This document discusses drug receptors and their role in mediating drug action. It describes the four main types of receptors: ligand-gated ion channels, G-protein coupled receptors, enzyme-linked receptors, and nuclear receptors. Ligand-gated ion channels directly open ion channels, while G-protein coupled receptors signal through G-proteins. Enzyme-linked receptors have intracellular enzyme domains, and nuclear receptors enter the nucleus to regulate gene transcription. Understanding receptors is important for rational drug design and determining mechanisms of drug action and selectivity.
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with pharmacokinetics : concept of linear and non-linear compartment models.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with pharmacokinetics : concept of linear and non-linear compartment models.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
ENZYME INHIBITION THE MOST IMPORTANT TOPIC FOR BIOLOGY AS WELL AS CHEMISTRY PEOPLES. WE HAVE HERE COVERED FOR THE PHARMA STUDENTS THIS WILL MAKE THEM EASY AS WE ARE COLLECTED ALL THE DATA A SINGLE PLACE WICH COVERS ALL THE COTENTS.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
The signal transduction pathway uses a network of interactions within cells, among cells, and throughout plant.
The external signals that affect plant growth and development include many aspects of the plant’s physical, chemical, and biological environments. Some external signals come from other plants.
Many signals interact cooperatively and synergistically with each other to produce the final response. Signal combinations that induce such complex plant responses include red and blue light, gravity and light, growth regulators and mineral nutrients .
For example the overall regulation of seed germination involves control by both external factors and internal signals.
This presentation is about the functioning of G-Protein coupled receptors. It also gives necessary information about the G-protein and it functions. It ends by explaining some of the faults associated with GPCR (G-PROTEIN COUPLED RECEPTORS).
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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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
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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
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
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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2. INTRODUCTION
Drugs produce their therapeutic effects
• by producing biochemical/ physical
changes in the target tissues
• of the host
• of the organisms which invade the host.
2
3. These changes are due to;
physical and chemical properties of
drug
action on the drug targets namely;
Receptors
Enzymes
Carrier molecules
Ion channels
3
4. To get drug action, it is essential that-
1. Sufficient concentration of drug reaches
the site of action
2. Remains there for a sufficient duration
3. The tissue is susceptible for drug action
4
5. Magnitude of drug action is proportional to
the concentration of drug at the site of action.
Receptor mechanism is very important to
understand the action and effect of a drug.
5
6. Receptor
component of a cell or organism
interacts with a drug
initiates the chain of biochemical events
leading to the drug’s observed effects
6
7. They have specific binding sites that are definite
in size and shape
Most are present on or near the membrane.
Some lie in the enzymes or genes
protein (polypeptide) in nature
7
8. HISTORY OF RECEPTORS
Langley and Ehrlich introduced concept of
receptor
Langley (1852 – 1925);
• studied the effects of atropine against
pilocarpine induced salivation in cats
• postulated that there was a receptive substance
in the nerve ending or gland cell with which
both atropine and pilocarpine are capable of
forming compounds
8
9. Ehrlich (1854 – 1915) observed that;
• certain dyestuffs acted selectively, staining some
cells more deeply or ina different way from other
cells
• suggested that drugs with selective actions on
particular cells could be developed
• Introduced the term “receptor”
9
10. Four major families of receptors;
ligand-gated ion channels (e.g. nicotinic ion
channel)
G-protein coupled receptors (e.g. α
adrenoceptor)
Enzyme linked receptors (e.g. insulin
receptors)
Nuclear receptors (e.g. glucocorticoid
receptors)
10
11. Receptors that do not fall into these four
receptor families;
Specific membrane ion pumps (e.g. Na+/K+
ATPase
Specific enzymes (e.g. 5-phosphodiesterase)
Structural proteins (e.g. colchicine to tubulin)
Cytosolic proteins< (e.g. ciclosporin to
immunophilins)
11
13. Type (I) Ligand-gated ion channels
coupled directly to membrane ion channels
Agonist binding
• opens the channel
• causes depolarization/ hyperpolarization/
changes in cytosolic ionic composition,
• depending on the ion that flows through.
13
14. control the fastest synaptic events in nervous
system
excitatory neurotransmitters such as Ach or
glutamate cause an increase in Na+ and K+
permeability
results in a net inward current
depolarizes the cell
generate an action potential
E.g. Nicotinic Receptor, GABA receptor, glycine
(inhibitory AA), excitatory AA-glutamate (kainate,
NMDA) and 5HT3 receptors
14
16. Type(II) G-protein coupled receptors (GPCR)
Seven α-helical membrane spanning
hydrophobic amino acid segments
run into 3 extracellular and 3 intracellular loops
Binding of the mediator molecule induces a
change in the conformation and
Enabling to interact with a G-protein lied at the
inner leaf of the plasmalemma.
