Topic 4: CVS Pharmacology

What are some examples of Loop diuretics? What is their mechanism of action? What % of filtrete does it excrete?

Frusemide, bumetanide

MOA: inhibit NaCl reabsorption in the thick ascending loop of henle luminal membrane. Inhibits the The Na⁺–K⁺–2Cl⁻ symporter (NKCC2) blocking Na+ K+ and Cl- reabsorption. In turn, water is excreted with these electrolytes.

15-25% filtrate excreted

Loop diuretics side effects?

• metabolic alkalosis

• hypoglycaemia, hyperuricaemia

• hypotension

• hypokalaemia, hyponatraemia

• hypovolaemia 

• ototoxicity (ear ringing) frusemide

What are some examples of potassium sparing diuretics? What are their MOA? Are they strong or weak?

Spironolactone (aldosterone antagonist)

• MOA: blocks binding of aldosterone therefore increasing excretion of Na+ and thus excretion of water

• limited diuretic action since it acts late in filtration process

Triamterene and Amiloride

• MOA: decreases Na+ permeability in luminal membrane therefore increasing Na+ excretion and thus water excretion.

• block sodium channels therefore decreasing Na+ reabsorption and increase water excretion

• limited diuretic action since it acts late in filtration process

What are the side effects of potassium sparing diuretics and what are their pharmacokinetics (absorption, half-life, excretion)

Spironolactone 

• SE: GIT upset, hyperkalaemia, metabolic acidosis 

• steroid effects causing gynaecomastia, menstrual disorders, testicular atrophy

• well absorbed from GIT 

• ½ life = 10 mins 

• onset of action = days 

Triamterene and Amiloride

• SE: hyperkalaemia, metabolic acidosis, skin rashes

• Triamterene well absorbed form GIT, onset = 1-2 hours, duration 12-16 hours

• Amiloride poorly absorbed, max action = 6 hours, duration 24 hours

What is an example of an osmotic diuretic? What is their MOA? 

Mannitol 25%

MOA: interferes with osmosis - causes high osmotic pressure in kidneys which drags water out. is freely filtered at glomerulus but not reabsorbed by nephron, since they remain in tubular lumen, they raise osmotic pressure of filtrate. osmotic pressure draws water out of tubular lumen and inhibits water reabsorption in areas that are water soluble 

What are some side effects of osmotic diuretics? What are the pharmacokinetics?

SE: electrolyte imbalance, dehydration, hypovolaemia

• non-toxic and excreted quickly

• not reabsorbed from glomerular filtrate

• hydrophilic, cannot be given orally therefore given intravenously 

What is an example of a carbonic anhydrase inhibitor? What is their MOA? 

acetazolamide

MOA: carbonic anhydrase catalyses conversion of CO2 into bicarbonate. acetazolamide is a non-competitve inhibitor of carbonic anhydrase. leads to: ↓ formation of H⁺ → less Na⁺/H⁺ exchange → ↓ Na⁺ reabsorption. ↑ excretion of Na⁺, HCO₃⁻, and water → causes alkaline urine and metabolic acidosis

What are the side effects of carbonic anhydrase inhibitors? What changes occur to acid-base balance?

SE: stevens-johnson syndrome, hepatic necrosis, haematological reactions, parasthesia

alkalinises urine, also dissolves renal calculi formed from acidic compounds

What are some other clinical effects of diuretics?

main effect: decrease BV to decrease BP (hypertension)

potassium sparing diuretics: used in heart failure, primary and secondary hyperaldonsteronism

osmotic diuretics: used for oedamtous states: intracranial pressure and renal failure

carbonic anhydrase inhibitors: treat glaucoma (decreased aqueous humor prod), intracranial pressure, main treatment and prophylaxis of altitude sickness

• hypoxia occurs at high altitudes causing alkalosis 

• acetazolamide reverses alkalosis by reducing blood pH and maintaining arterial O2

Why are potassium supplements often given during diuretic therapy? What alternatives are there to potassium therapy?

Since many diuretics cause potassium loss so must be supplemented in order to maintain normal function of heart, brain and skeletal muscle. Alternatives include using a K+ sparing diuretic or increase dietary potassium intake.

What are the dangers associated with hyper- and hypokalaemia?

Hypokalaemia: <3.5mmol/L. hyperpolarises cell membranes.

• Cardiac arrhythmias (especially with digoxin)

• Muscle weakness, cramps, paralysis

• Respiratory depression

• Constipation / ileus

Hyperkalaemia: >5 mmol/L. depolarises cell membranes.

• Cardiac arrhythmias (e.g. ventricular fibrillation, asystole)

• Muscle weakness or paralysis

• Cardiac arrest

What are the main physiological events in platelet aggregation and blood coagulation?

