Posts Tagged ‘ vagus ’

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.

Testing Cranial Nerves

Introduction

Cranial nerves arise from the brain directly (unlike spinal nerves which arise from the spinal cord). There are twelve pairs of cranial nerves, varying in length – from supplying nearby structures of the head to the Vagus nerve (X) which is the longest nerve in the body.

Cranial nerves may carry:

  • Sensory information only, i.e. information from an organ to the brain
  • Motor information only, i.e. information from the brain to an organ
  • Both sensory and motor information

Cranial nerves may also be either:

  • Afferent – Meaning to carry sensory information into the central nervous system
  • Efferent – Meaning to carry motor information away from the central nervous system
Cranial Nerve Type of Nerve Fibre Function
Olfactory (I) Sensory Carries sensory information from the olfactory bulb to the brain
Optic (II) Sensory Carries sensory information from the eye to the brain
Oculomotor  (III) Motor Enables the eye to make small, intricate movements
Trochlear (IV) Motor Supplies the extrinsic muscles of the eye
Trigeminal  (V) Both Receives sensory information from the face and supplies motor fibres involved in mastication
Abducens (VI) Motor Supplies the extrinsic muscles of the eye
Facial (VII) Both Supplies motor fibres for facial movements and receives sensory information from ‘anterior taste’
Vestibulocochlear (VIII) Sensory Carries sensory information from the vestibule (balance) and cochlear (hearing) of the inner ear
Glossopharyngeal (IX) Both Carries sensory information from posterior taste (posterior tongue and pharynx) and supplies muscle fibres of the pharynx
Vagus (X) Both Carries sensory information from the pharynx and larynx. Supplies muscle fibres of the larynx as well as; visceral motor fibres to the heart and various thoracic and abdominal organs (including the gastrointestinal tract)
Accessory (XI) Motor Supplies muscle fibres of the neck and shoulders
Hypoglossal (XII) Motor Supplies muscle fibres of the tongue

Testing Cranial Nerves

There are certain tests which can be done to ensure that a cranial nerve is working properly. The tests differ between the nerves due to their different functions. Each test usually has a reflex response which signifies that the cranial nerve is undamaged. The tests have been written primarily with animals in mind, but the majority of these are also observable in humans.

Cranial Nerve Test of Afferent Nerve Test of Efferent Nerve
Olfactory (I) A strong smell is used to test the aversion reflex. If the cranial nerve was undamaged the subject would respond to the smell
Optic (II) Avoiding creating air movement, a finger or hand is thrust towards the eye. If the optic nerve is undamaged, the subject will employ the menace reflex and close the eyelid in response to the finger/hand
Oculomotor (III) Testing eye muscles- Usually tested alongside nerves IV & VI, the movement of the eye and eyelid is observed in response to a stimulus. If this nerve is damaged, the pupils of the eye at rest point down & out

Pupillary reflex- Shining a light into the pupil of one eye should result in the constriction of both pupils

Trochlear (IV) Tested alongside nerve III & VI, if this nerve is damaged a strabismus (abnormal eye alignment) in an up & in direction will be apparent
Trigeminal (V) Touching the skin around the eye will result in the palpebral reflex (closing of the eyelids in response to the touching of the skin). If the nerve is damaged, this will not occur. Also, touching the cornea itself should result in the corneal reflex (closing of the eyelids in response to the touching of the cornea). Again this is absent if the nerve is damaged Should the efferent nerve become damaged, you will be able to observe a drooping jaw in the subject
Abducens (VI) Tested alongside nerve III & IV, if this nerve is damaged a strabismus in a medial, inward direction will be apparent
Facial (VII) The corneal reflex may be tested to check for damage to the nerve. In animals with motile pinna (external ear – not motile in humans), the handclap reflex can be tested. If the nerve is not damaged the pinna will move in response to a loud clap If the efferent nerve is damaged, drooping ears and facial paralysis may be observed. Ptosis (drooping of the eyelid) can also be observed. The menace and palpebral reflexes may be tested to check for nerve damage
Vestibulocochlear (VIII) Testing the Cochlea- The handclap reflex is tested. If the pinna do not respond, this may indicate damage to the nerve.

Testing vestibular responses- In response to altering the orientation of an animal i.e. tilting the body down to face the floor slightly, the neck will self right the head so the head is facing forwards if the nerve is undamaged (tonic neck reflex). If the nerve is damaged, animals may tilt their head with the ear down on the side of lesion/damage. Further observations include nystagmus – spontaneous eye movement, moving slowly in a lateral direction and then returning with a quick eye movement. The direction of the slow movement indicates the side of the lesion/damage

Glossopharyngeal (IX) Bilateral damage to the nerve results in the loss of the gag reflex. Observations that this nerve is damaged include dysphagia – difficulty swallowing
Vagus (X) Similarly to nerve IX, lack of the gag reflex and observing dysphagia can indicate damage. Laryngeal paralysis can be observed with damage, this can cause loss of ability to speak/bark etc. and loud noises when inhaling. Other respiratory and cardiovascular anomalies may arise if damaged.
Accessory (XI)
Hypoglossal (XII) If the nerve is damaged, minor dysphagia and a drooping tongue may be observed – often drooping to the side of damage/lesion if damage is unilateral