This document describes various preclinical models used to screen drugs acting on the autonomic nervous system. It discusses models for screening sympathomimetics, sympatholytics, parasympathomimetics, and parasympatholytics. For sympathomimetics and sympatholytics, in vivo models include measuring blood pressure in dogs, the rabbit eye model, and the cat spleen model. In vitro models include the isolated frog heart and rabbit intestine preparations. For parasympathomimetics and parasympatholytics, in vivo models measure blood pressure responses and miosis in rabbit eyes, while in vitro models use the isolated heart, ileum, frog muscle, and trachea.
Preclinical Screening of Antiasthmatic DrugsShubham Kolge
Bronchial asthma is characterized by both bronchoconstriction and airway inflammation which leads to bronchial hyperresponsiveness to various stimuli. Different mediators are implicated in asthma. As the precise etiology is not known and multiple biochemical processes are triggered by different causative factors, it is difficult to have a single drug which can effectively and simultaneously act upon different mediators. This led to an intense search for potent and safe antiasthmatic drugs. This presentation intends to compile different screening methods for the evaluation of new candidate drugs with potential for the treatment of asthma. These include in vitro, in vivo, receptor binding and enzymatic methods.
Preclinical Screening of Antiasthmatic DrugsShubham Kolge
Bronchial asthma is characterized by both bronchoconstriction and airway inflammation which leads to bronchial hyperresponsiveness to various stimuli. Different mediators are implicated in asthma. As the precise etiology is not known and multiple biochemical processes are triggered by different causative factors, it is difficult to have a single drug which can effectively and simultaneously act upon different mediators. This led to an intense search for potent and safe antiasthmatic drugs. This presentation intends to compile different screening methods for the evaluation of new candidate drugs with potential for the treatment of asthma. These include in vitro, in vivo, receptor binding and enzymatic methods.
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
In this slide contains diabetics, classification, symptoms, complication, invivo and invitro screening models of anti diabetics.
Presented by: GEETHANJALI ADAPALA (Department of pharmacology).
RIPER, anantapur
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
In this slide contains diabetics, classification, symptoms, complication, invivo and invitro screening models of anti diabetics.
Presented by: GEETHANJALI ADAPALA (Department of pharmacology).
RIPER, anantapur
DIPLOMA IN PHARMACY PHARMACOLOGY LAB MANUAL.pdfSumit Tiwari
DIPLOMA IN PHARMACY PHARMACOLOGY LAB MANUAL.pdf
Introduction to experimental pharmacology and pharmacy. Sources of drugs
2. Study of action of drugs on the rabbit's eye
3. Study of effect of drugs on ciliary movement of frog's oesophagus
4. Study of effect of drugs on frog's rectus muscle preparation
5. Effect of cardiac stimulants and depressants on perfused frog's heart
6. Effect of drugs on dog's blood pressure and respiration - computer assisted learning (CAL)
method
7. Evaluation of analgesics by chemical method
8. Effect of saline purgative on frog intestine and the use of Oral Rehydration Solution.
9. Preparation of solution for test dose of penicillin
10. Study of action of antidepressants on mice
11. Study of anorectic and locomotor activity of amphetamin and fenfluramine.
A. Adrenergic neurotransmitters and their biosynthesis and metabolism, adrenergic receptors their distribution and actions mediated by them
B. Sympathomimetics
1. Direct acting: SAR, Endogenous catecholamines,
a) Alpha adrenergic agonists: Phenylephrines, Methoxamine, Naphazoline, Xylometazolines, Oxymetazoline, Clonidines, Guanabenz, Methyldopa
b) Dual agonist/antagonist: Dobutamine
c) Beta adrenergic agonists: Isoproterenols, Metaproterenol, Terbutalins, Albuterol, Salbuterol, Bitolterol, Ritodrine
2. Indirect acting: Hydroxyamphetamine, Propylhexedrine
3. Mixed acting: Ephedrine, Metaraminol
C. Adrenolytics:
1. Alpha blockers:
a) Non selective: Tolazoline
b) Irreversible blockers: Phenoxybenzamines
c) Alpha1 blockers: Prazosins, Doxazosin, Tamsulosin
d) Alpha2 blockers: Yohimbine, Coryanthine
2. Beta blockers: SAR
a) Non selective blockers: Propranolols, Nadolol, Pindolol, Timolol, Sotalol
b) Beta1 blockers: Acebutolol, Atenelol, Esmolol, Metaprolols
c) Betablockers with alpha1 antagonistic activity: Labetalol, Carvedilol
Your sympathetic nervous system is best known for its role in responding to dangerous or stressful situations.
