There are a multitude of effective antihistamines, now more correctly classified as H1-histamine antagonists. They differ little from each other except in duration of action and the degree of drowsiness, the commonest side effect.

General Indications

Nasal allergy (hay fever or allergic rhinitis), urticaria (prevention and treatment) and pruritus associated with skin disorders. In allergic emergencies chlorpheniramine maleate 10mg i.m., i.v. may be life saving. Dimenhydrinate is primarily an antiemetic (see p. 408).

Side Effects

All antihistamines cause sedation to some degree. Patients vary widely in their response and a single dose may produce severe sedation within minutes in some patients. This is potentiated by alcohol and other sedatives and patients MUST BE WARNED about this and not to drive until they are sure that sedation is not occurring.

In some individuals, especially children and the elderly, and in overdose, bizarre Central Nervous System side effects can occur. Anti-cholinergic effects (dry mouth, blurred vision, urinary retention, constipation and palpitations) may be dose limiting.

Drug Selection - General Principles

Choice of antibiotic for the treatment of bactericidal infections must be made with two factors in mind:

(i) The known or likely organism involved:

(ii) Patient factors.

(1) Rational treatment re-quires a diagnosis. In many cases there is only one microbic cause and antibiotic choice is easy. Many other diseases, e.g. pneumonia or urinary tract infection, are caused by any of a number of different bacteria and laboratory help is required.

In mild illness and where laboratory facilities are out of reach, treatment may be justifiably begun without such help. In severe illnesses e.g. meningitis, septicaemia, a bacteriologic diagnosis is mandatory.

The blind prescribing of antibiotics for unexpected fevers usually leads to greater difficulty in establishing a diagnosis and must be avoided. The casual prescribing of antibiotics for “flu-like” illness remains, as always, bad medical practice.

(2) The Patient

The patient’s history must be meticulously taken for drug allergies. The presence of liver or renal disease, age and immuno compromised status must be considered.

Rational therapy may be illustrated by the case of a woman with dysuria and nausea in early pregnancy. The causative organism is reported to be resistant to ampicillin but sensitive to nitrofurantoin (high risk of nausea), gentamicin (given i.m. and should be avoided in pregnancy), tetracycline and Co-trimoxamole (both should be avoided in pregnancy) and cephalexin. The Penicillins and cepha-losporins are safest in pregnancy so cephalexin, although costly, is clearly the drug of choice in this case.

The following principles or rules should be observed when antibiotics are considered. Viral infections, in general, should not be treated with antibiotics.

Local sensitivities of com-mon pathogens should be ascertained from the hospital microbiologist.

The dose must be tailored to the patient, as in (1) above.

The route and times in relation to meals must be considered.

Broad Spectrum Antibiotics should not, in general, be used if a narrow spectrum drug will do.

Costly antibiotic should not be used if an inexpensive one is equally suitable.

Drug Selection - General Principles

Choice of antibiotic for the treatment of bactericidal infections must be made with two factors in mind:

(i) The known or likely organism involved:

(ii) Patient factors.

(1) Rational treatment re-quires a diagnosis. In many cases there is only one microbic cause and antibiotic choice is easy. Many other diseases, e.g. pneumonia or urinary tract infection, are caused by any of a number of different bacteria and laboratory help is required.

In mild illness and where laboratory facilities are out of reach, treatment may be justifiably begun without such help. In severe illnesses e.g. meningitis, septicaemia, a bacteriologic diagnosis is mandatory.

The blind prescribing of antibiotics for unexpected fevers usually leads to greater difficulty in establishing a diagnosis and must be avoided. The casual prescribing of antibiotics for “flu-like” illness remains, as always, bad medical practice.

(2) The Patient

The patient’s history must be meticulously taken for drug allergies. The presence of liver or renal disease, age and immuno compromised status must be considered.

Rational therapy may be illustrated by the case of a woman with dysuria and nausea in early pregnancy. The causative organism is reported to be resistant to ampicillin but sensitive to nitrofurantoin (high risk of nausea), gentamicin (given i.m. and should be avoided in pregnancy), tetracycline and Co-trimoxamole (both should be avoided in pregnancy) and cephalexin. The Penicillins and cepha-losporins are safest in pregnancy so cephalexin, although costly, is clearly the drug of choice in this case.

