This document discusses drugs affecting the renin-angiotensin system and cardiac electrophysiology. It begins by providing an overview of the renin-angiotensin system (RAS), including that renin cleaves angiotensinogen to form angiotensin I which is converted to angiotensin II by ACE. Angiotensin II causes vasoconstriction, sodium retention, and increased blood pressure. The document then focuses on ACE inhibitors, describing their mechanism of blocking angiotensin II formation, uses in hypertension and heart conditions, and examples such as captopril, enalapril, and lisinopril.
Hello everyone.....I shared a pdf file containing the deep knowledge about HYPERLIPIDEMIA AND THE PHARMACOLOGY OF ANTI-HYPERLIPIDEMIC DRUGS . In the B.pharma 5th semester...there is an most important topic ANTI-HYPERLIPIDEMIC DRUGS in the subject Pharmacology -II so i uploaded this file to help the students about this most important topic.....if u want this assignment in any format....feel free to DM me on my gmail id.....careof22@gmail.com.....THANK YOU
5-Hydroxytryptamine & it’s Antagonist is a Topic in Pharmacology which will defiantly Help You in pharmacy field All information is related to pharmacology drug acting and it's effect on body. it is collage project given by our department i would like to share with you.
Utilization of radioactive isotopes in the investigation of biogenetic studiesMs. Pooja Bhandare
Isotopes: TWO TYPES OF ISOTOPES,Radioactive isotopes.
Stable isotopes, Radiolabelled Tracers ( Radiolabelled compounds), Radiotracer Technique, Steps in Tracer Technique,
Selection of Radioisotopes.
Preparation of Radioisotopes.
Introduction/Insertion of Radiolabelled compound in biological system (Plant part) Seperation and determination of labelled compound in various biochemical reaction, Preparation of labelled compounds : Insertion of Radiolabelled compound in plant part, Root feeding, Stem feeding, Direct Injection, Floating Methods, Spray technique, Separation or Isolation of Radiolabelled compound and detection of radioisotope labelled compound. Detection and assay of Radioactive labelled compound, Detector system used (Analysis of Isotopic content). Method in Tracer Technique,
Precursor – Product sequence
Double and Multiple Labelling
. Competitive Feeding,Sequential Analysis
Applications of Tracer Technique
Calcium channel blockers - Medicinal chemistry for B.Pharm.Purna Nagasree K
This ppt describes about the drugs used as calcium channel blockers, their mechanism of action, metabolism and Structure activity relationship of dihydropyridines
A condition in which the heart is unable to pump sufficient blood
to meet the metabolic demand of the body and also unable to receive it back because every time after a systole.
Isolation, Identification and Analysis of PhytoconstituentsDr. Siddhi Upadhyay
Isolation, Identification and Analysis of Phytoconstituents
a) Terpenoids: Menthol, Citral, Artemisin
b) Glycosides: Glycyrhetinic acid & Rutin
c) Alkaloids: Atropine,Quinine,Reserpine,Caffeine
d) Resins: Podophyllotoxin, Curcumin
Hello everyone.....I shared a pdf file containing the deep knowledge about HYPERLIPIDEMIA AND THE PHARMACOLOGY OF ANTI-HYPERLIPIDEMIC DRUGS . In the B.pharma 5th semester...there is an most important topic ANTI-HYPERLIPIDEMIC DRUGS in the subject Pharmacology -II so i uploaded this file to help the students about this most important topic.....if u want this assignment in any format....feel free to DM me on my gmail id.....careof22@gmail.com.....THANK YOU
5-Hydroxytryptamine & it’s Antagonist is a Topic in Pharmacology which will defiantly Help You in pharmacy field All information is related to pharmacology drug acting and it's effect on body. it is collage project given by our department i would like to share with you.
Utilization of radioactive isotopes in the investigation of biogenetic studiesMs. Pooja Bhandare
Isotopes: TWO TYPES OF ISOTOPES,Radioactive isotopes.
Stable isotopes, Radiolabelled Tracers ( Radiolabelled compounds), Radiotracer Technique, Steps in Tracer Technique,
Selection of Radioisotopes.
Preparation of Radioisotopes.