In these situations, your sympathetic nervous system activates to speed up your heart rate, deliver more blood to areas of your body that need more oxygen or other responses to help your get out of danger.
Its nerve fibers arise from the thoracic and lumbar regions of the spinal cord.
The autonomic ganglia are the synapses between preganglionic and postganglionic neurons. The postganglionic axons then go to the visceral effectors.
Acetylcholine is a neurotransmitter releases in the preganglionic nerve endings and Noradrenaline at postganglionic nerve endings.
The drugs which mimic the action sympathetic division are called sympathomimetics.
They show similar actions as that of catecholamines.
Sympathomimetic
They act by either by directly interacting with adrenergic receptors (alpha or beta) or stimulation of the adrenergic nerve endings.
Types of drugs that act on Autonomic Nervous System and there is a link about loosing body Weight in a faster way , you must try it . The offer is limited
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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
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
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.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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.
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
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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2. Nervous System
It is an organ system containing a network of specialized cells called neurons
that coordinate the actions of an animal and transmit signals between
different parts of its body
Autonomic Nervous Systems
The autonomic nervous system is a component of the peripheral nervous
system that regulates involuntary physiologic processes including heart
rate, blood pressure, respiration, digestion, and sexual arousal etc.
3.
4. SYMPATHOMIMETICS
INTRODUCTION
Sympathomimetics are the agents that mimic the activity of adrenaline
(epinephrine) in the periphery. Adrenaline is secreted by adrenal medulla in
mammals. Nor-adrenaline (norepinephrine) is a predominant neurotransmitter of
the sympathetic system, which acts on sympathetic receptors (α and B).The
sympathetic receptors are mainly found in heart, blood vessels, branchi, uterus,
GI tract, and eye. Stimulation of sympathetic nerves by adrenaline or electrical
stimuli may trigger the following responses: heart rate acceleration, blood
pressure stimulation, mydriasis in the eye, increased stroke volume in the heart,
coronary arteries dilatation, constriction of pulmonary vessels, bronchial muscle
relaxation, inhibition of gastric secretion, gastrointestinal sphincters contraction,
and stimulation of the uterus.
5. Animal models used for screening sympathomimetics
In Vivo models
1. Bioassay of adrenaline by monitoring blood pressure in dogs
2. Rabbit eye model
3. Cat spleen model
4. Spinal cat model
In Vitro model
1. Bioassay of adrenaline using rabbit intestine
2. Isolated frog heart preparation
6. 1. Bioassay of adrenaline by monitoring blood pressure in dogs:
Measuring the blood pressure is the main parameter to evaluate adrenaline and other
sympathomimetics. When adrenaline is injected by iv. route to the animals, blood
pressures (systolic and diastolic) elevate rapidly to a peak due to sympathetic
stimulation and then rapidly decreases below the base line before returning to the
baseline (i.e. biphasic response).
Method:
• Healthy dogs are selected and anesthetized with barbiturate (25 mg/kg. iv.) and
acclimatized for blood pressure monitoring.
• Blood pressure is monitored by a kymograph after cannulating carotid artery
• The standard solution of adrenaline (4% w/V in 0.1 HCI) is prepared and different
dilutions of adrenaline are prepared by diluting it with saline. A suitable diluting
concentration is 1: 10,000. Test sample solution is also prepared in saline. Animals
should be given atropine sulphate (1 mg/kg. iv.) to eliminate vagal action
IN-VIVO MODELS
7. • Adrenaline is injected into the femoral vein through the venous cannula and two
successive responses of the same dose of adrenaline are recorded. The
observation of similar response after administration of the same dose of
adrenaline indicates that there is no variation in B.P. that the animal is now ready
for the assay.
• Then the test and the standard samples are given
Interpretation:
Sympathomimetics raise the blood pressure. The potency of the test sample is
estimated by comparing the rise in blood pressure of the test sample with that
produced by the standard preparation of adrenaline.
8. 2. Rabbit eye model:
The iris of eyes is composed of two types of muscle fibres, the circular and the radial.
