Posts Tagged ‘ peristalsis ’

Opioid Analgesics (Morphine) & Equine Colic (Butorphanol)

Introduction

The primary effect of opioids is to temporarily remove pain when used at therapeutic levels; this is done by binding to opioid receptors found primarily in the central nervous system (some receptors are found in the gastrointestinal tract). When larger doses are given, opioids can induce beneficial and non-beneficial pharmacological effects such as sedation, respiratory depression or constipation. The term given to non-synthetic opioids is opiates; opiates are derived from the naturally occurring opium alkaloids found in the resin of the opium poppy.

The main uses of opioids include:

  • Treatment of acute pain (e.g. post-operative)
  • Palliative care to alleviate serve chronic pain (e.g. cancer)
  • Surgical premedication regimes (due to their calming, sedative action – also reduces the amount of post pain relief required)
  • Neuroleptanalgesia (a state of quiescence, altered awareness, and analgesia produced by a combination of an opioid analgesic and a neuroleptic – a tranquilliser). And neuroleptanaesthesia (a form of anaesthesia achieved by the administration of a neuroleptic agent, a narcotic analgesic, and nitrous oxide with oxygen. Induction of anaesthesia is slow, but consciousness returns quickly after the inhalation of nitrous oxide is stopped)
  • Restraint
  • Antitussive (the alleviating or suppressing coughing)

Pharmacology

The body naturally releases endogenous opioid peptides or endorphins which bind to opioid receptors in the body. There are three primary receptor types, each with different functional responses and these are:

  • μ (mu) – Responsible for supraspinal (above the spine) analgesia, respiratory depression, euphoria and physical dependence of opioids (misuse and abuse of opioids)
  • κ (kappa) – Responsible for spinal analgesia, miosis (pupil constriction of the eye) and sedation
  • δ (delta) – Responsible for hallucinations and dysphoria (agitation and anxiety)

Exogenous opioids (synthetic or natural) mimic the body’s own endogenous opioids and are therefore able to bind to the above receptors – resulting in a response specific to the receptor they bound.  Opioids are able to either stimulate or depress the receptors, meaning opioid drugs can be classes as; agonists, antagonists or both – agonists-antagonists. Agonists bind to receptors and induce pharmacological responses whereas antagonists bind to receptors and do not produce a response, this makes them able to counteract the effect of other drugs or endogenous compounds.

Agonists are used for the primary reasons listed earlier, mainly analgesia. Examples of opioid agonists are:

  • Morphine
  • Pethidine
  • Methadone
  • Fentanyl
  • Etorphine.

Antagonists are primarily used to reverse the effects of agonists i.e. analgesia. They do this by binding to μ and κ opioid receptors, which together are responsible for analgesia. Examples of opioid antagonists include:

  • Naloxone (Narcan)

Agonists-Antagonists have both agonistic and antagonistic properties. This means they are able to antagonise the pure agonists (e.g. morphine) at μ and κ opioid receptors but they also have their own milder agonistic effects. The agonist effect is sufficient enough to be used as analgesics. Examples of opioid agonists-antagonists include:

  • Butorphanol
  • Pentazocine (Fortral)
  • Nalorphine
  • Diprenorphine (Revivon)
  • Buprenorphine (Temgesic)

The principal usage of opioids in medication is for analgesia. Analgesia is the loss of pain perception. Opioids effect both the physical and psychological perception of pain, physically blocking or raising the threshold of pain stimulation and removing the association of pain with fear. Associated with analgesia is sedation which is not considered hazardous, respiratory depression (which can also be associated with opioid analgesia) however can be a distressing side effect. A list of unwanted opioid effects includes:

  • Sedation
  • Excitement
  • Respiratory depression
  • Cough suppression
  • Nausea
  • Vomiting
  • Constipation

Opioid Selection

There are many opioids available for use, each with different properties, when selecting an opioid it is important to consider its potency, how quickly it acts (speed of onset) and how long it lasts (duration). The best analgesics are those which have a mild potency, rapid onset and a long duration of effect. When combining an opioid with a neuroleptic for neuroleptanalgesia, the desired properties of the opioid are slightly different; strong potency, rapid onset and brief period of duration.