16
17. G-protein
G-protein consists of three subunits (α, β, and γ
subunits).
In the inactive state, GDP is bound to α subunit.
Activation leads to displacement of GDP by GTP.
Activated Gα-GTP dissociates from β, and γ
subunits, then associates with an effector
protein, and alters its functional state
17
18. The α-subunit slowly hydrolyzes bound GTP
to GDP
Gα-GDP rejoin the β and γ subunits.
The βγ dimer can activate receptor-operated
K+ channels, inhibit voltage gated Ca2+
channels and promote GPCR desensitization
at higher rates of activation.
18
19. The important G proteins with their action on
the effector;
Gs: Adenylyl cyclase activation, Ca2+ channel
opening
Gi: Adenylyl cyclase inhibition, K+ channel
opening
Go: Ca2+ channel inhibition
Gq: Phospholipase C activation
19
20. one receptor can utilize more than one G-
protein (agonist pleiotrophy), e.g.
Receptor Coupler
Muscarinic M2 Gi, Go
Muscarinic M1, M3 Gq
Dopamine D2 Gi, Go
β-adrenergic Gs
α1-adrenergic Gq
α2-adrenergic Gi, Go
20
21. Three major effector pathways of GPCRs
a) Adenylyl cyclase: cAMP pathway
activation of adenylyl cyclase results in
intracellular accumulation of second
messenger cAMP
cAMP functions mainly through cAMP-
dependent protein kinase
PK phosphorylates and alter the function of
many enzymes, ion channels, transporter,
transcription factors and structural proteins
21
22. b) Phospholipase C: IP3-DAG pathway
activation of phospholipase C hydrolyses
membrane PIP2 to generate the second
messengers IP3 and DAG
Inositol trisphosphate (IP3)
• diffuses to cytosol
• mobilizes Ca2+ from endoplasmic reticular depots
Diacylglycerol (DAG)
• remains within the membrane
• recruits protein kinase C (PKc)
• activates it with the help of Ca2+
22
23. Activated PKc
• phosphorylates many intracellular proteins
• mediates various physiological responses
Triggered by IP3, the released Ca2+ mediates
and modulates
• contraction,
• secretion/transmitter release,
• eicosanoid synthesis,
• neuronal excitability,
• membrane function, metabolism etc. 23
24. c) Channel regulation
The activated G-proteins (Gs, Gi, Go)
• can open or inhibit ionic channels specific
for Ca2+ and K+
• without the intervention of any second
messenger like cAMP or IP3
hyperpolarization/ depolarization/ changes in
intracellular Ca2+ can occur
24
25. Gs
• opens channel in myocardium and
skeletal muscles
Gi and Go
• opens K1+ channels in heart and smooth
muscle
• inhibit neuronal Ca2+ channels
Direct channel regulation is mostly the
function of βγ dimer
25
29. Type(III) Enzyme-linked receptors
lie partially outside and partially inside the
cell membrane
consist of extracellular ligand binding
domain linked to intracellular domain by
single transmembrane helix.
Intracellular portion is enzyme in nature.
(protein kinase generally and guanylyl cyclase
in some cases)
29
30. The commonest protein kinases are receptor
tyrosine kinases (RTKs)
RTKs phosphorylates tyrosine residues on the
substrate proteins.
E.g. insulin, epidermal growth factor (EGF),
Nerve growth factor (NGF) and many other
growth factor receptors
30
32. Type(IV) Nuclear receptors
intracellular (cytoplasmic or nuclear) soluble
proteins which respond to lipid soluble
chemical messengers that penetrate the cell
When the hormone binds to the receptor
protein
• the receptor dimerizes
• the DNA binding regulatory segment folds
into the requisite configuration.
32
33. This dimer
• moves to the nucleus
• binds other co-activator/ co-repressor
proteins which have a modulatory influence
on its capacity to alter gene function
The whole complex
• attaches to specific DNA sequences of the
target genes
• facilitates or repress their expression
• specific mRNA is synthesized/repressed on
the template of gene 33
34. This mRNA directs synthesis of specific proteins
which regulates activity of the target cells
E.g.corticosteroid, sex hormone and thyroid
hormone receptor stimulates transcription of
genes by binding to specific DNA consequences.
