Hello and welcome to the Animal Care Learning Alliance webinar, a practical guide to propenter filing in practise. The main focus of this webinar is to look at the many pharmacological effects of propentroyin and its uses in practise. The pharmacological effects of propentophilin are mediated through potentiation of a chemical called adenosine.
One of the main triggers for adenosine release by cells is in response to reduced tissue oxygenation or hypoxia. Where many of the effects are geared towards improving tissue oxygenation, such as vasodilation. Propentophilin potentiates these effects.
By preventing adenosine reuptake into cells and hence prolonging its action. The major cellular component of blood is red blood cells, which contain haemoglobin, which carries oxygen from the lungs to the tissue cells. Smaller platelet cells also play a vital role involved in blood clotting.
Oxygenated blood is delivered to tissues from the heart via arteries which branch out into smaller vessels called arterioles and finally lead to very narrow thin-walled capillaries. It is only at the level of the capillary vessels that gas exchange and nutrient delivery to the tissue cells takes place. Blood then leaves the capillary bed via venues which lead to veins which return blood back to the heart.
Arteriovenous shunt vessels also exist. These are between arterios and venues, and they can bypass the capillary bread. The amount of blood which flows through the capillary bed for oxygen delivery is dependent upon factors such as blood pressure and the diameter of the arteries and arterioles feeding the tissue.
But another very important determinant of capillary blood flow is the viscosity or flow properties of the blood. Anything which increases blood viscosity will reduce capillary flow. And two important factors which determine blood viscosity are the flexibility of the red blood cells and the degree of platelet clumping or aggregation.
Potentiation of adenosine enhances tissue oxygenation by potent vasodilation, especially of the afferent arterio, which results in increased blood delivery to the capillary bed. What sets propentoyin apart from most other vasodilators is that it also has a direct effect on the blood itself to improve its flow properties through capillaries by reducing its viscosity. It does this by reduction in aggregation of platelet cells and increased flexibility of the red blood cell as it squeezes through the capillaries.
The end result of these combined efforts is that more blood flows through the capillaries as opposed to the arteriovenous shunts, resulting in an improvement in tissue oxygenation. It's also worth noting that increased capillary profusion will also improve delivery of nutrients to tissues and for patients on some drug therapies, drug delivery to tissues is also likely to be enhanced. When with adenosine receptors located throughout the body, the enhanced tissue oxygenation effects of perpentohiolin are widespread across multiple body systems.
Unlike some other Xanthee drugs, propentophilin is also able to penetrate the blood brain barrier, causing improvements in cerebral oxygenation. In the central nervous system, adenosine also modulates neurotransmitters such as dopamine and glu glutamate and also stimulates nerve growth factor. In addition to the effects on the microcirculation already described, propentophilin also increases the density of capillaries distributed through tissues such as skeletal muscle and the myocardium of the heart.
In addition to improving the microcirculation in the cardiac myocardium, the propentophilin is also a mild positive inotrope and so increases the contractility and output of the heart. Although some inotropic drugs have the disadvantage of increasing the workload of the heart, propentophilin also produces a concurrent arterio dilation, reducing the outflow resistance so that the cardiac workload remains unchanged. The ability of the red blood cell to deform and flex is very important for capillary flow, considering the fact that the diameter of the capillary is often less than the diameter of the red blood cell.
In this footage of blood travelling through a capillary, it can be seen that red blood cells have to stack together in single file, as they have to flex and squeeze through the capillary. This stacking allows maximum exchange of oxygen between the red blood cell and the surrounding tissue cells. But blood flow can be severely impaired in conditions which reduce the flexibility of the red blood cell wall.
In human medicine, red blood cell flexibility has been the focus of significant research and has been shown to decrease not only with age but also in specific medical conditions. Exposure to excess free radicals has also been shown to reduce red blood cell flexibility. Any reduction in red blood cell flexibility will increase blood viscosity and potentially reduce tissue oxygenation.
