Drug Class 13: Corticosteroids/Glucocorticoids

13.1: Inhaled corticosteroids (ICS) [For Asthma]

-Beclomethasone, Budesonide, Ciclesonide (Active metabolite-Des-ciclesonide), Fluticasone, Prednisolone (Solo-Active metabolite of Prednisone)

*Most potent and consistently effective class of medications for long-term control of asthma in both adults and children.

  • Mechanism of Action (Corticosteroids)

1. Glucorticoids readily cross cell membranes and bind with high affinity to specific nuclear receptors. Following binding, transcription  and protein synthesis altered.

-May inhibit leukocyte infiltration at the site of inflammation.

-Reduce/Inhibit mediators of inflammation

-Suppression of the humoral immune responses.

2. Regulate gene expression which results in glucocorticoid effects

-Glucocorticoid effects: Gluconeogenesis, proteolysis (breaks down proteins), lipolysis (breaks down fats), Suppression of inflammation and immune responses (useful in asthma)

-Unwanted mineralocorticoid effects:  Hypertension, sodium and water retention, potassium loss

3. Inhibits Phospholipase A2 which prevents downstream production of inflammatory mediators (e.g. Prostaglandins-PGI2, PGE2, PGD2, Thromboxane A2, Leukotrienes such as LTE4, LTC4, LTD4)

-Reduces inflammation which is evident in asthma.

Note: Corticosteroids may have predominantly glucocorticoid effects but tend to have some/minimal mineralocorticoid effects as well (becomes side effects when treating asthma)

For ICS Mechanism of action,

1. Decreased IgE synthesis (triggers mast cell degranulation)

2. Increased number of b-adrenergic receptors on leukocytes

3. Decreased Arachidonic acid metabolism (Decreases PGs and LTE released)

  • Precautions (ICS has a predominant systemic action so these precautions are less crucial)

1. Latent TB– May be reactivated. Consider treatment with isoniazid

2. Peptic ulcer disease-Corticosteroids may increase the risk of peptic ulcers

***3. Diabetes-Corticosteroids worsen diabetes control and may cause hyperglycemia in non-diabetics.

4. Hypertension, Heart failure

-May be worsened due to sodium and water retention side effects (mineralocorticoid effects)

5. Psychiatric disorders-May be exacerbated

6. Glaucoma-Intraocular pressure may be increased

7. Osteoporosis

8. Myasthenia gravis

-Increased muscle weakness may occur during the first few weeks of treatment with corticosteroids, seek specialist advice.

9. Infections (Corticosteroids are immunosuppressive)

-Increase the risk and severity of infection.

*Use with caution if patient has a history of recurrent infections. 

-The decision to start or continue corticosteroids in a patient depends on various factors e.g. type of infection (active or latent), its severity, whether the infection can be treated or controlled and the indication for the drug.

*Seek specialist advice if unsure.

10. Intra-articular injection (Not applicable here-ICS)

Contraindicated in patients with infective arthritis, skin or soft tissue infections near joint (risk of introducing bacteria into joint) or a prosthetic joint.

11. Surgery

-Patients with hypothalamic-pituitary adrenal (HPA) suppression due to corticosteroids or taking replacement doses of corticosteroids for adrenal insufficiency should be given corticosteroids for protection against adrenal crisis during surgery and for 24-48 hours afterwards. 

-Wound healing may be delayed by pharmacological doses of corticosteroids.

12. Children (Effects do not apply to ICS)

-Chronic use of corticosteroids (at pharmacological doses) may retard growth (Effects do not apply to ICS).

-Follow growth and development carefully.

-Catch-up growth may occur after corticosteroid withdrawal

13. Pregnancy

*Use the lowest safest dose for the shortest possible time. Budesonide is the preferred ICS for pregnancy (Most gestational data available)

-No treatment is more serious for fetus and ongoing pregnancy.

-Corticosteroid use in early pregnancy (before 12 weeks) may slightly increase risk of orofacial clefts.


*Hydrocortisone, prednisone, prednisolone, methylprednisolone are preferred for maternal disorders as placental transfer is limited.

*Betamethasone and dexamethasone are preferred for fetal disorders as placental transfer is greater.

  • Adverse effects/Side effects (ICS related)

-These adverse effects occur when corticosteroids are used at pharmacological doses.

Note: *Inhaled corticosteroids only have systemic actions when given in high doses.

-Short courses of high dose systemic treatment cause fever adverse effects than prolonged courses of lower doses.

Practice points: Reduction of systemic absorption can be achieved by using Metered dose inhaler with a spacer. Then, rinse mouth with water and gargle. Spit out water to reduce oral side effects.

Practice points:  Monitor Dosage and side effects.

(a) Systemic Side effects (Common):

1. Mineralocorticoid effects (Na+ reabsorption and K+ excretion, Increases BP). Sodium and water retention.

-Prednisolone, Prednisone, Methylprednisolone, Hydrocortisone (most significant) and cortisone has mineralocorticoid effects.

2. Adrenal suppression (adrenal cortex does not see the need for adrenal production of corticosteroids)

3. Increased susceptibly to infections, Masking of signs of infection

4. Edema (relatd to mineralocorticoid effects)

5. Hypertension (related to mineralocorticoid effects)

6. Hypokalemia (related to mineralocorticoid effects)

7. Hyperglycemia (Increased gluconeogenesis)

8. Dyslipidemia (Increased lipolysis)

9. Osteoporosis (Inhibition of collagen/cartilage formation), Fractures

10. Increased appetite

11. Delayed wound healing (Immunosuppression), Skin atrophy

12. Bruising

13. Acne

14. Hirsutism

15. Growth retardation in children

16. Myopathy

17. Muscle weakness and wasting

18. Fat redistribution (Cushing’s syndrome-Fat distributes around waist/abdomen area). Classical moon face appearance. Buffalo hump.

19. Weight gain

20. Amneorrhea- absence of a menstrual period in a woman of reproductive age

21. Psychiatric effects-Euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour. Delirium and psychosis are less common.

22. Posterior subcapsular cataracts-Cataracts that affect the back of the lens

*Amenorrhea-Absence of menstruation in women of reproductive age.

(b) Systemic side effects (Infrequent):

-Osteonecrosis (particularly of the femoral and humeral heads, Ocular hypertension, glaucoma

-For intra-articular injection: Refer to AMH 2012.

(c) Systemic side effects (Rare):

-Peptic ulceration, hypersensitivity reactions, tendon rupture (especially of Archilles tendon), Central serous chorioretinopathy

***Specific side effects for ICS: Important for asthma

1. Dysphonia (Hoarseness)

-Caused by deposition of ICS on vocal cords and myopathy of laryngeal muscles (occurs up to 1/3 of those using ICS)-Very common

-Less occurance with breath-activated delivery (BAI)

-Method of inhalation leads to protection of vocal cords by false cords.

2. Oral candidasis (Opportunistic Fungal infection due to Candida Albicans)

-Can be prevented by using spacer device or by gargling after use of the inhaler.

  • Comparative information

-Corticosteroids with minimal mineralocorticoid properties (e.g. Prednisolone and prednisone) or no mineralocorticoid properties (e.g. Beclomethasone, Dexamethasone and triamcinolone) are generally preferred for use as immunosuppressants or anti-inflammatory agents.

Acronym: TBe De But-To be debuted (no mineralocorticoid effects). P and P-Partially (some mineralocorticoid effects)

*Higher levels of fluticasone causes significant reduction in adrenal cortisol production

  • Counselling points

-Take the tablets or oral liquid with food to help reduce stomach upset.

-Tell the doctor immediately if patient has any signs of infection.

-This medication may affect patient’s mood (psychiatric effects). Cause problems with sleeping. Talk to the doctor if patients have any concerns.

*Do not stop taking this medication suddenly unless doctor tells patient otherwise. The doctor may need to be reduce dose gradually when intending to stop treatment (avoid withdrawal symptoms-Fatigue, Weakness, body aches, Joint pain)

-Tell all health professionals (doctors, dentists, surgeons, pharmacists, nurses etc) that the patient is treated with corticosteroids (or have taken them in the past). If patient becomes ill or intending to have surgery, the dose of medicine may need to be increased.

-Consider wearing a Medic Alert (r) Bracelet/ Steroid card detailing treatment (Only required when treated with high doses of corticosteroids)

*Warn patient that medication of ICS is not instantaneous. Time is required (since transcription is altered). Tell patient it will take days to see maximal response. 

  • Practice points

-Measure blood glucose, weight, BP acid and electrolytes at baseline. Then do so each week for the first month of treatment

-Watch for signs/symptoms of infection. Signs of infection may be masked.

-Measure BMD at baseline if likely to require chronic treatment (>3 months) or repeat courses. Evaluate and manage other risk factors for osteoporosis and consider need for drug treatment to prevent bone loss.

-Monitor for cataracts and glaucoma in patients on long term corticosteroids.


-Under periods of stress (e.g. trauma, surgery, infection, blood loss), dose of corticosteroids may need to be increased.

*Refer to AMH 2012 for specific points on Intra-articular injection (used for joints-RA)

  • Types of ICS (In alphabetical order)

1. Beclomethasone

-Synthetic halogenated inhaled glucocorticoid (has Cl)

Beclomethasone structure (Contains Cl halogen so beClomethasone)

  •  Clinical Indications:

(a) Treatment of steroid-dependent asthma (unusually hard to control type of asthma)

(b) For relieving symptoms associated with allergic or non-allergic rhinitis

(c) Preventing recurrent nasal polyps following surgical removal

(d) Prevention of neo-natal respiratory distress syndrome

(e) Intradermal administration of dermatological disease [not relevant for ICS form]

(f) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid, osteoarthritis, acute gout, tendonitis [not relevant for ICS form]

  • Precautions

-Breast feeding: Safe to use

-Pregnant women: Safe to use (CAT A-AUS)

  • Pharmacokinetics

-Nasal inhalation absorption (minimal absorption systemically)

-Oral inhalation absorption (Drug is absorbed rapidly from lungs and GIT). Some of the oral inhaled dose is absorbed systemically, but usually not sufficient to exert therapeutic effects.

