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
??
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.
COX-LOX Dual Inhibition- Tepoxalin (Zubrin)
Dual inhibitors are drugs able to block both COX-1 and COX-2 as well as 5- LOX arachidonic acid pathways. Leukotrienes (produced by LOX activity) are power inflammatory mediators: leukotriene B3 is chemotactic, recruiting and activating inflammatory WBCs. Leukotrienes C4 and Leuk. D4 are potent vasoconstrictors (renal vasoconstriction). In the presence of NSAIDs which are COX inhibitors, arachidonic acid metabolism may be shunted to the LOX pathway, leading to increase leukotriene production. In the kidneys, this could lead to vasoconstriction, resulting in ischaemia and renal failure. It is postulated that dual inhibitors provide broad anti-inflammatory effects with reduced renal and GI side effects. Discontinued in humans due to hepatotoxicity. LOX-COX has veen released for veterinary use.
Leukotriene inhibitors
Most NSAIDs decreased cyclo-oxygenase activity without any appreciable effect on lipoxygenase produced leukotrienes. Leukotrienes contribute significantly to the inflammatory response through a variet of effects on smooth muscle, and vascular permeability and on neutrophil aggregation, degranulation, chemotaxis and on lymphocytes. Leukotriene receptor antagonists have the potential to target more specifically the inflammatory mechanisms of chronic inflammatory diseases like asthma.
What are glucocorticoids used for?
Locally- opthalmic, ear or skin preparations, topically, or as intraarticular or intralesional injection.
Used for adrenal disorders- in treatment of Addison’s disease (deficiency of glucocorticoids (cortisol) and mineralocorticoids (aldosterone), and for non-adrenal disorders- inflammatory, allergic, and auto-immune diseases.
What does control of glucocorticoid release depend on?
Hypothalamic- Pituitary Axis (HPAA)
What does Adrenocorticotrophic hormone (ACTH) do? And what does Corticotrophin-releasing factor (CRF) do?
Stimulates synthesis and release of glucocorticoids from adrenal cortex.
CRF from the hypothalamus regulates ACTH release and is in turn regulated by neural factors and negative feedback effects of plasma glucocorticoids.
* CRF is increased from the hypothalamus by psychological factors, excessive heat or cold, injury, pain, or infection
* ACTH has only minimal effect on mineralocorticoid production. Mineralocorticoid production is stimulated by the RAAS and by plasma electrolyte concentrations.
What is meant by the long feedback loop? And the short feedback loop?
Long feedback loop- CRF release is suppressed by high levels of glucocorticoids.
Short feedback loop- CRF release is suppressed to a lesser extent by blood ACTH.
What is the molecular mechanism of action of steroid receptors?
Glucocorticoid effects involve interactions between steroids and intracellular receptors. They enter the cell and bind to cytoplasmic receptor. After binding with the steroid, the receptor becomes activated, exposing a DNA binding domain. Steroid-receptor complexes form pairs, then move to the nucleus and bind to steroid response elements in the DNA. The response is to either repress or induce transcription of particular genes. Repression involves inhibition of transcription factors that normally switch on genes for COX-2, various cytokines, and the inducible form of nitric oxide synthase. INduction involves formation of specific messenger RNA’s, which direct synthesis of specific proteins e.g. enzymes involved in metabolic processes, lipocortin that inhibits phospholipase A in the inflammatory response.
** most nuclear mediated actions have an onset of pharmacological effects that requires several hours
** high doses of glucocorticoids (as used sometimes in the treatment of shock) have rapid effects that are probably mediated by cell surface receptors that modulate ion channels and vascular permeability.
What are the three major types of physiological and pharmacological effects of glucocorticoids?
- general effects on metabolism, water and electrolyte balance
- Negative feedback effects on the anterior pituitary and hypothalamus
- Anti-inflammatory and immuno-suppressive effects
What are the metabolic effects of glucocorticoids on carbohydrates?
