Pharmacology Flashcards
Autacoids
Local hormones- released from cells to have effects on other cells locally. Ex) histamine and serotonin; endogenous peptides such as ANG and bradykinin; eicosanoids (products of fatty acid oxygenation) e.g. PG
Why are autacoids important?
Mediators of inflammatory process
Where is the histamine?
Mast cell pool (packed with preformed granules of histamine waiting to be released- massive release of histamine at once) * basophils- “circulating mast cells” AND non mast cell pool- gastric mucosa- enterochromafin cells. (continuously producing histamine)- also a range other tissues in the body and released for a range of functions.
H1
Vasodilation, increased vascular permeability- locally. Contraction of most smooth muscle (other than vasc). (Broncho-constriction occurs when histamine binds to H1 receptors in the airways). Histamine sensitizes nerve endings to pain and promotes itch. When histamine release occurs systemically, a fall in blood pressure and blood volume may occur.
H2
Gastric acid secretion, cardiac function: increased force and rate. Control of acid secretion. Binding of histamine to H2 receptors in the heart increases the rate and force of cardiac contraction, and in the stomach increases acid secretion. Histamine in the CNS is associated with wakefulness.
H3
CNS
H1 antagonist
Anti allergy, first generation and second generation, (cardiac side effects). Used in the treatment of inflammatory conditions such as bites and stings nad hives and hay fever. H1 receptor antagonists cross the blood brain barrier and cause sedation. This is a limiting side effect in their use for conditions such as hay fever and eczema. Second generation antagonsits have been developed that are less lipid soluble and therefore do not cross the BBB and are non-sedating. In animals, sedating effects can be useful- such as the animal does not scratch and inflict self trauma that further excacerbates the inflammatory conditon.
H2 antagonists
Treatment of gastric ulceration, hepatic metabolism
H3 antagonists
CNS side effects (phenotiazine derivatives)
First and second generation antihistamines
Capacity of the drug to cross the blood brain barrier (its lipid solubility)- second generation is less lipid soluble therefore sedation less likely
Chlorpheniramine, prochlorperazine, promethazine- veterinary examples of what? Are they first or second generation? What does that mean?
H1 antagonists, anti allergy drugs, first generation- therefore lipid soluble- therefore will bind to H3 receptors and cause drowsiness
Where is serotonin located?
GI tract (enterochromaffin cells and enteric neurones), platelets, and CNS
How do you increase the amount of serotonin in circulation?
SSRIs. Which block the breakdown of serotonin.
Physiological and pathophysiological roles of serotonin CNS & periphery
Many- CNS- appetite, mood, sleep, pain, perception, vomiting Periphery- smooth muscle contraction, gut, uterus, vascular +/- platelet aggregation, nociceptor activation
Eicosanoids
Products of fatty acid oxygenation (i.e. result of cell membrane turnover or breakdown), not stored pre-formed in tissue or cells, very short half lives, implicated in control of many physiological processes, major role in inflammation. They include prostaglandins, thromboxane, and leukotrienes. In contrast to other autacoids, they are not found preformed in tissues or cells- they are formed de novo from cell membrane phospholipid and have very short half lives- seconds to minutes. All eicosanoid receptors are G protein coupled receptors. Through second messenger pathways they produce a range of responses in many different tissue types.
Generation of eicosanoids slide
Early step in inflammatory process
Prostanoids (name them and what are they)
Products of the enzyme fatty acid cyclo-oxygenase
A number of different prostanoids are produced in different tissues.
The inflammatory response is always accompanied by the release of prostanoids- PGE2 and PGI2. Mast cells release PGD2, PGE2, PGI2, and PGD2- are all potent vasodilators- so contribute to increased blood flow and the redness of acute inflammation.
The prostainoids also potentiate the effect of bradykinin in sensitizing nerve endings to pain and the PGE series are involved in production of fever and the hypothalamic regulation of body temperature.
Prostanoids also important through normal homeostasis. Formation of prostaglandins mediated by consititutive form of COX have an imp. role in maintaining blood flow to organs and tissues. Some have antiaggregatory effects (PGI2) on platelets, thromboxane promotes activation and adhesion of platelets.
They also control gastric acid release, and like histamine, they sensitize nerve endings to pain.