-OAA: typically occurs in a few days but full effects can take as long as 1-4 weeks to be apparent.

Note: Without a spacer, approximately 10-25% of a spacer device, approx 10-25% of the orally inhaled dose will enter the respiratory tract. The rest will be deposited in the mouth or oropharynx and swallowed.

∴ Use a spacer to maximise percentage of medication delivered into lungs.

  • Practice Points

-Can be injected directly into affected soft tissue (e.g. bursitis, myostitis)

-Symptom relief usually occurs 2-4 hours for intra-articular injection, and is maintained for at least 4 weeks.

2. Budesonide (Not found in AMH 2012)

Budesonide structure(Budesonide)

-May be Administered via intranasal inhalation (once a day dosing), oral inhalation or orally for various conditions

-Potent glucorticoid with weak mineralocorticoid activity.

-Less desirable side effect profile when compared to other Intranasal steroids.

-Inhaled budesonide (via oral or nasal) possess high topical anti-inflammatory activity but low systemic activity.

  • Clinical indications: (a) Allergic rhinitis (Intranasal inhalation) (b) Asthma (oral inhalation) (c) Crohn’s disease (orally)
  • Pharmacokinetics: 

1. First pass metabolism after oral absorption (oral inhalation/nebulisers). Inactivated extensively in the liver.

-Very low systemic effects (6% of the dose reaches systemic circulation)

∴ Preferred for children or when high doses of ICS are required.

2. Only 20% of the dose reaches the systemic circulation (nasal inhalation)

3. Ciclesonide (Modern and recent version)———Prodrug

Ciclesonide structure (ciclesonide-Notice the ester group present, it is a pro-drug)

-Non-halogenated glucocorticoid which is beneficial in treating inflammatory conditions such as allergic rhinitis and asthma.

Clinical indications: (a) Asthma (b) Allergic rhinitis

+Drug has a low systemic bioavailability following intranasal or oral inhalational administration which limits systemic side effects such as adrenal suppression.

The active metabolite of ciclesonide, des-ciclesonide is 100-120x more potent than ciclesonide.

  • Pharmacokinetics:

1. Lung/Mucosal Metabolism: Esterases in the nasal and lung mucosa hydrolyse ciclesonide to a biologically active metabolite, des-ciclesonide (100-120x more potent than parent)

2. Hepatic Metabolism (Liver): CYP3A4 and CYP2D6 metabolises des-ciclosonide furthur.

3. Administered by intranasal inhalation or oral inhalation.

4. Oral bioavailability is negligible.

5. OAA: following intranasal administration is 24-48 hours. Desired effects observed after 1-2 weeks in those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis. 

4. Dexamethasone (Indications not specific)-Not for asthma or COPD

Dexamethasone structure

-Halogenated corticosteroid

  • Clinical indications: (a) Multiple myeloma (b Lymphoma (c) Some leukemias (Need to research on this) (d) Post-operative or chemotherapy induced nausea and vomitting (d) CROUP (e) Cerebral edema due to malignancy
  • Precautions: 

1. Breastfeeding-Limited data avilable. Consider using alternative corticosteroid (e.g., prednisolone or budesonide)

  • Adverse effects/Side effects


1. Transient itching

2. Burning or tingling in perineal area (after IV bolus)

*Perineal- region of the body and surrounding structures

  • Administration advice

-Give IV injection over 1-3 minutes

  • Practice points

-Can be given by intra-articular or soft tissue injection for local effect.

-Use of adjuvant IV dexamethasone (starting for bacterial meningitis is controversial). Recommended if S.pneumoniae is suspected in adults or H.influenza in children

-When treating penicillin-resistant pneumococcal meningitis, consider reduced CSP penetration of vancomycin due to corticosteroids.

5. Fluticasone (for asthma, COPD treatment and other conditions)

Fluticasone structure

-Contains fluorine (so Fluticasone). Synthetic Steroid with medium potency.

  • Clinical indications:

(a) Relieve inflammatory and puritic manifestations of dermatoses (skin diseases) and psoriasis. [TOPICAL]

(b) Allergic and non-allergic rhinitis [Intranasal inhalation-Fluticasone furoate]

(c) Asthma [Oral Inhalation]

(d) Used clinically for certain patients with COPD.

fluticasone furoate (Intranasal inhalation-Allergic Rhinitis)

  • Pharmacokinetics

-Most of a dose following intranasal adminstration of fluticasone is swallowed with metabolism in the gut and partial absorption with extensive first pass metabolism (CYP3A4)

*First pass metabolism eliminates all/most of the systemic effects. 

-Absorption following topical administration to the skin is usually minimal and depends on such factors as the vehicle and integrity of the epidermis.

-Due to primary absorption from the lungs, the oral inhalation aerosol usually results in systemic bioavailability of about 30%  of the delivered dose.

-Bioavailability of the oral inhalation powder is approx 14%

6.  Hydrocortisone/cortisol —(Indications not specific but can be used for Asthma)

Hydrocortisone.Cortisol structure

  • Clinical Indications: (a) Autoimmune or inflammatory conditions (b) Adrenal insufficiency (Glucocorticoid replacement) (c) Anaphylaxis (as an adjunct to management) (c) Asthma
  • Precautions: Breast feeding (safe to use). Pregnancy-Safe to use (May cause maternal disorders so avoid use over long periods of time) 

7. Methylprednisolone (given as methylprednisolone sodium succinate or methylprednisolone acetate)-For severe asthma and other conditions

Methylprednisolone (Additional methyl group attached at C6)

  • Clinical indications (for MTP sodium succinate): (a) Anaphylaxis (as an adjunct to management) (b) Acute severe asthma (c) Autoimmune or inflammatory disease (d) Acute transplant rejection (e) Acute exacerbation of multiple sclerosis (MS)
  • Clinical indications (for MTP acetate): (a) Autoimmune or anti-inflammatory conditions (Intramuscular) (b) Adjunctive treatment for inflammatory arthritis (e.g. osteoarthritis, rheumatoid) (c) Gout (d) Tendonitis (intra-or peri articular injection)
  • Precautions:

– IV administration of methylprednisolone acetate-CONTRAINDICATED       WHY? Release acetate ions?

-Breastfeeding (safe to use). *Give dose immediately after a feed and wait 4 hours before the next feed.

  • Administration advice

Methylprednisolone sodium succinate

-Rapid IV administration of high doses may cause arrhythmia, cardiovascular collapse or cardiac ARREST.

-Infuse IV doses of >250 mg over at least 30 mins and doses of <250 mg over at least 5 mins.

  • Practice points 

-Improves rate of recovery from exacerbation of MS.

Methylprednisolone acetate can also be given by intradermal injection for local effect.

8. Prednisolone/Prednisone (Can be used for acute asthma and various other conditions)

*Need to know which is the active metabolite and which is the prodrug

Prednisolone vs Prednisone

(Notice that prednisone has the ketone group at C11 whereas prednisolone has an OH/hydroxyl group at C11)

*Prednisone is the prodrug (needs to be reduced to OH in the liver). Prednisolone is the active metabolite (Has the OH group)

Prenisolone (Solo steroid-Active-metabolite).  Prednisone (Still a son, needs to grow up-Prodrug)

-Hepatically activated prodrug.

  • Clinical indications:

(a) Severe, persistant, Acute asthma  (b) Autoimmune and inflammatory diseases (c) Acute transplant rejection (d) Acute gout (e) CROUP (f) Inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe-[OPTHALMIC SOLUTIONS] (g) May be used for multiple myeloma, lymphoma, some leukemias [CHECK TREATMENT PROTOCOL]

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

  • Precautions:

-Breastfeeding: Safe to use. Take dose immediately after a feed and wait 4 hours before the next feed. Doses up to 80mg have been studied.

  • Practice Points:

-Prednisone is converted to active prednisolone in the liver and vice versa (via CYP3A4 inducer)

Prednisolone (Active metabolite) is used for CROUP when dexamethasone oral liquid is unavailable.

*CROUP-respiratory condition that is usually triggered by an acute viral infection of the upper airway. The infection leads to swelling inside the throat, which interferes with normal breathing and has symptoms of coughstridor, and hoarseness

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

-When asthma is stabilised, dose should be reduced or eliminated due to the side effects associated with chronic administration.

-Short courses of treatment may be used in moderate to severe exacerbations.

-If long term therapy is required, the lowest possible effective dose should be used.

9. Triamcinolone (can be used for asthma and other conditions)

Triamcinolone structure

-Long acting, synthetic corticosteroid given topically, orally, injection or by inhalation.

  • Clinical indications: 

(a) Autoimmune or Inflammatory diseases (Intramuscular injection) (b) Dermatological disease (Intradermal injection) (c) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid or osteoarthritis) (d) Acute Gout (e) Tendonitis (intra- or peri-articular injection)

  • Precautions

-Breastfeeding (data is limited). Diffusion into breast milk is low?

  • Adverse effects/Side effects

-Systemic adverse effects may arise from intra-articular and intra-dermal administration.


Local administration: Intra-articular pain, flare, hyperpigmentation

  • Practice Points

-Use triamcinolone 10mg/ml for intra-articular injection of doses <5 mg and for intradermal injection

-Intravitreal (injection into eye) triamcinolone is used to treat conditions such as diabetic macular edema, indication is not recommended by manufacturer!

Risk of adverse effects such as: Increased intraocular pressure, cataract formation, endophthalmitis and visual disturbances

*Endophthalmitis-is an inflammation of the internal coats of the eye

Immunology: Anti-histamines and Immunosuppressant drugs

Part 1: Anti-histamines

What is histamine?

-Naturally occuring amine that is found in most body tissues in a inactive bound form (histamine+heparin+protein)

-Important component of mast cell granules and released in response to stimuli such as physical trauma or antigen-antibody reactions.

