Metabolic Disorders (Ketosis in Cattle)

Ketosis is a common disease of adult cattle. It is also known as Acetonemia or Ketonemia. It typically occurs in dairy cows in early lactation and is most consistently characterized by partial anorexia and depression. Rarely, it occurs in cattle in late gestation, at which time it resembles pregnancy toxemia of ewes. In addition to inappetence, signs of nervous dysfunction, including pica, abnormal licking, incoordination and abnormal gait, bellowing, and aggression, are occasionally seen. The condition is worldwide in distribution but is most common where dairy cows are bred and managed for high production.

Etiology & Pathogensis:

The pathogenesis of bovine ketosis is incompletely understood, but it requires the combination of intense adipose mobilization and a high glucose demand. Both of these conditions are present in early lactation, at which time negative energy balance leads to adipose mobilization, and milk synthesis creates a high glucose demand. Adipose mobilization is accompanied by high blood serum concentrations of nonesterified fatty acids (NEFAs). During periods of intense gluconeogenesis, a large portion of serum NEFAs is directed to ketone body synthesis in the liver. Thus, the clinicopathologic characterization of ketosis includes high serum concentrations of NEFAs and ketone bodies and low concentrations of glucose. In contrast to many other species, cattle with hyperketonemia do not have concurrent acidemia. The serum ketone bodies are acetone, acetoacetate, and β-hydroxybutyrate (BHB).

There is speculation that the pathogenesis of ketosis cases occurring in the immediate postpartum period is slightly different than that of cases occurring closer to the time of peak milk production. Ketosis in the immediate postpartum period is sometimes described as type II ketosis. Such cases of ketosis in very early lactation are usually associated with fatty liver. Both fatty liver and ketosis are probably part of a spectrum of conditions associated with intense fat mobilization in cattle. Ketosis cases occurring closer to peak milk production, which usually occurs at 4–6 wk postpartum, may be more closely associated with underfed cattle experiencing a metabolic shortage of gluconeogenic precursors than with excessive fat mobilization. Ketosis at this time is sometimes described as type I ketosis.

The exact pathogenesis of the clinical signs is not known. They do not appear to be associated directly with serum concentrations of either glucose or ketone bodies. There is speculation they may be due to metabolites of the ketone bodies.

Epidemiology:

All dairy cows in early lactation (first 6 wk) are at risk of ketosis. The overall prevalence in cattle in the first 60 days of lactation is estimated at 7%–14%, but prevalence in individual herds varies substantially and may exceed 14%. The peak prevalence of ketosis occurs in the first 2 wk of lactation. Lactational incidence rates vary dramatically between herds and may approach 100%. Ketosis is seen in all parities (although it appears to be less common in primiparous animals) and does not appear to have a genetic predisposition, other than being associated with dairy breeds. Cows with excessive adipose stores (body condition score ≥3.75 out of 5) at calving are at a greater risk of ketosis than those with lower body condition scores. Lactating cows with subclinical ketosis are also at a greater risk of developing clinical ketosis and displaced abomasum than cows with lower serum BHB concentrations.

Clinical Findings:

In cows maintained in confinement stalls, reduced feed intake is usually the first sign of ketosis. If rations are offered in components, cows with ketosis often refuse grain before forage. In group-fed herds, reduced milk production, lethargy, and an “empty” appearing abdomen are usually the signs of ketosis noticed first. On physical examination, cows are afebrile and may be slightly dehydrated. Rumen motility is variable, being hyperactive in some cases and hypoactive in others. In many cases, there are no other physical abnormalities. CNS disturbances are noted in a minority of cases. These include abnormal licking and chewing, with cows sometimes chewing incessantly on pipes and other objects in their surroundings. Incoordination and gait abnormalities occasionally are seen, as are aggression and bellowing. These signs occur in a clear minority of cases, but because the disease is so common, finding animals with these signs is not unusual.