Prostaglandins, thromboxanes, leukotrienes, prostacyclin
Eicosanoids in inflammation
Arachidonic acid pathway and the formation of eicosanoids
COX 1 Constitutive
One form of Cyclo-oxygenase. Prostainoids are the products of this pathway. COX 1 Constitutive- Present in most cells, including platelets, and expressed most of the time. Involved in homeostasis and normal physiological functions. Present in several organ e.g. blood vessels of kidney, gut, and heart
** Inhibition of COX 2 is mainly responsible for the therapeutic effects of NSAIDs in relieving pain and inflammation, while characteristic side effects of NSAIDs are caused by suppression of COX-1**
COX 2 Inducible
An induced enzyme, responsible for prostanoid production in inflammatory cells in response to injury and inflammation. Expression of COX 2 is induced by inflammatory mediators e.g. interleukin 1 and endotoxins. Induced in inflammatory cells in response to inflammation (vs. COX 1 which is expressed all the time)
** Inhibition of COX 2 is mainly responsible for the therapeutic effects of NSAIDs in relieving pain and inflammation, while characteristic side effects of NSAIDs are caused by suppression of COX-1**
Biological action of Prostacyclin PGI2
Predominantly from vascular endothelium, vasodilation, inhibition of platelet aggregation
Biological actions of the prostanoids- PGD2
Predominantly from mast cells, vasodilation, inhibition of platelet aggregation
What is the limiting factor often in NSAIDs?
Side effects
What are the 3 uses of NSAIDs?
Anti-inflammatory, analgesic, antipyretic
(these effects relate to inhibition of arachidonate cyclo-oxygenase and the formation of prostanoids)
How are these effects mediated?
By reducing production of PGs and therefore- reducing PGEs activity on nerve endings, reducing the vasodilatory effects of PGs, reducing the pyretic effect of PGs
What are the side effects of NSAIDs?
In humans, NSAIDs are responsible for nearly 25% of all adverse drug effects.
- GI (protective role of PGs (PGE2) on the stomach lining, without ulcers)- reduced blood flow and erosion
- renal (reduced blood flow and necrosis)- acute renal insufficiency results from inhibition of the biosynthesis of prostanoids (PGE2, PGI2) involved in the maintenance of renal blood dynamics and in particular the compensatory vasodilation that accompanies activity of the vasoconstrictor agents, angiotensin, and noradrenaline
- haematological (reduced platelet activation and prolonged bleeding)- impair platelet activity by inhibiting thromboxane formation. At pharmacological doses aspirin selectively and irreversibly inhibits platelet cyclo-oxygenase and platelet aggregation defects caused by aspirin can last up to 1 week
How do NSAID’s affect platelet activation and adhesion?
Aspirin- an irreversible cyclo-oxygenase inhibitor. Inhibition of cyclo-oxygenase mediated thromboxane synthesis in platelets, decreased platelet aggregation, and decreased vasoconstriction.
lecture 9. slide 27?
lecture 9. slide 27?
Cox 2 selective? “icam” is Cox 2 selective
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Cox 2 selective drug- massive side effects- GI or renal side effects
What is a danger of NSAIDs with humans?
Appropriate amount of vasodilation. In the presence of NSAID, less dilation- which is not a good thing regarding coronary dilation. Therefore increased risk in myocardial infarction. There is a requirement to have function COX 2 in order to generate the homeostatic prostaglandins.
Mechanisms of NSAID renal toxicity
Once arachidonic acid has been formed from phospholipids- there are two ways the pathway can go- if you use a NSAID and knock out COX then you push the arachidonic pathway down the LOX pathway and therefore promote vasoconstriction (because LOX forms the vasoconstriction mediators). Therefore, drugs on the market now inhibiting both COX/LOX therefore finding a balance between vasodilation and constriction. Because if you block one or the other it is upsetting the balance of vasoconstriction and vasodilation that normally occurs.
OsteoArthritis Drugs (name 2)- what are their aims?
Cartophen- dogs (polysulphated polysaccharide) (anticoagulant activity leading to improved circulation to joint, and reduced pain- however used with care if coagulation disorder is likely- esp. post op)
Adequan- horses (polysulphated glycosaminoglycan)
The Chondroprotective Agents: Disease Modifying Osteoarthritis Drugs (DMOAD’s)- retard degranulation of articular cartilage in osteoarthritis, and may have a positive effect on chondrocyte metabolism and stimulate synthesis of hyaluronan (major component of synovial fluid- resp for maint. of viscosity, soft tissue lubrication and protection of articular cartilage from mechanical damage).
Hyaluronan limits migration of leucocytes into the joint, inhibits release of inflammatory mediators from activated PMNs and acts as a scavenger of reactive oxygen radicals released from PMNs.
