Pharmacology: Diuretics and Autacoids
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Questions and Answers

What is the primary mechanism by which thiazide diuretics decrease blood pressure in the short term?

Thiazide diuretics increase water and sodium excretion, which decreases plasma volume.

Why are thiazide diuretics ineffective in patients with poor kidney function?

They require sufficient kidney function for drug efficacy, particularly when creatinine clearance is poor.

What role does spironolactone play when used with thiazide diuretics?

Spironolactone is a potassium-sparing diuretic that prevents heart remodeling and maintains potassium levels.

What is a significant adverse effect associated with the use of sodium nitroprusside in hypertensive emergencies?

<p>Cyanide toxicity is a significant adverse effect due to the production of cyanide ions.</p> Signup and view all the answers

How does labetalol counteract reflex tachycardia during hypertensive treatment?

<p>Labetalol is an α and β blocker that does not induce reflex tachycardia due to its balanced blockade.</p> Signup and view all the answers

What distinguishes autacoids from local hormones in terms of their production?

<p>Autacoids are produced by many tissues rather than specific endocrine glands.</p> Signup and view all the answers

List two therapeutic uses of prostaglandins.

<p>Prostaglandins are used as abortifacients and to inhibit secretion of gastric acid in peptic ulcers.</p> Signup and view all the answers

Name two examples of H1 antihistamines.

<p>Cetirizine and Diphenhydramine are examples of H1 antihistamines.</p> Signup and view all the answers

What is the mechanism through which mifepristone is used in the abortion process?

<p>Mifepristone is administered orally followed by vaginal misoprostol to induce abortion.</p> Signup and view all the answers

How do prostaglandins enhance mucosal resistance in the context of gastric ulcers?

<p>Prostaglandins enhance mucosal resistance by promoting the production of protective mucus and bicarbonate.</p> Signup and view all the answers

Define anaphylaxis and describe its potential impacts on various body systems.

<p>Anaphylaxis is a sudden, severe allergic reaction that can affect the skin, respiratory, gastrointestinal, and cardiovascular systems.</p> Signup and view all the answers

What are some adverse effects associated with the use of mifepristone and misoprostol?

<p>Adverse effects include infection, hemorrhage, and retained tissue.</p> Signup and view all the answers

Identify the purpose of H2 antihistamines in relation to gastric acid secretion.

<p>H2 antihistamines inhibit gastric acid secretion, helping to manage conditions like peptic ulcers.</p> Signup and view all the answers

What is the primary mechanism of action of glucocorticosteroids like prednisone?

<p>They reduce T-cell populations by binding to intracellular receptors and acting as transcription factors to downregulate gene expression.</p> Signup and view all the answers

What are three potential complications of untreated hypertension?

<p>Myocardial infarctions, congestive heart failure, and renal damage.</p> Signup and view all the answers

Identify two risk factors associated with the development of essential hypertension.

<p>Stressful lifestyle and high dietary intake of sodium.</p> Signup and view all the answers

How does secondary hypertension differ from essential hypertension?

<p>Secondary hypertension is caused by other diseases, while essential hypertension has no identifiable secondary cause.</p> Signup and view all the answers

What role do diuretics play in the management of hypertension?

<p>Diuretics help reduce blood pressure by decreasing blood volume through increased urination.</p> Signup and view all the answers

What is the significance of angiotensin II in hypertension?

<p>Angiotensin II is a potent vasoconstrictor that increases blood pressure and contributes to the narrowing of blood vessels.</p> Signup and view all the answers

Name one potential adverse effect of long-term corticosteroid therapy.

<p>Osteoporosis is a common side effect of long-term corticosteroid use.</p> Signup and view all the answers

What is sodium nitroprusside, and how does it function in hypertensive emergencies?

<p>Sodium nitroprusside is a derivative of nitric oxide that acts as a potent vasodilator.</p> Signup and view all the answers

What are the major adverse effects associated with cyclosporine administration?