Introduction/Insertion of Radiolabelled compound in biological system (Plant part) Seperation and determination of labelled compound in various biochemical reaction, Preparation of labelled compounds : Insertion of Radiolabelled compound in plant part, Root feeding, Stem feeding, Direct Injection, Floating Methods, Spray technique, Separation or Isolation of Radiolabelled compound and detection of radioisotope labelled compound. Detection and assay of Radioactive labelled compound, Detector system used (Analysis of Isotopic content). Method in Tracer Technique,
Precursor – Product sequence
Double and Multiple Labelling
. Competitive Feeding,Sequential Analysis
Applications of Tracer Technique
Calcium channel blockers - Medicinal chemistry for B.Pharm.Purna Nagasree K
This ppt describes about the drugs used as calcium channel blockers, their mechanism of action, metabolism and Structure activity relationship of dihydropyridines
A condition in which the heart is unable to pump sufficient blood
to meet the metabolic demand of the body and also unable to receive it back because every time after a systole.
Isolation, Identification and Analysis of PhytoconstituentsDr. Siddhi Upadhyay
Isolation, Identification and Analysis of Phytoconstituents
a) Terpenoids: Menthol, Citral, Artemisin
b) Glycosides: Glycyrhetinic acid & Rutin
c) Alkaloids: Atropine,Quinine,Reserpine,Caffeine
d) Resins: Podophyllotoxin, Curcumin
Cardiovascular tests are used to assess the function of the heart and to identify the disorders associated with the pathological heart function. Following are the tests used to assess cardiovascular function
A Power point presentation on Betalactam antibiotics suitable for undergraduate medical students. This Ppt is already presented in theory class lectures to the students of NEIGRIHMS, Shillong, Meghalaya
A Powerpoint presentation on drugs excretion and elimination suitable for UG medical students. This ppt is already presented to my students in one of the theory classes.
A PowerPoint presentation on "NSAIDS" suitable for reading by UG and PG Medical/Paramedical students of Pharmacology and Pharmacy sciences. This Ppt. is prepared for academic purpose only and already presented to my students in one of the theory classes of mine.
- 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
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
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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
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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
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Cardiac electrophysiology and pharmacology - drdhriti
1. CARDIAC ELECTROPHYSIOLOGY AND
DRUGS AFFECTING RENIN-
ANGIOTENSIN SYSTEM
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong
2. Drugs of Cardiovascular System
• Drugs having major action on Heart and Blood vessels and
used in various important cardiac disease conditons.
• They act directly on heart structures or via Autonomic
Nervous system (ANS), Central Nervous System (CNS),
Kidney, Autacoids or Hormones:
1. Cardiac Glycosides
2. Sympathomimetics
3. Anticholinergic Drugs
4. Antiarrhythmics
5. Electrolytes
6. Thrombolytic
7. Anticoagulants
8. Antihypertensive
9. Analgesics
3. Recall Heart Anatomy !
1. Right Coronary
2. Left Anterior Descending
3. Left Circumflex
4. Superior Vena Cava
5. Inferior Vena Cava
6. Aorta
7. Pulmonary Artery
8. Pulmonary Vein
9. Right Atrium
10. Right Ventricle
11. Left Atrium
12. Left Ventricle
13. Papillary Muscles
14. Chordae Tendineae
15. Tricuspid Valve
16. Mitral Valve
17. Pulmonary Valve
18. Aortic Valve (Not pictured)
4. Recall Heart Physiology !
• SA node
• AV Junction
• Bundle of His
• His-Purkinje
• Myocardial cells
• Electrical potential
• Autonomic Nervous
system
8. Cardiac
Electrophysiology
• Recall: to function efficiently, heart needs to contract
sequentially (atria, then ventricles) and in synchronicity
• Relaxation must occur between contractions (not true for
other types of muscle [exhibit tetany contract and hold
contraction for certain length of time]
• Coordination of heartbeat is a result of a complex,
coordinated sequence of changes in membrane potentials
and electrical discharges in various heart tissues
9. Myocardial Cells
• 2 types – Pacemaker and non
pacemaker
– Pacemaker and conducting cells –
SAN, AVN, Bundle of His and
Purkinje`s fibres
– Non pacemaker – Working
Myocardial Cell (WMC) or CMC
• Sinus rhythm means rhythm
originates in SAN
• Sinus tachycardia means tachycardia
but rhythm originates in SAN – fever,
exercise etc.
• Tachycardia = heart rate > 100 per
minute
• Sinus Bradycardia = heart rate < 60
per min.
• Escape rhythm: Rhythm which is not
generated by SAN, but other, e.g.
AVN or bundle of His etc.
10. Cardiac Action Potential -
Five phases (0,1,2,3,4)
• Phase 0 – opening of fast Na channels and rapid
depolarization
• Drives Na+ into cell (inward current), changing membrane
potential
• Transient outward current due to movement of Cl- and K+
• Phase 1 – initial rapid repolarization
• Closure of the fast Na+ channels
• Phase 0 and 1 together correspond to the R and S waves of the
ECG
• Phase 2 - plateau phase
• sustained by the balance between the inward movement of Ca+
and outward movement of K+
• Has a long duration compared to other nerve and muscle tissue
• Normally blocks any premature stimulator signals (other muscle
tissue can accept additional stimulation and increase contractility
in a summation effect)
• Corresponds to ST segment of the ECG.
