration it’s the # of binding sites
64
65. General Principles of Drug Therapy
Plasma Proteins (2) Example
Thyroxine (thyroid hormone T4)
> 99% bound to plasma proteins (PPB)
The main carrier is the acidic glycoprotein thyroxine-binding
globulin [Thyroxine Binding Globulin (TBG)]
very slowly eliminated from the body, and has a very long half-
life
65
66. General Principles of Drug Therapy
Drugs Binding Primarily to Albumin
barbiturate probenecid
benzodiazepines streptomycin
bilirubin sulfonamides
digotoxin tetracycline
fatty acids tolbutamide
penicillins valproic acid
phenytoin warfarin
phenylbutazone
66
67. General Principles of Drug Therapy
Drugs Binding Primarily to
α1-Acid Glycoprotein
alprenolol lidocaine
bupivicaine methadone
desmethylperazine prazosin
dipyridamole propranolol
disopyramide quinidine
etidocaine verapamil
imipramine
67
68. General Principles of Drug Therapy
Drugs Binding Primarily to
Lipoproteins
amitriptyline
nortriptyline
68
69. General Principles of Drug Therapy
Bone Reservoir
Tetracycline antibiotics (and other divalent metal ion-chelating
agents) and heavy metals may accumulate in bone
They are adsorbed onto the bone-crystal surface and eventually
become incorporated into the crystal lattice
Bone then can become a reservoir for slow release of toxic
agents (e.g., lead, radium) into the blood
69
70. General Principles of Drug Therapy
Adipose Reservoir
• Many lipid-soluble drugs are stored in fat
• In obesity, fat content may be as high as 50%, and in
starvation it may still be only as low as 10% of body weight
• 70% of a thiopental dose may be found in fat 3 hr. after
administration (see next slide)
70
71. General Principles of Drug Therapy
Thiopental
A highly lipid-soluble i.v. anesthetic
Blood flow to brain is high, so maximal brain concentrations
brain are achieved in minutes and quickly decline
Plasma levels drop as diffusion into other tissues (muscle)
occurs
Onset and termination of anesthesia is rapid
The third phase represents accumulation in fat (70% after 3 h)
Can store large amounts and maintain anesthesia
71
72. General Principles of Drug Therapy
Thiopentalconcentration
(aspercentofinitialdose)
100
50
0
minutes
1 10 100 1000
blood
brain
muscle adipose
72
Thiopental (2) Graphic Illustration
73. General Principles of Drug Therapy
GI Tract as Reservoir
Weak bases are passively concentrated in stomach from blood
because of large pH differential
Some drugs are excreted in bile in active form or as a conjugate
that can be hydrolyzed in intestine and reabsorbed
73
In the above two cases, and when orally administered drugs
are slowly absorbed, GI tract serves as a reservoir
74. General Principles of Drug Therapy
Redistribution
Termination of drug action is normally by biotransformation /
excretion, but may also occur as a result of redistribution
between various compartments
Particularly true for lipid-soluble drugs that affect brain and heart
74
75. General Principles of Drug Therapy
Placental Transfer
Drugs cross the placental barrier primarily by simple passive
diffusion
Lipid-soluble, nonionized drugs readily enter fetal bloodstream
from maternal circulation
Rates of drug movement across placenta tend to increase
towards term as tissue layers between maternal blood and
fetal capillaries thin
75
76. General Principles of Drug Therapy
Clinical Pharmacokinetics
Fundamental hypothesis:
A relationship exists between the pharmacological or toxic
response to a drug and the accessible concentration of the
drug (e.g., in blood)
Important parameters:
volume of distribution (Vd)
clearance (CL)
bioavailability (F)
76
77. General Principles of Drug Therapy
Volume of Distribution
Volume of distribution (Vd) relates the amount of drug in
the body to the plasma concentration of drug (Cp)
**The apparent volume of distribution is a calculated space
and does not always conform to any actual anatomic
space**
Note: Vd is the fluid volume the drug would have to be
distributed in if Cp were representative of the drug
concentration throughout the body
77
78. General Principles of Drug Therapy
Total body water
plasma
interstitial
volume
intracellular
volume
42 liters
27 liters
15 liters
12 liters
3 liters
plasma volume
interstitial volume
extracellular
intracellular
78
79. General Principles of Drug Therapy
At steady-state plasma concentration (Css):
total drug in body (mg)
Vd
= ------------------------------
plasma conc. (mg/ml)
79
80. General Principles of Drug Therapy
Example of Vd
• The plasma volume of a 70-kg man ~ 3L, blood volume ~
5.5L, extracellular fluid volume ~ 12L, and total body
water ~ 42L.
• Givens: If 500 mg of digoxin were in his body, Cp would be
~ 0.7 ng/ml
• Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value
10 times total body volume! Huh?
• Digoxin is hydrophobic and distributes preferentially to
muscle and fat, leaving very little drug in plasma
• The digoxin dose required therapeutically depends on
body composition
80
81. General Principles of Drug Therapy
Clearance (CL)
• Clearance is the most important property to consider when a
rational regimen for long-term drug administration is designed
– The clinician usually wants to maintain steady-state drug
concentrations known to be within the therapeutic range
– CL = dosing rate / Css
– CL = rate of elimination / Css
– (volume/time) = (mass of drug/time) / (mass of drug/volume)
81
82. General Principles of Drug Therapy
Clearance (2)
• Clearance does not indicate how much drug is removed but,
rather, the volume of blood (or plasma) that would have to be
completely freed of drug to account for the elimination rate.
– CL is expressed as volume per unit time
82
83. General Principles of Drug Therapy
Sum of all process
contributing to
disappearance of drug
from plasma
Drug in plasma at
concentration of 2 mg/ml
Drug concentration in plasma is less
after each pass through elimination /
metabolism process
Drug molecules disappearing from
plasma at rate of 400 mg/min
CL = 400 mg/min
2 mg/ml
= 200 ml/min
83
Remember:
CL = dosing rate / Css
CL = rate of elimination / Css
Clearance (3)
84. General Principles of Drug Therapy
Clearance (4)
Example: cephalexin, CLp = 4.3 ml/min/kg
• For a 70-kg man, CLp = 300 ml/min, with renal clearance
accounting for 91% of this elimination
• So, the kidney is able to excrete cephalexin at a rate such that
~ 273 ml of plasma is cleared of drug per minute
• Since clearance is usually assumed to remain constant in a
stable patient, the total rate of elimination of cephalexin
depends on the concentration of drug in plasma
84
85. General Principles of Drug Therapy
85
Clearance (5)
Example: propranolol, CLp = 12 ml/min/kg or 840
ml/min in a 70-kg man
The drug is cleared almost exclusively by the liver
Every minute, the liver is able to remove the amount of drug
contained in 840 ml of plasma
NB:
Clearance of most drugs is constant over a range of
concentrations
This means that elimination is not saturated and its rate is
directly proportional to the drug concentration:
this is a description of 1st-order elimination
86. General Principles of Drug Therapy
86
CL in a given organ may be defined in terms of blood flow and
[drug]
Q = blood flow to organ (volume/min)
CA = arterial drug conc. (mass/volume)
CV = venous drug conc.
rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)
CL in a given organ
88. General Principles of Drug Therapy
Further study:
88
eNotes: GP- General Principles of Drug Action
Drug-Receptor Interactions, Morris ZS, Golan DE and (or)
Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and
Concentration-Response Relationships
Enzyme kinetics Notes
MedPharm Wiki| PK and PD, Pgs. 73-88
Pharmacology Course Website