The following principles or rules should be observed when antibiotics are considered. Viral infections, in general, should not be treated with antibiotics.

Local sensitivities of com-mon pathogens should be ascertained from the hospital microbiologist.

The dose must be tailored to the patient, as in (1) above.

The route and times in relation to meals must be considered.

Broad Spectrum Antibiotics should not, in general, be used if a narrow spectrum drug will do.

Costly antibiotic should not be used if an inexpensive one is equally suitable.

The treatment of tuberclosis can be divided into two phases, an initial phase where three drugs are used and a second or continuation phase where two drugs are used. The recommended regime is an initial phase of Isoniazid, Rifampicin and either Streptomycin or Etham-butol for two months and a continuation phase of Isoniazid and Rifampicin for seven months i.e. a total treatment time of nine months.

Isoniazid is still considered to be the primary drug for chemotherapy of tuberculosis. Cautions/Side Effects Patients on long term Isoniazid should be given Pyridoxine Hydrochloride prophylactically. Rifampicin is a potent inducer of liver enzymes and may provide important interactions with other drugs. (see p. 42)

Used in the treatment of Human Immuno Deficiency Virus (HIV) infection, prevention of mother to child transmission of the HIV virus and occupational post exposure prophylaxis.

HIV Life Cycle

In order for viruses to reproduce, they must infect a cell. HIV's genes are carried in two strands of RNA, while the genetic material of human cells is found in DNA. In order for the virus to infect the cell, a viral enzyme called reverse transcriptase makes a DNA copy of the virus's RNA in a process called "reverse transcription". Without reverse transcriptase, the viral genome cannot become incorporated into the host cell, and cannot reproduce.

Once the viral RNA has been reverse-transcribed into a strand of DNA, the DNA can then be inserted into the DNA of the lymphocyte. The viral enzyme called "integrase" facilitates incorporation of the viral DNA into the host cells DNA. This new DNA is called "proviral DNA”.

Activation of the host cells results in the transcription of viral DNA into messenger RNA (mRNA), which is then translated into viral proteins. The new viral RNA forms the genetic material of the next generation of viruses.

The polypeptide sequence which mRNA produces is assembled in a long chain that includes several individual proteins (reverse transcriptase, protease, integrase). Before these enzymes become functional, they must be cut from the longer polypeptide chain. Viral protease cuts the long chain into its individual enzyme components and processes other HIV proteins into their functional forms that facilitate the production of new viruses.

Reverse Transcriptase Inhibitors

Reverse transcriptase inhibitors are divided into two classes-nucleoside analogues and non-nucleoside reverse tran-scriptase inhibitors based on their structure and how they inhibit reverse transcriptase.

Nucleoside analogues, the first class of HIV drugs to be developed, work by incorporating themselves into the virus’ DNA, making the DNA incomplete and therefore unable to create a new virus. Non-nucleoside inhibitors work at the same stage as nucleoside analogues, but attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA.

Nucleoside Analogues

• abacavir (Ziagen®)
• AZT, ZDV, zidovudine (Retrovir®)
• lamivudine (3TC ®)
• zidovudine/lamivudine (Combivir®)
• d4T stavudine (Zerit®)
• ddI didanosine (Videx®)

Non-nucleoside inhibitors

• nevirapine (Viramune®)
• delavirdine (Rescriptor®)
• efavirenz (Stocrin™)

Protease Inhibitors

HIV protease is required for HIV replication and formation of mature, infectious viral particles. This processing function is inhibited by protease inhibitors, resulting in production of noninfectious viral particles:

• ritonavir (Norvir®)
• indinavir (Crixivan®)
• nelfinavir (Viracept®)

FIRST-LINE THERAPY

Regimens should be chosen on the basis of their potency, tolerability, reported adverse effects and potential reactions with other drugs, convenience, and likelihood of patient compliance. Also to be considered are possible alternative treatments if the first regimen fails.