<p>Adverse effects of cyclosporine include anaphylactic reactions, hypertension, hyperkalemia, tremor, hirsutism, and gum hyperplasia.</p> Signup and view all the answers

How does tacrolimus compare to cyclosporine in terms of potency and episodes of transplant rejection?

<p>Tacrolimus is 10 to 100 times more potent than cyclosporine and results in fewer episodes of transplant rejection.</p> Signup and view all the answers

What is the mechanism of action for sirolimus?

<p>Sirolimus binds to mTOR (mammalian target of rapamycin), inhibiting cell cycle progression and T cell activation.</p> Signup and view all the answers

What precautions should be taken when using tacrolimus regarding diet?

<p>Absorption of tacrolimus is decreased when taken with high fat meals, so dietary considerations are important.</p> Signup and view all the answers

List the adverse effects of sirolimus.

<p>Adverse effects of sirolimus include hyperlipidemia, headache, nausea, diarrhea, hypertension, leukopenia, and thrombocytopenia.</p> Signup and view all the answers

What specific patient population is particularly at risk for insulin-dependent diabetes mellitus when treated with tacrolimus?

<p>Black and Hispanic patients are especially at risk for developing insulin-dependent diabetes mellitus when treated with tacrolimus.</p> Signup and view all the answers

What pharmacokinetic properties are shared among tacrolimus, sirolimus, and cyclosporine?

<p>All three drugs are highly plasma protein bound and have significant metabolism via CYP3A4, leading to extensive drug interactions.</p> Signup and view all the answers

How is azathioprine metabolized, and what implications does this have for lymphocytes?

<p>Azathioprine is converted to 6-mercaptopurine, which affects lymphocytes by impairing the purine salvage pathway.</p> Signup and view all the answers

What distinguishes the adverse effects of the combination of cyclosporine and sirolimus from tacrolimus and sirolimus?

<p>The combination of cyclosporine and sirolimus is more nephrotoxic compared to the combination of tacrolimus and sirolimus, which is less toxic.</p> Signup and view all the answers

What role do glucocorticoids play in the treatment regimen for patients receiving tacrolimus?

<p>Glucocorticoids are used in conjunction with tacrolimus to reduce episodes of transplant rejection.</p> Signup and view all the answers

What are the main common causes for histamine release in the body?

<p>Food, insect stings, medicines, and latex.</p> Signup and view all the answers

What is the biosynthesis process of histamine from histidine?

<p>Histamine is synthesized from the decarboxylation of the amino acid histidine by the enzyme histidine decarboxylase.</p> Signup and view all the answers

Identify the primary receptors that histamine binds to and their associated actions.

<p>Histamine binds to H1 and H2 receptors, which are involved in smooth muscle contraction and gastric acid secretion, respectively.</p> Signup and view all the answers

How does histamine contribute to the response in allergic reactions and anaphylaxis?

<p>Histamine release leads to smooth muscle contraction, increased capillary permeability, and stimulation of secretions.</p> Signup and view all the answers

What distinguishes H3 and H4 receptors from H1 and H2 receptors in terms of expression?

<p>H3 and H4 receptors are expressed in only a few cell types, while H1 and H2 receptors are widely expressed.</p> Signup and view all the answers

What role does enzyme inactivation play in regulating histamine levels in the body?

<p>Inactive histamine is rapidly inactivated by enzymes if not stored, preventing unnecessary inflammation.</p> Signup and view all the answers

Describe the mechanism of action of H1 antihistamines in the context of allergic responses.

<p>H1 antihistamines inhibit the release of mediators from mast cells and basophils, and down-regulate pro-inflammatory cytokine production.</p> Signup and view all the answers

What is the significance of the seven transmembrane helical domains in histamine receptors?

<p>The seven transmembrane helical domains enable G protein-mediated second messenger systems crucial for receptor function.</p> Signup and view all the answers

What are the primary targets of the drug Ramipril?

<p>Ramipril primarily targets the angiotensin-converting enzyme (ACE) in the renin-angiotensin-aldosterone system.</p> Signup and view all the answers

What is the mechanism of action for Losartan?