34
36. IMPORTANCE OF RECEPTOR CONCEPT
IN CLINICAL PRACTICE
1. Receptors largely determine the quantitative
relationship between concentration of drug
and pharmacologic effect
2. responsible for selectivity of drug action
3. mediate the action of agonists and antagonists
36
37. Functions of receptors
1.Ligand binding
2.Message propagation(Signaling)
Functional domains within the receptor;
• ligand-binding domain
- spatially and energetically suitable for
binding the specific ligand
• effector domain
- which undergoes a functional
conformational change
37
38. Receptor Effectors System
a receptor may be…….
exerted directly on its cellular target(s),
effector proteins or
conveyed by intermediary cellular
signaling molecules called transducers
38
39. Signal transduction
Pathway from;
• ligand binding to conformational changes in the
receptor
• Receptor interaction with an effector molecule (if
present) and
• other downstream molecules called second
messengers
This cascade of receptor-mediated biochemical
events leads to a physiological effect
39
40. Second messengers
intracellular signaling molecules released by
the cell
in response to exposure to extracellular
signaling molecules - the first messengers
Second messengers initiates cellular signaling
through a specific biochemical pathway
40
41. Second messengers (Contd)
trigger a series of molecular interactions that
alter the physiologic state of the cell
Well-studied second messengers
• cyclic AMP
• cyclic GMP
• cyclic ADP-ribose
• inositol phosphates
• Diacylglycerol
• nitric oxide, etc.
41
42. 42
Receptor occupation theory
Most drugs bind to receptor by forming
• Hydrogen bond
• Ionic bond
• Van der Waals bond
These weak bonds are reversible.
In a few cases, drugs forms
• relatively permanent covalent bond
43. Affinity
• the tendency of drug to bind with the receptor
• to have affinity the chemical structure of the
drug and the receptor must be complementary
Efficacy (Intrinsic activity)
• the capacity of drug to induce a functional
change in the receptor
44. Potency
Potency of a drug depends on
• Affinity of receptors for binding the drug
• Amount of the drug(weight) in relation to its
effect
44
45. A B R max
Response
Log concentration
Drug A is more potent than Drug B
45
46. Maximal efficacy
The clinical effectiveness of a drug depends on
• its maximal efficacy
• its ability to reach the relevant receptors.
It is determined by
• mode of interaction of drug with receptors
(as partial agonists, antagonists, etc.) or
• characteristics of receptor–effectorsystem.
46
48. 48
Agonists
- have both receptor affinity and efficacy
There are three types of agonists;
1. Full agonists
2. Partial agonists
3. Inverse agonist
49. 49
Full agonists
- have affinity and maximal efficacy
Partial agonists
- have affinity and submaximal efficacy
Inverse agonists
- bind with the constitutively active receptors
and stabilize them
- reduce the activity (negative intrinsic activity)
- produce effect that are specifically opposite to
those of agonist
51. Antagonists
• bind to the receptor but do not activate
generation of a signal.
• prevent the natural agonist fromexerting its
effects.
• only affinity, no intrinsic activity
Two types of Antagonist
Competitive antagonist or surmountable
antagonists.
Non-competitive or non-surmountable
antagonists. 51
52. Competitive or Surmountable
effect can be overcome by more drug
(agonist).
The higher the concentration of antagonist
used, the more drug (agonist) you need to
get the same effect
56. Spare receptors
Although the receptor occupation is
proportionate to drug concentration, not all the
receptors are occupied by the drug.
Some receptors called “spare receptors” remain
unaffected
said to be “spare” as maximal biologic response
is elicited without occupying full complement
of available receptors.
56
57. Receptor Regulation
a) Receptor desensitization (Down-regulation)
continuous stimulation with agonists generally
results in a state of desensitization
• adaptation
• refractoriness
• down-regulation)
Effects to the same concentration of drug
diminished.
This phenomenon, called tachyphylaxis
• occurs rapidly
• important therapeutically.
57
58. Desensitization can result from;
Temporary inaccessibility of the receptor to
agonist or
Promote sequestration of receptor from the
membrane (internalization)
Fewer receptors being synthesized and
available at the cell surface
58
59. b) Supersensitivity/ Up-regulation
Supersensitivity to agonists follows chronic
reduction of receptor stimulation.
Following withdrawal from prolonged
receptor blockade (e.g. long-term
administration of β adrenergic receptor
antagonists)
59
60. Supersensitivity can result from;
unmasking of receptors
synthesis and recruitment of new receptors
(up-regulation)
accentuation of signal amplification by the
transducer
60
61. References:
1. Basic and clinical pharmacology by
Bertram G. Katzung, 12th edition (2012)
2. Pharmacology by H. P. Rang, M.M. Dale,
J.M. RITTER, 7th Edition (2012)
3. Essentials of Medical Pharmacology by
KD Tripathi, 7th Edition (2013)
4. Pharmacology by George M. Brenner,
Craig W. Stevens, 4th Edition (2013)
61