The circular muscles are controlled by the parasympathetic system and the radial ones
are innervated by sympathetic system. The stimulation of sympathetic and
parasympathetic nerves produces mydriasis and miosis effect respectively and their
paralysis produces opposite effects. Local administration of sympathomimetic drugs on
eye dilates the pupil. They activate the B₂ receptor on the eye and cause the ciliary
muscle relaxation and produce mydriasis effect.
Method:
• Healthy young rabbits (2-3 kg) are used in this model. Animals are divided into
different groups: control (vehicle treatment), standard (adrenaline treatment) and test
group (test sympathomimetic treatment).
• 0.1 % adrenaline hydrochloride solution is used as a standard.
9. • Eyes of rabbits are washed with distilled water and left for 5 min.
• Vehicle/adrenaline/test drug is applied topically to their respective groups and
measured the pupil diameter
• Calculate the mean diameter in each group.
Interpretation:
Mean pupil diameter of standard and test groups are compared with the control
group. The topical administration of adrenaline or other sympathomimetics increases
the pupil diameter and produce mydriasis effect in the eye
10. 3. Cat Spleen model:
Sympathomimetics contract the spleen and release the transmitter. Released nor-
adrenaline can be measured by collecting spleen, venous effluent and analyze the
noradrenaline content. Nor-adrenaline content is analyzed after radioactive labelling.
Method:
• Healthy cats (2-4 kg) are used in this model. Cats are anesthetized by a sutitable
anesthetized agent.
• The animal is dissected to expose spleen.
• The splenic nerves are cut to avoid the release of catecholamine from other sites.
• The adrenal glands are also removed to avoid the release of pressure amines
• Heparin is administered intravenously to prevent blood clotting.
• The abdominal region is filled with warm paraffin and aerated with a carbogen (a
mixture of 95 % O₂ and 5% CO₂)
11. • Vehicle/adrenaline sympathomimetic is injected into the splenic artery to contract
spleen and to release the transmitter.
• Nor-adrenaline is measured by scintillation counter for radioactivity measurement
Interpretation:
The nor-adrenaline content after administration of adrenaline or test
sympathomimetics are compared with the vehicle-treated value. The
sympathomimetics increase the release of noradrenaline. The different doses of the
test compound are used to compare with standard.
12. IN-VITRO MODELS
1. Bioassay of adrenaline using rabbit intestine:
Adrenergic B₂ receptors are found in the intestinal smooth muscles. Activation of
sympathetic B, receptors relaxes the intestine via CAMP pathway, Rabbits, guinea
pigs, rats are used in this model.
Method:
• A healthy rabbit (2-3 kg) method is described. Rabbit is sacrificed and is dissected
out to isolate the duodenum in Tyrode solution.
• A small piece of duodenum is suspended in the organ bath containing Tyrode
solution at 37.5°C.
• Standard solution of adrenaline is made as described in the previous method.
• Test sample solution is also prepared in saline.
• The muscle is allowed to stabilize for 30 min.
13. • Rhythmic contractions are recorded by isotonic frontal writing lever on the
kymograph.
• After recording baseline, adrenaline (1 µg/ml, 2 µg/ml, 4 µg/ml) is administered in
an increasing order up to ceiling effect with proper washing interval.
• The test sample is administered and matched with the standard.
• Adrenaline relaxes the duodenum and the same property is taken up to
consideration for finding out the potency of the test sample.
14. 2. Isolated frog heart preparation:
Isolated heart preparation is used to evaluate the sympathomimetic activity on the
heart. The sympathomimetics like adrenaline and isoprenaline increase the heart rate
and force of contraction due to activation of B₂ receptor on heart, while
noradrenaline administration has little effect on heart rate because nor-adrenaline
generally acts on a receptor.
Method:
• A healthy frog is sacrificed by pithing and dissected to expose the heart.
• A curved needle is inserted in the apex and attached to a startling heart lever for
recording contractions on the kymograph.
15. • After recording baseline (basal heart rate), Adrenaline (2 µg/ml)/ test
sympathomimetics are administered and recorded the response.