<p>Losartan acts as an angiotensin II receptor blocker (ARB), inhibiting the effects of angiotensin II on blood vessels.</p> Signup and view all the answers

How does Hydrochlorothiazide function to manage hypertension?

<p>Hydrochlorothiazide is a thiazide diuretic that works by inhibiting sodium reabsorption in the distal convoluted tubule.</p> Signup and view all the answers

What effect does the binding of epinephrine to A1 receptors have on blood vessels?

<p>Binding of epinephrine to A1 receptors causes vasoconstriction of arteriolar smooth muscle.</p> Signup and view all the answers

Why might black patients respond better to diuretics and calcium channel blockers?

<p>Black patients typically have a different physiological response to antihypertensive medications, often showing better efficacy with diuretics and calcium channel blockers.</p> Signup and view all the answers

What are the common first-line therapies for managing hypertension?

<p>The common first-line therapies for managing hypertension include thiazide diuretics.</p> Signup and view all the answers

How can poor patient compliance affect hypertension treatment outcomes?

<p>Poor patient compliance is a major reason for treatment failure in hypertension management.</p> Signup and view all the answers

What considerations should be made regarding the age of patients when prescribing antihypertensive medications?

<p>Elderly patients are often favored to receive calcium channel blockers, ACE inhibitors, and diuretics, while β-blockers and α-antagonists may be less effective.</p> Signup and view all the answers

Study Notes

Systems Pharmacology and Chemotherapeutics

  • Course code: SCPCB3-B44
  • Institution: Eduvos
  • Eduvos (Pty) Ltd is registered as a private higher education institution.
  • Registration certificate number: 2001/HE07/008
  • Higher Education Act, 101, of 1997

Antihistamines

  • This is lesson 1.
  • Covers H1 and H2 antihistamines.

Autacoids

  • Prostaglandins:
    • Mifepristone
    • Misoprostol
    • Abortion: Oral administration: mifepristone followed by vaginal administration of misoprostol (24 hours later). Adverse effects: infection, hemorrhage & retained tissue.
    • Peptic ulcers: Inhibit secretion of gastric acid. Also enhances mucosal resistance in patients with gastric ulcers using NSAIDs.
  • H1 Antihistamines:
    • Acrivastine
    • Cetirizine
    • Chlorpheniramine
    • Cyclizine
    • Desloratidine
    • Diphenhydramine
    • Dimenhydrinate
    • Doxepin
    • Doxylamine
    • Fexofenadine
    • Hydroxyzine
    • Loratidine
    • Meclizine
    • Promethazine
  • H2 Antihistamines:
    • Cimetidine
    • Ranitidine

H1 antihistamines

  • Antihistamine pharmacology
  • Visual Mnemonic

Introduction - Autocoids

  • Autocoids include:
    • Prostaglandins
    • Histamine
    • Serotonin
  • Formed by the tissues upon which they act.
  • Differ from local hormones because they are produced by many tissues, rather than in specific endocrine glands.

Prostaglandins

  • Further details on prostaglandins are included from page 7 in the presentation

Histamine

  • Site of action: Lungs, skin, gastrointestinal tract (GIT)
  • Increasing levels in mast cells and basophils
  • Synthesis: Decarboxylation of the amino acid histidine by histidine decarboxylase. Enzyme produced by neurons, gastric mucosa parietal cells, mast cells (stored in granules), and basophils.
  • If not stored, rapidly inactivated by enzymes.
  • Stimuli examples: bacterial toxins, bee stings, trauma, allergies, and anaphylaxis.

Anaphylaxis

  • "markedly improved susceptibility to a specific protein after a suitable incubation period" (Charles Richert, 1902)
  • Sudden, severe, potentially fatal, systemic allergic reaction. Can affect skin, respiratory, gastrointestinal, and cardiovascular systems.
  • Common causes: food, insect stings, medicines, latex.