-Various chemicals such as tubocurarine, morphine, some anti-histamines,  snake venome and proteolytic enzymes can cause release as well.

-The triple response of Lewis is a cutaneous response that occurs from firm stroking of the skin, which produces an initial red line, followed by a flare around that line, and then finally a wheal. [Subtypes involved: H1 and H2 receptors]

Physiological function of histamine:

1. In body epithelia, it is released in repsonse to invasion by foreign substances.

2. In glands, mediates part of the normal secretory process.

3. In most cells near blood vessels where it plays a role in regulating microcirculation.

Action of histamine

Smooth muscles: Cause smooth muscles to contract (not including arterioles but larger arteries). Stimulation of human uterus is insignificant. Brisk attack of bronchospasm may be induced in subjects who have allergy esp. asthma.

1. Dilate arterioles, with a consequent fall in blood pressure.

2. Dilate capillaries

3. Pruritic (Cause itchiness)

4. Gastric secretion (Increased acid and pepsin concentration in gastric juices)

5. Metabolism (Formed from the amino histidine and metabolised minaly by deamination and by methylation)

  • Types of Histamine receptors (H1, H2, H3)

h1: Anti-histamine usually refers to H1-receptor antagnoists (which is affects various allergic and inflammatory mechanisms)

h2: Recently developed, main effect is on gastric secretion (e.g. cimetidine)-‘Cement ti dine’

h3: Experimental and investigational tools.

1.1 H1 antagonists (Anti-histamines)

-Considerable structural similarity to histamine, adrenaline, serotonin and acetylcholine. Thus, may affect or block one another.

-H1 anti-histamines have sedative, antimuscarinic or even alpha antagonist effects.

-As such, H1-anti-histamines can be used as hypnotics, antitussives, expectorants, in motion sickness and in parkinson’s disease.

-if used for its anti-histamic effect, the above uses will become adverse effects.,

1. 2Mechanism of action: 

  • Decrease histamine-mediated contraction of smooth muscles in the bronchi, the intestine and in the uterus.
  • Reduce the increased vascular permeability caused by histamine.
  • Sedation
  • Prevent motion sickness

1.3 Clinical Uses/Indications:

-For allergic reactions including hay fever, urticaria, insect bites, drug hypersensitivities. Drugs that lack sedative effect are preferred (e.g. fexofenadine-(Fatso fiend-a dine) or cetirirzine)

-Used as anti-emetics for the prevention of motion sickness or other causes of nausea, especially those with associated with vertigo (e.g. labyrinthine disorders) [Loratadine]

-For sedation (e.g. promethazine found in Phenergen)

1.4 Side effects

-Depends on the effects that the drug is prescribed for. This means that if a drug is used for peripheral actions, the CNS activity is unwanted and vice versa.

-When used for their sedative or anti-emetic actions, some of the CNS effects are dizziness, tinnitus and fatigue are unwanted.

Precautions: Excessive doses may cause excitation and convulsions in children. (!st generation anti-histamines) For children, sedation may be induced and learning ability will be affected. Severe effects are unusual following ovedoses of 1st generation anti-histamines.

-Altering the structure of some drugs may prevent them from entering BBB and less unwanted Adverse effects (e.g. loratadine)—>More polar


*Peripheral actions on CNS activity is always unwanted!!! When used for sedative or anti-emetic actions (eg. dryness of the mouth, blurred vision, constipation, retention of urine)

*Gastrointestinal disturrbances and Allergic dermatitis can follow after application

1st generation anti-histamines: Hydroxyzine, Bromazine, Mepyramine

2nd generation anti-histamines (Agents with no sophoric effect): Loratadine, Cetirizine, Mizolastine, Terfenadine, Astemizole (Terfenadine and astemizole are non-sedating alternatives to first-generation compounds, inhibits several ion channels) *Disturbing arrhythmias were described for these two drugs.

3rd generation anti-histamines (Non-cardiotoxic, non-sedative agents): Fexofenadine (Children who have overdose can be managed at home)

Part 2: Immunosuppressant drugs

2. 1Generabl Mechanism of action:

1. Inhibits IL-2 production or action (e.g. cyclosporin, tacrolimus, sirolimus/rapamycin)

2. Inhibitors of cytokine gene expression (e.g. corticosteroids)

3. Act by cytotoxic mechanisms (e.g. cyclophosphamide, chlorambucil)- Prevents cell proliferation

4. Inhibits purine or pyrimidine synthesis (e.g. azothioprine, myclophenolate mofetil)

5.  Blocks cytokines and receptors mediating immune responses (e.g. antibodies)

2.2 Clinical Indications

1. To suppress tissue regection after transplant

2. To suppress graft versus host disease in bone marrow transplant.

3. To treat autoimmune diseases (psoriasis, ulcerative colitis, systemic lupus erythematosus/SLE, idiopathic thrombocytopenic purpura/ITP)

2.3 Types of immunosuppressant drugs

1. Cyclosporin

-Fungal peptide (cyclic 11 amino acids, invaluable role in organ transplant)

Mechanism of action:

  • Decreased clonal proliferation of T cells, primarily by inhibiting IL-2 release and decreasing expression of IL-2 receptor
  • Reduced induction of and clonal proliferation of cytotoxic T-cells from precursor CD8+ cells
  • Reduced function of effector T-cells that mediate cell-mediated responses
  • Some reduction of T-cell dependent responses

***Main effect by preventing IL-2 transcription

Antigen binds to T-cell receptor–>Increase in intracellular Ca2+–>Ca2+ plus calmodulin stimulates phosphatase, calcineurin, that activates various transcription factors–>Transcription of IL-2 genes–>Cyclosporin binds with a cystolic protein called cyclophilin–> The resulting complex inhibits calcineurin–>Inhibits IL-2 production and T-cell proliferation does not occur.

Unwanted effects:

1. Nephrotoxicity (probably due calcineurin inhibition)-Limiting factor in certain patients (Esp with renal failure)

2. Hypertension

3. Hepatotoxictiy

4. Less crucial side effects (Anorexia, lethargy, hirsuitism, tremor, parasthesia, gingival hyperplasia, gastrointestinal disturbances)

+No depressant effects on bone marrow

2. Tacrolimus

Mechanism of action: Macrolide antibiotic with a similar mode of action to cyclosporin but the internal receptor is not cyclophilin but immunophilin known as FKBP/FK binding protein. The complex inhibits calcineurin in the same way. 

Side effects:

-Similar to cyclosporin. Hypertension and Nephrotoxicity not that serious here.

-Thrombocytopenia and hyperlipidemia may occur but reversible by reducing the dose.

3. Glucocorticoids-Discusssed previously

4. Azathioprine

-Interfers with purine synthesis and is cytotoxic. Used widely for the control of tissue rejection in transplants. Drug is metabolised to give mercaptopurine (analogue which inhibits DNA synthesis)

-Both cell-mediated and antibody-mediated immune reactions are depressed by this drug since it inhibits clonal proliferation in the induction phase of the immune response by cytotoxic effects on dividng cells. Main unwanted effect is depression on bone marrow.

5. Alkylating agents

-Two alkyl groups which can form covalent bonds with cell substituents. Can cross link two nucleophilic sites such as N7 of guanine in DNA.

Mechanism of action: During DNA replication, the result is base substitution, base excision or chain breakage. Eventually, cell dies by apoptosis.

(a) Cyclophosphamide-Cytotoxic agent with powreful immunosuppressive effects. Particular action on lymphocytes during the clonal proliferation phase and inhibits both anti-body and cell-mediated immunity

(b) Chlorambucil-Similar in action and effects to cyclophosphamide

6. Mycophenolate mofetil

-Derivative of fungal antibiotic.

-Metabolised into mycophenolic acid in the body which inhibits proliferation of both T and B lymphocytes by inhibiting inosine monophosphate dehydrogenase (enzyme needed for purine biosynthesis)

-T-cells and B-cells need this pathway. So inhibiting this pathway has rather specific effects.

*When used with cyclosporin and steroids, it is effective in suppressing kidney transplant rejection.

7. Immunoglobulins

-Antibodies against human lymphocytes or their surface proteins.

-When derived from animal sources, the antibodies themselves are potent antigens which limits their usefulness.

-Using genetic engineering, the antibodies can be humanised to combine the Fab region to the Fc region.

8. Polyclonal

-Anti-lymphocyte immunoglobulin and anti-thymocyte immunoglobulin are obtained from horses which are immunised against human lymphocytes or feotal thymus tissue respectively.

-Binding of the antibodies cause complement activation and lysis of target cells.

-Unwanted effects: Due to the presence of foreign proteins and subsequent immune response. Anaphylaxis can occur and immune complexes can lodge into kidney causing nephritis.

9. Monoclonal

-Directed against surface components of T-cells.

CD3-Group of peptides responsible for epxression of T-cell receptors at the cell surface.

CD4-Essential co-receptor on T-helper cells

IL-2 receptor-Needed for clonal proliferation of T-cells

-Initial doses of anti-CD3 can cause severe side effects. Fever, hypotension, pulmonary edema, nephropathy and encephalopathy which is thought to be due to cytokine release can occur. Pre-treatment with steroids is required to mitigate these effects.

10. Anti-TNF humanised antibodies

Clinical uses: Ankylosing Sponylitis, Crohn’s disease, Psoriasis, Psoriatic arthritis, Rheumatoid arhritis

-Very effective though the vary in effectiveness with different disease, adverse reactions are unusual but as they inhibit immunity some increase in infections have been noted.

*It is advised that a patient suffering from infections to stop Adalimumab (Humira) treatment.

*Increased in liver enzymes (AST and ALT) and formation of autoantibodies similar to early SLE have been reported.

(a) Infliximab (Remicade): Mouse-Human antibody to TNF-a

(b) Etanercept (Enbrel): Construct of human TNF receptor and IgG which binds to TNF-a and prevents its action. Effectiveness may decrease over time, perhaps due to antibody formation and less effective in obese patients, maybe due to adipocytes being a source of TNF-a.