As opioids can have an effect on the gastrointestinal system, (as opioid receptors are also found in the gastrointestinal tract) if they are to be given orally then they must have low lipid solubility.

Another point to consider is whether to use an agonist or an agonist-antagonist as both are able to produce analgesia. The main consideration is that pure agonists are more reliable and predictable than agonist-antagonists, but the agonist-antagonists produce fewer side effects such as vomiting, sedation and respiratory depression. Also as agonist-antagonists have antagonistic effects, any further use of analgesics may be compromised.

Below is a comparison of the potency of certain opioids relative to morphine, the most potent being Etorphine. Etorphine (or Immobilon) is extremely powerful and typically only used to immobilise large mammals (e.g. elephants). Due to its potency it can prove lethal to man.

Drug Relative Potency
Meperidine 0.1
Morphine 1
Butorphanol 1-2
Hydromorphone 10
Alfentanil 10-25
Fentanyl 75-125
Remifentanil 250
Sufentanil 500-1,000
Etorphine 1,000-3,000

Opioids are often used as part of a pre-medication routine i.e. before surgery as a pre-emptive form of analgesia. This is because once pain has been established (i.e. during surgery) pain relief drugs prove less effective. As a result larger doses would be needed to prevent the pain which increases the onset of associated side effects e.g. respiratory depression.

Examples of Opioids and their Properties:

Morphine

Morphine (agonist) is considered the standard opioid with all other forms of analgesia being compared against it. It is the most potent natural analgesic, more potent derivatives have been artificial synthesised. Morphine produces a mixture of stimulant and depressant actions depending on the size of the dose as well as the species and absence or presence of pain.

Differences between the species can be observed e.g. in the dog, the cortex is depressed and little excitement is produced. In the cat, very small doses are able to induce excitement and in the horse morphine will not produce excitement if no pain is present (effect is less predictable in horses however). Despite this morphine is safe to use in all species as long as the correct dosage is used, the presence of excitement tends to increase with dose.

The duration of morphine is about 4 hours in all species, it is eventually metabolised by the liver. It is normally injected subcutaneously at a dose of around 0.1mg/Kg (in dogs and cats).

Use of morphine can either stimulate the medulla (which is followed by depression of the medulla) or directly depress the medulla.

Morphine has a number of effects on the gastrointestinal tract. Initially it may invoke vomiting and defaecation which is followed by constipation. Constipation is due to local effects on the small/large intestinal opioid receptors. Segmental tone of the intestines increases, along with sphincter tone but the action peristalsis decreases. This increases the time taken for intestinal contents to pass.

Other areas affected by morphine include:

  • The chemoreceptor trigger zone (CTZ) of the medulla is stimulated by morphine – this induced vomiting.
  • The occulomotor centre is stimulated which is responsible for producing miosis.
  • The cough centre is depressed – reducing coughing but making post-operation mucus accumulation a possible problem.
  • The vagal centre is stimulated, which increases gastrointestinal activity and is responsible for the initial defaecation. If a large dose is administered bradycardia may be induced (slowed heart rate <60bpm) by myocardium depression.
  • The respiratory centre is easily depressed by morphine, even with a low dose. This is due to a reduced response to elevated CO2 levels. The mechanisms involved in the regulation of respiratory rhythm are also affected – contributing to the overall depression of the respiratory centre.

Butorphanol

Butorphanol (agonist-antagonist) is a widely used sedative and analgesic in dogs, cats and horses – combined with tranquillisers for sedation. It is around 1-2 times as potent as morphine, but it does have a slightly shorter duration of action at around 2-3 hours (Morphine – 4 hours). It has a much less profound effect on the respiratory system as the dose increases compared to morphine.

One major use of Butorphanol is for intravenous administration in the horse (0.1mg/Kg) to alleviate abdominal pain associated with torsion, impaction, intussusception (intestinal prolapse) and spasmodic colic.