Histamine

  • Chemical structure shown.
  • Discovered by Sir Henry Dale, experiments using guinea pigs and dogs.
  • Additional details are shown in pages 11

Biosynthesis of Histamine

  • Depicts the chemical conversion from histidine to histamine with histidine decarboxylase.

Release of histamine

  • Released in response to stimuli (e.g., bacterial toxins, bee stings, trauma, allergies, anaphylaxis).
  • Usually released in conjunction with other mediators.

Mechanism of action

  • Histamine binds to H1, H2, H3, and H4 receptors.
  • H1 and H2 receptors are widely expressed, targets for certain drugs.
  • H3 and H4 receptors are expressed in a few cell types.

Receptors

  • Contain seven transmembrane helical domains.
  • G protein-mediated second messenger systems.
  • H1 receptors: smooth muscle contraction, increasing capillary permeability.
  • H2 receptors: gastric acid secretion.

H1 Antihistamines-Actions

  • Inhibition of mediator release from mast cells & basophils.
  • Down-regulation of certain transcription factors.
  • Decreased production of pro-inflammatory cytokines.

Histamine H1 Receptor Blockers

  • First generation:

    • Older, inexpensive.
    • Penetrate CNS: sedation.
    • Interact with various receptors: cholinergic, adrenergic, or serotonin receptors.
    • Low specificity.

  • Second generation:

    • Specific for H1 receptors.
    • Do not penetrate the BBB.
    • Least sedation.
    • Examples: Desloratidine, Fexofenadine, Loratidine

  • H1 antihistamine therapeutic uses (Page 24):

    • Allergic and inflammatory conditions (rhinitis, urticaria).
    • Ineffective in most cases of bronchial asthma.
    • Systemic anaphylaxis: epinephrine is the preferred treatment.
    • Motion sickness and nausea (e.g., diphenhydramine, dimenhydrinate, cyclizine, meclizine, hydroxyzine).
    • Somnifacients (e.g., diphenhydramine and doxylamine).

Relative potential for sedation

  • Loratidine & Fexofenadine have a lower potential to induce drowsiness.

First Generation H1 Antihistamines

  • Mechanism of action does not directly inhibit histamine formation/release.
  • Blocks receptor mediated responses.
  • Older, cheaper.
  • Penetrates the blood brain barrier (CNS sedation).
  • High affinity for various receptors including cholinergic, adrenergic, & serotonin receptors.
  • Low specificity.

Second Generation H1 Antihistamines

  • Mechanism of action: specific to H1 receptors
  • Doesn't cross the blood-brain barrier.
  • Least likely to cause sedation.
  • Examples: desloratidine, fexofenadine, loratidine

Pharmacokinetics (Page 26)

  • Oral administration: well absorbed
  • Half-life: 4-6 hours
  • Meclizine: longer t1/2 (12-24 hours)
  • More effective prophylactically

Effects of H1 Antihistamines at Various Receptors

  • Shown on page 27
  • Potential side effects like dry mouth, cholinergic, -adrenergic, sedation, dopamine, serotonin

Adverse effects

  • CNS: sedation, tinnitus, dizziness, lassitude, incoordination, blurred vision, tremors
  • Dry mouth
  • Anticholinergic effects

Drug interactions

  • Potentiation of effects of other CNS depressants (e.g., alcohol).
  • May exacerbate anticholinergic activity with MAOI's.

Overdoses

  • Acute poisoning: hallucinations, excitement, ataxia, convulsions, cardiorespiratory collapse,

H2 Receptor Blockers

  • Therapeutic uses:
    • Inhibit gastric acid secretion by reducing intracellular cAMP levels
  • Examples: Cimetidine, Ranitidine, Famotidine, Nizatidine.
  • Useful in the treatment of ulcers.

Immunopharmacology

  • Immunosuppressive drugs—used in
    • Organ transplant rejection prevention.
    • Autoimmune diseases.