(c) Adalimumab (Humira): Fully human monoclonal antibody to TNF-a. Slightly more effective than Enbrel in psoriasis and injections are once a fortnight as compared to once a week with Enbrel.

(d) Efalizumba (Raptiva): Recombinant humanized monoclonal to CD11a. Part of the integrin molecule LFA-1 involved in immune cell extravsation. Withdrawn from market due to progressive multifocal leukoencephalopathy (PML)

11. Rapamycin (Sirolimus)

-Macrolide antibiotic like tacrolimus

Mechanism of action: Binds to intracellular immunophilin, FKBP. However, complex does not bind to calcineurin nor does it affect IL-2 gene transcription. Interferes with IL-2 signal transduction pathway, blocking the cell cycle of activated T cells in G1 phase.

-It also competes with tacrolimus for FKBP but their effects are additive.

-Nephrotoxicity and hypertension not serious problems. Hyperlipidemia and ITP responds to reduction in dosage.

12. Future drug developments 

a) Sulphated polysaccharides

-Sulphated glycosaminoglycans (GAGs) such as chondroitin sulphate and heparan are major constituents of cell membranes and extracellular matrix (ECM)

-GAGs represent the endogenous ligand for the sulphated polysaccharide receptors on cells.

*Sulphated polysaccharides, phospho-sugars and the oligosaccharide-processing inhibitor castanospermine represent promising new drugs with a novel mode of action.

Mechanism of action of drugs above: Inhibition of migration across vascular endothelium and entry into tissue parenchyma at sites of inflammation. Prevents the accmuluation of leukocytes in inflammatory foci. The drugs may halt the progression of inflammatory dieases such as rheumatoid arthritis.

b) Immunosuppressants

Brequinar sodium: An anti-metabolite that inhibits de-novo (on the spot) pyrimidine synthesis

Mizoribine: An inibitor of purine synthesis

-Monoclonal antibodies: To cytokines, cytokine receptors and adhesion molecules. There is also the possiblity of inducing specific tolerance to donor antigens by blocking T-cell activation and inducing T-cell apoptosis.

c) Anti-rheumatoid agents

-Cytokine-targeted therapies including anti-TNF-a antibodies, soluble TNF receptor to remove TNF-a.

d) 5-lipooxygenase inhibitors

-Prevents the conversion of arachidonic acid to 5-HPETE. Thus, they prevent leukotriene production. Useful for asthma treatment.

e) Phosphodiesterase inhibitors

-To increase cAMP concentrations in cells thus reducing activation.

Anti-hypertensives Part III (Adrenergic Receptor Antagonists)

*This section will be expanded upon. 

Part 1: Alpha receptor antagonists

(a) Non-selective



(b) alpha 1 selective

Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin, Indoramin, Urapidil, Bunazosin

(c) a2 selective-Yohimbine

1.1 Alpha 1 Receptor antagonists

Mechanism of action: Blockade of alpha 1 adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines. This results in a decrease in BP due to decreased TPR. The magnitude depends on the activity of the sympathetic nervous system. Decreases in BP is smaller in supine position than in upright subjects. Decreases also enhanced by low blood volume.

  • For most a-receptor antagonists, fall in BP is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention.
  • These compensatory reflexes are worsened if the antagonist also blocks alpha 2 receptors on periperal sympathetic neurons which leads to enhanced release of NAdr. Increased stimulation of B1 postsynaptic receptors in the heart and on JGA cells.
  • Since a1 receptors are blocked, the endogenous catecholamines will bind to other receptors (B2 receptors). This triggers vasodilation which means that Adr now becomes a vasodepressor (presor responses are inhibited).

Drug 1: Prazosin (Potent and selective a1 receptor antagonist)-Used frequently in hypertension  

-The affinity for a1 adrenergic receptors is 1000x that for a2 adrenergic receptors.

Mechanism of action:

1. Major effect is that due to the blockage of a1 receptors in arterioles and veins, leading to a fall in TPR and venous return to the heart.

2. Also acts in CNS to suppress sympathetic outflow. ***Prazosin appears to depress baroreceptor reflex in hypertensive patients.

3. *Prazosin and related drugs tend to have favourable effects on serum lipids in humans–>Decreases LDL and triglycerides while increasing concentrations of HDL 

-Decreases cardiac preload and thus have little tendency to increase cardiac output and heart rate (compared to vasodilators which have minimal dilatory effects on veins)

Pharmacokinetics of Prazosin:

-Well absorbed with bioavailability of 50-70% and peak plasma concentration is 1-3 hours after oral dose.

-Prazosin binds with greatest affinity a1-acid glycoprotein (only 5% of the drug is free). Diseases may change the free fraction.

-Extensively metabolised in the liver (plasma half life, 2-3 hours, may be prolonged to 6-8 hours in CHF)

-In treatment of hypertension, the duration of action is 7-10 hours.

Adverse effects:

*First dose effect (marked postural hypotension and syncope which may occur 30-90 mins after initial dose)

-Risk is minimised by limiting the initial dose (e.g. 1mg at bedtime, increasing dosage slowly and introducing additional anti-hypertensive drugs cautiously)

1.2 Alpha 2 Receptor agonists (+)

Mechanism of action: Activation of alpha 2 receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a decrease in BP

Drugs that are a2 receptor agonists: Clonidine and methyldopa (CAT A-AUS) [Methyldopa can be used during pregnancy!]

Note: Yohimbine is an a2 receptor antagonist (Just good to know)

1.3 Non-selective Alpha antagonists

-Phentolamine (‘Non’-Friend told amine). Competitive alpha receptor with similar affinities for a1 and a2 receptors.

Clinical indications: (a) Short term control of hypertension in patients with pheochromocytoma (adrenal tumour producing Adr and NAdr) (b) Useful for treatment of hypertensive cases that follow the abrupt withdrawl of clonidine (c) Sexual dysfunction-Can be administered bucally, orally or intracavernously (injection at the base of the penis) into penis 

1.4 Alpha 1 selective

Part 2: Beta Receptor antagonists [B-blockers can be distinguished by relative specificity of B1 over B2, intrinsic sympathomimetic activity, capacity to block B-receptors, differences in lipid solubility, capacity to induce vasodilation, pharmacokinetic properties] 

(a) Non-selective (first generation)

Propranolol, Pnebutolol, Pindolol, Nadolol, Timolol (3P NoT)

(b) B1 selective (Second Generation)

Atenolol, Acebutolol, Bisoprolol, Metroprolol, Esmolol (ABME) 

(c) Non-selective with additional cardiovascular actions (Third Generation)

Carteolol, Carvedilol, Bucindolol, Labetalol

(d) B1 selective additional cardiovascular actions (Third Generation)

Betaxolol, Celiprolol, Nebivolol

-Additional features of certain b-blockers: 

Carteolol (NO production, beta 2 receptor agonism), Labetalol (A1 receptor antagonist), Carvedilol (Ca2+ entry blockade and antioxidant activity), Betaxolol (Ca2+ channel blockade)

2.1 Mechanism of action: Antagonists inhibits interaction of NAdr, Adr and sympathomimetic drugs with B receptors. Effects of B-adrenergic antagonists may be predicted from the consequences of B-receptor stimulation (due to effects of elevated cAMP) 

*Note: Beta-blockers generally do not reduce blood pressure in patients with normal BP but lower BP in patients with hypertension.

***Reduction of B1-stimulated renin release from JGA cells is a contributing mechanism!!!

-Long term administration of B-blockers to anti-hypertensive patients decresae peripheral vascular resistance.

2.2 Comparison of various B-blockers

-Propranolol interacts with B1 and B2 with equal affinity. No ISA and doesn’t block a receptors.                                               *Hepatic metabolism CYP 1A2, 2C19, 2D6, 3A4. Individual variation in                                                                                                                                                                                                                           hepatic clearance of propranolol contributes to variability in plasma                                                                                                                                                                                                                           concentration (20x) after oral administration. Propranolol readily enters                                                                                                                                                                                                                     the CNS.

-Pindolol is a weak partial B-agonist (ISA). ISA drugs preferred when diminished cardiac activity or bradycardia.                    *Hepatic metabolism by 2D6.

-Metoprolol is a B1-selective antagonist.                                                                                                                                            *Extensive first pass metabolism. Wide variability in t1/2 based on genetic                                                                                                                                                                                                                  differences in 2D6 activity. t1/2 (normally 3-4 hrs) can double in CYP2D6                                                                                                                                                                                                                    poor metabolisers, who have 5x higher risk for adverse effects compared                                                                                                                                                                                                                  to normal metabolisers.

-Atenolol is a B1-selective antagonist.                                                                                                                                                 *Largely excreted by kidneys; dosage should be reduced when creatinine                                                                                                                                                                                                                   clearance is <35ml/min

2.3 Adverse effects and precautions

1. Exacebate heart failure 

2. Bradycardia (life-threatening bradycardia with partial or complete AV conductoin defects). Caution in patients taking other drugs (e.g. verapamil or various anti-arrhythmic agents which may impair sinus node function or AV conduction)

3. Raynaud’s syndrome-Cold extremities while taking B-blockers

4. Increased response after abrupt B-blocker withdrawal

5. Blunt recognition of hypoglycemia and delayed recovery from insulin-induced hypoglycemia

6. Depression, sleep disturbances, fatigue

7. Bronchoconstriction

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)


Part 1: NSAIDs


Prostaglandin, Leukotriene pathway

-COX 1, COX 2 and COX 3 genes are all present

-These genes (COX 1 and 2) essentially code for the two different enzymes/proteins. They are isoforms/isoenzymes of each other but catalyze essentially the same reaction.

Function of COX-1:

-always present in most cells throughout the body (constitutive) and catalyzes the formation of PGs involved in physiological processes

-In the stomach, COX-1 catalyzes the synthesis of PGE2, PGI2 which has cyto-protective actions and maintains the lining of the gastrointestinal mucosa.