Equine Colic

The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. Some examples are:

  • Spasmodic colic – Increased peristaltic contraction
  • Impactive colic – Caused by irritation to the lining of the bowel or ileum due to diet or ingestion of large amounts of sand/ dirt
  • Obstructive colic – Obstruction of the bowel by large food masses
  • Flatulent colic – Build of intestinal gases causing distension and pain
  • Parasitic colic – Intestinal pain from parasites such as roundworm or tapeworm
  • Idiopathic colic – From another cause which remains unknown

There are also many diagnostic tests for equine colic:

  • Increased heart rate with decreased circulating volume
  • Distinctive behavioural signs
  • Auscultation – Listening to internal body sounds
  • Abdominocentesis – The extraction of fluid from the peritoneum which can be useful in assessing the state of the intestines
  • Nasogastric Intubation – Insertion of a tube from the nose to the stomach which can be used to drain excess liquid from the stomach – for therapeutic reasons and for diagnosis
  • Rectal/Faecal examination

There are also many drugs/treatments available to treat the symptoms:

  • Analgesics
  • Spasmolytics
  • Lubricants/laxatives
  • Antizymotics – Used against disease producing organisms e.g. bacteria
  • Anthelmintics – Used against parasites
  • Fluid therapy

The major analgesics used against colic are α2-agonists (xylazine, romifidine and detomidine), opioids (butorphanol) and NSAIDs (flunixin).

Butorphanol is usually used alongside small doses of xylazine, romifidine and detomidine. This is because it has minimal effects on the cardiovascular system (which is not true for xylazine, romifidine and detomidine). Both butorphanol and the α2-agonists have a duration of around 2-3 hours and they both reduce intestinal motility/activity.

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Comparative Digestion

Introduction

The method of digestion which an animal uses depends on its diet i.e. carnivore, herbivore or omnivore. For example not all mammals are carnivores (e.g. dogs and cats), herbivorous mammals include rabbits, chinchillas, guinea pigs etc.

Generally, carnivores consume animal tissue which is similar to their own; therefore all the body needs to do is break down the tissue and absorb the different components which can then be used in the carnivores own body. Omnivores have very similar digestive systems to carnivores with the addition of a caecum.

Herbivores consume plant matter which is more difficult to break down than tissue. Therefore herbivores have evolved fermentation systems which contain specific microflora, the microflora breakdown the plant material releasing useful nutrients which the herbivore utilises.

Digestion by Diet:

Carnivores

Because meat is easily digested, the gastric system of carnivores is typically short and simple. They are monogastric meaning they have only one stomach (unlike a ruminants’ stomach which has four chambers). Due to the ease at which components required for growth are obtained from food, some carnivores have lost the ability to synthesis them (e.g. cats are unable to synthesis taurine).

The teeth of carnivores are sharp and strong, this makes it easy to rip and tear meat from bones of prey. When possible, the meat is broken down further by the teeth to ensure maximum surface area for digestion by enzymes in the stomach and small intestines. True carnivores do not have digestive enzymes in their saliva.

Due to the lack of salivary enzymes, food spends little time in the mouth of a carnivore, it is shortly swallowed and travels down the oesophagus. The oesophagus is a tube which runs from the pharynx (back of the oral cavity) to the stomach. The walls of the oesophagus are protected from damage by food by stratified squamous epithelium arranged in longitudinal folds, this also allows for expansion as the food travels down to the stomach. Food is passed down the oesophagus by peristalsis which is the contraction and relaxation of longitudinal and circular muscles, pushing food down to the stomach in wave like motion.

The next stop is the stomach, the stomach has multiple roles in digestion, including:

  • A reservoir for food
  • A sterilising chamber, due to the low pH (high acid content – HCL)
  • A churning chamber to mix food with digestive gastric juices a
  • The initial site of protein digestion, primarily by pepsin – secreted by the epithelial lining of the stomach

Food is moved to the next site of digestion, the small intestine, by peristalsis. The small intestine is a long and narrow ‘tube’ with a structure and epithelium that maximises surface area. This is important because the small intestine is the primary site of digestion by enzymes. Food continues to travel along the small intestine by peristalsis. The small intestine can be divided into the duodenum, jejunum and the ileum. The pancreatic duct connects the pancreas to the duodenum – the majority of the digestive enzymes enter the small intestine by this duct. To aid in lipid digestion, bile is secreted by the liver (stored in the gallbladder). Bile emulsifies lipids which gives them a larger surface area, increasing enzyme efficiency.