Decreased uptake and utilitation of glucose and increased gluconeogenesis. This causes a tendency to hyperglycaemia (diabetes).
What are the effects of glucocorticoids on proteins?
Increased catabolism; reduced anabolis leading to muscle wastinga nd weakness with chronic exogenous glucocorticoid use.
What are the effects of glucocorticoids on fats?
Enhanced lipolysis. However, glucocorticoids also cause an increase in apetite, thereby stimulating hyperinsulinaemia, which results in lipogenesis. Chronicglucocorticoid excess therefore produces redistribution of fat.
What are the negative feedback effects of glucocorticoids?
Endogenous and exogenous glucocorticoids have negative feedback effects on CRF and ACTH production, thus inhibiting glucocorticoid release. Long term administration causes atrophy of the adrenal cortex, taking many months to return to normal.
What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?
Glucocorticoids inhibit both the early (heat, pain, swelling redness, etc.) inflammation and also later stages of wound healing and repair. Affect all inflamm. reactions irrespective of cause e.g. microbes, physical, or chemical stimuli, allergy, auto-immune, etc. These are actions resulting in the inhibiton of COX-2 and phospholipase, ecosanoid production, and also inhibition of transcription of genes for cytokine production e.g. interleukins, cell adhesion factors, etc. Overall reduction in acute and chronic inflamm. but also decreased healing and diminution in the protective aspects of the inflammatory response.
Vascular events related to glucocorticoid use
Reduced vasodilation, decreased fluid exudation as a result of decreased production of prostanoids, as a result of inhibition of expression of COX-2 and lipocortin suppression of phospholipase A
Cellular events from glucocorticoid use
IN areas of acute inflamm. decreased influx and activity of leucocytes; in areas of chronic inflamm. decreased activity of mononuclear cells, decreased proliferation of blood vessels, inhibition of fibroblast function and deposition of collagen, and in lymphoid areas, decreased clonal expansion of T and B cell populations and decreased activity of cytokine secreting T cells.
Synthetic glucocorticoids
Manufactured to increase their anti-inflamm potency and to reduce mineralocorticoid effects (sodium and therefore water retention)
Duration of action
Glucocorticoids can be increased by modification of the steroid molecule. This also means prolonged suppression of HPAA. There are no clinical advantages that outweigh this problem.
Free vs. bound cortisol. Where are glucocorticoids metabolized?
Only about 4% of cortisol is free in the plasma, the rest is bound with high affinity to CBG (corticosteroid binding globulin). Glucocorticoids are metabolised in the liver.
What are some side effects of glucocorticoids?
Mainly seen with prolonged systemic use as anti-inflamm or immuno suppressive agents.
* Suppression of response to infection, leading to increase susceptibility of infections
* Suppression of endogenous glucocorticoid synthesis leading to secondary adrenocortical insufficiency
* Metabolic actions
* Iatrogenic Cushing’s syndrome
Most common side effects in dogs:
* polyuria and polydipsia (inhibit release and action of Antidiuretic hormone)
*Stimulate appetite- weight gain
* Skin and connective tissue- reduce collagen synthesis- thinning of skin- increased bruising- reduced rate of wound helaing- dystrophic skin sometimes
*GI- micronodular cirrhosis and hepatomegaly. Gastric ulceration
* immunological effects
* Reproductive system- induce parturition. Teratogenic effects early in pregnancy.
Calcineurin inhibitors
Target the specific steps in the activation of immune cells. i.e. Cyclosporine inhibits early T cell activation and inhibits synthesis of several cytokines, esp. IL-2 (which inhibits further T cell proliferation) & T cell cytotoxic activity is reduced.
Cyclosporine is specific to lymphocytes, which spares other rapidly dividing cells and leaves non specific defence mechanisms functional.
