Stages in viral replication:

• Attachment and penetration (stage 1);
  
• uncoating (stage 2);
  
• components of virus are synthesized (stage 3);
  
• virus particles are assembled (stage 4);
  
• virus is released (stage 5).

Gamma globulin (IgG) – Assumed to block penetration of virus (stage 1); anaphylactoid shock should always be considered.

Amantadine & Rimantadine

MOA: Prevent viral uncoating (stage 2).

Toxicity: CNS (dizziness, confusion, seizures).

Therapeutic place: Antiparkinsonian agent; prophylaxis of influenza A2 virus.

Contraindications: Epileptics, pregnancy.

Idoxuridine – antimetabolite; (thymidine analogue)

MOA: Disrupts DNA synthesis (stage 3). Only active against DNA viruses.

Pharmacokinetics: Prodrug that must be triphosphorylated by virus. Inactivated by liver.

Toxicity: Associated with IV administration – hepatotoxic, teratogenic, mutagenic, carcinogenic. Minimal toxicity when used topically.

Therapeutic place: Only approved for treatment of HSV infections of the eyelid, conjunctiva, and cornea.

Vidarabine – antimetabolite; purine analogue

MOA: Inhibits viral DNAP (stage 3). Only effective against DNA viruses.

Pharmacokinetics: Topical and IV. Prodrug that must be metabolized to a triphosphate. Reduce dose if patient is taking allopurinol for gout.

Toxicity: Topical adminstration is okay. Systemically causes GI and CNS toxicity, hepatotoxicity, carcinogenic/teratogenic/mutagenic.

Therapeutic place: Used primarily for topical ophthalmic administration (HSV keratoconjunctivitis). Used systemically for HSV encephalitis. Effective against HSV, VZV, and vaccinia.

Interferon

MOA: Cellular cytokines with antiviral activity that bind to receptors to stimulate the synthesis of proteins that interfere with all stages of viral replication.

Therapeutic place: Useful for some melanomas, chronic hepatitis B & C, Kaposi’s sarcoma.

Acyclovir – antimetabolite; guanosine analogue

MOA: Inhibits DNAP (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated. Excreted by the kidney (probenecid inhibits secretion).

Resistance: Becoming a problem.

Toxicities: Low

Therapeutic place: EBV, VZV, HSV keratitis, HSV

Gangiclovir – Used to treat CMV in AIDS patients.

Cidofovir – Antimetabolite; cytosine analogue; disphosphate is the active drug; nephrotoxicity limited with concomitant use of probenecid and IV saline.

Sorivudine – Antimetabolite; pyrimidine analogue; used to treat VZV; will cause severe bone marrow depression when administered with 5-fluorouracil.

Ribavirin

MOA: Inhibits viral RNA synthesis (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated.

Toxicity: Death, diminished pulmonary function, and CV problems in patients with CHF.

Therapeutic place: Aerosol used to treat severe lower respiratory tract infections due to syncytial virus. Also used in combination with interferon to treat hepatitis C.

Trifluridine – Antimetabolite; thymidine analogue

MOA: Stage 3 inhibitor of viral DNA synthesis by virtue of its incorporation into viral DNA.

Pharmacokinetics: Topical agent only. Very short half-life (20-30 min).

Toxicity: Palpebral edmea and transient burning of the eyes.

Therapeutic place: Topical treatment of epithelial keratitis of HSV.

Contraindications: Pregnancy

Foscarnet

MOA: Inhibits RNA polymerase and reverse transcriptase (stage 3)

Pharmacokinetics: Deposits into bone (binds with calcium)

Toxicity: Hypocalcemia and hypomagnesia.

Therapeutic place: IV adminstration for CMV retinitis.

Drug interactions

Vidarabine-Allopurinol – severe neurotoxicity

Acyclovir-Probenecid – decrease in acyclovir elimination

Latent period – Time from point of infection to point of diagnosable infection

Detection of antibodies to virus – window period of 3 mos to 1 year; ELISA, EIA, and Western blotting; blood draw (1-3 wks), rapid (SUDS) available in 5-30 min, oral mucosa (OraSure), urine (less sensitive).

Detection of the virus – days to 2 wks; detection of RNA via PCR or branched chain DNA; detection of HIV viral protein (p24 usually done).