Immune System Overview

  • Shown diagrammatically, but lacks significant detail beyond labels on the diagram itself

Organ Transplant Rejection Prevention

  • Induction drugs: Powerful antirejection medicines used at the time of transplant.
  • Maintenance drugs: Antirejection medications for long term use.
  • Rejection agents: Medications for treating rejection episodes.

Immunosuppressive drugs

  • Selective inhibitors of cytokine production & function (e.g., cyclosporine, everolimus, sirolimus).
  • Anti-bodies (e.g., alemtuzumab, antithymocyte globulins, basiliximab, daclizumab, muromonab-CD3).
  • Immunosuppressive antimetabolites (e.g., azathioprine, mycophenolate mofetil, mycophenolate sodium).
  • Adrenocorticoids (e.g., methylprednisolone, prednisolone, prednisone)

Earlier immunosuppressants

  • Non-selective, suppressing both humoral and cell-mediated parts of the immune system

Introduction—Rx use

  • Use in autoimmune diseases.
  • Use in organ/tissue transplantation.

Selective Inhibitors of Cytokine Function & Production

  • Various cytokines with their corresponding actions are described.

CD (clusters of differentiation)

  • Ability to act as receptors, expressed by lymphocytes and antigen presenting cells
  • Includes examples like CD80, CD86, CD3, CD28, CD25 (IL-2 receptor).

Mechanism of action: Cyclosporine

  • CsA diffuses into T cells, preventing NFATC from entering the nucleus, and thus preventing cytokine production.
  • Binds to cyclophilin, forming a complex that binds to calcineurin (a type of phosphatase).

Cyclosporine (CsA)

  • Cyclic peptide extracted from a soil fungus.
  • More effective with a glucocorticoid.
  • Rx uses: organ transplant rejection, RA alternative to methotrexate, psorasis.
  • Mechanism of action: preferentially suppresses cell-mediated immunity.

Adverse effects: Cyclosporine

  • Nephrotoxicity (avoid coadministration with nephrotoxic drugs)
  • Hepatotoxicity
  • Development of life-threatening infections (e.g., herpes, cytomegalovirus, lymphoma).
  • Anaphylaxis (on parenteral administration)
  • Hyperkalemia

Tacrolimus (TAC)

  • Used in liver and kidney transplants.
  • Preferred over cyclosporine due to fewer rejection episodes.
  • Lower doses of glucocorticoids are necessary.
  • Mechanism of action: similar to cyclosporine, binds to a different immunophilin (FKBP-12).

Mechanism of action: Cyclosporine & Tacrolimus (Diagrammed on page 47)

  • Depicts the molecular interactions involved in the immunosuppressive action of both drugs.
  • Shows the interactions with NFATc, signaling, and cytokine production.

Tacrolimus - Pharmacokinetics

  • Absorption is decreased with high fat meals.
  • Highly concentrated in erythrocytes/plasma protein.
  • Oral absorption is incomplete and variable, requiring dosage adjustment.
  • Metabolised by CYP3A4.
  • Extensive drug interactions

Tacrolimus - Adverse effects

  • More severe than CsA.
  • Nephrotoxicity, neurotoxicity, tremors, seizures, hallucinations.
  • Development of insulin-dependent diabetes mellitus (especially in Black & Hispanic patients.)
  • Does not cause gingival hyperplasia or hirsutism.

Sirolimus (SRL)

  • Macrolide from soil fungus fermentations, equipotent to CsA.
  • Rx uses: after renal transplantation, in conjunction with glucocorticoids & CsA and in cardiac vascular stents.
  • Mechanism of action: inhibits mTOR signaling, preventing T cell proliferation

Sirolimus - Pharmacokinetics

  • High fat meals decrease absorption.
  • Highly plasma protein bound.
  • Metabolised by CYP3A4. Same drug interactions as CsA & TAC.
  • Elimination: feces

Sirolimus - Adverse effects

  • Combination of CsA & SRL is more nephrotoxic
  • Hyperlipidemia, headache, nausea, diarrhea, hypertension, leucopenia & thrombocytopenia

Immunosuppressive Antimetabolites

  • Used in combination with CsA, TAC & glucocorticoids

Azathioprine

  • Converted to 6-mercaptopurine (6-MP)
  • 6-MP converts to thioinosinic acid (a nucleotide analogue)
  • Mechanism of action: inhibits purine synthesis, primarily affecting rapidly dividing lymphocytes.