** used in IMHA, perianal fistulae, for atopy, and opthalmic conditions.
**BUT toxic to the kidneys. Better in terms of specificity compared to glucocorticoids**
Cushing’s Syndrome and the opposite is Addison’s Disease
Overproduction of glucocorticoids. “Cushingoid” signs.
Addisons- Hypoactive adrenal cortex (atrophy)- not enough glucocorticoids. Gradually reduce glucocorticoids.
Chronic overuse of glucocorticoids can cause either.
Appropriate dose of shortest acting effective agent
*anti-inflamm. 1 mg/kg
* immunosuppressant 2 mg/kg
* cytotoxic (close to immunosuppressant but necessary because immunosuppressant is fatal)
*shock/cerebral oedema- 10-20 mg/kg (one time) (acts in a different way)
*alternate day therapy- half life of 48 hours- only works if short acting drug
* avoid abrupt cessation
Leukotriene Inhibitors
Involved because leukotrienes are involved in chemotaxis. Bronchodilators. Important in treating asthma in cats. Off label use- specialists at the moment
Myelotoxic agents
Means “toxic to bone marrow”
“sledge hammer” immunosuppressant agent.
Changing DNA- reducing DNA synthesis- affecting proliferation of cells.
e. g. Cyclophosphamide- mustard gas is an alkylating agent. But also causes T cell and B cell lymphopaenia–> immune suppression. Side effects (because it alkylates DNA)- prevents strands from pulling apart properly- so prevents DNA synthesis- selectively targets cell populations with a high replication rate- why it targets WBCs. So also effects gut, mucous membranes, oral cavity and other cells in the bone marrow and skin– because of high replication rate.
e. g. Azathioprine- miscoding of RNA- greatest effect on humoral immunity- side effect of myelosuppression
Characteristics of cancer cells
Uncontrolled proliferation
Dedifferentiation and loss of function
Invasiveness
Metastasis
(benign can be fatal, i.e. cranial)
What is the cell cycle regulated by?
Positive forces (promote the cell cycle)- growth factors, cyclins (proteins, promote progression through the cell cycle), cyclin dependent kinases (new drug targets if you inhibit enzyme, you stop the cell cycle)
Negative forces- p53 gene**- checkpoint 1 (recognize damaged DNA and stop the cell from entering the cell cycle), Rb gene- checkpoint 1 (same as p53), checkpoint-2 ?
What does Rb gene and p53 gene do in the cell cycle? What does p53 do?
Acts as a brake keeping the cell in cycle G1 by inhibiting the genes necessary for the entry into S phase; phosphorylation by the cdks releases the brake. The p53 protein stops the cycle here if there has been DNA damage.
General principles of cytotoxic anti-cancer therapy?
Selective toxicity i.e. toxicity to the tumour cells greater than toxicity to normal cells
* most act at specific sites in the cell cycle
* neoplasms that are most susceptible are those with greatest “growth fraction”
However, if the cancer cells are sitting in G0 then they are not susceptible- just as susceptible as the rest of the cells in the body
If a lesion is 10 cm, estimate 10^11 cells. If an anti cancer drug has a kill rate of 99.9%, 10^8 cells remain
Variability in cancer cells in a tumour on which part of the cell cycle they are in, causes what problem?
Not all will be properly targeted by the chemotherapeutic drugs
Problems with cytotoxic anti-cancer therapy?
Normal cells that proliferate rapidly are more susceptible to damage by anti-neoplastics, many antineoplastics cause damage to DNA, (newer are more targeted in their action e.g. receptor binding), cells with damaged DNA that cross the G1/S boundary will undergo apoptosis if p53 gene is intact
What side effects will you see rapidly?
GI disturbances, ulcers in the mouth, vomiting, diarrhoea because gut cells divide rapidly. Bone marrow cells 7-14 days
Kinds of resistance to anti-cancer drugs
Resistance can be primary or acquired during treatment. Just like to antimicrobial agents.
