Case 20- Pharmacology

Question 1

What lipoproteins is atherosclerosis associated with

Answer 1

Atherosclerosis is strongly associated with elevated concentrations of low density lipoproteins, Triglycerides and decreased levels of high density lipoproteins. Anti-hyperlipidaemic drugs prevent the onset of atherosclerosis.

Question 2

Types of Lipoproteins

Answer 2

HDL, LDL, VLDL

Question 3

Ezetimibe

Answer 3

Prevents cholesterol absorption by inhibiting the transport of cholesterol into the blood

Question 4

Fibrates

Answer 4

Enhances the activity of lipoprotein lipase and reduce secretions of VLDL from the liver

Question 5

Resins

Answer 5

Binds to bile acids, reducing its reabsorption. By preventing the recycling of bile acids, this diverts hepatic cholesterol to synthesis of new bile acids, reducing the amount of cholesterol

Question 6

Statins

Answer 6

Inhibits the enzyme HMG CoA reductase which synthesises cholesterol in the liver. Statins, resins and fibrates increase LDL uptake in the liver

Question 7

The 5 main classes of drugs used to treat hyperlipidaemia

Answer 7

1. HMG-CoA reductase inhibitors (statins)
2. Fibrates
3. Cholesterol absorption inhibitors- Ezetimibe, Bile-acid binding resins
4. Nicotinic acid
5. Omega fatty acids

Question 8

Examples of HMG-CoA reductase inhibitors (Statins)

Answer 8

Simvastatin, Lovastatin, Atorvastin (long lasting)

Question 9

HMG-CoA reductase inhibitors (Statins)

Answer 9

Short acting statins are more effective at bedtime to reduce peak cholesterol synthesis in the early morning. Simvastatin and lovastatin are inactive prodrugs. It undergoes extensive first pass effect via CYP3A4 and glucuronidation pathways except rosuvastatin. Drug interactions can happen when other drugs are metabolised in this pathway.

Question 10

The QRISK score needed to start treatment

Answer 10

10%

Question 11

Statins MoA

Answer 11

• Inhibits the enzyme HMG CoA reductase in cholesterol synthesis- only contributes a small amount but the liver then compensates by increasing the number of high affinity LDL receptors which clear LDL and VLDL from the blood
• Upregulates LDL receptor synthesis, LDL is cleared from plasma into liver cells and there is decreased hepatic cholesterol synthesis. Reduces LDL and TG, increases HDL

Question 12

Clinical use and side effects of Statins

Answer 12

• Primary Hyperlipidaemia
• Secondary Hypercholesterolaemia i.e. raises HDL by 20%
• Secondary prevention of MI and stroke in patients with atherosclerosis
Side effects= Headaches and myalgia, Nausea and insomnia, rise in serum transaminase, rashes and angioedema. Contraindicated in pregnancy as teratogenic

Question 13

Fibrates examples and Pharmacokinetics

Answer 13

Examples= Gemfibrozil, Fenofibrate, Bezafibrate
Pharmacokinetics=  high degree of protein binding to albumin. Metabolised by CYP3A4, potential for drug interactions, primarily excreted by the kidneys.

Question 14

Fibrates

Answer 14

Agonists at PPAR-alpha nuclear receptor which regulates lipid metabolism
• Reduces TG and VLDL by increasing synthesis of lipoprotein lipase by adipose tissue and stimulating fatty acid oxidation in the liver
• Increases expression of apoA-I and apoA-II which increases HDL
• Increases hepatic LDL uptake
• Decreases VLDL, TG and LDL. Increases HDL

Question 15

Fibrates- Clinical use and side effects

Answer 15

• Hypertriglyceridemia
• Mixed hyperlipidaemia- raised TG and cholesterol
Side effects= Nausea, Skin rashes (Gemfibrozil), Decreased WBC, Increased risk of gallstone (Clofibrate), Myopathy/Rhabdomyolysis (with statins)

Question 16

Cholesterol absorption inhibitors

Answer 16

1) Ezetimibe

2) Bile acid-binding: Colestipol, Cholestyramine

Question 17

Ezetimibe MoA and Pharmacokinetics

Answer 17

MoA= inhibits intestinal absorption of cholesterol by interfering with the NPCILI transport protein. Reduces enterohepatic recycling of cholesterol. Doesn’t affect TG or bile acids. Mainly reduces LDL and VLDL
Pharmacokinetics- Administered orally and absorbed into intestinal epithelial cells. It is extensively metabolised into an active metabolite. Enterohepatic recycling slows elimination

Question 18

Ezetimibe clinical use and side effects

Answer 18

Clinical use- treatment of hyperlipidaemia in combination with statins
Side effects= Diarrhoea, abdominal pain, headache, rash and angioedema. Secreted in breast milk contraindicated in breast feeding