AIDS – 10^6 virus particles, <200>

Advanced HIV infection – 10^6 virus particles, <50>

HAART therapy – 2 RTIs and at least 1 PI or Efavirenz (NNRTI). Results of therapy are expected to show 1 log unit decrease at 8 weeks and no detectable virus at 4-6 months after initiation of treatment. Failed therapy should change at least 2 agents that are not likely to show cross-resistance with drugs given previously.

The goal of HIV antiviral therapy is to get the HIV viral load as low as possible and keep it there as long as possible. The majority of therapies affect the virus directly (RTIs and PIs), although some do affect the host by limiting virus activity in host.

Life cycle of HIV and key points for potential therapy –

1. Binding to host cell (experimental);

2. RT;

3. Integrase (no drugs);

4. Protease;

5. Immune system stimulators (experimental);

6. Host ribonucleotide reductase.

Nucleoside analogues (NRTIs) – Prodrugs. Must be formed into triphosphate nucleotide to be incorporated into DNA. Administered orally, with bid dosing. Competitive inhibitors to reverse transcriptase at the nucleotide binding site.

• Abacavir (ABC) – Good CSF penetration; life-threatening hypersensitivity.

• Didanosine (ddI) – Pancreatitis, peripheral neuropathy; ddI decreases the absorption of any drug that requires gastric acidity for absorption; synergistic effects with any drug that causes pancreatitis or peripheral neuropathy.

• Lamivudine (3TC) – Called Combuvir when combined with AZT; also used for treatment of hepatitis B; pancreatitis in pediatric patients.

• Stavudine (d4T) – DO NOT COMBINE WITH AZT; additive effect with any drug that causes peripheral neuropathy (ddI, ddC, INH).

• Zalcitabine (ddC) – TID dosing; peripheral neuropathy, pancreatitis, hepatitis (must monitor liver enzyme levels); additive effect with any drug that causes peripheral neuropathy.

• Zidovudine (AZT) – Good CNS penetration; bone marrow suppression (anemia, neutropenia), myopathu, macrocytosis, hepatitis; antagonistic to d4T; marrow suppression precludes concurrent use with ganciclovir or other marrow suppressants.

Non-nucleoside analogues (NNRTIs) – These agents DO NOT require activation. Orally administered with. Cross-resistance DOES NOT develop between NNRTIs and NRTIs. Cross resistance DOES occur within class. Noncompetitive inhibitor of RT. Most metabolized in liver and excreted by kidney.

• Delavirdine – Inhibits p450 enzymes; requires gastric acidity so caution with ddI.

• Nevirapine – Severe but transient rash on trunk, face, and mucous membranes; induces p450 enzymes; reduces indinavir levels.

• Efavirenz – Dizziness and “disconnected” feeling; induces p450; avoid clarithromycin.

Nucleotide analogues – Not FDA approved

• Adefovir – Obvious CNS penetration; severe nephrotoxicity and CNS effects; induces p450; reduces indinavir levels.

• Tenofovir

Protease inhibitors – Even in combination therapy resistance develops and it can be cross-resistance to compounds from within the same class.

• Amprenavir – Excreted in feces; rashes, diarrhea, nausea; inhibits p450; rifampin decreases amprenavir levels dramatically; efavirenz lowers levels 40%.

• Indinavir – Taken while fasting or with light, low-fat meal; biliary metabolism; dessication likely; kidney stones; lipodystrophy; inhibits p450; levels increased by delavirdine and nelfinavir; levels reduced by nevirapine and grapefruit juice; ddI reduces absorption

• Lopinavir

• Nelfinavir – Diarrhea; inhibits p450; biliary metabolism.

• Ritonavir – Biliary metabolism; GI intolerance, paresthesias, taste perversions; potent inhibition of p450; ddI decreases absorption; increases levels of AZT and saquinivir.

• Saquinavir – Fatal arrhythmias when used with cisapride; do not combine with indinovir; levels increased by grapefruit juice; levels increased by ritonavir.

Host’s ribonucleotide reductase

• Hydroxyurea – Inhibits cellular ribonucleotide reductase, inhibiting formation of deoxynucleotides. This leads to induction of cellular kinases causing increased phosphorylation of NRTIs. Metabolized in liver and excreted in lungs and urine. Use only if ddI is being used. Considered salvage therapy. Bone marrow suppression, GI intolerance, and increased risk of neuropathy. Contraindicated in renal failure.