Function of COX-2:

-Inducible (capable of being formed/activated) isoform found mainly in inflammatory and immune cells (neutrophils, macrophages, mast cells)

-Pro-inflammatory cytokines (INF) and growth factors induce COX-2.

-The making of COX-2 is triggered by exposure of inflammatory cells to certain stimuli (endotoxin, interferon, cytokines/IL-1)

-The making of COX-2 is inhibited by steroids and IL-4.

1. Thus, it may play a role in cell growth and will cause inflammation.

2. Hyperalgesic and proinflammatory prostaglandins production. COX-2 is responsible for generation of hyperalgesic and pro-inflammatory PGs (namely PGI2 and PGE2).

3. Colon Cancer.

-COX-2 is strongly expressed in human colon cancer cells

***NSAIDs are believed to delay the progress of colon tumors progression (by apoptosis)

***NSAIDs also reduces the risk of developing Alzhemier’s disease which is thought to involve an inflammatory component (chronic use of NSAIDs reduces risk)

4. Induce fever and transmission of pain.

-COX-2 are also present constitutively (always there) in the CNS (central nervous system).

-Thus it may be involved in fever and nerve transmission of pain.

5. Ovulation and Birth processes.

-Prostaglandins catalysed by COX-2 are also involved in ovulation and birth processes (Myometrial contraction)


1.1 Generations of NSAIDs

-Traditional NSAIDs include aspirin, ibuprofen (Advil, Motrin, etc.), naproxen (e.g., Aleve) and many other generic and brand name drugs. A newer NSAID is celecoxib (Celebrex), which doctors call a “COX-2 inhibitor” or a “COX-2 selective” NSAID.

1.2 Mechanisms of NSAIDs

-NSAIDs exert their actions primarily by inhibiting the production of Prostaglandins (PGs)

-Although there is no common structural motiff, the mechanism of NSAIDs would be to inhibit COX (cyclooxygenase)

1.3 Effects of NSAIDs


1. Anti-pyretic (Reduce temperature)

-Normal body temperature is regulated in the hypothalamus.

-During an inflammation, bacterial endotoxins causes the release of IL-1, IL-6 from macrophages. These cytokines are considered pyrogens which means it causes fever.

-These cytokines cause the generation of prostaglandins in the hypothalamus which causes the elevation of set-point for temperature.

***NSAIDs block the production of these prostaglandins thus normal temperature is not affected by NSAIDs.

2. Analgesic (Reduces Pain)

-When tissues are inflamed/damaged, pain is usually associated.

***NSAIDs decrease the production of prostaglandins that sensitize nociceptors to inflammatory mediators such as bradykinin.

-They are effective against pain of mild to moderate intensity in conditions such as:

Arthritis, bursitis, pain of muscular and vascular origin, toothache, dysmenorrhea, pain of post-partum states and pain of cancer metastases in bone.

Definition: Bursitis (Inflammation in one or more burses/sacs of synovial fluid in the body)

All the conditions mentioned above are associated with increase prostaglandin synthesis.

Note: Their maximum efficacy is much lower than opioids in relieving pain however, they do not cause addiction/dependence.

Note: When used in combination with the opioids, they may decresae post-operative pain while reducing the requirement for opioids by up to 1/3.

3. Anti-inflammatory

-NSAIDs affect those components of the inflammatory and immune response in which the byproducts of COX-2 play a major role.

  • Vasodilation
  • Oedema (by an indirect action in which vasodilation facilitates and potentiates the action of mediators such as histamine which increases permeability of post-capillary venules.
  • Pain (analgesic effects-Refer to (b))

NSAIDs may have complex inflammatory effects that may be deterimental:


1. NSAIDs may enhance the production of pro-inflammatory cytokines such as TNF by preventing the negative feedback of prostaglandin E. TNF causes sudden onset of shock and organ failure.

2. Impair oxygen dependent killing activities of neutrophils. This is associated with the use of ibuprofen but not flurbiprofen or indomethacin.

3. NSAIDs could exacerbate tissue damage in the long term.

-Some prostaglandins (PGI and PGE) reduce the generation of oxygen radicals, decrease lysosomal enzyme release and inhibit lymphocyte activation.

-Using NSAIDs to inhibit production of these prostaglandins will have opposite effects.

-This is found in Osteoarthritis patients prescribed with a strong COX inhibitor (indomethacin) as compared to a weaker inhibitor (azapropazone).


4. Platelet inhibitory effects

-Platelet function is affected because Thromboxane A2 production is prevented.

-This effect can be used to prevent vascular occlusion or platelet aggregation.

*Low dose Aspirin is the drug of the choice.


5. Prolongation of gestation and labour

-Prostaglandin synthesis (esp. PGF2) by the uterus increases substantially in the hours before parturition (childbirth).

*Inhibition of prostaglandin synthesis (e.g. by indomethacin) prolongs labour or prevents pre-mature labour.


1.4 Side effects of NSAIDs

1. Gastrointestinal disturbances.

*Massive GI bleeding (due to inhibition of prostacyclins which has protective gastrointestinal effect), Stomach Ulcers

-Mucosal prostaglandins inhibit acid secretion and has a cytoprotective effect by promoting the secretion of mucus.

-Inhibition of prostaglandin synthesis by inhibition of COX-1 is believed to account for erosions, ulcerations due to NSAIDs.

Toxicity is relative to anti-inflammatory effect (thus the least toxic NSAID is paracetamol) (most toxic drugs being azapropazone and piroxicam)

Note: Prophylatic use of a prostaglandin analogue such as misoprostol is advisable.


2. Skin Reactions (2nd most common side effect)

Mild Rashes, Urticaria (hives) and photosensitivity reactions. More serious and potentially fatal diseases occur but are rare.

*Occurs especially with Mefenamic acid (10-15%)and Sulindac (5-10%). 


3. Severe rhinitis and asthma

-In some susceptible patients exposed to NSAIDs (particularly aspirin)


***4. Acute Renal failure

Three types of effects of NSAIDs on renal function.

(a) Renal Blood Flow (Perfusion decreases)

*Synthesis of PGI2 and PGE2 inhibited (which functions as vasodilators)

-Insignificant in healthy individuals but can be severe in those already with renal disease affecting blood flow and Glomerular filtration.

(Elderly, pre-existing renal conditions, hepatic cirrhosis, cardiac failure, diuretic therapy)

-Acute Renal Impairment occurs upon starting the drug, however effects are reversible if treatment discontinued promptly.


(b) Allergic type interstitial nephritis

-Rare but Severe

-Manifests itself as acute renal failure  accompanied by proteinuremia (loss of proteins in urine)

-Frank Nephrotic Syndrome may occur (Heavy Proteinuria, Hypoalbuminia, Edema)

Note: Fenoprofen is likely to cause such renal damage!


(c) Analgesic nephropathy

-Mixtures of NSAIDs taken repeatedly cause severe and irreversible renal damage (esp. chronic interstitial nephritis, renal papillary necrosis and acute renal failure)

-Effects due partially to -Ischemia through inhibition of locally produced prostaglandins which as vasodilators.

-People who take high doses tend to exhibit analgesic nephropathy.

Note: Phenacetin likely to cause analgesic nephropathy (Paracetamol and NSAIDs also found to do so)

*** When NSAIDs are used in joint diseases (requires fairly large doses and prolonged use), there is a high incidence of side effects.



Part 2: Salicylates and Aspirin

Properties of these drugs:

-Aspirin (acetylsalicylic acid) and Salicylic Acid

-Aspirin itself is relatively insoluble but its calcium and sodium salts are readily soluble. Methylsalicylate is used topically in liniments.


Drug 1: Aspirin

(a) Mechanism of action of aspirin:

***Aspirin is unique among NSAIDs because it irreversibly inhibits COX by acylating the active site of the enzyme.

-By inhibiting COX, it prevents the formation of products including thromboxane, prostacyclin and other prostaglandins.

-Highly protein bound (95%)

Thus, the duration of action is not directly related to plasma concentration because of its irreversible nature of action.


(b) Therapeutic Effects

1. Anti-platelet effects

-Platelets (no nucleus) cannot regenerate the COX enzyme as nucleated cells can. This means that thromboxane production will only resume after new platelets are made and released into circulation (life-span around 8 days)


***Therapeutically: This means that anti-platelet effect can be readily achieved with low doses.

Indications: It is used primarily to decrease the risk of arterial thrombosis in patients who had suffered myocardial infarction or severe artherosclerosis.

It is also used post-coronary artery bypass, angioplasty or stenting (life time use) and in patients with a tendency to suffer thrombotic stroke.


2. Colon Cancer

-Sustained use of aspirin reduces the risk of colon cancer.


(c) Side Effects

  • Local effects

1. Gastrointestinal effect (Focal erosive gastritis-gastric mucosal erosion caused by damage to mucosal defenses).

-Bleedings also occur which is worsened by anti-platelet effects.

  • Systemic effects

2. Salicylism (Aspirin poisoning) can occur due to repeated ingestion of large doses. This syndrome consists of tinnitus, vertigo, decreased hearing and sometimes nausea and vomitting.

3. Skin rashes

4. Worsening of asthma in aspirin-sensitive individuals (inhibition of vasodilating prostaglandins)

5. Reye’s Syndrome

-Aspirin is contraindicated in children below 12 years of age.

-Brain (severe encephalitis occurs) and liver (fatty liver) affected.

-Usually occurs after a viral infection (Influenza) and has a mortality of 20% to 40%.


6. Altered Acid-Base and Electrolyte balance

-Lead to compensated respiratory alkalosis, uncompensated respiratory acidosis and metabolic acidosis (aspirin dessociates in blood to release H+)


Metabolic acidosis: occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body

Respiratory alkalosis:  increased respiration (hyperventilation) elevates the blood pH

Compensation: Drop in Bicarbonate ion concentration due to the need to neutralise excess H+


(d) Drug interactions

*Potentially hazardous increase in effect of warfarin. Aspirin displaces it from plasma proteins and partly because of its anti-platelet effect.

-Aspirin on its own reduces urate secretion. It interferes with uricosuric agents such as probenacid.