Diagnosis:

The clinical diagnosis of ketosis is based on presence of risk factors (early lactation), clinical signs, and ketone bodies in urine or milk. When a diagnosis of ketosis is made, a thorough physical examination should be performed, because ketosis frequently occurs concurrently with other peripartum diseases. Especially common concurrent diseases include displaced abomasum, retained fetal membranes, and metritis. Rabies and other CNS diseases are important differential diagnoses in cases exhibiting neurologic signs.

Cow-side tests for the presence of ketone bodies in urine or milk are critical for diagnosis. Most commercially available test kits are based on the presence of acetoacetate or acetone in milk or urine. Dipstick tests are convenient, but those designed to detect acetoacetate or acetone in urine are not suitable for milk testing. All of these tests are read by observation for a particular color change. Care should be taken to allow the appropriate time for color development as specified by the test manufacturer. Handheld instruments designed to monitor ketone bodies in the blood of human diabetic patients are available. These instruments quantitatively measure the concentration of BHB in blood, urine, or milk and may be used for the clinical diagnosis of ketosis.

In a given animal, urine ketone body concentrations are always higher than milk ketone body concentrations. Trace to mildly positive results for the presence of ketone bodies in urine do not signify clinical ketosis. Without clinical signs, such as partial anorexia, these results indicate subclinical ketosis. Milk tests for acetone and acetoacetate are more specific than urine tests. Positive milk tests for acetoacetate and/or acetone usually indicate clinical ketosis. BHB concentrations in milk may be measured by a dipstick method that is available in some countries, or by the electronic device mentioned above. The BHB concentration in milk is always higher than the acetoacetate or acetone concentration, making the tests based on BHB more sensitive than those based on acetoacetate or acetone.

Treatment:

Treatment of ketosis is aimed at reestablishing normoglycemia and reducing serum ketone body concentrations. Bolus IV administration of 500 mL of 50% dextrose solution is a common therapy. This solution is very hyperosmotic and, if administered perivascularly, results in severe tissue swelling and irritation, so care should be taken to ensure that it is given IV. Bolus glucose therapy generally results in rapid recovery, especially in cases occurring near peak lactation (type I ketosis). However, the effect frequently is transient, and relapses are common. Administration of glucocorticoids, including dexamethasone or isoflupredone acetate at 5–20 mg/dose, IM, may result in a more sustained response, relative to glucose alone. Glucose and glucocorticoid therapy may be repeated daily as necessary. Propylene glycol administered orally (250–400 g/dose [8–14 oz]) once per day acts as a glucose precursor and is effective as ketosis therapy. Indeed, propylene glycol appears to be the most well documented of the various therapies for ketosis. Overdosing propylene glycol leads to CNS depression.

Ketosis cases occurring within the first 1–2 wk after calving (type II ketosis) frequently are more refractory to therapy than cases occurring nearer to peak lactation (type I). In these cases, a long-acting insulin preparation given IM at 150–200 IU/day may be beneficial. Insulin suppresses both adipose mobilization and ketogenesis but should be given in combination with glucose or a glucocorticoid to prevent hypoglycemia. Use of insulin in this manner is an extra-label, unapproved use. Other therapies that may be of benefit in refractory ketosis cases are continuous IV glucose infusion and tube feeding.

Prevention and Control:

Prevention of ketosis is via nutritional management. Body condition should be managed in late lactation, when cows frequently become too fat. Modifying diets of late lactation cows to increase the energy supply from digestible fiber and reduce the energy supply from starch may aid in partitioning dietary energy toward milk and away from body fattening. The dry period is generally too late to reduce body condition score. Reducing body condition in the dry period, particularly in the late dry period, may even be counterproductive, resulting in excessive adipose mobilization prepartum. A critical area in ketosis prevention is maintaining and promoting feed intake. Cows tend to reduce feed consumption in the last 3 wk of gestation. Nutritional management should be aimed at minimizing this reduction. Controversy exists regarding the optimal dietary characteristics during this period. It is likely that optimal energy and fiber concentrations in rations for cows in the last 3 wk of gestation vary from farm to farm. Feed intake should be monitored and rations adjusted to meet but not greatly exceed energy requirements throughout the entire dry period. For Holstein cows of typical adult body size, the average daily energy requirement throughout the dry period is between 12 and 15 Mcal expressed as net energy for lactation (NE_L). After calving, diets should promote rapid and sustained increases in feed and energy consumption. Early lactation rations should be relatively high in nonfiber carbohydrate concentration but contain enough fiber to maintain rumen health and feed intake. Neutral-detergent fiber concentrations should usually be in the range of 28%–30%, with nonfiber carbohydrate concentrations in the range of 38%–41%. Dietary particle size will influence the optimal proportions of carbohydrate fractions. Some feed additives, including niacin, calcium propionate, sodium propionate, propylene glycol, and rumen-protected choline, may help prevent and manage ketosis. To be effective, these supplements should be fed in the last 2–3 wk of gestation, as well as during the period of ketosis susceptibility. In some countries, monensin sodium is approved for use in preventing subclinical ketosis and its associated diseases. Where approved, it is recommended at the rate of 200–300 mg/head/day.

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Recent Trends in Feed Assessment

 Professor Dr. Ravi Ravindran* says that “Feed assessment is the basis for feed formulation and routine feed evaluation offers critical highlights”. Matrix values need to be updated and to bring nutrient supply closer to target requirements, lower nutrient wastage into environment and improve sustainability.

Introduction:

Routine and proper ingredient evaluation is central to precise and cost-effective feed formulations. The matrix values used in formulations, whether from tabular values, prediction equations or research data, are based on ingredient evaluation research. The aim of feed evaluation is to provide the nutritionists with reliable data on the variability in digestible and metabolisable nutrient contents in feed ingredients, so that the variation within ingredients could be incorporated into matrix values. Furthermore, the predicted future growth of the poultry industry will have a profound effect on the demand for ingredients and search for ‘alternative raw materials’. When using such poorly digested alternative ingredients, formulation based on digestible nutrients is a requisite and, better feed evaluation practices become even more pertinent.

Basic principles of poultry feed evaluation:

Two fundamental features from the basis of feed evaluation in poultry.

Ileal digestibility:

First, it is well accepted that determination of digestibility of nutrients in poultry should be based on the analysis of ileal digesta. The only exception is the determination of apparent metabolizable energy (AME), which involves total collection of excreta and the metabolisability is calculated as the difference between dietary energy input and excreta energy input. 

Composition of assay diets:

Second, three different methodologies (direct method, difference method and regression), varying in the composition of assay diets, are used in digestibility assessments of a nutrient. None of these methods are prefect and, each methodology has its own strengths and weaknesses.

Protein evaluation:

During the past 30 years, the basis of feed formulation has slowly shifted from total amino acids (AA) to the digestible AA system, which has enabled us to meet AA requirements more precisely and to increase the range and inclusion levels of alternative ingredients, while maintaining performance levels. Initially, AA digestibility measurement was based on excreta analysis. During the 1980’s, the precision-fed rooster assay was popular but this assay has since lost global acceptance because of ethical issues. 

Currently, use of ileal-based broiler digestible AA is widely accepted. Considerable published data have now become available on the ileal AA digestibility of raw materials. A major issue with these data however, is the wide variability reported in digestibility estimates. There are two sides to the observed variation namely, (i) inherent variability expected in raw materials and (ii) the differences arising from methodological differences employed in different research stations. The latter is a real concern. Results from a collaborative study, involving three research stations, exemplifies the variability that may occur due to differences in assay procedures (Table 1).

Table 1: Apparent ileal digestibility coefficients of crude protein and select amino acids in maize determined at three research stations, using station protocols.

