PCY Exam 2 Revision Notes PDF

**TOPIC 1: DIABETES** ===================== **Normal functioning** ---------------------- +-----------------------------------+-----------------------------------+ | **Hyperglycaemia** | **Hypoglycaemia** | +===================================+=======================...

**TOPIC 1: DIABETES** ===================== **Normal functioning** ---------------------- +-----------------------------------+-----------------------------------+ | **Hyperglycaemia** | **Hypoglycaemia** | +===================================+===================================+ | 1. Blood sugar is too high | 1. Blood sugar is too low | | | | | 2. Beta cells from pancreas | 2. Alpha cells in pancreas | | released | release glucagon | | | | | 3. **Release insulin** \> acts | 3. Glycogenolysis: glycogen is | | on liver | converted into glucose **(by | | | glucagon)** | | 4. Liver absorbs glucose and | | | acts on adipose tissue + | 4. Glucagon can also synthesis | | skeletal muscle in storage as | more glucose from amino acids | | glucose as GLYCOGEN | and fats | | | | | 5. Reduced blood sugar | 5. Blood sugar rises | +-----------------------------------+-----------------------------------+ | Insulin spikes most meal to store | Glucagon slowly increases post | | the glucose we have just consumed | meal to lower the blood conc. | +-----------------------------------+-----------------------------------+ **Type I vs Type II** --------------------- Diabetes: imbalance between insulin demand and insulin availability (excessive thirst, excessive urination) +-----------------------+-----------------------+-----------------------+ | | **Type I** | **Type II** | +=======================+=======================+=======================+ | **Overall** | Auto-immune attack | Reduced sensitivity | | | against beta cells | of receptors to | | | | insulin = reduction | | | Reduction in beta | in glucose uptake | | | cells\> less insulin | | | | released \> less | | | | binding = less uptake | | | | of glucose | | +-----------------------+-----------------------+-----------------------+ | **Demographic** | Juvenile onset | Slow onset, later in | | | | life | | | Usually, lean | | | | | Usually, obese | +-----------------------+-----------------------+-----------------------+ | **Complications** | **Vascular:** | | | | increased risk of MI | | | | and stroke | | | | | | | | Neuropathy: leading | | | | cause of kidney | | | | failure | | | | | | | | Retinopathy: visual | | | | problems | | | | | | | | Diabetic foot: cause | | | | of foot ulcers that | | | | can require | | | | amputation | | +-----------------------+-----------------------+-----------------------+ **Treatment of Type 1** ----------------------- +-----------------------------------+-----------------------------------+ | | **Hypoglycaemic agents | | | (injection)** | +===================================+===================================+ | **Aim** | To mimic normal pancreatic | | | function of insulin regulation | | | throughout the day | +-----------------------------------+-----------------------------------+ | **Types** | - Recombinant DNA insulin is | | | most effective = identical to | | | normal pancreatic insulin | | | | | | - Porcine insulin = differs by | | | 1 amino acid | | | | | | - Bovine insulin = differs by 3 | | | amino acids | +-----------------------------------+-----------------------------------+ | **Uses** | Structure can be modified to | | | alter half-life of injectable | | | insulin. Combinations are used | | | | | | - Short-acting: useful for | | | post-meal to spike insulin | | | | | | - Long acting: to maintain | | | levels throughout the day | +-----------------------------------+-----------------------------------+ | **Dosing** | - No standard; has individual | | | variability | | | | | | - Injection sites rotated to | | | minimise allergic reactions | +-----------------------------------+-----------------------------------+ | **Side-effects** | Hypoglycaemia, antibodies to | | | foreign insulin, local allergic | | | reactions | +-----------------------------------+-----------------------------------+ | **Complications** | **\*\*Ketoacidosis:** Missed | | | insulin dose/ body not responding | | | to insulin (insulin deficiency) | | | | | | 1. Insulin deficiency | | | | | | 2. No uptake of glucose | | | | | | 3. Glucagon released to | | | compensate | | | | | | 4. Glycogenesis occurs to form | | | new glucose \> hyperglycaemia | | | | | | 5. Still no insulin so body uses | | | fat for energy | | | | | | 6. Acidic ketones produced | | | | | | 7. Metabolic acidosis | | | | | | 8. Thirst, frequent urination, | | | fruity breath | | | | | | Treatment: with insulin IV | +-----------------------------------+-----------------------------------+ **Treatment of Type 2** ----------------------- +-----------------+-----------------+-----------------+-----------------+ | **Key Drugs** | **Metformin | **Sulfonylureas | **Sodium | | | (1^st^ | ** | glucose | | | choice)** | | co-transporter | | | | | inhibitors | | | | | (SGLT2)** | +=================+=================+=================+=================+ | **Mechanism** | Increased | Enhance insulin | Decreases | | | sensitivity to | release from B | amount of | | | glucose | cells \> helps | glucose | | | produced (NOT | to increase | reabsorbed in | | | via insulin | insulin | the kidneys | | | release) | sensitivity | | | | | | = more glucose | | | [Acts on | 1. Binds to | excreted by | | | liver]{.underli | KATP | urine | | | ne} | channel on | | | | (decreases | Beta cells | Helps bring | | | gluconeogenesis | | sodium AND | | | ) | 2. K+ channel | glucose across | | | | closed and | from the | | | [Acts on | blocked | filtrate into | | | muscle]{.underl | | the cell (down | | | ine} | 3. Membrane | the | | | (increases | depolarisat | concentration | | | glucose uptake) | ion | gradient) | | | | | | | | [Acts on | 4. Ca 2+ | | | | lipids]{.underl | enters | | | | ine} | | | | | (reduces LDL + | 5. Induces | | | | VLDL in plasma) | exocytosis | | | | | of insulin | | | | | from beta | | | | | cell | | +-----------------+-----------------+-----------------+-----------------+ | **Excretion** | Has a High FE | | SGLT2 also | | | -- not | | blocks the | | | metabolised but | | re-uptake of | | | excreted | | glucose so it | | | unchanged in | | is excreted via | | | kidneys | | urine | | | | | | | | Short ½ life + | | | | | duration of | | | | | action | | | +-----------------+-----------------+-----------------+-----------------+ | **Side | Weight loss | Hypoglycaemia | Weight loss | | effects** | | | | | | | Weight gain | Lower blood | | | | (can stimulate | pressure | | | | appetite) | (preventing | | | | | re-uptae of | | | | | sedum | +-----------------+-----------------+-----------------+-----------------+ | **Examples** | Can be combined | Glycade | Forxiga | | | with | | | | | sulfonylurea | | | | | | | | | | Diabex, | | | | | Diaformin | | | +-----------------+-----------------+-----------------+-----------------+ **Other less common** **Thiazolidinediones (glitazones)** - Synthetic exogenous agonists - Primary expressed in adipose tissue - Increased lipogenesis, enhancing uptake of glucose and [increasing insulin sensitivity] - Can also act on liver and muscle - Promotes transcription of genes in insulin signalling - Can increase incidence of bladder cancer, anemia, cholesterol levels **Acarbose** - Delays digestion + carbohydrate absorption - Does not affect insulin secretion or weight gain **Incretin mimetics + dipeptidyl peptidase** - Increase among of incretin hormones \> which stimulate pancreas to produce insulin - Reduce secretion of glucagon **TOPIC 2: HAEMOSTASIS AND THROMBOSIS** ======================================= **Clot formation** ------------------ **Step 1: Vascular spasm:** Vasoconstriction after injury to blood vessel. Slows blood flow through/from damaged vessel **Step 2: Platelet plug formation**: positive feedback loop 1. Platelets adhere to exposed collagen 2. Cytokines released to attract more platelets 3. Platelets aggregate to form platelet plug **Step 3: Blood coagulation** Intrinsic and extrinsic pathway ultimately results in the formation of a mesh fibrin clot (thrombosis) to seal the vessel. **Pro-coagulant drugs** ----------------------- Used rarely: haemophilia, excessive anti-coagulant medication, haemorrhage, newborns **Main drug is Vitamin K**: Essential for the formation of clotting factors (in their active form) 1. Vitamin K epoxide reductase converts vitamin K from oxidised form to reduced form (active form) 2. Active form converts inactive clotting factors to active clotting factors 3. Switched **Clinical use** - Orally/IV (w/ bile salts to aid absorption) **Anti-coagulant drugs** ------------------------ **Drug 1: Heparin** **MOA:** inhibits coagulation via anti-thrombin III (blocks conversion of prothrombin to thrombin) 1. Heparin binds to anti-thrombin III 2. Prevents activation from thrombin **ROA:** given intravenously and subcutaneously as are large molecules + charged \*\* need to do an in vitro test first **Low molecular weight heparin (LMWH):** - Doesn't require clotting test - Similar MOA but less impact on thrombin - Key differences with heparin: subcutaneous only, is a significantly smaller molecule, longer half-life (=less frequent dose) **Drug 2: Warfarin** **MOA:** Inhibits reduction of Vitamin K to its active form (competitive inhibition of Vitamin K epoxide reductase enzyme) - Inhibits production of clotting factors - Takes several days for effects to develop (as already pre-formed and activated clotting factors need to be degraded) **ROA:** orally (total absorbance from GI) - Small Vd \> binds to plasma proteins - Should not be given in early pregnancy (can cross placenta) or later stages **Clinical uses** - DVT - Thromboembolism associated with MI etc. **Interactions** - Drugs increasing effect of warfarin: antibiotics, alcohol, anabolic steroids - Drugs decreasing effect of warfarin: vitamin K/foods with vitamin K., St John's Wort\*, barbiturates **Other Drugs** --------------- **Thrombolytic/Fibrinolytic Drugs** **Main type (endogenous) :** Tissue plasminogen activator (tPA) - **Is a protease** **MOA:** Fibrinolysis 1. tPA converts plasminogen (inactive form circulating in body) to plasmin (active form) 2. Plasmin breaks down fibrin **Clinical uses:** pulmonary embolism, MI, ischaemic stroke - [Consideration:] short window (3 hours) post stroke as it has become lodged + killing tissue as blood supply has been cut off. Only small number of patients suitable for this. - Example: streptokinase (given IV ASAP after MI) **Anti-platelet Drugs** **MOA:** slow/prevent activation of platelets from forming clots **Example:** Aspirin - ROA: orally (low dose -- lasts 8-10 days) - Irreversibly inhibits cyclo-oxygenase (COX) \> reducing production of thromboxane - Thromboxane: powerful vasoconstrictor, released from platelets at sign of injury to signal to other platelets to aggregate) **Clinical uses:** commonly used after surgery to decrease rate of secondary clots forming **Anti-fibrinolytic drugs** **MOA:** Prevent breakdown of fibrin clot - Interferes with formation of plasmin from plasminogen \> promoting blood clotting by preventing them from being broken down **Clinical uses:** - During surgery to prevent blood loss - Prolonged menstrual period