*Should not be used in gout.


Drug 2: Paracetamol

-Its analgesic efficacy is equal to that of aspirin but only has mild anti-inflammatory effects (at therapeutic doses).

(a) Mechanism of action: Inhibits prostaglandin synthesis in the brain (COX-3) but hardly at all in the periphery. Does not affect platelet function.


(b) Metabolism of paracetamol (Normally and Overdose)

Step 1: Normally inactivated in the liver by conjugation as glucuronide (Phase II) and sulphate.  However, with higher doses, the enzymes for these pathways are exhausted.

Step 2: The mixed function oxidases take over and convert paracetamol to the toxic metabolite N-acetyl-b-benzoquinone imime. 

Step 3: With higher doses of paracetamol, glutathione is depleted and toxic intermediate accumulates

Step 4: This toxic intermediate binds to macromolecules in the cells causing death. Liver failure occurs.

Note: Agents which stimulate glutathione production (e.g. acetylcysteine or methionine) can prevent liver damage if given early.


(c) Side effects:

-Fatal liver and renal damage at toxic doses (2-3x maximum therapeutic dose) can cause serious, potentially damages.


Drug 3: COX-2 specific inhibitors

-It was hypothesised that the undesirable side effects of NSAIDs such as gastric erosion and renal dysfunction are due to inhibition of COX-1

-The anti-inflammatory (therapeutic) effects are due to inhibition of COX-2.

-Inhibitory potency and selectivity of the 1st generation NSAIDs (refer to 1.1 for NSAID classes) for COX-1 and COX-2 vary greatly

Side note: Some NSAIDs (ketoprofen) are relatively COX-1 selective, some (ibuprofen and naproxen) are essentially non-selective, while others (diclofenac) are selectively to COX-2.

Side Note: Inhibitory effects of NSAIDs on gastric PG synthesis correlate with COX-1 inhibitory potency in blood and with COX-1 selectivity but not with COX-2 inhibitory potency (i.e COX-2 affinity does not affect gastric PG synthesis but COX-1 does)

-However. even COX-2 selective NSAIDs still had sufficient anti-COX 1 activity to cause potent inhibition of gastric PG.

-Thus, at therapeutic concentrations, none of NSAIDs spare gastric COX-1 activity.

-In general, NSAIDs have a comparable efficacy but different safety profiles due to their differences in ability to inhibit COX-1 at therapeutic doses.

∴ We can evaluate NSAID selectivity by comparing their IC50 values (i.e. drug concentration at 50% inhibition of enzyme)

Drug selectivity= (COX-2 IC-50)/ (COX-1 IC-50)

-Smaller ratio indicates that the drug is more selective towards COX-2 (because smaller value of COX-2 means higher affinity)


  • Celecoxib (Highly COX-2 selective~375 times)

-Indications: Rheumatoid and osteoarthritis

-At therapeutic doses, its plasma concentration does not reach the level required for COX-1 inhibition.

-In clinical trials, celecoxib showed effective anti-inflammatory activity with virtually no gastrointestinal adverse effects (compared to placebo)

  • Rofecoxib (withdraw from market)

-Prostaglandin I2 was previously shown to be main cyclooxygenase product in endothelium (inhibits platelet aggregation, causing vasodilation, preventing the proliferation of vascular smooth muscle cells (in. vitro)

-Thus, it was assumed that PGI2 was derived mainly from COX-1 which was found constitutively in endothelial cells.

However, this assumption was incorrect. COX-2 was the dominant source and may result in cardiovascular events. Further Explained below.

∴Point to note,  PGI2 comes primarily from COX-2


Cardiovascular effects:

-Thromboxane A2 is produced from COX-1 (Recall prostaglandin pathway)

-Thromboxane A2 has prominant effects in blood and vessels (Promotes Platelet aggregation, vasoconstriction and vascular proliferation).

-The cardiovascular effects of PGI2 (in vitro) contrast with the effects of Thromboxane A2 (i.e PGI2 inhibits platelet aggregation, has vasodilation effects).

Aspirin and traditional NSAIDs inhibit both thromboxane A2 and prostaglandin I2.


Explanation why cardiovascular risk is higher:

-COX-2 selective inhibitors prevent PGI2 production in endothelial cells (express COX-2). However, it does not affect platelet’s thromoboxane A2 production.

-However, the coxibs leave the thromboxane A2 generation unaffected due to the lack of COX-2 in the platelets. 

-This reduces PGI2 levels in comparison to Thromboxane A2 (COX-1 unaffected, very minimal Cox-2 present).

-Thus the protective anti-coagulative effect of PGI2 is decreased.

-Without this protective anti-coagulative property, there is an increase risk of thrombus, myocardial infarction and ciruclatory problems.

-Thus in a single action of depressing PGI2 formation results in the,

1. elevation of blood pressure

2. acceleration of atherogenesis

3. Patients receiving coxibs are more likely to have an exaggerated thrombotic response when atherosclerotic plaque ruptures.

*Selective inhibitors of COX-2 remain a rational choice for patients at low cardiovascular risk who had serious gastrointestinal events, especially while taking traditional NSAIDs.

*Avoid Coxibs in patients who have cardiovascular disease or are at risk.



Pharmacological treatment of angina-Part II (Calcium channel blockers)

Tissue definitions:

Striated muscle: Voluntary Skeletal muscle, Cardiac Muscle

Smooth muscle: Involuntary-blood vessels, gut, uterus

Peripheral Blood vessels: Vessels that are outside the heart and brain in the systemic circulation (e.g. carotid artery–>Supplies blood to brain, renal artery, femoral, illiac arteries)

Read more: http://www.wisegeek.com/what-is-peripheral-circulation.htm


(a) Introduction

-Voltage sensitive Calcium channels (L-type) mediate entry of extracellular Calcium ions into smooth musclecardiac myocytes and SA, AV nodal cells in response to electrical depolarisation.

-In both smooth muscle and cardiac myocytes, calcium ions is a trigger for contraction.

-Calcium channel antagonists, inhibit Calcium channel function.


  • In smooth muscles, this leads to relaxation, especially in arterial beds
  • These drugs may also produce negative inotropic (decrease force of contraction) and chronotropic (decrease frequency/HR) effects in heart


Types of calcium channel blockers (CCBs) approved for clinical uses:

-Phenylalkylamines, dihydropyridines, benzothiazepines, diphenylpiperazines and one diarylaminopropylamine

Verapamil (phenylalkylamine)

Diltiazem (Benzothiazepines)–>Both cardiac and periphery

Mibefradil –>Non Selective


*Commonly used CCBs: Verpamil, Diltiazem, [Amlodipine, Nifedipine, Felodipine, Nimodipine-All DHPR]


Note: Although all of them bind to the a1 subunit of the L-Type calcium chanels and reduce calcium influx, there are fundamental differences amongst verapamil, diltiazem and DHPR

-Differences include pharmacological characteristics, drug interactions and toxicities


(b) Mechanisms of action of CCBs:

1. All CCBs relax arterial smooth muscle, with little effect on most venous beds so they do not affect cardiac preload significantly

***The marked peripheral vasodilation can be seen with DHPR (accompanied by robust baroreceptor-reflex mediated increase in sympathetic tone).


2. In cardiac muscle, CCBs can produce a negative inotropic effect (Decrease in force) and negative chronotropic effect.

-Sympathetic tone: Rate of firing of sympathetic neurons


3. In the SA and AV nodes, depolarisation depends predominantly on Calcium ions movement through the slow L-type channel.

*Compared to DHPR, verapamil not only reduces the magnitude of calcium current through L-type channels but also decreases the rate of channel recovery.


Verapamil and diltiazem depresses the rate of SA pacemaker firing and slows AV conduction–> Thus it can be used to treat supraventricular tachyarrhythymias.



(c) Unique properties of each class


  • Dihydropyridines (DHPR)

-Nifedipine (prototype DHPR) [Selectively dilates arterial resistance vessels]

-The decrease in arterial blood pressure elicits baro-receptor mediated sympathetic reflex which results in tachycardia and positive inotropy

However, this increase in heart contractility is not suficient to compensate for the vasodilation.


  • Other DHPRs (amlodipine, felodipine, Nicardipine, Nimodipine)

-Similar cardiovascular effects with nifedipine

Amlodipine–>Less reflex tachycardia, possibly due to its long t1/2 (35-50 hrs) which produces minimal peaks and troughs in plasma concentrations.

*These DHPRs do not cause myocardial depression and lack negative chronotropic effects, thus they are less effective in monotherapy (only drug used) of stable angina.

For Stable angina, Verapamil, diltiazem or a B-adrenergic antagonist is preferred.

Nimodipine–>Lipid soluble and can be used to relax cerebral vasculature (Enters BBB)

-Effective in inhibiting cerebral vasospasm and can be used to treat patients with  neurological defects associated with cerebral vasospasm after subarachnoid hemorrhage.


  • Verapamil and Diltiazem

Although verapamil does cause vasodilation, reflex tachycardia is blunted or abolished by the negative chronotropic effects on the heart.

Verapamil reduces peripheral vascular resistance (↓TPR) and blood pressure (↓BP) with minimal changes in heart rate


-In patients with congestive heart failure (occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body), IV verapamil can cause a marked decrease in contractility and left ventricular function–>Worsens condition.


-Relief of exercise induced angina (Stable angina) seen with verapamil is due primarily to a reduction in oxygen demand.


Diltiazem  decreases both heart rate (modest negative chronotropic effects) and mean arterial blood pressure. 


Summary (Point to note): While both drugs produce similar effects on the SA and AV node, the negative inotropic effect of diltiazem is smaller. Thus decrease in heart rate is observed.



(d) Metabolism and Pharmacokinetics of CCBs

1. First-pass metabolism and absorption. Although absorption of these drugs are high, bioavailability is significantly reduced by first pass hepatic metabolism.