The small intestine joins to the large intestine, which consists of the caecum, colon and rectum. In carnivores the caecum has no function (as it is used in herbivores/omnivores as a site of bacterial fermentation of plant matter). The colon absorbs minimal nutrients from the ingested food; instead its primary role is the reabsorption of water, vitamins and electrolytes from the mixture of food, saliva and gastric & pancreatic juices passing through. This prevents excessive water loss and therefore dehydration. The remnants are excreted via the rectum and anal sphincters.

Herbivores

Herbivores only consume plant material which is very difficult to digest. No vertebrates make an enzyme capable of breaking down cellulose, the tough sugar that makes up plant cell walls which is unfortunate as its digestion yields glucose. As the diet includes large amounts of fibre the digestive tract of herbivores is comparatively much longer than carnivores, due to fibre being much more difficult to digest.

To overcome this herbivores have developed a symbiotic relationship with a population of microflora that inhabit a specialised region of the gut for fermentation e.g. the caecum or rumen of ruminants. The microflora population of the gut is able to breakdown cellulose and use the glucose for its own metabolic needs. As a waste product of this process, the microflora population releases volatile fatty acids (e.g. acetate, butyrate & propionate) which the herbivore utilises for energy. The production of these fatty acids is known as fermentation (fermentation also produces heat which keeps the animal warm).

There are two types of fermenting herbivores, those which ferment in the foregut and those which ferment in the hindgut. The difference between them is the site of fermentation and the organ used for fermentation; the attributes of the fermentation chamber remain the same however – Anaerobic, plenty of fluid, regulated pH, steady nitrogen supply and the correct temperature.

  • Foregut Fermentation – The majority of foregut fermenters are ruminants (including cow, sheep, goat, ox and deer) who ferment their food before it reaches the ‘true’ stomach. The stomach of a ruminant exists as four chambers which are the rumen, reticulum, omasum and abomasum (true stomach). Non-ruminant foregut fermenters (e.g. camels, llamas and whales) do not have the four distinct chambers; instead they simply have modifications to the gut before the true stomach which allows them to ferment. Ruminants digest food more efficiently than hindgut fermenters as they are able to consume food into the rumen – the site of fermentation, allow microbial digestion and then regurgitate the ‘cud’ and chew it some more. This means by the time the ingested food reaches the abomasum, all the extractable nutrients have been metabolised (some microflora from the rumen may also be digested in the abomasum which increases nutrient intake).
  • Hindgut Fermentation – Hindgut fermenters (e.g. e.g. elephant, horse, guinea pig, rabbit, herbivorous reptiles, e.g. tortoise and herbivorous birds) have a digestive system very similar to carnivores, except due to the large amounts of fibre and other difficult-to-digest components of the diet, the complete digestive tract is much longer. Hindgut fermenters also have a working, enlarged caecum which is the site of bacterial fermentation. The process of fermentation is the same as that of foregut fermenters, however as the caecum is located after the stomach and small intestine, the majority of food reaches the caecum undigested. Bacterial fermentation occurs in the caecum and colon allowing some volatile fatty acids to be absorbed, but then the digested food is excreted (along with the microflora). This is why some hindgut fermenters are seen eating their faeces – the food making up the faeces has been digested by the microflora making it of nutritional value. The ingestion of the faeces allows the restoration of the microflora population.

The foregut fermenter herbivores are a lot more efficient as the food is digested on the first pass through the digestive system. Unfortunately for hindgut fermenters digestion is more difficult; however they do have the ability to expel their microflora population which is useful during times such as hibernation.

Omnivores

Omnivores consume both meat and plant matter; they have a digestive system very similar to carnivores but also have a working caecum (not as well adapted as in herbivores). Due to this flexibility they are able to consume a wide diet, which has also prevented them losing the ability to synthesise certain products in the body (as in carnivores).

The process of digestion is extremely similar to carnivores, except a few minor adaptations which allow them to digested plant matter – although not as efficiently as herbivores.