• Sympathomimetics accelerate the heart rate
• Observed heart rate is compared with basal heart rate
This method is now absolute due to ethical constraints
16. SYMPATHOLYTICS
INTRODUCTION
The Sympatholytics are the agents that inhibit the action of the sympathetic nervous
system by blocking the sympathetic receptors (a and B). The sympatholytics, eg
phentolamine, prazosin, propranolol, atenolol, etc. are clinically used for the treatment
of cardiovascular diseases. They decrease the blood pressure and heart rate, relax the
vascular smooth muscle, inhibit the mydriasis effect in the eye, and inhibit the relaxing
effects in tracheal chain induced by sympathetic system activation
17. Animal models used for screening sympatholytics
In Vivo Models
1. Adrenergic antagonism in the rodent's eye
2. Blood pressure response in dogs
3. Cardiovascular response in rats
4. Nictitating membrane prolapses in cats
In Vitro Models
1. Isolated frog heart Preparation
2. Isolated aortic muscle strips
3. Isolated guinea pig tracheal chain
18. 1. Adrenergic antagonism in rodent's eye:
Sympathomimetics like noradrenaline, adrenaline, and isoprenaline induces the
mydriasis. This effect is blocked by α and β blockers. a-blockers (e.g. prazosin,
phenoxybenzamine) block the action of noradrenaline, α and β blockers (e.g.
labetalol, carvedilol) block the action of adrenaline, and β blockers (e.g. propranolol,
atenolol metoprolol) block the action of isoprenaline.
Method:
• Albino rats (120-150 g) or albino mice (25-30 g) are employed in this model
• Experimental animals are divided into control (vehicle) and tests group (test
preparations)having 4-6 animals in each.
• Vehicle/test drugs are administered subcutaneously to therespective groups.
• After 30 min of vehicle/test drugs administration, nor adrenaline(0.1 mg/kg, i.v.) or
adrenaline (0.05 mg/kg, i.v.) or isoprenaline (20 mg/kg, i.v.) are injected
IN-VIVO MODELS
19. • The pupil diameters of each animal is measured. The mean value in each group is
reported
Interpretation:
Mean pupil diameter of test groups is compared with control group. The
sympatholytic drugs antagonize the mydriasis effects of sympathomimetics.
Therefore, the pupil diameter of test groups is lesser than the control group
20. 2. Blood pressure response in dogs:
Sympatholytics decreases the blood pressure by blocking α and β receptors. This
model is also used to determine the specific receptor antagonizing property of test
compound by using specific receptor agonist. Rats and cats are also used to monitor
changes in blood pressure induced by drugs.
Method:
• Male Mongrel dogs (15-20 kg) are used in this model.
• Animals are anesthetized with methohexital (10 mg/kg. iv.), and maintained with
nitrous oxide and oxygen at 4:2 proportion in a non-rebreathing system using a
respiratory pump.
• Animals are immobilized by succinylcholine (1 mg/min).
• Left carotid artery is cannulated and connected to a blood pressure recorder.
• The femoral vein is cannulated for drug administrations.
21. • Atropine is also injected (2 mg/kg) at the start of the experiment to avoid reflex
vagal action.
• Phentolamine mg/kg) or propranolol (1 mg/kg) is used as a standard
sympatholytic drug.
• After recording the baseline, vehicle/standard/test drug is administered via the
femoral vein and blood pressure is recorded.
• Blood pressure of standard and test drugs are compared with vehicle treatment
Interpretation:
Sympatholytics decrease the blood pressure as compared to vehicle. Specific
sympatholytics like a blocker also block the response of a agonist like noradrenaline
on blood pressure.
22. IN-VITRO MODELS
1. Isolated frog heart preparation:
Isolated heart preparation is also used to evaluate the sympatholytic activity on the
heart. The sympatholytic like propranolol reduces the heart rate by blocking of β1,
receptor or membrane stabilizing effect on the heart.
Method:
• Baseline recording (basal heart rate)
• propranolol (200 ug/ml)/test Sympatholytics are administered and record the
response by using force transducer on physiograph.
• Observed heart rate is compared with basal heart rate
• Similarly, effect of sympatholytics on sympothomimetics induced changes in the
heart rate can also be evaluated.
Interpretation:
Sympatholytics reduce the basal or sympathomimetics induce increase in heart rate
23. PARASYMPATHOMIMETICS
INTRODUCTION
Parasympathomimetic drugs are also known as cholinomimetic/cholinergic drugs.