	Station 1	Station 2	Station 3	SEM	p≤
Crude protein	0.73	0.85	0.80	0.027	0.05
Lysine	0.63	0.83	0.79	0.036	0.05
Methionine	0.84	0.92	0.86	0.029	0.16
Threonine	0.62	0.77	0.73	0.023	0.05
Average1	0.76	0.87	0.83	0.030	0.05

1Average of 17 amino acids

In a follow-up study, which used a common agreed protocol, the between station variation was eliminated. These results highlight the need for a consensus protocol for use not only in the measurement of digestibility of AA, but of all nutrients to enable better comparison of data generated across research stations working in ingredient evaluation.

Confusion about the terminology used to describe the AA digestibility estimates becomes clear to anyone perusing the available digestibility data. For each AA, there are at least six possible values, and combinations thereof, to describe the digestibility for poultry: apparent or true or standardized; rooster or broiler; and excreta or ileal. Many end-users often do not know which values are being used in their matrixes. Currently, the term ‘standardized ileal digestibility (SID)’is being increasingly used in the poultry industry. Compared to other terms, SID is the one relevant to the way we formulate diets. It is additive and aligned with the ideal protein concept.

Energy evaluation:

The use of appropriate energy system is another critical issue because of the importance of energy to bird performance and diet cost. An ideal energy system must be easy to measure, predictive of bird performance, additive in feed formulations and independent of bird factors. However, energy metabolism is too complex to meet all these ideals. 

Since the 1950’s, apparent metabolizable energy (AME) has been the system of choice of describing available energy for poultry. True metabolizable energy became popular in the 1980’s but has since lost favor owing to ethical issues. Currently, the AME is the widely accepted system to describe favoured system in the foreseeable future. It is not a perfect system, with several limitations (Table 2). However, it is familiar and universal, and its limitations are overlooked.

Table 2: Limitations of AME

Ingredient values may not be additive in formulations

Variations in published data due to: Methodology differences, including bird factors (age, gender, production stage) Ingredient factors

Does not take account of energy lost as heat

Net energy (NE) system, a refinement of the AME concept, has received attention from time to time. In theory, NE will more closely describe the energy available in an ingredient for bird’s metabolic functions and is more predictive of animal performance. It is, however, difficult to assay, costly and time consuming. To be acceptable, its economic advantage over the AME system needs to be demonstrated.

Phosphorus evaluation:

Globally there are growing concerns about phosphorus (P) excretion from intensive animal operations into the environment. Gradual depletion of global feed phosphates deposits is another concern. These issues are driving research into P digestibility in order to efficiently use and conserve the finite P resources.

A related issue is the considerable confusion that exists regarding the terminology to describe P that is available to the bird (e.g. available P, non-phytate P and retain-able P). Use of a sound criterion to assess P availability. One key finding from recent research is that, contrary to common premise, non-phytate P does not equate to digestible P suggesting that broilers are able to utilize a portion of phytate-bound P in feed ingredients.

Calcium evaluation:

Measurement of Ca digestibility in poultry has received relatively little attention in the past due to the cheap availability of limestone, the major source of Ca in poultry diets. However, the move towards a digestible P system necessitates a closer look at digestible Ca because of the close relationship between Ca and P during and after absorption.

It is widely assumed that Ca in common Ca sources (limestone, meat and bone meal, dicalcium phosphate) is highly available, but recent studies have shown that this is not true (Table 3).

Table 3: True digestibility of calcium of feed ingredients (%).

Feed ingredient	Calcium digestibility (%)
Meat and bone meal	50 (range, 41-60)
Limestone	55 (range, 43-71)
Dicalcium phosphate	35 (range 28-45)
Monocalcium Phosphate	35 (range, 32-45)
Canola meal	30
Fish meal	25
Poultry by-product	30

 Sources: Naveed Anwar (2017), Phd Thesis; Laura David (unpublished PhD thesis)

In Vitro methods:

Simple in vitro digestion assays have the potential to yield useful indication of nutrient digestibility (Table 4).