Bad combinations – d4T+AZT, ddC+ddI, ddC+d4T (peripheral neuropathy); ddC+3TC (resistance); NNRTI combinations (lack of known synergy)

Pregnancy – Only drug shown to reduce risk of perinatal HIV transmission is AZT. Initiated at 14-24 weeks of gestation and continued to onset of labor. IV AZT during labor until delivery. AZT for newborn for first 6 weeks of life beginning 8-12 hrs after birth.

Post exposure prophylaxis – Initiate therapy within 72 hrs (1-2 hrs if possible). AZT+3TC+indinavir/ nelfinavir. Check HIV RNA levels at 14 days and discontinue if undetectable.

Hypertension is the most common cardiovascular condition. A persistent and sustained high blood pressure has damaging effects on the heart, brain, kidneys and eyes. Hypertension is generally classified into two types.

• Primary or essential hypertension: In more than 95% of cases, there is no specific underlying cause. These patients are said to have essential hypertension.
  
• Secondary hypertension, seen in about 5% of cases, can be due to specific disease or drug.

Table : Classification of BP for adults

• Systolic blood pressure (SBP) is the maximum pressure recorded during ventricular systole.
• Diastolic blood pressure (DBP) is the minimum pressure recorded during ventricular diastole.
• Pulse pressure (PP): SBP – DBP
• Mean arterial pressure (MAP): DBP + 1/3 PP.

Fig: Sites of action of the major groups of antihypertensive drugs

Classification:

1. ACE Inhibitors:

Captopril, Enalapril, Lisinopril, Ramipril, Benazepril

2. Angiotensin II – receptor antagonists:

Losartan, Candesartan, Irbesartan, Valsartan

3. Calcium channel Blockers (CCB):

Nifedipine SR, Amlodipine, Nicardipine, Nimodipine, Felodipine, Verapamil, Diltiazem.

4. Diuretics:

   1. Thiazides and related agents – Hydrochlorothiazide, Chlorthalidone.

   2. Loop diuretics: Furosemide, Bumetanide, Torsemide.

   3. Potassium sparing diuretics – Amiloride, Triamterene, Spironolactone

5. Sympatholytic drugs:

   1. Centrally acting agents: Clonidine, Methyldopa

   2. Ganglion blockers: Trimethaphan

   3. Neuronal blockers: Reserpine,

   4. Alpha Adrenergic blockers

• Nonselective: Phenoxybenzamine, Phentolamine
• Selective: Prazosin, Terazosin

5. Beta Adrenergic blockers: Propranolol, Atenolol, Metoprolol

6. Vasodilators:

1. Arteriolar – Hydralazine, Minoxidil, Diazoxide
   

2. Arterial and venodilator: Sodium Nitroprusside.

1. inhibit the generation of angiotensin II which is a potent vasoconstrictor.

2. inhibit the degradation of bradykinin which is a potent vasodilator

3. stimulate the synthesis of vasodilating PGs through bradykinin and

4. reduce sympathetic nervous system activity.

They also reduce aldosterone production hence sodium and water retention. All these actions contribute to their anti hypertensive effect.

ACE inhibitors dilate both arteries as well as veins, hence they reduce afterload and preload.

ACE inhibitors are preferred antihypertensive agents in younger age group. They are used in all forms of hypertension, especially in patients with diabetes, CHF and renovascular hypertension. ACE inhibitors are preferred in patients with diabetes because they delay or prevent the progression of renal complications.

Pharmacokinetics: ACE inhibitors are usually given orally. In emergency, enalaprilat can be given intravenously. Food reduces the absorption of captopril and ramipril hence they should be given 1 hour before meals. They poorly cross the BBB; metabolized in the liver and excreted in urine.

Adverse effects*

Cough (Dry cough) is due to increased bradykinin levels. Appearance of cough is the indication to stop the drug.

Angioedema

Proteinuria

Taste alteration, Teratogenic effect (growth retardation and neonatal death) – hence contraindicated in pregnancy.

Severe hypOtension may occur 1-2 hours after taking the first dose. Hence ACE inhibitors should be started with a small dose and then gradually increased.

NeutroPenia

Rash

Itching

Loss of appetite, nausea, vomiting and diarrhoea.