Acetylcholine is an endogenous neurotransmitter. Parasympathomimetic drugs
stimulate the action of the parasympathetic nervous system by activating the
cholinergic receptors (muscarinic M and/or nicotinic N receptor) and/or increasing
the availability of acetylcholine Muscarinic receptor mainly present in the gastric
glands (M1 receptor) heart (M2 receptor), and smooth muscles (M3 receptor) and their
activation causes the gastric secretion, cardiac depression, and smooth muscle
contraction. Nicotine receptors are present in the autonomic ganglion (NN receptor)
and neuromuscular junction (NM receptor) and their activation cause the stimulation
of autonomic ganglion and skeletal muscles
24. Animal models used for screening parasympathomimetics
In Vivo Models
1. Blood pressure response in anesthetized animals
2. Miosis effect on rabbit eye
In Vitro Models
1. Isolated heart Preparation
2. Isolated ileum preparation
3. Frog's rectus abdominis muscle preparation
4. Isolated tracheal chain preparations
25. IN-VIVO MODELS
Blood pressure response in anesthetized animals:
Parasympathetic stimulation produces fall in blood pressure due to vasodilatation. The
acetylcholine (2 ug) is used as a standard. Blood pressure response depends upon the dose
of acetylcholine. Acetylcholine at 2 ug causes fall in blood pressure without any changes in
heart rate, while at high dose (50 µg) produces fall in blood pressure along with
bradycardia due to cardio-inhibition. In this model, dogs, cats and rats can be used. This
model is used to evaluate the cholinomimetic and anticholinesterase activity.
Method:
• Animals are anesthetized with a suitable anesthetic agent and prepared for blood
pressure monitoring.
• Animals are kept on artificial respiration.
• The carotid artery is cannulated for recording blood pressure.
26. • The femoral vein is cannulated for injecting acetylcholine or test drugs.
• After stabilization, acetylcholine (1-6 ng)/test drug is injected and blood pressure is
recorded.
Interpretation:
The fall in blood pressure after administration is compared with the fall by the
standard acetylcholine preparation
27. 2. Miosis effect on rabbit eye:
Parasympathomimetics like carbachol, pilocarpine, and physostigmine contract the
(miosis) and decrease the intraocular pressure by muscarinic (M3 receptor) action.
Parasympathetic system modulates the eye accommodation through the control of
circular muscles in the eye The activation of M3 muscarinic receptors causes ciliary
muscle contraction, resulting in decrease in diameter of the ring of ciliary muscle.
Method:
• Male rabbits (2-3 kg) are generally used in this model.
• Animals are divided in different groups: control (vehicle treatment), standard, and
test group.
• 0.5-2% pilocarpine and/or 0.25-0.5% physostigmine ophthalmic solution is used as
a standard.
• Eyes of rabbits are washed with distilled and left for 5 min.
28. • Vehicle/standard/test drug is applied topically to their respective groups and
measured the pupil diameter.
• Calculate the mean pupil diameter in each group.
Interpretation:
Mean pupil diameter of standard and test groups are compared with the control group.
The topical administration of standard or other parasympathomimetics decrease the
pupil diameter and produce mitotic effect
29. 1. Isolated heart preparation:
Isolated heart preparation model is also used for evaluation of parasympathetic system
similar to the sympathetic system. Parasympathomimetics like acetylcholine (2 ug)
decrease the force of contraction and heart rate by activation of My receptor on heart,
while parasympatholytic (atropine, 20 ug) administration has little effect on the heart
but opposes the effect of parasympathetic stimulation. In this model, frog's or rabbit's
heart is used. The detailed methodology is similar as described in chapter Animal
models for screening sympathomimetics
IN-VITRO MODELS
30. PARASYMPATHOLYTICS
INTRODUCTION
Parasympatholytics or anticholinergic drugs reduce the activity of parasympathetic
nervous system and antagonize the action of acetylcholine by blocking cholinergic
receptors. The blockade of muscarinic receptors abolish the action of acetylcholine
and produce spasmolytic activity on bronchial and GI smooth muscles, pupil dilation,
inhibit gastric secretions and increase the heart rate. Moreover, antagonism of
nicotinic receptor produces ganglionic inhibition and relaxes the skeletal muscle.