Table 4: Pros and cons of in vitro assays:

Limitations	Value
Not possible to accurately simulate the complex in vivo biochemical and physiological processes	Screening of feed additivies
Anti-nutritional factors, dietary dry matter and fiber, endogenous protein secretions, activity of gut enzymes, and gut bacteria not mimicked in vitro	Ranking of feedstuffs by digestibility
Assays should include lipases, carbohydrases etc. as these affect release of proteins from food matrix	Predicting in vivo nutritive value directly or in combination with measures of chemical constituents

Digestion and absorption processes in the animal, however, are too complex and simulation in laboratory is not possible. Nevertheless, the use of in vitro techniques is attractive because such assays are relatively simple, rapid and reproducible, and avoid the use of animals. While in vitro data are useful scrrening samples, they cannot be used in practical feed formulations.

Near-infrared relectance spectroscopy (NIRS):

Many feed mills routinely use NIRS technology to predict the protein moisture, fat, and ash contents of feed ingredients on an on-going basis. The investment on rapid tests, however, should be extended to the measurement of AME or digestible nutrients (especially digestible AA) to formulate the diets precisely. The success of NIRS in ruminant nutrition suggests that the NIRS is capable of predicting energy values for poultry, but it remains to be seen if this is practically feasible.

By:

*Dr. Ravi Ravindran (V.Ravindran@massey.ac.nz) is Professor of Poultry science with the Monogastric Research Centre, Massey University New Zealand.

Vitamins

 

Vitamins are substances that a body needs to grow and develop normally. There are 13 vitamins which are required for the body to grow normally. They are

• Vitamin A
• B vitamins (thiamine, riboflavin, niacin, pantothenic acid, biotin, vitamin B-6, vitamin B-12 and folate)
• Vitamin C
• Vitamin D
• Vitamin E
• Vitamin K

There are two types of Vitamins:

Fat Soluble Vitamins:

Vitamin A, D, E & K are known as fat soluble vitamins, because they are soluble in organic solvents. They absorbed and transport same like fat.

Water Soluble Vitamins

Vitamin B (Complex) & C are water soluble. 

VITAMIN A

 

Functions:

Essential for growth, vision and maintenance of epithelial lining.

Easily oxidized in feed

Normal values in feed:

            Layer                           Breeder                     Broiler

            3000 IU/lb                   2000 IU/lb                2000 IU/lb

 

Deficiency Signs:

• On deficient diet signs begin to appear at about 20 days
• Retarded growth and ruffled feathers
• Decreased egg production and hatchability
• Watery discharge from nostrils & eyes (Roup)
• Xerophthalmia
• Decreased sperm count and motility in cocks

 

 

 

VITAMIN D

 

Chemistry:

• Cholecalciferol  D3  melts at 114 to 117C has four double bonds
• Ergocalciferol D2 melts at 166C has three double bonds

Functions:

• Absorption of calcium and phosphorus in bone
• Eggshell development

 

 

Sources:

Sunlight and fish liver oils.

Levels: (IU)

Broiler ration:              1,00,0000      

Breeder Rations:         2,000,000      

 

Deficiency symptoms

• Rickets, Soft-shelled egg, Calcium crystals on eggshells,
• Lowered egg production, reduced hatchability

 

 

VITAMIN E

 

Chemistry:

 

• Eight naturally occurring forms two groups,
• Saturated and unsaturated

Functions:

Productivity of the cells and for blood formation

Sources:

Whole grains and alfalfa meal

Levels: [IU]

Breeder ration             2000

Broiler ration               2000

Deficiency Symptoms

• Nutritional encephalomalacia
• Male sterility
• Embryonic mortality

 

 

VITAMIN K

 

Chemistry

• K1 (phyllquinone)
• K2 (multiprenylmenaquinone)
• K3 (menaphthone)

Functions

• Synthesis of prothrombin
• Blood clotting

Sources

Alfalfa meal, meat scrap and fish meal

 

 

Levels: [mg]

            Broiler ration   Starter             2,000  

                                    Grower            1,000

                                    Finisher           1,000

Deficiency symptoms:

• Hemorrhagic syndrome
• Rupture of blood vessels

 

 

VITAMIN C

 

Chemistry:

• Vitamin C is present in two forms oxidized and reduced
• Both forms are biologically active