11. Cardiac Action Potential
– contd.
• Phase 3 – repolarization
– K+ channels remain open,
– Allows K+ to build up outside the cell, causing the cell
to repolarize
– K + channels finally close when membrane potential
reaches certain level
– Corresponds to T wave on the ECG
• Phase 4 - resting phase (resting membrane
potential)
• At (-90mv) stable
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle
13. Cardiac Action Potential – Pacemaker
Cells – slow channels
• Present in SAN and AVN and His –Purkinje cells
• Most characteristic feature is in Phase-4, or slow diastolic depolarization
• After repolarization membrane potential decays spontaneously and
sudden automatic depolarization
• Therefore capable of generating own impulses
• Normally SAN has steepest phase-4
• Characteristics:
• Initiation at higher threshold (less negative (-75mv)
• Slow depolarization
• Low overshoot (+10mv), low amplitude
• Very slow a propagation
• Phase-1 and 3 are not clearly demarcated
• Can occur in fibres depolarized too much to support fast channels
14. Drugs Affecting Renin - Angiotensin System
What is Renin – Angiotensin System?
(Physiological Background)
15. RAS - Introduction
• Renin is a proteolytic enzyme and also called
angiotensinogenase (plasma ɑ2 globulin)
• It is produced by juxtaglomerular cells of kidney
• Renin acts on a plasma protein – Angiotensinogen (a
glycoprotein synthesized and secreted into the bloodstream
by the liver) and cleaves to produce a decapeptide
Angiotensin-I
• Angiotensin-I is rapidly converted to Angiotensin-II
(octapeptide) by Angiotensin Converting Enzyme (ACE –
dipeptidyl carboxypeptidase) (present in luminal surface of
vascular endothelium)
• Furthermore, degradation of Angiotensin-II by peptidases
produce Angiotensin-III
16. Types – Circulating RAS and Tissue RAS
• Circulating: Renin is the rate limiting factor of AT-II release
– AT-I is less potent (1/100th) than of AT – II
– Plasma t1/2 of Renin is 15 minutes
– AT-I is rapidly converted to AT-II by ACE (AT-II half life 1 mim)
– Degradation product is AT-III
– Both AT-II and AT-III stimulates Aldosterone secretion from Adrenal
Cortex (equipotent)
• Tissue RAS:
– Extrinsic local RAS: Blood vessels capture Renin and Angiotensinogen
to produce local AT-II
– Intrinsic local RAS: Many tissues Heart, brain, blood vessels, kidneys,
adrenals have all components of RAS in their cells – produce locally
– Important factor in these organs
17. RAS – Physiologcal Regulation
Vasoconstriction
Na+ & water
retention
(Adrenal cortex)
Kidney
Increased
Blood Vol.
Rise in BP
It is secreted in
response to:
• Decrease in arterial
blood pressure – also fall
in BP and blood volume
• Decrease Na+ in macula
densa
• Increased sympathetic
nervous activity
(-)
(-)
18. Actions of Angiotensin-II - CVS
Powerful vasoconstrictor particularly arteriolar and venular
direct action
by release of Adr/NA release (adrenal and adrenergic nerve endings)
increased Central sympathetic outflow
• Promotes movement of fluid from vascular to extravascular
• More potent vasopressor agent than NA –promotes Na+ and
water reabsorption and no tachyphylaxis
• Overall Effect – Pressor effect (Rise in Blood pressure)
Cardiac action:
• Increases myocardial force of contraction (Ca++ influx promotion)
• Increases heart rate by sympathetic activity, but reflex bradycardia
occurs
• Cardiac output is reduced
• Cardiac work increased (increased Peripheral resistance)
• No arrhythmia - in contrast to NA
19. Chronic effects of Angiotensin-II
• Ill effects on chronic basis of exposure (Mitogenic effect!)