Azathioprine - Pharmacokinetics

  • Erratic absorption from oral route
  • Does not cross the blood-brain barrier.
  • Dose reduction needed in hyperuricemic patients taking allopurinol.

Azathioprine - Adverse effects

  • Bone marrow suppression, nausea, vomiting
  • Mutagenic and carcinogenic, concomitant use with ACE-I's or cotrimoxazole can worsen risk in renal transplant patients, leading to leukopaenic response.

Mycophenolate mofetil

  • Replacing azathioprine, used in heart, liver, & kidney transplants.
  • Highly plasma protein bound.
  • Coadministration with magnesium/aluminium antacids & cholestyramine decreases absorption.
  • Mechanism of action: inhibits inosine monophosphate dehydrogenase (IMPDH), blocking guanosine phosphate synthesis which is essential for DNA synthesis in T & B cells

Mycophenolate mofetil - Adverse Effects

  • Pain, diarrhea, leukopenia, opportunistic infections, lymphoma, sepsis

Antibodies

  • Immunization methods (rabbits, horses): producing polyclonal antibodies
  • Hybridoma technology: fusing mouse Ab-producing cells with immortal plasma cells to create monoclonal antibodies
  • Recombinant DNA technology: humanizing mouse genes

Antithymocyte Globulins

  • Polyclonal antibodies targeting T-cell precursors (thymocytes)
  • Primarily used in hyperacute rejection phase of allografts
  • Mechanisms: complement-mediated destruction, antibody-dependent cytotoxicity, apoptosis, opsonization.
  • Antibody-bound T-cells are then phagocytosed in liver & spleen
  • Result: lymphopenia & impaired T-cell responses

Antithymocyte Globulins

  • Does not affect the humoral part of the immune system.
  • Potential side effects: chills & fever, leukopenia, thrombocytopenia, anaphylaxis, skin rashes, infections.

Muromonab-CD3 (OKT3)

  • Monoclonal antibody targeting CD3 protein on T cells.
  • Therapeutic applications: acute and steroid-resistant renal allograft rejection, cardiac and hepatic transplants, prior to bone marrow transplantation.
  • Mechanism of action: blocks the antigen recognition site, disrupting T cell function, and reducing immune response.

Muromonab-CD3 - Pharmacokinetics

  • IV administration.
  • Extensive metabolism.
  • First administration can trigger a cytokine storm.
  • Pre-medication with steroids, diphenhydramine, and acetaminophen is often given.

Muromonab-CD3 - Adverse Effects

  • Ranges from mild flu-like illness to life-threatening cytokine storm (fever, CNS effects, seizures, encephalopathy, edema, meningitis).
  • Contraindications: pregnancy/breastfeeding, heart failure, seizure disorder

IL-2 Receptor Antagonists

  • Humanised antibody (e.g., Daclizumab) and chimerized antibodies (e.g., Basiliximab, mBasiliximab)
  • Therapeutic uses: prevention of acute rejection in renal transplantation. Usually used in conjunction with CsA or corticosteroids.

IL-2 Receptor Antagonists - Mechanism of action

  • Bind to IL-2 receptors, preventing T-cell proliferation.
  • Basiliximab is more potent than daclizumab

IL-2 Receptor Antagonists - Pharmacokinetics

  • IV administration
  • Daclizumab (longer half-life)

IL-2 Receptor Antagonists - Adverse effects

  • Both are well tolerated.
  • GIT effects are possible

Glucocorticoids (Adrenocorticoids)

  • Prednisone, methylprednisolone, used in transplantation and autoimmune conditions (e.g., RA, SLE).
  • Mechanism of action: reduce T-cell populations by binding intracellular cytoplasmic receptors.
  • Then dimerizes to translocate to the nucleus, acting as a transcription factor to shut-off gene expression in immune cells.