Question 19

Bile acid-binding resins: Colestipol, Cholestyramine MoA and Pharmacokinetics

Answer 19

MoA= binds to bile acids in the gut, preventing reabsorption, diverting hepatic cholesterol to Bile acid synthesis reducing cholesterol levels in the liver, upregulates LDL receptors increasing LDL removal from the blood.
Less effective then Ezetimibe, often second choice
Pharmacokinetics= administered by mouth, not absorbed systemically, stays in the GIT

Question 20

Bile acid-binding resins: Colestipol, Cholestyramine clinical use and adverse effects

Answer 20

Clinical use= primary hypercholesterolemia when statins are contraindicated, pruritis in patients with partial biliary obstruction
Adverse effects= constipation, bloating, malabsorption of vitamin K, ascorbic acid. Interferes with absorption of certain drugs like warfarin

Question 21

Nicotinic drugs- Niacin MoA

Answer 21

1. Reduces VLDL synthesis in the liver- reduces VLDL and LDL
2. In adipose tissue it activates a signalling pathway that reduces hormone sensitive lipase activity- reduces TG
3. Reduces catabolic rate for HDL- increases HDL
4. Increases clearance of VLDL by activating lipoprotein lipase- reduces TG
5. Causes decreased LDL, VLDL, TG and increased HDL

Question 22

Nicotinic drugs- Niacin Pharmacokinetics and clinical use

Answer 22

Pharmacokinetics- readily absorbed by GIT following oral administration, metabolised in the liver and excreted in the kidneys
Clinical use- adjunct of statins, used in Hypercholesterolemia, Hypertriglyceridemia with low levels of HDL

Question 23

Adverse effects of Nicotinic drugs- Niacin

Answer 23

Cutaneous flushing which is associated with pruritis and palpitations and is reduced with treatments of aspirin and other NSAIDs. Dose-dependent nausea and abdominal discomfort. There is moderate elevation of liver enzymes to severe hepatotoxicity. Can cause gout

Question 24

Omega 3 fatty acids (fish oil)

Answer 24

MoA= reduces plasma TG concentrations but increases LDL by an unknown mechanism
Other effects- inhibits platelet function causing prolongation of bleeding time and reduction of plasma fibrinogen. Has anti-inflammatory effects
Pharmacokinetics= oral absorption and bioavailability of these PUFA is a complex processes which is influenced by age, fat content of the meal, position of the fatty acids etc.

Question 25

Omega 3 fatty acids (fish oil) Pharmacokinetics, Clinical use, Adverse effects

Answer 25

Pharmacokinetics= oral absorption and bioavailability of these PUFA is a complex processes which is influenced by age, fat content of the meal, position of the fatty acids etc. Clinical use- Hypertryglyceridemia, prevention of recurrent events after MI Adverse effects= Gi complaints (abdominal pain, diarrhoea), Rash, Pruritis, Bleeding tenderness, May increase LDL

Question 26

Class 1 of Hyperlipoproteinemia

Answer 26

``` LP elevated- Chylomicrons Cholesterol- + TG- +++ Atherosclerosis risk- NE Drug treatment ```

Question 27

Class 2a of Hyperlipoproteinemia

Answer 27

``` LP elevated- LDL Cholesterol- ++ TG- NE Atherosclerosis risk- High Drug treatment- Statin, Ezetimibe ```

Question 28

Class 2b of Hyperlipoproteinemia

Answer 28

``` LP elevated- LDL + VLDL Cholesterol- ++ TG- ++ Atherosclerosis- High Drug treatment- Fibrates, statins, nicotinic acid ```

Question 29

Class 3 of Hyperlipoproteinemia

Answer 29

``` LP elevated= beta VLDL Cholesterol- ++ TG- ++ Atherosclerosis risk- Moderate Drug treatment- Fibrate ```

Question 30

Class 4 of Hyperlipoproteinemia

Answer 30

``` LP elevated- VLDL Cholesterol- + TG- ++ Atherosclerosis risk- moderate Drug treatment- Fibrates ```

Question 31

Class 5 of Hyperlipoproteinemia

Answer 31

``` LP elevated- Chylomicrons + VLDL Cholesterol- + TG- ++ Atherosclerosis risk- NE Drug treatment- Fibrate, niacin, fish oil and statin combination ```

Question 32

Drugs for blood clotting disorders

Answer 32

1. Anticoagulants- modify blood clotting mechanisms i.e. Heparin and oral anticoagulants 2. Antiplatelet agents- inhibits COX-1 activity to inhibit platelet aggregation i.e. Aspirin 3. Thrombolytic/Fibrinolytic agents- break down fibrin i.e. Streptokinase, Alteplase

Question 33

The 4 classes of anticoagulants

Answer 33

1. Heparin and low molecular weight Heparins 2. Warfarin 3. Selective factor Xa inhibitors 4. Direct thrombin (factor IIa) inhibitors i.e. Lepirudin (parenteral), Dabigatran (oral) Anticoagulants target various factors in the coagulation cascade thereby preventing formation of a stable fibrin mechwork.