Mdr- multi drug resistance gene
Codes for production of transport protein, P-Glycoprotein on ATP dependent efflux pump that expels many unrelated drugs from cytoplasm. If you inactivate P-Glycoprotein, you can keep the drug where you want it to work.
How can you overcome P-glycoprotein drug resistance?
Co-admin of pump inhibitors with cytotoxic agents, adminsiter agents that keep it in the cell, give drugs that are not carried by the particular p-glycoprotein transport pump, or some drugs exploit the pump by using the pump itself to kill the cell
How do we overcome drug resistance?
Combination drug therapy
Large doses intermittently rather than small continuous doses (this also allows bone marrow recovery in between treatments)
Alkylating agents (cytotoxic drug)
e.g. cyclophosphamide (also bone marrow suppressant drug, but pretty crude because you are knocking it out), cisplatin, chlorambucil
Earliest anti cancer drugs- e.g. mustard gas
Form covalent bonds between and within DNA strands
DNA damage leads to apoptosis
Antimetabolites (cytotoxic drug)
(understand how they work, but not all the details)
All going to affect DNA synthesis either by Folate antagonism, pyrimidine analogue, purine analogue, and L-asparaginase (tx of canine lymphoma- selectively required by neoplastic cells- so a bit more targeted)
Cytotoxic antibiotics
Direct action on DNA-intercalate with DNA
e.g. doxorubicin
Paclitaxel “taxol”
Plant derivative. Microtubule inhibitors, so prevent spindle formation in mitosis- so chromatin can’t line up so they can’t divide. (this is now routine treatment for breast cancer)
Hormone therapies
Effective if you have a hormone sensitive tumour (at some point the neoplastic cells likely change the cells to make them insensitive)
- Antioestrogens
- Antiandrogens
- Glucocorticoids e.g. for lymphoma (also improve appetite and mood)- at high doses they directly cause apoptosis of lymphocytes
Treatment for lymphoma, for example
It is complex, a lot of drugs, and ongoing
i.e. antihistamine- for sedation and prevent histioenergic responses, antinausea, glucocorticoids, etc. some weeks no meds to recover. “if disease free at week 104, stop all treatment”
Antiangiogenic therapy
Deprive the tumour of nutrition by targeting angiogenesis
Mechanisms of Vasoconstriction
Collagen exposed on damaged blood vessel wall, platelets stick to collagen and “activate,” ADP and 5-HT released from platelets, 5-HT is a powerful vasoconstrictor
Mechanism of Platelet Activation and Adhesion
* ADP from activated platelets causes others to activate and change shape
* Granule contents are secreted (e.g. ADP, 5-HT)
* mediators are synthesised (e.g. Thromboxane)
* platelets aggregate and adhere via fibrinogen bridging between GPIIb/IIIa receptors (glycoprotein receptors- sometimes drug targets)
* Soft plug formed
Adherent and activated platelet
Steps of platelet activation
Stimuli for platelet activation
Collagen, thrombin, thromboxane, ADP
Mechanism of Fibrin Deposition
Fibrin is formed from fibrinogen (a soluble plasma protein)
Thrombin cleaves fibrinogen–> fibrin (insoluble monomers)
Activation of prothrombin
A cascade reaction where inactive precursors are activated in series- each giving rise to more of the next
Two pathways in the cascade: Extrinsic (in vivo): damaged tissues release thromboplastin & Intrinsic (in vitro): exposed collagen or other material, negative charges e.g. glass
Coagulation cascade what is important?
A small signal (FXII) leads to a large amount of product (fibrin)
Each step leads to formation of more product i.e. amplification
The “factors” are proteases
The extrinsic pathway is faster than the intrinsic pathway (that has many more steps)
Control of blood coagulation is by:
*Enzyme inhibitors e.g. antithrombin III–> cascade inhibition
* Fibrinolysis by plasmin
Virchow’s triad
Increased risk of inappropriate coagulation:
Hypercoagulability, blood stasis, and vessel damage
Anticoagulants can affect what three things?