Glucocorticoids - Adverse effects (Long-term)

  • Negative calcium balance, impaired wound healing, osteoporosis, increased risk of infections, euphoria/depression

Antihypertensives

  • Introduction: Systolic >140mmHg & Diastolic >90mmHg, leads to conditions like myocardial infarctions, congestive heart failure, renal damage, cerebrovascular incidents.
  • Frequency of concomitant diseases: (e.g. angina, diabetes, hyperlipidemia, heart failure) common in hypertensive patients
  • Risk factors: stressful lifestyle, high sodium intake, obesity, smoking.
  • Aetiology: essential (most common) hypertension, secondary hypertension (caused by other diseases). Black and male populations often have higher risk.

Antihypertensive Drugs

  • Diuretics (e.g., amiloride, bumetanide, chlorthalidone, eplerenone, furosemide, hydrochlorothiazide, metolazone, spironolactone, triamterene)
  • β-blockers (e.g., atenolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, propranolol, timolol)
  • ACE Inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril)
  • Angiotensin II receptor antagonists (ARBs) (e.g., azilsartan medoxomil, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan)
  • Calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil)
  • α-blockers (e.g., doxazosin, prazosin, terazosin)
  • Renin inhibitors (e.g., aliskiren)
  • Other (e.g., clonidine, diazoxide, hydralazine, minoxidil, sodium nitroprusside)

What are the targets for the following three drugs:

- Ramipril (ACE-I) : Angiotensin-converting enzyme  (ACE)
- Losartan (ARB): Angiotensin-receptor
- Hydrochlorothiazide (diuretic): Sodium reabsorption in the distal convoluted tubule of the nephron

Major factors affecting blood pressure

  • Arterial blood pressure is directly influenced by cardiac output and peripheral resistance. Cardiac output is related to heart rate and contractility. Peripheral resistance is related to arteriolar volume, blood volume, and venous tone.

Mechanisms for controlling blood pressure

  • Short-term control: sympathetic nervous system & baroreceptors (aortic arch & carotid sinuses)
  • Long-term control: renin-angiotensin-aldosterone system & baroreceptors (kidney)

Treatment strategies

  • Reduce cardiovascular & renal morbidities & mortality
  • First-line therapy: Thiazide diuretics
  • Inadequately controlled: Add a β-blocker. If still uncontrolled, add a vasodilator.

Individualized treatment

  • Considerations for specific patient populations: black and elderly patients may respond better to diuretics or CCBs, rather than β-blockers or ACE inhibitors. Comorbidities need to be taken into consideration.

Concomitant disease & drug classes

  • Chart showing drug classes indicated for treating hypertension in patients with a variety of comorbidities.

Patient compliance

  • Lack of compliance is a major reason for treatment failure.
  • Asymptomatic patients should still be diagnosed early to prevent complications.
  • Adverse effects (e.g., β-blockers causing impotence) need to be carefully weighed for individual patients to optimize compliance levels

Thiazide diuretics-

  • First-line treatment for hypertension.
  • Actions: increases urine output and excretion of water and sodium. Which decreases plasma volume, decreases cardiac workload, and decreases renal blood flow in the short term. Peripheral vascular resistance is decreased in the long term. Simultaneous administration of potassium-sparing diuretics is possible.
  • Preventing heart remodeling.

Thiazide diuretics - Pharmacokinetics

  • Oral administration.
  • Ineffective in patients with poor kidney function (creatinine clearance < 50 ml/min).
  • Ligands for organic acid secretory system.
  • Potentially competes with uric acid for elimination.
  • Side effects include hypokalemia, hyperuricemia, and hyperglycemia.