– Directly: Induces hypertrophy, hyperplesia and increased cellular
matrix of myocardium and vascular smooth muscles – by direct
cellular effects involving proto-oncogens and transcription of growth
factors
– Indirectly: Volume overload and increased t.p.r in heart and blood
vessels
• Hypertrophy and Remodeling (abnormal redistribution of muscle mass)
– Long standing hypertension – increases vessel wall thickness and
Ventricular hypertrophy
– Myocardial infarction – fibrosis and dilatation in infarcted area and
hypertrophy of non-infarcted area of ventricles
– CHF – progressive fibrotic changes and myocyte death
– Risk of increased CVS related morbidity and mortality
• ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling
21. Actions of Angiotensin-II
• Adrenal cortex: Enhances the synthesis and release of
Aldosterone
– In distal tubule Na+ reabsorption and K+ excretion
• Kidney: Enhancement of Na+/H+ exchange in proximal tubule
– increased Na+, Cl- and HCO3 reabsorption
– Also reduces renal blood flow and promotes Na+ and water retention
• CNS: Drinking behaviour and ADH release
• Peripheral sympathetic action: Stimulates adrenal medulla to
secrete Adr and also releases NA from autononic ganglia
22. Angiotensin Receptors
• 2 (two) subtypes: AT1 and AT2 – most of known Physiologic
effects are via AT1
– Both are GPCR – A1 is important
• Utilizes various pathways for different tissues
– PLC-IP3/DAG – Ca++: AT1 utilizes pathway for vascular smooth muscles
by MLCK
– Membrane Ca++ channels: Ca release - aldosterone synthesis, cardiac
inotropy, CA release - ganglia/adrenal medulla action etc.
– DAG: PKc – promotion of cell growth
– Adenylyl cyclase: in liver and kidney (AT1)
– Intrarenal homeostatic action: Phospholipase A2, LT and PG
production
– Long term effects on smooth muscles and myocardium – MAP kinase,
TAK2 tyrosine protein kinase and PKc
23. Angiotensin-II – Pathophysiological Roles
1. Mineraocorticoid secretion
2. Electrolyte, blood volume and pressure homeostasis: Renin is released
when there is change in blood volume or pressure or decreased Na+
content
– Reduction in tension in afferent gromerulus - Intrarenal
Baroreceptor Pathway activation – PG production - Renin release
– Low Na+ conc. in tubular fluid – macula densa pathway – COX-2
and nNOS are induced – release of PGE2 and PGI2 – more renin
release
– Baroreceptor stimulation increases sympathetic impulse – via
beta-1 pathway – renin release
• Renin release – increased Angiotensin II production – vasoconstriction
and increased Na+ and water reabsorption
• Rise in BP – decreased Renin release - Long term stabilization of BP is
achieved – long-loop negative feedback mechanism
24. Role of Angiotensin-II – contd.
• Short-loop negative feedback mechanism:
– activation of AT1 receptor in JG cells – inhibition of Renin
release
– Long term stabilization of salt and water intake
• Pharmacological importance:
– Drugs Increasing Renin release:
• ACE inhibitors and AT1 antagonists enhance Renin release
• Vasodilators and diuretics stimulate Renin release
• Loop diuretics increase renin release
– Decrease in Renin release:
• Beta blockers and central sympatholytics
• NSAIDs and selective COX-2 inhibitors decrease Renin release
25. Role of Angiotensin-II – contd.
3. Hypertension
4. Secondary hyperaldosteronism
Inhibitors of RAS:
• Sympathetic blockade
• ACE inhibitors
• AT1 receptor antagonists
• Aldosterone antagonists
• Renin inhibitory peptides and Renin specific antibodies
27. Captopril
• MOA:
– ACEIs block action of ACE – so no AT-II
– Also increases plasma kinin level (temporary)
• Depends on Na+ status and level of RAS
• In normotensives:
– With normal Na+ level – fall in BP is minimal
– But restriction in salt or diuretics - more fall in BP
• Renovascular and malignant hypertension – greater fall in BP
• Essential hypertension: 20% hyperactive RAS and 60%
hypoactive in RAS
– Contributes to 80% of maintainence of tone – lowers BP
– But no long term relation of fall in BP by captopril and PRA activity
28. Captopril – contd.
• Actions:
– Decrease in peripheral Resistance
– Arteriolar dilatation and increased compliance of larger arteries
– Fall in Systolic and Diastolic BP
No effect on Cardiac output
No interference with capacitance vessels - No Postural hypotension
No reflex sympathetic stimulation
Can be used safely in IHD patients
Renal blood flow is maintained – greater dilatation of vessels
Basal level of aldosterone decreased
• Pharmacokinetics:
• 70% absorbed, partly metabolized and partly excreted unchanged in urine
• Food interferes absorption
• T1/2 = 2 Hrs (6-12 Hrs)
29. Captopril – Adverse effects
• Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs
• Hyperkalemia in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level)
• Hypertension: CHF and diuretic patients
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes, urticaria etc
• Dysgeusia: loss or alteration of taste
• Foetopathic: hypoplasia of organs, growth retardation etc
• Neutropenia
• Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
30. ACE inhibitors - Enalapril
• It’s a prodrug – converted to enalaprilate
• Advantages over captopril:
– Longer half life – OD (5-20 mg OD)
– Absorption not affected by food
– Rash and loss of taste are less frequent
– Longer onset of action
– Less side effects
31. ACE inhibitors – Ramipril (Cardace)
• It’s a popular ACEI now
• It is also a prodrug with long half life
• Tissue specific – Protective of heart and kidney
• Uses: Diabetes with hypertension, CHF, AMI and cardio protective in
angina pectoris
• Blacks in USA are resistant to Ramipril – addition of diuretics help
• Dose: Start with low dose; 2.5 to 10 mg daily
• EBM Reports: 1) improves mortality rate in early AMI cases 2) reduces the
chance of development of AMI 3) reduces the chances of development of
nephropathy etc. (1.25, 2.55 … 10 mg caps)
32. ACE inhibitors – Lisinopril (Lipril/Listril)
• It’s a lysine derivative
• Not a prodrug
• Slow oral absorption – less chance of 1st dose
phenomenon
• Absorption not affected by food and not
metabolized – excrete unchanged in urine
• Long duration of action – single daily dose
• Doses: available as 1.25, 2.5, 5, 10 1nd 20 mg tab
– start with low dose
33. ACE inhibitors and hypertension
• 1st line of Drug:
– No postural hypotension or electrolyte imbalance (no fatigue or
weakness)
– Safe in asthmatics and diabetics
– Prevention of secondary hyperaldosteronism and K+ loss
– Renal perfusion well maintained
– Reverse the ventricular hypertrophy and increase in lumen size
of vessel
– No hyperuraecemia or deleterious effect on plasma lipid profile
– No rebound hypertension
– Minimal worsening of quality of life – general wellbeing, sleep
and work performance etc.
36. Losartan
• Competitive antagonist and inverse agonist of
AT1 receptor
• Does not interfere with other receptors except
TXA2
• Blocks all the actions of A-II - vasoconstriction,
sympathetic stimulation, aldosterone release
and renal actions of salt and water
reabsorption
• No inhibition of ACE
37. Losartan
• Theoretical superiority over ACEIs:
– Cough is rare – no interference with bradykinin and other ACE
substrates
– Complete inhibition of AT1 – alternative pathway remains for ACEIs
– Result in indirect activation of AT2 – vasodilatation (additional benefit)
– Clinical benefit of ARBs over ACEIs – not known
• However, losartan decreases BP in hypertensive which is for long period
(24 Hrs)
– heart rate remains unchanged and cvs reflxes are not interfered
– no significant effect in plasma lipid profile, insulin sensitivity and
carbohydrate tolerance etc
– Mild uricosuric effect
38. Losartan – contd.
• Pharmacokinetic:
– Absorption not affected by food but unlike ACEIs its bioavailability is
low
– High first pass metabolism
– Carboxylated to active metabolite E3174
– Highly bound to plasma protein
– Do not enter brain
• Adverse effects:
– Foetopathic like ACEIs – not to be
administered in pregnancy
– Rare 1st dose effect hypotension
– Low dysgeusia and dry cough
– Lower incidence of angioedema
• Available as 25 and 50 mg tablets
39. Losartan/ARBs - uses
• Hypertension
• CHF
• MI
• Diabetic Nephropathy
• Combination with ACEIs
40. Important
• ACEIs – Pharmacological actions and ADRs
• Therapeutic uses of ACEIs
• Role of ACEIs/ARBs in management of
Hypertension
• Losartan
Calcium – L and T types; L – all myocardial cells, T type – Pacemaker cells; Sodium – voltage gated channel; Potassium – voltage gated, inward current and background
RAS is important in case of normal physiological maintainance of homeostasis. RAS plays an important role in development of hypertension. In most of the cases of hypertension PRA is seen to be raised. The long term effects of persistenly active PRA leads to cardiac hypertrophy (ventricular) and remodelling and also coronary artery hypertrophy and remodelling. Therefore by blocking of the hypertension can be controlled by blocking of ACE practically in most of the hypertensive cases.
ACE inhibitors have many indications apart from the hypertension which will be talked when particular diseases are talked, For you now you have to remember is that what are the they are the first line of agent now in most of the cases of hypertension specially in young person and persons with ventricular hypertrophy. In practice they are used as first line of agent as monotherapy or in combination with diuretics and beta-blockers. The advantages of ACEIs are