* Mnemonic for adverse effects of ACE inhibitors: ‘ CAPTOPRIL’

Hyperkalemia may be seen in patients with renal insufficiency and when combined with K⁺ sparing diuretics.

Drug Interactions

Tetracyclines X ACE inhibitors: Absorption of tetracycline is reduced.

ACE inhibitors X Potassium sparing diuretics: Simultaneous administration of these drugs can cause dangerous hyperkalemia.

ACE inhibitors X Lithium: ACE inhibitors retard the renal elimination of lithium and potentiate its toxicity.

ACE inhibitors X NSAIDs: NSAIDs by inhibiting PG synthesis promote Na⁺ and water retention on chronic use. Thus, they decrease the antihypertensive effect of ACE inhibitors.

Therapeutic uses of ace inhibitors:

1. Hypertension: Use of ACE inhibitors reduce the incidence of heart disease in hypertensive patients. ACE inhibitors are useful in all grades of hypertension. They prevent or retard myocardial hypertrophy and remodeling.

2. Congestive cardiac failure: ACE inhibitors should be prescribed to all patients with impaired left ventricular function. For explanation see Ch: (Pg ).

3. Myocardial Infarction (MI): ACE inhibitors should be started within 24 hours in patients with MI. They have shown both short-term and long-term improvement in survival.

4. Diabetic Nephropathy: ACE inhibitors and Angiotensin II receptor blockers (ARBs) are the preferred drugs in diabetic nephropathy as they control both systemic hypertension and intraglomerular pressure. They reduce the rate of progress from microalbuminuria to macroalbuminuria and delay the development of end stage renal disease. Therefore, ACE-inhibitors are the preferred antihypertensives in diabetics.

5. Scleroderma renal crisis: ACE inhibitors produce dramatic improvement in patients with renal crisis and accelerated hypertension.

Table: Pharmacokinetic features of ACE inhibitors

Losartan Candesartan

Valsartan Irbesartan

Angiotensin II has two types of receptors AT1 and AT2. Most of the effects of angiotensin II are mediated by AT1 receptors. They are vasoconstriction, aldosterone secretion and the release of noradrenaline from sympathetic nerve endings. The role of AT2 receptors is not known. ARBs competitively inhibit the binding of angiotensin II to AT1 receptor subtype. ARB’s produce effects similar to those of ACE inhibitors. The efficacy and tolerability are also similar to ACE inhibitors. Losartan is less potent than ACE inhibitors, whereas other ARBs, candesartan, valsartan and irbesartan are equipotent to ACE inhibitors. ARBs do not affect bradykinin production.

Side effects:

ARBs are better tolerated compared to ACE inhibitors. They cause headache, hypotension, weakness, rashes, nausea, vomiting and teratogenic effects. They may cause hyperkalemia in patients with renal failure or in patients on K+ sparing diuretics. They are much less likely to produce cough or angioedema. ARBs are used in hypertension, CCF & diabetic nephropathy. The efficacy and tolerability of ARBs are similar to those of ACE inhibitors. ARBs are mainly indicated in patients who develop cough with ACE inhibitors. ARBs also reduce the progression of nephropathy in patients with diabetes.

Thiazides and related drugs are the most widely used drugs for uncomplicated hypertension. Chlorothiazide, hydrochlorothiazide and chlorthalidone are the commonly used thiazides.

Mechanism of action

Thiazide diuretics are used in uncomplicated mild to moderate hypertension and have a long duration of action. They should be administered in a low dose i.e., 12.5 mg of hydrochlorothiazide or chlorthalidone. If the antihypertensive response is not adequate, the dose can be increased upto 25 mg per day. Beyond this dose thiazides are not safe. Potassium sparing diuretics are usually given with thiazides to counteract the K⁺ loss.

Adverse effects:

Hypokalemia, hyperglycemia, hyperuricemia, hyperlipidemia, hypercalcemia, impotence and decreased libido.

Advantages with thiazide diuretics-

i) Have long duration of action,

ii) Cheaper,

iii) Well tolerated even in elderly patients.

Loop diuretics have shorter duration of action therefore, they are not used in hypertension except in the presence of renal or cardiac failure.

• The thiazides act in the distal tubule to decrease sodium reabsorption (inhibits Na/Cl transporter).

  • As a result of decreased sodium and chloride reabsorption, a hyperosmolar diuresis ensues.