Now, let's have a look at the impact of platelet clumping on the microcirculation. In this footage, the platelets appear as little white beads sticking to each other and the capillary wall. When the blood vessel is damaged, platelets are supposed to clump together at the area of leakage and form the early stages of a blood clot to effectively seal the vessel.
Abnormal clumping of these cells can, however, occur in several medical conditions, particularly those which result in stagnation or reduced blood flow. Clumping of these platelets can not only slow blood flow through narrow capillaries, but in more severe cases can cause obstruction. As we have seen, this potentiation of adenosine has many effects, all of which lead to improved blood flow and oxygenation of all body tissues.
Another problem often associated with ageing is accumulation of free radicals. Free radicals are produced as byproduct of tissue metabolism and are highly toxic unless immediately detoxified by the body's natural defences in the form of antioxidants such as adenosine and various vitamins such as vitamin E and C. It is known that as cells age, free radical production exceeds detoxification, leading to reduced cellular function and cell death.
The brain is one of the most susceptible organs to the damaging effects of free radical accumulation. Due to its high metabolic rate and limited capability to regenerate damaged nerve cells. Propentophilin offers some defence against free radical damage by potentiating the antioxidant effects of adenosine.
Capentophilin is also a potent bronchodilator, which has been shown to have equivalent bronchodilation to amiophilin, which is a prodrug of the other veterinary licenced bronchodilator, theophylin. In addition to improving blood and oxygen delivery to tissue cells, propentophilin also improves oxygen loading of the blood in the lungs. These bronchodilator effects will also reduce signs such as coughing and wheezing, often seen with airway disease.
Unlike some drugs which are licenced for treatment of a specific medical condition, prevent a filing is licenced for use in any situation where increased blood profusion and tissue oxygenation is required and can often be used as a supplement to other therapies. Propentophilin can be used in any condition where increased peripheral myocardial or cerebral blood profusion is required. Typical usage in practise includes general use in senior dogs, cognitive dysfunction syndrome.
Vestibular syndrome and possible further uses include any condition where bronchodilation is required, such as chronic bronchitis. It is widely recognised that dogs are on on average living longer compared to say 20 years ago. And this is the result of both improved nutrition, but also significant advances in the medical care offered by veterinary practises.
Practises are seeing an increasing number of dogs in the senior age category. Which is estimated to account for a third of the total 10 million population of dogs in the UK. The increased prevalence of senior dogs means that more cases of age-related degenerative diseases are seen, such as arthritis and age-related behaviour problems like cognitive dysfunction syndrome or CDS.
Although many of these conditions are multifactorial, reduced tissue oxygenation and accumulation of free radicals often forms a significant component of the tissue ageing and degeneration. When tissues become deprived of oxygen through reduced blood perfusion, cells have to undergo anaerobic metabolism in order to function. But this is an inefficient form of metabolism.
If oxygen deprivation is prolonged, organ function will decline, particularly in organs of high oxygen demand such as the brain and myocardium. This can lead to reduced cognition, reduced cardiac output from the heart, and generalised weakness from the skeletal muscle. Cognitive dysfunction syndrome or CDS for short.
Is a neurodegenerative disorder in dogs which shows similar pathology to Alzheimer's in humans. Other terms often used for this condition are canine dementia or canine senility. Although the true cause of these conditions is not fully understood, hypoxia from decreased blood profusion coupled with accumulation of free radicals are thought to play a major role.
Although diagnosis of CDS is ultimately made by brain histopathology, CDS is often suspected in dogs which show some or all of the following group of signs, which are collectively described under the acronym DISHA. Disorientation Interaction changes. Sleep wake cycle alterations, house soiling, and activity changes.
Although the dishes signs cover most of the behavioural changes seen in CDS, they are not all encompassing. And other behavioural problems such as separation anxiety, developing an older dog could also point to CDS. Dogs may also groom themselves less or be content to sit where they have just soiled.