Potassium-sparing diuretics

  • Shown on page 98

β-blockers

  • First-line therapy for hypertension & heart failure
  • Propranolol: blocks β1 and β2 receptors. CI: asthma
  • Metoprolol & Atenolol: Block β1 receptors

β-blockers - Actions

  • Decrease cardiac output and peripheral resistance. -Decrease renin and aldosterone production. This results in a decrease in blood pressure.

β-blockers - Pharmacokinetics

  • Not indicated

β-blockers - Adverse Effects

  • Alterations in serum lipids (increased TAGs, decreased HDLs).
  • Abrupt withdrawal can cause rebound hypertension

Angiotensin-converting Enzyme Inhibitors (ACE inhibitors)

  • First line if first-line agents are not effective (or ineffective in black and elderly patients)
  • ACE-I's + diuretics: effective in black and white patients.
  • Useful in slow progression of diabetic nephropathy, decrease in albuminuria, heart failure after myocardial infarction

ACE inhibitors - Actions

  • MOA: Decreases angiotensin II production, causing vasodilation and decreased peripheral resistance, decreased aldosterone production, decrease in sodium and water retention which all decreases blood pressure.
  • Reduced activity of the sympathetic nervous system.

ACE inhibitors - Adverse effects

  • Altered taste, potassium level monitoring (avoid with spironolactone), foetotoxic, reversible renal failure; close observation required for first dose. First dose syncope is possible as a result. Angioedema is possible.

Angiotensin Receptor Blockers (ARBs)

  • Losartan, irbesartan
  • Actions: Vasodilation, block aldosterone release, lower blood pressure, decreased salt and water retention.
  • Adverse effects: less risk of cough & angioedema, otherwise similar to ACEIs. Foetotoxic

Renin Inhibitors

  • Aliskiren
  • Acts earlier in RAAS than ACE-I's & ARBs
  • Use in combination with diuretics, ACE-Is, ARBs, or CCBs.
  • Fixed-dose combination with valsartan & hydrochlorothiazide.
  • Side effects: diarrhea, cough, angioedema, hyperkalemia (with valsartan). CI: pregnancy.

Calcium Channel Blockers

  • First generation, second generation, third generation dihydropyridines (Nifedipine, Amlodipine) are further detailed. Phenylalkylamine (Verapamil). Benzothiazepine (Diltiazem)
  • Therapeutic uses: natriuretic effect, doesn't require diuretic addition
  • Hypertension with issues like asthma, diabetes, angina, peripheral vascular disease.
  • Short half life (t1/2) requires repeated dosing. Sustained-release options available.

α-adrenoreceptor agents

  • α1-blockers: (Prazosin, doxazosin, terazosin): decrease peripheral vascular resistance, lower arterial blood pressure. Minimal change to CO, renal blood flow, GFR. Salt & water retention can occur.
  • α-agonists (Clonidine): Rx for mild to moderate hypertension that has not responded to diuretics. Does not decrease renal blood flow or GFR, thus useful in hypertension + renal disease. Causes sodium and water retention

α-Methyldopa

  • a2 agonist adrenergic outflow from CNS. Decreases peripheral resistance. Decreased blood pressure. CO is not affected. Useful in renal insufficiency hypertension
  • Adverse effects: Sedation, drowsiness

Vasodilators

  • Produce relaxation of vascular smooth muscle, decrease resistance, decreased blood pressure
  • Some examples include hydralazine and minoxidil.

Hypertensive Emergency

  • High blood pressure requiring immediate treatment (DBP >150 mmHg, SBP >210 mmHg or DBP >130 mmHg with complications).
  • Complication examples include: encephalopathy, cerebral hemorhage, aortic stenosis.
  • Treatment options include sodium nitroprusside, labetolol, fenoldopam, and nicardipine. IV administration is needed with caution.

Comparison of Treatments

  • Comparison of onset and duration of action (tabled on page 139).

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This quiz covers key concepts related to pharmacology, focusing on thiazide diuretics, their mechanisms, and related medications. Explore the roles of various drugs in blood pressure regulation and their therapeutic uses. Test your understanding of adverse effects and specific pharmacodynamics.

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