With osteoarthritis, loss of cartilage, impaired blood flow. Cartilage is a string bag with balloons inside it. If you land on that when you fall- balloons could burst or it could help soften the fall. The cartilage can break down- the string back can fall apart or the aggrecan molecules (balloons) can break down. IN arthritis, drugs are attempting to retard degradation of articular cartilage. Improved joint circulation and reduced pain. And stimulate production of hyaluronan in synovial fluid.
What are some of the most notable biological effects of histamine related to H1 receptor binding?
Vasodilation and vascular permeability locally. When histamine increases systemically, a fall in blood pressure and blood volume may occur. Histamine released in airways can cause broncho-constriction. Histamine sensitizes nerve endings to pain and promotes itch.
How are leukotrienes and prostanoids generated?
Through the activation of different enzymatic pathways, cell membrane degradation following trauma or release of inflammatory mediators results in the generation of leukotrienes (lipoxygenase pathway) and prostainoids (cyclo-oxygenase pathway)
Prostacyclin PGI2
Predominantly from vascular endothelium, vasodilation, inhibition of platelet aggregation
PGD2
Predominantly from mast cells, vasodilation, inhibition of platelet aggregation
Thromboxane
Predominantly from platelets, vasoconstriction, platelet aggregation
PGE stimulates
contraction of bronchial and GIT smooth muscle, relaxation of bronchial, vascular, and GIT smooth muscle, inhibition of gastric acid release, increased gastric mucus secretion (i.e. cytoprotective), contraction of pregnant uterus and GIT smooth muscle, PGE2 is a mediator of fever
PGF2
Acts on FP receptors in smooth muscle and corpus luteum, produced in the uterus of non pregnant mares, cows, sows, and ewes and causes luteolysis, causes contraction of uterus muscles during parturition
Primary uses of PGs in vet medicine presently
To control oestrus in cows and to induce parturition in cows.
Opthalmology PGF2alpha is used to treat glaucoma
GI PGE- Misoprostol- a stable analogue of PGE is used for its cytoprotective effects in gastric ulceration. Increases mucosal blood flow and mucus production, decreases gastric acid production.
How do you control inflammation?
Prevent release of cellular or plasma mediators, inhibiting their actions or treating pathophysiological responses to them. The vast array of mediators and pathways in inflammatory processes means that there is no single pharmacological agent with complete anti-inflammatory efficacy and the role of inflammatory mediators in normal homeostatic mechanisms also means that significant adverse effects may limit anti-inflammatory use.
Anti-pyretic effect of NSAIDs
Normal body temperature is regulated by hypothalamus. Fever occurs when there is a disturbance to the normal “set point.” NSAID’s reset the “thermostat” by inhibition of prostaglandin activity. Prostaglandins are produced in the hypothalamus in response to stimulation by interleukins released during inflammatory process.
Analgesic effect of NSAID’s
Mainly effective against pain associated with inflammation or tissue damage, because they decrease production of prostaglandins that sensitize nociceptors to inflammatory mediators such as bradykinin and 5HT. They are effective in pain of arthritis, muscular origin, tumour metastasis to bone and post-op pain.
Anti-inflammatory effects of NSAIDs
There are many chemical mediators in the inflammatory and allergic response, and each facet of the response- vasodilation, cell accumulation etc can be produced by several mechanisms. NSAIDs reduce - vasodilation (due to inhibition of vasodilator PG’s (PGE2 and PGI2)
- oedema (reduced vessel permeability)
- pain
** NSAIDs have no effect on the processes that contribute to tissue damage in chronic inflammatory condition and by inhibiting cytoprotective PG activity, they may actually exacerbate tissue damage
Aspirin
Acetyl salicylic acid. Anti-platelet activity and also anti-inflammatory actions. Inhibition of COX, salicylate inhibits formation and release of kinins, and stabilizes lysosomes. Dramatic species differences in biotransformation and elimination of half lives (1 hour in horses, 37 hours in cats). Aspirin is a compound that cats glucuronidate poorly- but can be used without toxicity if dosed every 2-3 days.
Paracemtamol
Analgesic and anti-pyretic effects, but only weak anti-inflammatory effects. Often classified as an NSAID, its mechanism of action does not involve inhibition of COX 1 or COX 2. The actions of paracetamol are now postulated to be mediated by COX 3 inhibition in the CNS. Narrow safety margin, especially in cats due to the absence of phase 2 glucuronidation or when these mechanisms are ovewhelmed- the drug undergoes Phase 1 metabolism to hepatotoxic intermediates, leading to death by liver failure.