  • Delivery of more sodium to the distal tubule results in potassium loss by an exchange mechanism.

• Thiazides also promote calcium reabsorption, in contrast to loop diuretics.

• The initial decrease in blood volume followed by a longer-termed reduction in vascular resistance appear to account for the hypotensive effects of the thiazides.

• Adverse Effects

  • Potassium depletion is a potentially serious side-effect that may require potassium supplementation and/or concurrent use of potassium-sparing diuretics.

  • Hyperuricemia may occur precipitating gout.

    • The increase in systemic uric acid is due to a decrease in the effectiveness of the organic acid secretory system.

  • Diabetic patient may have difficulty in maintaining proper blood sugar levels.

• Furosemide (Lasix), bumetanide (Bumex), and ethacrynic acid (Edecrin) are "high-ceiling" loop diuretics acting primarily at the ascending limb of the loop of Henle.

  • The effectiveness of these agents is related to their site of action because reabsorption of about 30 - 40% of the filtered sodium and chloride load occurs at the ascending loop.

  • Distal sites are not able to compensate completely for this magnitude of reduction of NaCl reabsorption.

• Loop diuretics increase urinary Ca²⁺ in contrast to the action of thiazides.

• Loop diuretics also increase renal blood flow by decreasing renal vascular resistance.

• These drugs are rarely used in the management of hypertension because of their short duration of action and the availability of better drugs.

• Adverse Effects

  • Ototoxicity

  • Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal excretion of uric acid by competition with renal secretory and biliary secretory systems.Therefore these agents can precipitate gout.

  • Potassium depletion.

• Methyldopa (Aldomet) is a prodrug which is metabolized to the active agent, alpha-methylnorepinephrine.

  • Alpha-methylnorepinephrine acts in the brain, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

• Methyldopa (Aldomet) produces no change in cardiac output in younger patients, but in older patients a decline in cardiac output results from reduced heart rate and stroke volume.

  • The reduction in stroke volume occurs due to increased venous pooling (decreased preload).

• Since renal blood flow and function is maintained during methyldopa treatment, methyldopa maybe valuable in managing hypertensive patients with renal insufficiency.

• Adverse Effects

  • Dry Mouth

  • Parkinsonian signs

  • Reduced libido

  • Hyperprolactinemia (gynecomastia, galactorrhea)

  • Bradycardia (in patients with SA nodal abnormality)

  • Hepatoxicity (avoid in patients with hepatic disease)

  • Positive Coombs' test (20%)

    • 1-5% of those with positive Coombs' develop hemolytic anemia (requiring immediate discontinuation of the drug)

• Antihypertensive:

  • Clonidine (Catapres) acts in the brain, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

  • Mechanism of action: centrally acting selective a₂ adrenergic agonist.

  • Especially effective in

    • management of severe hypertension or

    • in renin-dependent hypertension

  • Transdermal clonidine (Catapres) patch: useful for surgical patients unable to take oral formulation

  • Clonidine (Catapres) reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance.

  • Reduction in stoke volume occurs due to increased venous pooling (decreased preload).

  • Clonidine (Catapres) does not interfere with cardiovascular responses to exercise.

  • Renal blood flow and function is maintained during clonidine treatment.

  • Clonidine (Catapres) has minimal or no effect on plasma lipids.

• Other Clinical Uses

• Analgesia--

  • Preservative-free clonidine administered into epidural/subarachnoid space (150-450 micrograms)-- dose-dependent analgesia

  • No respiratory depression, nausea, vomiting, delayed gastric emptying or pruritus -- effects associated with opioids

    • Probable Mechanism: activation postsynaptic a₂ receptors in the spinal cord substantia gelatinosa

      • Clonidine (Catapres) & morphine: no cross-tolerance when used concurrently in neuraxial analgesia

  • Side effects of neuraxial clonidine (Catapres)

    • hypotension, sedation, dry mouth

• Preanesthetic Medication:

  • Oral clonidine (Catapres) (preanesthetic medication):

    • Enhances intrathecal morphine + tetracaine (pontocaine) for postoperative analgesia (no increase in morphine-related side effects)

    • Preanesthetic clonidine (Catapres) also:

      • Reduces reflex tachycardia that may be caused by direct laryngoscopy for tracheal intubation

      • Reduces intraoperative blood-pressure heart rate lability

      • Reduces plasma catecholamines levels

      • Significantly decreases anesthetic requirements for inhaled (MAC) and injected agents.