Question 34

Heparin and low molecular weigh

Answer 34

* A family of sulphated mucopolysaccharides found in the secretory granules of mast cells * Inhibits coagulation by activating antithrombin III which is a strong inhibitor of serum protease or clotting factors * AT III is a naturally occurring inhibitor of thrombin and clotting factor IX, Xa, XI and XII * In the presence of heparin, AT III becomes x1000 more active and inhibition of clotting factors is instantaneous * Both the extrinsic and intrinsic pathway are inhibited * Heparin and AT III form a complex with the clotting factors inhibiting them

Question 35

What does Heparin bind to

Answer 35

* To inhibit Thrombin, Heparin must bind to AT III and IIa | * To inhibit Xa, Heparin only has to bind to AT III

Question 36

Low molecular weight Heparins

Answer 36

Are fragment of natural heparins, synthetic heparins which have more consistent activity and predictable course of action. For example, Enoxaparin, dalteparin and Tinzaparin. LMWHs inactivates factor Xa by binding to antithrombin III. Heparin and LMWH have immediate onset of action. They are not absorbed in the gut so cant be given orally. LMWH have a longer half life so can be given less frequently

Question 37

Heparin characteristics

Answer 37

Route of administration= IV or SC. Both Heparin and LMWH are inactive orally Half-life= Shorter then LMWH. Heparin must be given frequently or as a continuous infusion Distribution= Large molecule, low Vd, do not cross the placenta Elimination= Metabolised partially by the liver and 20-50% excreted unchanged in the urine

Question 38

LMWH characteristics

Answer 38

Route of administration= SC, greater bioavailability Half-life= Longer, OD-BID dosing Distribution= Large molecule, low Vd, do not cross the placenta Elimination- mainly eliminated in the urine, contraindicated in renal failure

Question 39

Side effects of Heparin and LMWH

Answer 39

Bleeding, hypersensitivity and heparin-induced thrombocytopenia and thrombosis, osteroporosis and hypoaldonsteronism.

Question 40

Heparin overdose and APTT

Answer 40

Heparin prolong APTT as it affects the intrinsic pathway more but LMWH does not. Heparin is a highly acidic molecule and overdose is treated by IV protamine (strongly basic protein) which neutralises it.

Question 41

Heparin clinical use

Answer 41

• Treatment for established venous thromboembolism • Prevention of venous thromboembolism- LMWHs are used to prevent post-operative venous thrombosis • Cardiac disease- reduces risk of venous thromboembolism in patients with angina and following acute MI • If long term anticoagulation is required heparin is only used to initiate anticoagulation therapy until oral anticoagulants take effect Heparin MoA- activation of antithrombin III

Question 42

Oral anticoagulant- Warfarin

Answer 42

Warfarin means that inactive clotting factors cant bind stably to the blood vessel endothelium and cannot activate clotting. Its an oral vitamin K antagonist used to treat and prevent blood clots. It has a low margin of safety and frequent blood tests are required to individualise the dose and prevent bleeding.

Question 43

Warfarin- vitamin K

Answer 43

Vitamin K is needed to activate the inactive clotting factors II, VII, IX, X. Warfarin competitively inhibits the enzyme Vitamin K reductase which is needed to convert the Vitamin K quinone form to the Vitamin K reduced form which the activates the inactive clotting factors. Mostly inhibits the extrinsic pathway.

Question 44

Warfarin facts

Answer 44

* Takes 1-2 days to be effective * The clotting factors with the smaller half-life’s (factor VII) are affected first * A small population of patients are genetically resistant to warfarin due to reduced binding to Vitamin K reductase * Side effects- bleeding and skin necrosis. Skin necrosis can be prevented by starting to Heparin and then switching to Warfarin. * Overdose is treated with Vit K or Fresh Frozen Plasma * Warfarin is a small, lipid-soluble molecule and is absorbed rapidly and almost totally from the GIT. Levels peak in the blood 0.5-4h after administration. * Low volume of distribution as its mostly protein bound (albumin), crosses the placenta (not suitable if pregnant

Question 45

Warfarin metabolism and excretion

Answer 45

Metabolism- action is terminated by metabolism in the liver by CYP450 enzymes, possible drug-drug interactions Excretion- metabolites are conjugated to glucuronide and excreted in urine and faeces

Question 46

Warfarin clinical use

Answer 46

* To prevent the progression or reoccurrence of venous thrombosis, pulmonary embolus * To prevent arterial thromboemboli in patients with atrial fibrillation or cardiac disease (including mechanical heart valve)

Question 47

Anticoagulants

Answer 47

* Acute anticoagulation usually starts with heparin and an oral anticoagulant i.e. warfarin * Heparin is rapidly effective= effect of Heparin is monitored by APPT. * In LMWH usually no monitoring is needed, has less side effects and fewer bleeding complications * Warfarin takes several days to achieve full anticoagulation. The effect of anticoagulant is monitored using the prothrombin time (converted to INR). Target INR is 2-3 (2.5) * Heparin covers the lag period and can be removed