31. Animal models used for screening parasympatholytics
In Vivo Models
1. Blood pressure response in Dogs
2. Mydriasis effect in eye
3. Acetylcholine-induced bronchoconstriction in guinea pigs
In Vitro Models
1. Isolated ileum preparation
2. Frog's rectus abdominis muscle preparation
3. Isolated heartpreparation
32. IN-VIVO MODELS
1. Blood pressure response in dogs:
Parasympatholytic like atropine increase the heart rate and it blocks the blood pressure
and heart rate response of acetylcholine.
Method:
• Dogs are anesthetized with a suitable anesthetic agent and prepared for blood
pressure and heart rate monitoring
• Animals are kept in artificial respiration.
• The carotid artery is cannulated for recording blood pressure.
• The femoral vein is cannulated for injecting atropine/acetylcholine/test
parasympatholytic drugs.
• After stabilization different doses of acetylcholine (2-10 ug/kg) are injected and
recorded the blood pressure and heart rate.
33. • A single dose of atropine standard (1 mg/kg)/test drug is administered and the
responses are monitored.
• Then again acetylcholine is injected in the same doses to record the blood pressure
and heart rate.
Interpretation:
The response of acetylcholine before and after parasympatholytics is compared. The
parasympatholytic agents block the responses of acetylcholine to increase the heart
rate
34. 2. Mydriasis effect in eye:
Parasympatholytics like atropine and tropicamide dilate the pupil by blocking the
muscarinic (M3 receptor) action on the eye.
Method:
Rabbits (2-3 kg), rats (150-200 g) and mice (25-30 g) are generally used in this
model. Animals are divided into different groups: control (vehicle treatment),
standard, and test group. In rabbits, vehicle/standard (0.1% w/v atropine)/test drugs
are applied topicallyand in rodents, drugs solution are injected intraperitoneally. Five
min after topical application and 30 min after intraperitoneally injection, pupil
diameters of each animal is monitored. Mean pupil diameter of each group is
calculated.
Interpretation:
Mean pupil diameter of standard and test groups are compared with the control group.
The administration of standard or other parasympatholytics increase the pupil
diameter and produce mydriasis effect in the eye
35. 3. Acetylcholine-induced bronchoconstriction in guinea pigs:
Acetylcholine causes the bronchi smooth muscle contraction resulting in hypoxia and
finally leads to convulsion. Histamine chamber (Fig. 221) is used in this method.
Acetylcholine (10%) is to be given as aerosol under a constant pressure 40 mm/Hg
from the inbuilt nebulizer of the histamine chamber. The time required for appearance
of preconvulsive dyspnoea symptoms are monitored. Parasympatholytics can delay the
occurrence of these symptoms.
Method:
• Guinea pigs are generally used in this model.
• Animals are divided into control and test group.
• Each animal is placed in histamine chamber before the treatment and exposed to
acetylcholine (10% aerosol) and the time required for appearance of preconvulsive
dyspnoea is recorded.
• After that, animals are removed from the chamber and left into the fresh air for 24
hours.
36. • Next day animals from the control group are treated with vehicle and animals of test
group are treated with the test parasympatholytic.
• Thirty min after the treatment, animals are placed again in histamine chamber with
acetylcholine (10%) aerosol) and the time for preconvulsive dyspnoea is recorded.
• Percent increase of preconvulsive time is calculated.
Interpretation:
Results of test group are compared with control group. If the test drug delays the
preconvulsive dyspnoea time, the drug is considered as a parasympatholytic agent
37. IN-VITRO MODELS
1. Isolated ileum preparation:
Similar to the assay of parasympathomimetics, gastrointestinal ileum preparation is
also a most common model for evaluating of parasympatholytic agents.
Parasympatholytics block the contractile response of parasympathetic stimulation. The
guinea pigs, rats, rabbits and cock is used to isolate the ileum. The percentage
inhibition of a parasympatholytic is recorded against acetylcholine-induced contraction.
Method:
• After stabilization of tissue preparation baseline is recorded on kymograph, then
dose response curve of standard acetylcholine solution (1 ug onward) is recorded
upto ceiling effect.
• The tissue is washed with a fresh Tyrode solution (2-3 time)
38. • Then a standard atropine (3.5 nM or 0.01 ug/ml concentration in an organ bath)/test
preparation (antagonist) is added in organ bath for 2-5 min and without washing
standard acetylcholine solution is added to record the response again with the same
dose
• Calculate the percentage inhibition response.