• Adverse Effects

  • Dry Mouth (xerostomia)

  • bradycardia (in patients with SA nodal abnormality)

  • Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors

• Reserpine inhibits the function of postganglionic adrenergic neurons, thus inhibiting sympathetic function.
• Reserpine binds to noradrenergic storage vesicles in central and peripheral sympathetic nerve terminals.
  • Storage vesicles become nonfunctional as a result of interacting with reserpine and lose the ability to store and concentrate norepinephrine (N.E.) and dopamine.
  • N.E. and dopamine leaking from vesicles are enzymatically destroyed in the cytoplasm and as a consequence little transmitter is released upon nerve ending depolarization.
• Depletion of transmitter in both the central and peripheral nervous system suggest that both sites by be important mediators of the antihypertensive response.
• Chronic adrenergic neuronal blockade by reserpine results in a reduction of cardiac output and peripheral vascular resistance.
• Adverse Effect
  • CNS effects predominate, including sedation, inability to concentrate, and depression.

• Guanethidine (Ismelin) inhibits the function of postganglionic adrenergic neurons, thus inhibiting sympathetic function.

• Guanethidine (Ismelin) uses the norepinephrine (N.E.) re-uptake transporter to reach its site of action, the neurosecretory vesicles.

  • Guanethidine (Ismelin) replaces norepinphrine in the vesicle and is released instead of the normal transmitter.

  • Guanethidine (Ismelin) is an inactive transmitter and the replacement of N.E. by an inactive agent is responsible for its antihypertensive effects (maintenance dosing).

• Adrenergic blockade by guanethidine (Ismelin) results in post-synaptic supersensitivity.

• Sympathetic blockade by guanethidine (Ismelin) produces:

  • venodilatation

  • reduction in cardiac output due to inhibition of cardiac sympathetic innervation

  • blockade of the sympathetic reflex arteriolar response to the reduction in cardiac output.

• Adverse Effects

  • Symptomatic hypotension (due to sympathetic reflex blockade)

  • Sexual dysfunction (delayed ejaculation)

  • Diarrhea

  • Guanethidine effects blocked by N.E. reuptake blockers (tricyclic antidepressants, cocaine, ephedrine, amphetamine, chlorpromazine )

1. Deliver the agent to the site desired
2. In the form that is required
3. In the proper vehicle
4. At the right concentration
5. Ensure it only acts where it is intended

• Only in dermatology and opthalmology can these principles be adhered to properly
• The eye, like the skin, is an exposed structure, therefore, it is open to the elements and it is possible to apply drugs directly to the surface via drops or ointments.

• Cornea
• Iris
• Conjunctiva
• Ciliary body

• The drug needs to be able to penetrate the cornea
• It needs to be in sufficient concentration as the fluid in the eye (aqueous and vitreous humor) will dilute the drug
• When applying something to the eye, the natural protective response is to produce tears. This is another factor which tends to dilute the drug.

Enzyme Properties:

*Major location: luminal proximal tubule membrane
*Activity: catalyzes dehydration of carbonic acid, H2CO3 , required for bicarbonate reabsorption
*blockade of carbonic anhydrase activity -- induces a sodium bicarbonate diuresis, reducing body bicarbonate levels

Carbonic anhydrase inhibitors:
*alkaline diuresis
*hyperchloremic metabolic acidosis
*Prototype: acetazolamide

Acetazolamide:
*well-absorbed orally
*excretion: tubular secretion -- proximal tubule
>>dose reduction in renal insufficiency
*At maximal carbonic anhydrase inhibition: 45% inhibition of bicarbonate reabsorption
>causes significant bicarbonate loss
>hyperchloremic metabolic acidosis
>limited effectiveness because:
bicarbonate depletion increases sodium chloride reabsorption
*reduction in aqueous humor and cerebrospinal fluid production

Clinical Application:
Glaucoma:
*decreases rate of aqueous humor production -- leads to a declining in intraocular pressure
*most common indication for use of carbonic anhydrase inhibitors

Dorzolamide: topical inactive carbonic anhydrase inhibitor.
*no diuretic or systemic metabolic effects
*reduction in intraocular pressure comparable to oral agents