Alterations in appetite may occur from either increased fussiness or a ravenous appetite with consistent begging for food. Reduced learning capability and reduced memory can also be seen. Numerous surveys show a wide variation in prevalence rates.
This is often due to difficulties in diagnosis. The true prevalence of CDS in senior dogs is unknown, but in a veterinary practise survey involving 479 dogs, only 1.9% of dogs aged 8 to 19 years had a veterinary diagnosis of CDS.
This would initially suggest that CDS has a fairly low prevalence. But if owners are surveyed with targeted behavioural questionnaires, a different picture comes to light. In an owner survey of 180 dogs, for instance, 28% of dogs aged 11 to 12 years showed at least one behavioural sign consistent with CDS, and this rose dramatically to 68% of dogs aged 15 to 16 years.
It is worth noting that dogs included in this survey had just been deemed clinically healthy by their annual veterinary checkover. In another owner survey, 75% of dogs, seven years or older showed at least one sign consistent with CDS, yet only 12% reported their concerns to the vet. The take home message from these surveys is that CDS is a significantly underdiagnosed condition.
One of the reasons for this is that it cannot be diagnosed by physical examination or standard laboratory tests, and behavioural observation in a practise setting is of limited value. The fact that only 12% of owners in the last survey voluntarily reported these CDS sites to their vets suggests that there is a perception amongst owners that these problems are simply part of the ageing process and could not be pointers to a significant medical condition. Diagnosis of CDS therefore requires a proactive approach by the practise based on raising awareness and detailed questioning of owners about their dog's behaviour in their home setting.
It is important to consider that behavioural changes in older dogs may also be the result of other underlying medical conditions. For example, any painful or uncomfortable conditions such as arthritis can lead to increased irritability, aggression, or fear of being handled. Deficits in vision and hearing may lead to disorientation in normally familiar surroundings.
Endocrine disease such as hypothyroidism can present as lethargy and altered sleep wake cycles, and how soiling may be seen in Cushing's disease. It's also worth remembering that as dogs get older, the likelihood of having degenerative disease in multiple systems increases. And so CDS will often not occur in isolation, which is why a whole body approach is required in senior healthcare.
CDS is therefore a diagnosis of exclusion, and so a thorough clinical examination is essential, coupled with full blood and urinalysis, so that other medical problems can be identified and appropriately managed first. As with many degenerative disorders. Once the condition has started, it is not possible to stop the process completely.
The aim of treatment is to delay the progression of the disease, restore mental function, retrain lost behaviour, and reestablish relationships. Behavioural therapy and environmental enrichment form a key part in the management of CDS. Changes to the environment can be made, for instance, to help the dog access important areas and resources more easily, thereby reducing anxiety.
Providing a more predictable daily routine, which includes short walks of say 5 to 10 minutes, more frequent feeding times, and periods of interactive play, which can slow down deterioration and help change the sleep-wake cycle. It has also shown that dietary modification and provision of supplements rich in antioxidants and essential fatty acids can improve cognition. Finally, use of drugs with pharmacological effects which address some of the underlying disease processes in CDS can help improve overall demeanour in these cases.
Ideally, CDS requires a combined approach of all three therapies. Finally, CDS will often not occur in isolation in senior dogs. Unlike some other drugs used in this condition, propentophilin does not just target the brain but conveys its beneficial effects across multiple body systems in the senior dog.
Geriatric vestibular syndrome is a disease of the vestibular apparatus of the middle ear. Vestibular syndrome can have many causes, and often it is idiopathic. Vascular compromise may however play a role, and propentopyin may help if this is the case, but literature is lacking and its use is very anecdotal.
Some vets may use it for vestibular syndrome, and some will not. As previously discussed, the pentophilin also has bronchodilator action. Which means it potentially aids in situations where bronchodilation would be beneficial.
In summary, propentophilin provides multiple beneficial effects across several body systems. Usage is not restricted to a specific medical condition. It's particularly suited to degenerative changes seen in the older dog, and unlike other senior dog medications, it does not just target the brain.