Functions

• Formation and maintenance of intercellular material
• Formation of hydroxyproline
• Tyrosine metabolism
• Conversion of Folic acid to folinic acid
• Embryo growth
• •

 

 

Source:

• Citrus fruits
• Not required for chicken ration b/c bird can synthesize it

Deficiency Problems:

Scurvy, ulcerated gums, loosening of teeth

 

 

 

 

 

Cholinergic Drugs

Direct acting cholinergic drugs (receptor activator)

Natural:

Drugs	Receptor type	Clinical uses
Pilocarpine	m+n	Produce myosis
Arecoline	m+n	Produce myosis
Muscarine	m	No use

Synthetic:

Drug	Receptor type	Clinical use (Produce)
Acetylcholine (proto type)	M+n	No use
Methacoline	M+little n	Atrial tachycardia
Carbacol	M+n	Ecbolic effect, myosis, Rx for intestinal impaction,
Bethanicol	m	Rx atony in bladder

 

Indirectly acting cholinergic drugs (cholinesterase inhibitor)

Reversible inhibitors

          Drug                                                                     Clinical uses

Edrophonium	Diagnosis of myasthenia gravis
Physostigmine (BBB)	↑GIT, ↑UB, Rx atropine toxicity, myosis
Neostigmine	Antidote for NM blockers,Rx myasthenia gravis, myosis, ↑GIT
Pyridostigmine	Rx chronic myasthenia gravis
Carbaryl compounds	Myosis, ↑GIT

Irreversible inhibitors (Organophosphate)

Drugs	Clinical uses
Diisoflorophosphate (isoflorophate)	Rx chronic open angle glaucoma
Tetraethylpyrophospahte (TEPP)	As above
Echothiophate	As above
Serine (nerve Gas)	As above
Parathion, melathion	Insecticides
Coumaphos (Asuntol),tricholrophon (neguvan)	Ectoparasitesites
Diclorvos (Ivermectin)	endoparasitesites

Cholinergic blocking agent (parasympatholytic)

Natural

Drugs (don’t block n receptors)	Clinical Uses
Atropine (proto type drug)	Antispasmodic, preanesthetic, ↓secretions, antidote for organophosphate, produce mydriasis (cycloplagia)
Scopolamine (BBB)	↓GIT in horses, mydriasis, sedative effect
Belladonna extract	Same

 

 Semi synthetic (atropine analogues)

Drug	Clinical uses
Homatropin	Poor mydriasis (cycloplagia)
Eucatropin	Poor mydriasis no cyclopalgia
Methyl scopolamine	As above
Methatropin	As above

Synthetic drugs

Drug	Clinical uses
Glycopyrolate	Preanaesthetic in Horses
Pirenzapine	Rx gastric ulcer, mydriasis no cyclopalgia
Tropicamide	Mydriasis
Propenthiline	Anti-diarrhoel, anti-colic pain

Adrenergic drugs

Direct acting (receptor activator)

Natural

Drugs	Receptor	Clinical uses
Epinephrine	α1,β1, α2, β2	Rx asthma, shock  open angle glaucoma, ↑ anesthetic period
Nor-epinephrine	α1,β1, α2	Rx shock
Dopamine	β1	Same

Synthetic drugs (α agonist)

Drug	Receptor	Clinical uses
Phenylephrine	α1	Rx nasal decongestant, produce tachycardia
Phenylpropanolamine	α1	Same
Methoxamin	α1	Same
Clonidine	α2	Tranqlizer effect
Xylazine	α2	Tranqlizer effect
Detomidine	α2	Tranqlizer effect
Medetomidine	α2	Tranqlizer effect

β agonist

Drug	Receptor	Clinical uses
Isoproterenol (isoprenaline)	β1 β2	Bronchodilator, ↑ force of contraction of heart
Dobutamine	β1	Rx congestive heart failure
Terbutaline	β2	Bronchodilator
Salbutamol	β2	Bronchodilator
Clenbutarol	β2	Bronchodilator, growth promoter
Metaproterenol	β2	Bronchodilator
Salmetrol	β2	Bronchodilator
Albutarol	β2	Bronchodilator
Ritodrine	β2	Bronchodilator
Isoruprine	β2	Tocolysis (delayed parturation)