Urinary Alkalinization:
*increased uric acid and cystine solubility by alkalinizing the urine (by increasing bicarbonate excretion)
*for prophylaxis of uric acid renal stones, bicarbonate administration (baking soda) may be required

Metabolic Alkalosis:
Results from:
*decreased total potassium with reduced vascular volume
high mineralocorticoid levels
*These conditions are usually managed by treating the underlying causes; however, in certain clinical settings acetazolamide may assist in correcting alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}

Acute Mountain Sickness:
Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of all of 3000 meters}; symptoms -- usually mild
In serious cases: life-threatening cerebral or pulmonary edema

*Acetazolamide reduces the rate of CSF formation and decreases cerebral spinal fluid pH.
*Prophylaxis against acute mountain sickness may be appropriate


Other Uses:some role in *management of epilepsy
*hypokalemic periodic paralysis
*increase urinary phosphate excretion during severe hyperphosphatemia.

Toxicity:
*hyperchloremic metabolic acidosis due to reduction of body bicarbonate stores

*renal stones:
*bicarbonate loss is associated with:
*phosphaturia
*hypercalciuria (calcium salts, relatively insoluble at alkaline pH)
renal potassium loss:
*increased sodium bicarbonate in the collecting tubule increases the lumen-*negative and in electrical potential -- enhances potassium excretion
>>counteracted by potassium chloride administration

Others:
drowsiness, parathesias
accumulation in renal failure (CNS toxicity)
hypersensitivity reactions

Contraindications:
hepatic cirrhosis

Fungal infections (mycoses), though not as frequent as bacterial or viral infections, have nonetheless been increasing in incidence in the human population over the last 15 years or so, largely as a consequence of increased numbers of cancer and immunocompromised patients, who are at greater risk owing to weakened immune systems and the chronic nature of the diseases. In addition, a number of fungal infections can be difficult to treat (oft referred to as ‘stubborn’), even when the offending organism is identified and appropriate therapy is applied. On the other hand, like bacteria, fungi have unique characteristics, distinct from their mammalian hosts, allowing for selective targeting of therapeutic drugs. Fungi are, however, much more complex organisms in comparison to bacteria, are in fact eukaryotic and often grow fairly slowly. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane.

Major fungal infections

The number of different kinds of fungi out there is vast, and, of course, some of them are pleasant to eat. Only a small subset is capable of infecting humans. The following is a very general breakdown of types of fungal infections that occur based on site of infection:

Cutaneous = skin, hair and nails Most common

eg. ‘Athlete’s foot’, Ringworm, and Tinea cruris

Mucocutaneous = moist skin and mucous membranes, Common

such as GI, perianal and vulvovaginal areas

eg. Candida albicans

Pulmonary/Systemic Less frequent

eg. Invasive Aspergillus, cryptococcal meningitis, pulmonary histoplasmosis; also, systemic candidiasis

Systemic fungal infections are more serious as they are usually more difficult to diagnose, are chronic in nature, and, in some cases, can become life-threatening. They occur more frequently in individuals with compromised immune systems (AIDS patients; transplant patients; cancer patients). Prophylactic treatment is sometimes indicated in AIDS patients and bone marrow transplant patients, but risk of developing resistance is high. Life-threatening infections require the use of more potent but much more toxic antifungals.

Superficial fungal infections are almost always caused by dermatophytes or yeasts. In some instances, they can be rather tenacious, requiring very long treatments, sometimes with both oral and topical drugs.

Amphotericin B

Cytolytic via ergosterol binding: Broad spectrum: mainly for life-

Forms pores in membrane threatening infections; given IV

via liposome suspension

oral: not absorbed - topical

Nystatin

Cytolytic via ergosterol (as for Topical only (too toxic for systemic

Amp B) use); for Candida

Flucytosine

Antimetabolite in combination only for meningitis (toxic to bone marrow) & blastomycoses

Griseofulvin

Antimitotic via microtubule Oral for dermatophytosis

Inhibition

Ketaconazole

Blocks ergosterol synthesis via Oral for mucocutaneous candidiasis;

P₄₅₀ inhibition (not selective) coccidoidal mycoses

Miconazole

Blocks ergosterol synthesis Topical for Candida; dermatophytes

Clotrimazole

oropharyngeal infection

Intraconazole

Selective block of ergosterol Oral (no CSF penetration) for

Dermatophytoses; Aspergillus;