Digestion by Species:

Many species have digestive systems very similar to those shown above; however there may be slight tweaks to the systems between the species, below are some examples.

Birds

Birds do not have teeth and so cannot chew; they are able to break up food however by using their beak. Only some species of bird (e.g. sparrow) are able to produce saliva with the amylase enzyme (for digestion of carbohydrates prior to the stomach).

When a bird swallows food, it passes down the oesophagus into a structure called the crop. The crop is primarily a storage area for food consumed by the bird, differing in size between species however certain adaptions in some species allow it to produce ‘crop milk’ which is rich in protein and fat and fed to the young during their first few days of life. Another adaptation found in one species so far, is that the crop acts as a foregut fermentation chamber.

The stomach of a bird exists as two parts, the proventriculus and the gizzard (ventriculus). As the bird is unable to chew, powerful muscles in the gizzard allow it to grind food up, the presence of grit in the gizzard aids this process.

From this point, the digestive system is similar to other species – small intestine, large intestine, etc.  until it reaches the end of the tract. At the end of the large intestine, the digestive tract opens into the cloaca which is simply a common exit, shared with the urinary and reproductive tracts. Shortly before the cloaca there is a pair of caecum or caeca, unlike the single caecum found in other species. (The caeca are rudimentary or absent in species such as hawks and parrots).

Rabbits

Rabbits are herbivorous hindgut fermenters able to rapidly pass food through their digestive system and quickly eliminate fibre. Due to this ability, he rabbit has remained small and agile, able to quickly escape predators.

Rabbits have a very typical herbivorous digestive system, the only differences are they are unable to vomit and have a large caecum.

One variation, which rabbits are well known for is that they consume their own faeces – coprophagia. This is due to them being hindgut fermenters and losing a fair amount of nutrients and vitamins in the faeces. The rabbit produces two forms of faeces:

  1. Hard, fibrous –No nutritional value
  2. Soft, caecotrophs – High protein content as well as vitamins B & K and volatile fatty acids. The caecotrophs are not digested/damaged in the stomach acid as a layer of mucus surrounds them and protects them, this allows all the nutrients and vitamins to be absorbed in the small intestine

Myomorphs (Rodents)

Myomorphs are omnivorous and have a very typical digestive system. Due to a structure between the oesophagus and cardiac region of the stomach however, it is almost impossible for them to regurgitate food.

Most of the rodents in this group lack a caecum or similar specific organ involved in the fermentation of cellulose, hamster however do have a foregut – similar to ruminants, which has a high pH and a large microflora population.

All myomorphs, like rabbits show some degree of coprophagia for the same reasons – to consume the vitamins and nutrients lost in the faecal pellets.

Sciuromorphs (Chipmunks)

Also an omnivore and has a very similar digestive system to myomorphs.

Hystricomorph (Guinea Pigs/Chinchilla)

The guinea pig is an herbivorous hindgut fermenter, which a large caecum for its body size – containing up to 65% of the total contents of the digestive tract at one time. As will myomorphs, guinea pigs exhibit coprophagia.

Chinchillas are very similar to guinea pigs, they have evolved however to survive on the nutritionally poor yet highly fibrous grasses of the Andes, this means over indulgence of highly nutritious treats (captive kept chinchillas) can cause fatal constipation or diarrhoea.

Chelonians (Turtles, Tortoises & Terrapins)

Chelonians lack teeth so have to use their horny, beak like structure to cut up food. The small intestine of chelonians is relatively short when compared to mammals. Like birds, reptiles have a common exit from the body – the cloaca (urinary, digestive and reproductive systems exit from here).

Snakes

Snakes are carnivorous and possess many teeth which are regularly replaced. Due to the shape of the snake (elongated) the digestive system remains the same, but all the organs are also elongated appropriately.

Lizards

The diets of lizards vary greatly, so the digestive system adapts accordingly, from herbivorous to insectivorous. Variations occur in the efficiency of the caecum (herbivorous/omnivorous lizards).

Fish

Predatory, carnivorous fish have ‘throat teeth’ located just before their oesophagus used for catching and holding prey. Structure of the digestive system are more tube shaped than in other species and can vary in length greatly, depending on the diet of the fish.