Indirectly acting adrenergic drugs

Releasers (team)

Drug	Clinical uses
Tyramine	Rx asthma, nasal decongestant, shock
Ephedrine	Rx asthma, nasal decongestant, shock
Amphetamine	CNS stimulator
Meteraminol	Rx asthma, nasal decongestant, shock

Re-uptake inhibitor

Drug	Clinical uses
Cocaine	Same as releasers
Triplanamine	Same as releasers
Imipramine	Same as releasers

MAO inhibitors

Drugs	Clinical uses
Tranylcypramine	Same as releasers
Isocarboxazide	Same as releasers
Phenalzine	Same as releasers

Adrenergic blocking agent

α antagonist

Drug	Receptors	Clinical uses
Phenoxybenzamine (dibenzyline)	α1  α2	Rx 4 pheocromocytoma, ↓BP, cause myosis
Phentolamine	α1  α2	↑GIT and secretions, diagonosis of pheocromocytoma
Azaptin	α1  α2	Same
Peperoxon	α1  α2	↓BP
Prazosin	α1	↓BP
Terazasin	α1	↓BP
Doxazosin	α1	↓BP
Ergotamine	α1	↓BP
Phenothiazine traqlizer (acepromazine)	α1	↓BP
Tolazolin	α2	Antidote for α2 agonist
Yohimbine	α2	Antidote for α2 agonist

β blockers

Used for treatment of angina pectoris, cardiac arrthymias, myocardial infarction, migraine, headache and glaucoma

Drug	Receptor	Clinical uses
Labetalol	α1,β1, α2, β2	Rx for hypertension, glaucoma
Propanolol	β1 β2	↓BP, glaucoma
Timolol	β1 β2	↓BP
Nidolol	β1 β2	Glaucoma, ↓BP
Oxprinolol	β1 β2	Glaucoma, ↓BP
Pindolol	β1 β2	Glaucoma, ↓BP
Atenolol	β1	↓BP
Acebutalol	β1	↓BP
Metoprolol	β1	↓BP
Esmolol	β1	↓BP
Butaxamin	β2	Bronchoconstrictor

Ganglionic stimulant

'         Nicotine (at low doses gangloinic stimulant, at high G blockers)

'         Lobeline

Gangloinic blockers

'         Hexamethonium

'         Pentamethonium

'         Tetraethylammonium

'         Trimethaphane (in human ↓BP)

'         Mecammylamine (in human ↓BP)

 

Neuromuscular blocking agents (muscle relaxants)

Stablizers (non depolizer and competitive)
Detubocurarine	In surgery to relax muscle
Metocurarine
Gallamine
Pencronium
Alcuronium
Vecoronium
Fazadinium

 

Depolizers (non stabilizer, non competative)

Decamethonium	To avoid gastric content during operation
Sexamethonium (saccenylcholine) (prototype drug)

 

Enzyme reactivator

'         Pralidoxime (2-PAM)

'         Obidoxime

 

Neurotransmitter blockers (binders)

'         Reserpine (Does not allow NT to go into vesicle)

'         Guanethidine, bretylium (Do not allow NT to come out from vesicle)

'         Cocaine (Does not allow re-uptake of NT in nerve endings)

Organs and the receptors

Receptor	Organ	Receptor	Organ	Receptor	Organ
β1	Heart	β2	SM of BV	β2	Sk Mus  BV
β2	Lungs, Uterus	β2	Urinary bladder	α2	Presynaptic Membrane
α1	BV	α1	Sphincters	α1	Radial muscle eye

Proto type drugs

1. Acetylcholine
2. Atropine
3. Tubocurarine
4. Sexamethanium
5. Primidine
6. Chloral hydrate
7. Chlorpromazine
8. Morphine