Coagulation (fibrin formation), platelets (adhesion and activation), and fibrinolysis
Procoagulant drugs example
Vitamin K
What are some injectable anticoagulants?
Heparin, low molecular weight heparins (used acutely for short term action)
What are some oral anticoagulants?
Warfarin for prolonged anticoagulant therapy
Heparin
Ehances activity of antithrombin III
* AT III is a natural inhibitor that inactivates Xa and thrombin
* Heparin binds AT III to expose active site
* LMW heparins: have same effect on factor Xa, less effect on thrombin, anticoagulant effects are similar
Low molecular weight heparin (clexane)
Not orally available, longer elimination half life, self adiminstration
Monitoring anti-coagulant effect of heparin
Ensure balance is appropriate and monitor heparin levels
Sweet mouldy clover disease
Compound in mould was an anticoagulant
Dicoumarol was the agent. Coumarin derivatives
Vitamin K
Essential for formation of clotting factors II, VII, IX, and X (2, 7, 9, 10)
These molecules require gamma carboxylation after synthesis
Reduced vitamin K is a cofactor in carboxylation of glutamate
Warfarin and all coumarin derivatives all compete with vitamin K
Warfarin
Only active in vivo (not like heparin- active in a test tube) because it doesn’t affect already active factors, only affects formation of the factor
* delayed onset of action (depends on the half life of the clotting factors)- can even be as long as a week
Adverse effects of warfarin and reversal?
* Haemorrhage (bleeding from mucosal surfaces and into body cavities)
Reversal- vitamin K (oral), phytomenadione natural vitamin K (IV), fresh frozen plasma
Rodenticide Poisoning- first and second generation?
Coumarin derivatives
First generation rodenticides- multiple feeds to have rodenticidal effect and shorter half life
Second generation rodenticides- single feed poisons, higher efficacy and longer half life
Monitoring effect by?
Prothrombin Time (PT)- time for clot formation of plasma after addition of Ca2+ and tissue factor
- extrinsic pathway
Warfarin “Moody drug”
Degree of anticoagulant effect has to be constantly monitored
Warfarin levels and anticoagulant effects are very labile
Orally active, rapidly absorbed, strongly bound to plasma protein 99% (unbound would be the active drug)
Drug interactions with warfarin
Impaired platelet aggregation e.g. aspirin
competition for plasma protein binding e.g. NSAIDs
Competition for Cytochrome P450 pathway so reduced warfarin clearance- increased availability e.g. cimetidine (H2 receptor blocker- gastric ulcer treatment), acute alcohol consumption
New anticoagulant agents
Low molecular weight, orally available, more predictable dose- response, reduced laboratory monitoring
Direct Factor Inhibitors (not affecting formation so not metabolism dependent)
Problem is there tends to be no antidote
Drugs affecting platelet activation and adhesion
* ADP receptor antagonists (e.g. clopidogrel)- direct platelet inhibitor– prevents platelets from binding and activating one another
* Aspirin- NSAID- irreversible inhibitor of COX. Decreased platelet activation by decreasing TXA2 (thromboxane), decreased vasoconstriction
Why is low dose aspirin?
Platelets are exposed to aspirin when they are in the portal vein, 90% is cleared first pass before it ever gets into the systemic circulation but the advantage of this is we can target the platelets without targeting the prostaglandin
Endothelial production of PGI2 is preserved!!
Control of blood coagulation: Fibrinolysis
By: Enzyme inhibitors e.g. antithrombin III
STREPTOKINASE or ALTEPLASE
Streptokinase
Fibrinolytic drug
Activates plasminogen
ingests the soluble fibrin on t he clot
Used IV
highly antigenic, single use only, use it a second time- anaphylactic reaction
Alteplase (used only in humans)
Fibrinolytic drugs
For myocardial or cerebral infarction
Very expensive