2. Onset of action. Effects are evident within 30-60 mins of an oral dose, with the exception of slowly absorbed and longer acting agents (amlodipine and felodipine) or slow release formulations (nifedipine)

3. Protein binding. All CCBs are extensively to plasma proteins. Half lifes vary widely.

4. Hepatic metabolism. Repeated oral administration will increase bioavailability and t1/2 due to saturation of hepatic  metabolism (CYP 450-used up)

(a) Diltiazem metabolism. Major Metabolite of diltiazem is desacetyldiltiazem which has only half the potency of diltiazem as a vasodilator.

(b) Verapamil metabolism. N-demethylation of verapamil results in the production of norverapamil (t1/2-10 hours) which is biologically active but much less potent than the parent compound.

(c) Metabolites of DHPR are inactive or weakly active.


*5. Patients with cirrhosis (liver damage where healthy cells are replaced by scar tissue). Bioavailabilities and half lives of CCBs  may be greatly increased due to lack of CYP450 enzymes. Dosage should be decreased accordingly.

*6. Elderly patients. Half lifes of these agents may be longer in them.

7. Racemic mixtures. With the exception of diltiazem and nifedipine, all CCBs are administered as racemic mixtures (equal amounts of enantiomers).



(e) Adverse Reactions of CCBs

-The most common side effects caused by CCBs, esp. the DHPR, are due to excessive vasodilation:

1. Dizziness, Headache, Flushing

2. Nausea/Gastroseophageal reflux-induced nausea (Physiologically, nausea is typically associated with decreased gastric motility and increased tone in the small intestine) + (often reverse peristalsis in the proximal small intestine)

-CCBs inhibit contraction of lower oseophageal sphincter, reflux occurs

3. Hypotension

4. Constipation (Smooth Muscles relax-Peristalsis does not occur) [Common side effect of verapamil]

5. Gingival hyperplasia

6. Peripheral oedema

7. Pulmonary oedema

8. Wheezing

9. Coughing

10. Worsened myocardial ischemia (due to nifedipine) especially with immediate release formulations.

  • May result from excessive hypotension and decreased coronary perfusion.
  • Coronary steal. Selective coronary vasodilation in non-ischemic regions when the ischemic regions are already maximally dilated, maximum perfusion already.
  • Increase in sympathetic tone and reflex tachycardia


(f) Drug interactions/Contraindications/Important Considerations

***Very Important: IV verapamil with a Beta blocker is contradindicated because of AV block and/or severe depression of ventricular function.

-Patients with ventricular dysfunction, SA or AV nodal conduction disturbances (Refer to mechanisms of action, Part C) or systolic blood pressures <90mmHg should not be treated with verapamil or diltiazem

-Concerns about the long-term safety of short-acting nifedipine because of abrupt vasodilation with reflex sympathetic activation.

-If sustained-release forms of nifedipine were used, there is no long-term adverse outcomes associated nor significant reflex tachycardia.

-With longer half life CCBs with favourable pharmokinetics (e.g. amlodipine or felodipine), there is less abrupt vasodilation, baroreceptor reflex less likely to be invoked.

Recommended drugs for various conditionsRecommended drugs for various conditions part 2

Refer to pg 9: Treatment of Angina Lecture Notes

Refer to pg 12: Treatment of Hypertension with CCBs


(g) Mechanopharmacological therapy: Drug-eluting Endovascular stents

Taxus stent FDA.jpg

  • Intracoronary stents: Scaffold that is placed into narrow, diseased vessels however no drug is released.

Major Drawback: Long term efficacy is limited by the subacte luminal restenosis within the stent (in-stent restenosis)

Possible causes: Smooth muscle proliferation within the lumen


Led to the development of drug-eluting endovascular stents

  • Drug eluting Endovascular stent: A peripheral/coronary scaffold placed into narrow, diseased peripheral/coronary arteries that slowly releases the drug to block cell proliferation and prevent fibrosis as well as clots.

Function: Ameliorate angina and reduce adverse events in patients with acute coronary syndromes.

*With concurrent local anti-proliferative therapies, drug-eluting stents can be really beneficial in clincal practice.


  • Two drugs used in intravascular stents: Paclitaxel and Sirolimus (rapamycin)


Paclitaxel Drug Profile:

Cytotoxic drug used in the treatment of cancer

-Anti-proliferative drug.

Mechanism: Inhibits cellular proliferation by binding to and forming rigid polymerized microtubules, thereby preventing cell division.


Sirolimus/Rapamycin Drug Profile:

Immunosuppresent/Antibiotic drug used in the treatment of autoimmune diseases, prevents tissue rejection in organ transplants


Mechanism: Binds to cytosolic immunophillin (FKBP 12). The FKBP-12 sirolimus complex inhibits the protein kinase mTOR, thus inhibitng cell cycle progression.

-Link to Pharmacology B: Lecture Immunosuppressants


*Immunophilin: endogenous cytosolic peptidyl-prolyl isomerases that interconvert between the cis and trans positions

*FKBP12:  binds the immunosuppressantsFK506 (tacrolimus) and rapamycin (sirolimus)

Note: Inhibition of cellular proliferation by sirolimus and paclitaxel not only affects vascular smooth muscle cell proliferation but also weaken the formation of an intaact endothelial layer within the stented artery



Important considerations of stents:

1. Stents might induce damage to the vascular endothelial layer. This leads to thrombosis. 

-To prevent thrombosis, patients are treated with anti-platelet agents, including Clopidogrel (up to 6 months) and aspirin (for life)

-Sometimes used in conjunctoin with IV administered GPIIB/IIIa inhibitors (class of antiplatelet medications)–>Includes Abciximab, Eptifibatide, Tirofiban


Note: Inhibition of cellular proliferation by sirolimus and paclitaxel not only affects vascular smooth muscle cell proliferation but also weaken the formation of an intaact endothelial layer within the stented artery.

Thus, anti-platelet therapy is continued for several months after intracoronary stenting with drug-eluting stents.

-Rate of restenosis with drug-eluting stents is reduced greatly compared to bare metal stents (However, there is an increased risk of thrombosis especially if anti-platelet therapy is stopped prematurely.)




Immunology: Anti Rheumatoid and Gout Drugs

Anti-Rheumatoid and Gout Medication

1. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

2. DMARDs (Disease modifying anti-rheumatic drugs)

3. Immunosuppressants (Azathioprine and Cyclosporin)

4. Glucocorticoids

5. Cytokine-targeted drugs

Pharmacology of NSAIDs:

-Reduce symptoms of disease but do not retard its progress. May make it worse.

-Release of lysosomal enzymes, the generation of toxic oxygen radicals and lympocyte activation are all controlled by prostaglandins (PGE2, PGI2)

-NSAIDs have also been shown to increase the production of inflammatory mediators such as IL-1

  • Thus the long term use of NSAIDs could exacerbate tissue damage
  • Arthritis progressed more rapidly with a strong COX inhibitor than a weak one

DMARDs–>A.K.A Slow Acting Anti-rheumatic Drugs/SAARDs

-Some of these drugs change the course of disease by retarding the structural damage to joint as well as reducing inflammation

-Often mechanism of action is not known.

  • DMARDs

1) Sulphasalazine

-First line choice of DMARD

(A) Introduction

-Can produce remission in active rheumatoid arthritis (RA), can also be used in chronic inflammatory bowel disease

-Doses used in RA are greater than those normally used in bowel disease. Thus side effects more likely.

*** Drug is often a combination of sulphonamide with its salicylate. It is split into its component parts by bacteria in the colon.

Mechanism of action is unclear-However, 5-amino salicylic acid produced in the colon is a toxic scavenger for free oxygen radicals produced by neutrophils


(B) Adverse effects

1. Gastrointestinal disturbances (Because drug is split into active metabolite in the GIT)

2. Malaise

3. Headache

4. Skin reactions and leukopenia (lack of leukocytes) can occur but are REVERSIBLE upon the stopping of drug

5. ***Impaired folic acid absorption neccessitating folic acid supplement (necessary for DNA synthesis)

-6. Decreased Sperm counts

7. Blood diseases such as aplastic anemia, agranulocytosis, absence of leukocytes, Megaloblastic anemia, purpura, thrombocytopenia (lack of platelets), hypoprothrombinemia, methemoglobinemia, congenital neutropenia, myelodysplastic syndrome.

8. Anaphylatic type reactions may occur in some patients

Nevertheless, it is a front-line drug used in the treatment/remission of RA.

  • GOLD compounds (includes salts)

-Used in patients whom diagnosis of RA has not been made, preferentially before any deformities have occurred

*Used in conjunction with anti-inflammatory analgesics (NSAIDS)

*Those with a high titre of Rheumatoid factor (RF) [This is an antibody IgM made against IgG] would tend to respond better

Sodium aurothiomalate (inj)

Auranofin (oral)

Aurothioglucose (inj)

(a) Mechanisms of action: (9 Pathways)

-Exert Anti-inflammatory, anti-analgesic, immunomodulating actions by modifying a variety of cellular and humoral immune response

***Inhibits mitogen-induced lymphocyte proliferation

-Reduce release and activity of lysosomal enzymes

-Decrease the production of oxygen radicals by phagocytes

-Inhibits the chemotaxis of neutrophils

-Reduce the release of mast cell mediators

-Release of serum immunoglobulins

-Reduce titre of RF in RA

-Auranofin but not aurothiomalate inhibits the induction of IL-1 and TNF-a

(b) Pharmacokinetics aspects:

Sodium aurothiomalate (i.m.) or aurofin (p.o)  are most commonly used

-Oral form is less effective but causes fewer and less side effects

-t1/2 is 7 days initially but increases with treatment, so drug is usually given weekly at first and then monthly subsequently.

-Distribution is wide (not only in inflammed synovium) but also in tissue macrophages, kidney and liver.                                                                   

-Gold remains in tissues some time after treatment is stopped with excretion being mostly renal but also GIT

(c) Adverse effects

-Serious toxic effects occur 1 in 10 (10%)

-If therapy is stopped early when symptoms occur, the incidence of toxic effects is relatively low.