Endemic mycoses

Fluconazole “ Oral (good CSF penetration) for

Meningitis; Candida; prophylactic

for marrow transplants & AIDS

Verconazole “ Latest triazole; oral and IV (good

CSF penetration) for Aspergillus;

Meningitis; Candida

Terbinafine inhibits squalene metabolism - Cutaneous mycoses

Naftifine squalene is toxic; also blocks

Ergosterol **

Caspofungin Blocks cell wall synthesis via IV: invasive candidiasis &

inhibition of beta (1,3)-D- aspergillus

Glucan synthesis

Caspofungin (most recently approved antifungal – Jan 2001)

Mechanism of action: inhibits beta (1,3)-D-glucan synthesis, blocking cell wall synthesis

Absorption: poor; highly protein; administered IV

Uses: active against a number of fungi, but particularly effective against invasive candidiasis and aspergillosis (promising new alternative to amphotericin) via once daily IV administration; no activity against cryptococcus

Adverse effects: fever, nausea, vomiting, flushing; some irritation at inj site; small elevation of liver enzymes

Naftifine and Terbinafine

Mechanism of action: inhibits fungal squalene metabolism

increased levels of squalene are toxic to fungi; also reduces ergosterol

Uses: effective for most cutaneous mycoses either topically (eg. tinea corporis

and tinea cruris) or, in the case of terbinafine, orally for nail infections (90% cure rate, without side effects)

[not effective against Candida]

Mechanism of action: inhibit fungal ergosterol biosynthesis

Itraconazole ***

Absorption: OK, low bioavailability (no CSF penetration)

- improved with food and low gastric pH

Uses: most potent of the azoles for systemic infections

drug of choice for persistent dermatophytic infections

effective against all types of Aspergillus infection

preferred agent for endemic mycoses (eg. Histoplasma)

Adverse effects:

- drug interactions (esp. non-sedating antihistamines)

(no effect on steroid biosynthesis; variable effect on mammalian P₄₅₀ system, less than with ketoconazole but still of potential concern)

Fluconazole

Absorption: good; used orally and IV (excellent CSF penetration)

Uses:

agent of choice for cryptococcal meningitis (unless life-threatening: use AmpB)

mucocutaneous candidiasis

prophylactically for bone marrow transplants and AIDS patients

Adverse effects: (widest therapeutic window) few and mild

concern for all azoles: newly observed emergence of resistant strains in AIDS

[resistance to azoles is otherwise fairly rare]

Voriconazole (most recently approved (2002) azole, derived from fluconazole)

Absorption: good; used orally and IV (good CSF penetration, however*)

Uses:

agent of choice for invasive Aspergillus

active against Candida (even those resistant to fluconazole), Cryptococcus and endemic mycoses, but ineffective against mucormycosis (soil saprophytes)

Adverse effects: sporadic visual disturbances* (~30%); hepatotoxicity (2-3%)

Mechanism of action: inhibit fungal ergosterol biosynthesis

selectively inhibit fungal cytochrome P₄₅₀ enzymes

Ketoconazole

(original oral ‘azole’, not as selective as newer azoles, ie. significant inhibition of mammalian P450 enzymes)

Absorption: low - improved with food and low gastric pH

used orally, but has very slow onset; poor CSF and urinary tract penetration

Uses:

mucocutaneous candidiasis

coccidioidomycosis (non-meningeal)

in shampoos for seborrheic dermatitis

(largely supplanted by more expensive itraconazole or fluconazole)

Adverse effects: (narrow therapeutic window) highly dose-dependent

- nausea and vomiting

- endocrine: interferes with adrenal and gonadal steroid synthesis*

- hepatotoxicity (rare but can prove fatal)

- drug interactions

-*action on human cytochrome P₄₅₀ (eg. warfarin; cyclosporine; and vice versa)

- decreased absorption of ketoconazole when administered with rifampin, H₂ antagonists or antacids

Miconazole and Clotrimazole

Absorption: extremely poor - both used topically: creams and, in the case

of clotrimazole, oral troches (=lozenges)

Uses: wide-spread, over-the-counter use as topical antifungals

vulvovaginal candidiasis

dermatophytic infections (eg. tineas corporis)

oropharyngeal thrush (candidiasis; alternatives to nystatin)