1. injury to intima/vessel wall causing exposure to tissue factor and collagen

2. platelets adhere to exposed collagen and become activated releasing granules. plts bind to each other via fibrinogen and GPIIb/IIIa receptors to temporarily seal injury 

3. blood clot forms from induction of chemical reactions of clotting factors. inactivated plasma proteins are converted to activated proteolytic enzymes or cofactors for enzymes 

4. end product = conversion of fibrinogen to insoluble fibrin strands via enzyme thrombin. Fibrin forms long insoluble strands in meshlike lattice to trap plts, RBC, WBC.

• requires Ca2+ for coagulation to occur

What are the causes of hemophilia and how can they be treated?

genetic cause: failure of clot to form due to defiency of clotting factors

treated with fresh plasma or concentrated preparations of missing factor

Which four enzymes undergo g-carboxylation? What substance is vital for this process?

Factors 2, 7, 9, 10

vitamin K is essential for synthesis

How is thrombin activated? What is the function of thrombin? what does it stimulate?

converted from plasma protein prothrombin to thrombin by factor X

cleaves fibrinogen to form fibrin

activates fibrinolipase which strengthens fibrin crossbridges

stimulates:

• platelet aggregation

• cell prolif

• SM contraction

How are the intrinsic and extrinsic pathways activated?

intrinisic: initiated by Hageman factor (factor 12) which is activated when exposed to collagen 

extrinsic: initiated by tissue damage and release of factor 3

What is thrombosis? What is the difference between arterial and venous thrombosis? What cellular changes occur in thrombosis? What happens when a portion of the thrombus breaks away?

• pathological condition resulting from inappropriate activation of haemostatic mechanisms and occurs in absence of bleeding 

  • venous: associated with stasis of blood, small plt components, large fibrin factor i.e. stasis of limbs

  • arterial: associated with atherosclerosis and has large plt elements 

• cellular changes: adhesion and activation of plts, fibrin formation

• thrombus may break away as embolus and travel downstream causing ischaemia and infarction 

What is the natural anticoagulant in humans? What is it’s MOA and what coagulation enzymes are affected by it?

heparin 

• binds to antithrombin III to increase its binding to thrombin by 100-1000x fold

• during clotting 85-90% of thrombin is adsorbed to fibrin threads, the rest are bound to antithrombin III to prevent clot from spreading

• also inhibits factor X

Discuss the different types of heparin and their actions.

Whole heparin:

• MW 40,000

• large size means it cannot be absorbed from gut and is given IV or SC (NOT IM)

• prophylactic following surgery 

• used post op to reduce DVT

• ½ life = 40-90 mins

LMWH:

• fragments increasingly used and have MW from 4K to 15K 

• Enoxaparin, dalteparin, danaparoid

• inhibits factor X ONLY

• SC admin 

• ½ life = 3-4 hours

  • allows better control of dosing 

• SE: haemorrhage, osteoporosis, occasional allergic reaction 

• measure APTT 

What is the antidote to heparin overdose?

Protamine

• binds heparin molecule to form complex → inhibits action of heparin

• SE: hypotension and bradycardia

• rapid injection may cause anaphylactic reaction

What is the main action of warfarin? How does warfarin act? What are the main factors determining its onset of action?

Is a vit K antagonist for prevention and treatment of VTE and stroke + clotting disorders

• prevents synthesis of vit K dependent coagulation factors 2, 7, 9, 10

  • inhibits Vit K reductase

• onset takes several days and depends on elimination of half lives of affected clotting factors

Pharmacokinetics of warfarin? Discuss the plasma protein binding properties of warfarin and its ramifications.

• orally active 

• strongly binds to plasma proteins and therefore means that total plasma concentration of warfarin is high but active portion is small

  • means it has potential to cause many drug interactions

  • also needs close monitoring

• metabolised by hepatic mixed function oxidase

What side effects occur with warfarin use?

• haemorrhage

• passes through placental barrier and is teratogenic in first months of pregnancy and causes intracranial haemorrhage in baby during delivery

Describe drug interactions that may increase or decrease the actions of warfarin.

Potentiate: drugs that:

• inhibit hepatic drug metabolism (CYP2C9)

• inhibit plt function

• displace warfarin from binding sites on plasma albumin 

• inhibit reduction of vit K

• decrease availability of vit K 

Interfere:

• vit K 

• drugs that induce hepatic enzymes (CYP2C9)

• drugs that reduce absorption 

Discuss Vitamin K. What kind of vitamin is it? What is it used for? How is it adminstered? what is required for its absorption?