1. Skin rashes

2. Proteinuria (Excess protein excreted in urine-Indicates microglomerular capillaries damaged)

3. Mouth Ulcers

4. Decrease in white blood cell number

5. Decrease in platelet number

6. Encephalopathy (Inflammation of brain membrane), peripheral neuropathy and hepatitis may occur

****Note: Treatment of serious adverse effects would be chelating agents such as Dimercaprol. 

  • Penicillamine (Dimethylcysteine)

-Dimethylcysteine is one of the substances produced by hydrolysis of penicillin. It is an effective chelator of many metals and is valuable in poisoning.


(a) Mechanisms of action: Mode of action is unclear

-75% of patients with RA respond to penicillamine

-Main response is not seen for several months!!!

-Purported mechanism:

Reduces RF and concentration of immune complexes in the plasma and sinovial fluid. Reduction of IL-1 generation and partly by preventing the maturation of newly synthesised collagen. 

Indications: The drug is a powerful chelating agent–>Thus, used in cases of heavy metal toxicity (Pb+ poisoning, Hg poisioning). Also used to treat Wilson’s disease (accumulation of copper in liver, kidneys and brain)

(b) Adverse effects

-Seen in 40% of patients treated and may require immediate cessation of therapy

1. Anorexia, nausea, vomitting

2. Disturbances in taste (zinc levels decrease)

3. Proteinuria in 20% of cases

4. Rashes and stomatitis (mouth ulcers)

5. Drop in platelet no. (thrombocytopenia)

6. Drop in white blood cell no. (Leukopenia), Aplastic anemia (Decrease in number of RBC and WBC, suppression in bone marrow)

***Should NOT BE GIVEN WITH GOLD COMPOUNDS  as it is a metal chelator

  • Chloroquine

-Anti-malarial drug

-Chloroquine has anti-inflammatory and immunomodulatory effects for Rheumatoid disease.

-Relatively non-toxic and achieves good response in 50% of patients

(a) Mechanism of action:

-Inhibits mitogen-induced lymphocyte cell proliferation

-Decreases leukocyte chemotaxis

-Decreases lysosomal enzyme release (concentrated in the lysosomes of phagocytic cells such as macrophages and interferes with the action of acid hydrolases stored there)

-Decreases generation of toxic oxygen radicals which induces respiratory burst

-Reduces the generation of IL-1

(b) Adverse Reactions

Accumulates in many organs (ESP. Eye)

1. Where it causes retinal damage that can be irreversibly damaged (for those on prolonged, high dose therapy), DISTURBANCES in vision, Difficulty in reading words

-In practice when used to treat RA, this occurs very rarely.

  • Methotrexate **** (VERY CRUCIAL DRUG) and Trimetoprim

-Folic acid antagonist which has immunosuppressing properties.

Indications for Methotrexate: Also used as a cytotoxic in cancer therapy and in treatment of severe psoriasis


(a) Mechanisms of action:

-Methotrexate inhibits dihydrofolic acid reductase (DHFR)

-Structurally similar to Folic acid

-Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of one-carbon groups in the synthesis of nucleotide and thymidylate (see below).

-No purines or thymidine formed since DHFR enzyme blocked. (Both trimethoprim and methotrexate work here)

Methotrexate impedes DNA synthesis, repair and cellular replication

Thus, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, bucal and intestinal mucosa, urinary bladder cells are more sensitive to this effect. 

When cell proliferatoin in malignant tissues is greater than normal tissues,  methotrexate may impair malignant growth but no damage to healthy tissues

Mechanism in RA: Unknown but might affect immune function

*Effects of methotrexate on articular swelling and tenderness can be seen as early as 3-6 wks.

*No clear evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect demonstrated on bone erosions and radiologic changes (deformity, joint impairment)

(b) Adverse effects

1. Ulcerative stomatitis

2. Leukopenia

3. Nausea

4. Abdominal distress

5. Other side effects (malaise, undue fatigue, chills and fevers, dizziness)

6. Decreased resistance to function/Increased susceptibility to viral/fungal/bacterial infections

-Pneumocystis carnii pneuomnia, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex etc

***7. Pulmonary system: Interstitial pneumonitis deaths have occurred. Chronic Interstitial obstructive pulmonary disease has occurred. Pulmonary fibrosis (excessive connective tissue made in lungs) can be a problem with long term use.

Incidence occurance: Elevated liver functions test (15%), nausea/vomitting 10%, Stomatitis 3%. Thrombocytopenia 3%,







-This is a metabolic and genetic disease due to an overproduction of purines (DNA) which leads to production and accumulation of uric acid.

-Characterised by intermittent attacks of acute arthritis produced by deposition of sodium urate crystals in the synovial tissues of joints (refer to top)


***Inflammatory response is invoked

–>Activates kinin, complement and plasmin system

–>Generation of lipo-oxygenase products (LTB4) + Local accumulation of neutrophils

–>These products/cells engulf the crystals by phagocytosis which causes generation of tissue-damaging toxic oxygen metabolites.

–>Lysis of cells with proteolytic enzymes occur

–>Urate crystals also induce production of IL-1,  TNF-a, IL-5, IL-6




***Certain drugs may influence the development of gout by causing:


(a) Overproduction of urate:

Why? Due to excessive cell destruction releasing nucleic acids. Excessive cell destruction occurs when myeloproliferative or lymphoproliferative disorders (e.g. leukemias) are treated with cytotoxic drugs.

(b) Underexcretion of urate:

-Caused by most Diuretic (Link to hypertension-THA), Aspirin (Link to NSAIDs lecture), alcohol and a rise in blood lactic acid that inhibits tubular secretion of urate.


(c) Diet may also cause development of gout. Purines are present in significant amounts that inhibits tubular secretion of urate.

-Patients should avoid excesses of foods that contain purines e.g. sweetbread, kidney and liver.

-Gout prone patients tend to be overweight and loss of weight lowers the plasma urate



Common Mechanisms by which Gout is reduced/treated: 

Mechanism 1: By inhibiting uric acid synthesis (allupurinol/Zyloprim) 

Mechanism 2: By increasing uric acid excretion (uricosuric agents: Probenacid and sulphinpyrazone)

Mechanism 3: By inhibiting leukocyte migration into joint (Colchicine)

Mechanism 4: By generating anti-inflammatory and analgesic effects (NSAIDS, corticosteroids either orally or injected into joint)


Mechanism 1: Inhibiting uric acid synthesis (Allopurinol)

-Inhibits synthesis of uric acid by inhibiting xanthine oxidase enzyme. It is an analogue of hypoxanthine and inhibits enzyme competitively

Allopurinol is readily absorbed from gut and metabolised in the liver to alloxanthine (xanthine oxidase inhibitor)

Allopurinol reduces concentration of relatively insoluble urates and uric acid in tissues while increasing the concentration of more soluble xanthines and hypoxanthines. Deposition of urate crystals in tissues is reversed and formation of renal stones is inhibited.


***Thus, allopurinol is a drug of choice for long term gout, but ineffective for acute gout attack and may make it worse!!!


Allopurinol Pharmacokinetics:

Given orally, well absorbed in GIT, half life is 2-3 hours, converted to alloxanthine which has t1/2 of 18-30 hours. Renal excretion is a balance between Glomerular filtration and probenacid-sensitive tubular reabsorption.


Allopurinol Adverse effects:

1. May cause acute gout. Why? Negative feedback mechanism???

2. Allergies

3. GIT disturbances


****Allopurinol drug interactions:

1. Prevent oxidation of active drug Mercaptopurine to an inactive metabolite (This Mercaptopurine is an anti-metabolite used in cancer chemotherapy–>This combination of drugs lead to dangerous potentiation)

2. Allopurinol  also potentiates effect of immunosuppressant azathioprine, anticancer drug cyclophosphamide  and oral anticoagulants (e.g. Warfarin)


Mechanism 2: Increased excretion of uric acid in kidneys (Probenacid and Sulphinpyrazone)





-Increase uric acid excretion by a direct action on renal tubule (competitively inhibits uric acid reabsorption in the proximal convoluted tubule) 

Probenacid and sulphinpyrazone


(a) Probenacid mechanism of action:

-Competitively inhibits the active transport of organic ions across the kidney tubule (PCT)

-Prevents both reabsorption from the tubular fluid and secretion into it, inhibition of urate reabsorption increases its excretion in the urine.

-Urine must be kept at pH 6 or above to prevent crystals of urate being formed in the urine.

-To achieve this, potassium citrate or sodium bicarbonate (urinary alkalinisers) are used alongside.


*Therapeutic Points: Probenacid should be used with urinary alkalinisers to prevent urate crystals from precipitating from urine.

(b) Adverse effects:

-Causes GIT upsets in some patients

-Blocking of renal tubular excretion prolongs effects of a range of organic acids such as penicillins, acyclovir (anti-viral for herpes) and naproxen (NSAID)


Mechanism 3: Inhibiting leukocyte migration into joint (Cholcicine)

-Akaloid compound

(a) Cholchicine mechanism of action:

-Colchicine binds to tubulin, resulting in depolymerisation of microtubules.

-Results in decreased cell motility and cell mitosis (cell cycle halted)

-Extravasation of inflammatory cells such as neutrophils affected


(b) Cholchicine pharmacokinetics

-Absorbed from gut, some metabolised in liver and some excreted unchanged in bile (i.e. bile, liver, gut)

-Enhances gastrointestinal toxicity

-Used either in moderate doses to treat an acute attack. Used in low doses for prolonged period of time to reduce risk of recurrent attacks.


(c) Cholchicine Adverse effects

1. Largely gastrointestinal (Nausea, vomitting and abdominal pain)

2. Severe diarrhea occurs

3. Renal damage can occur. Blood disorders rarely occur


*Effects might be due to inhibition of mitosis in the rapidly reproducing cells of GI mucosa


Mechanism 4: NSAIDs (Aspirin/Salicylates)

****Should be avoided in the treatment of gout as even small doses will competitively inhibit urate excretion, causing urate to be retained.