• fat soluble therefore require bile salts for absorption and is why bile resins inhibit its absorption

• used in warfarin overdose 

  • up the dose of vit K to increase clotting factor formation

• essential for formation of clotting factors 

• oral or IV injection

What are the direct thrombin inhibitors? What are their MOA and routes of admin? include SE and clinical uses

Dabigatran:

• prevent VTE and used for non-valvular atrial fibrillation with high risk of stroke 

• MOA: reversibily inhibit both free and fibrin bound thrombin which prevents the conversion of profibrin to fibrin.

• SE: gastritis, dyspepsia, GI bleeding

• oral admin

Rivaroxaban:

• prevent VTE and used for non-valvular atrial fibrillation with high risk of stroke 

• MOA: selectively inhibit factor Xa which blocks thrombin production 

• SE: peripheral oedema, itch, skin blisters

• oral admin

Why is dipyrimadole used as an antiplatelet drug? What is its common side effect?

• main function: prevention of stroke and TIA 

• is a phosphodiesterase inhibitor and increases cAMP

• reduces plt adhesiveness 

• oral and IV admin

• SE: headache and GIT problems 

What are examples of GP IIb and IIIa inhibitors? What are their MOA, clinical uses, adminstration and SE?

Tirofiban, eptifibatide, abciximab

• for unstable angina and non-STEMI

• MOA: binds glycoprotein IIb and IIIb receptors to prevent plts binding together

• IV admin

• SE: bleeding, thrombocytopenia 

What are examples of P2Y12 antagonists? What are their MOA, clinical uses, adminstration and SE?

Clopidogrel, prasugrel 

• irreversibly block the P2Y₁₂ ADP receptor on platelet

• This inhibits ADP-mediated activation of the GPIIb/IIIa receptor complex, which is essential for platelet aggregation.

• Result → Reduced platelet activation and aggregation, preventing thrombus formation.

• antiplatelet drug

• oral admin

• SE: bleeding

Describe the mechanism of action of abciximab and its side effects. Is it used in monotherapy?

Abciximab is a GP IIb/IIIa receptor antagonist that blocks fibrinogen binding and prevents platelet aggregation.
Main side effects: bleeding and thrombocytopenia.
Not used alone — always combined with aspirin and heparin.

Why is aspirin used as an antiplatelet drug. Describe its mechanism of action, dosage and major side effects.

• clinical uses: acute coronary syndrome, symptomatic atherosclerosis 

• MOA: binds COX irreversibly and inhibits TXA2 synthesis 

  • plts cannot regenerate COX enzymes since they do not have nucleus

• dose: 75-300mg/day

  • low dose daily prevents COX enzymes from being able to produce thromboxane in plts 

  • plts continuously replaced every 7-10 days therefore take small dose everyday

• SE: GIT distubances

List four (4) dietary sources of iron?

• meat (liver and kidney)

• green veges, peas, beans, oatmeal, eggs, chocolate, dried fruits

What proteins are associated with storage and transport of iron?

ferritin: storage

transferrin: transport

all iron is protein bound or incorporated into protein structures

What are the symptoms associated with iron deficiency anaemia?

blood Hb falls below normal range

• weakness

• lethargy

• headache

• dizziness

• rapid weak pulse

• palpitations

How can drugs affect iron absorption?

interfere with iron absorption from gut

• Phosphates

• Tannates (tea)

• Tetracyclines

enhance iron absorption from gut

• Ascorbic acid

Discuss the treatment of iron deficiency anaemia.

treat with iron supps

• RBC defect repaired within 30-60 days and treatment takes 3-6 months

• oral admin on empty stomach 

• DO NOT combine with milk, antacids, tea

• SE: constipation, stained teeth

Red cell transfusion is inappropriate therapy unless immediate increase in O2 delivery is required

What are the two properties of iron? What is the daily requirements? 

1. ability to exist in several oxidation states 

   1. Fe2+ = ferrous

   2. Fe3+ = ferric

2. tendency to form stable complexes 

chief function: synthesis of Hb (65%)

men = 5mg/day

women and children = 15mg/day

pregnant women = 30 mg/day

How is iron absorbed, transported, stored and excreted?

absorption:

• GIT absorbs iron as Fe2+ bound in heme

• non-heme iron is in Fe3+ state and must be converted to ferrous form prior to absorption

  • gastric acid lowers pH → converts Fe3+ to Fe2+

• site of absorption = epithelial cells of upper duodenum

• erythropoietin increases iron absorption

• in iron deficiency: Fe2+ absorption increased

transport:

• ferritin passes Fe3+ to transferrin

• in liver and spleen Fe3+ = conveyed from transferrin to ferritin in cells

• ferritin can aggregate to haemosiderin

storage:

• iron stored in epithelial cells to ferritin

• always protein bound

loss:

• shedding and exfoiliation of:

  • epidermal cells of skin, hair and nails

  • mucosal cells of gut and respiratory tract

  • epithelial cells of urinary and genital tracts 

• bile, sweat and urine