The initial regimen should include two nucleoside reverse transcriptase inhibitors (nRTIs) and one or two protease inhibitors (PIs) or two nRTIs and a nonnucleoside reverse transcriptase inhibitor Combinations of agents from all three classes, considered an aggressive regimen, may be appropriate for patients at high, short-term risk of disease progression.

Drug Interactions

Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are metabolized by the CP450 system and cause many drug interactions, which include:

• Imidazole antifundals
• Some macrolide antibiotics e.g.
  • clarithromycin
  • Cimetidine
  • ‘Statin’ antilipemics
  • Phenytoin, carbamazepine

Cytotoxic drugs and corticosteriods are used as therapy for malignant diseases and as immunosuppressants. Because of the potential toxicity of cytotoxic drugs and the complexity of most dose regimes used in treating malignant diseases, advice on indications and dosage is not given, but should be sought from detailed specialist literature and/or appropriate consultation.

Their use should be undertaken or supervised by clinicians experienced in their use.

It must be emphasized that:-

(i) all tumours are not sensitive to chemotherapy and inappropriate and futile drug administration is to be deprecated as it can only increase morbidity;

(ii) Dosages must be individualised with even more care than usual, with respect to age, weight, liver and renal disease etc.

(i) Chemotherapy has to be administered by doctors/nurses trained/experienced in its usage.

(ii) Extravasation of the injected drug has to be avoided by taking appropriate precautions. Any such accidental event has to be instituted to reduce/minimize the sequelae of such extravasation. An algorithm of management of extravasation should be visibly displayed in the chemotherapy administration area. When in doubt, DO NOT INJECT.

(iii) Flow charts of blood counts and other parameters have to be meticulously maintained.

(iv) Reasons for dose reduction, if any, have to be clearly mentioned.

(v) Patients should be counseled about the side effects of chemotherapy before administering the first dose. It should be administered only after obtaining informed consent from the patient.

(vi) Follow the manufacturer’s recommendations while reconstituting the drug with diluent.

(vii) Adequate antinausea drugs should be prescribed for the patient.

(viii) Colony stimulating factors may have to be considered in some patients.

Before treatment is commenced the cause of blood loss must be diagnosed. Iron may be given orally or parenterally. The rate of haemoglobin response is not faster when iron is given parenterally and therefore the rapid cure of the anaemia is not met. Iron dextran can be given as a course of intramuscular injections or in selected cases as a total dose infusion given intravenously over 6 - 8 hours. Indications for parenteral therapy:

(1) Malabsorption

(2) Genuine intolerance to oral therapy

(3) Uncooperative patient Oral iron therapy involves use of simple iron salts which are the most economical and contain the highest dosages of iron. Maximum iron absorption occurs in the duodenum and prolonged release preparations often deliver iron to parts of the small intestine where absorption is poor. These preparations have no therapeutic advantage to justify their cost. Iron should be prescribed three (3) times daily after meals to (avoid gastric intolerance). The need is to supply 150 - 200 mg of elemental iron daily.

These are used to prevent thrombus formation or the extension of an existing thrombus. Heparin combines with antithrombin and is an immediate acting inhibitor of the thrombin/fibrinogen reac-tion. Heparin can be given s.c. (prophylaxis), i.m. (not recommended) or i.v.

Effects are short lived and therefore continuous i.v. infusion seems to be associated with better results and fewer complica-tions, under carefully controlled conditions, e.g. in an Intensive Care Unit or with an infusion pump. Hemorrhage can be treated with protamine sulphate. One mg neutralizes 100 units of heparin.

Oral anticoagulants act by inhibiting the hepatic synthesis of the vitamin K dependent clotting factors. It makes 36 - 48 hours for the anticoagulant effect to develop and so if immediate effect is required then heparin must be started simultaneously and given 2 - 5 days.

Laboratory control of prothrombin time is essential. Drugs such as phenyl-butazone, indomethacin, sali-cylates and clofibrate increase the effect of oral anti-coagulants while barbiturates diminish its effect. Hemorrhage should be treated by omission of the drug (if mild) or with i.m. or i.v. vitamin K. Sensitivity is rare with warfarin but more common with phenindione.

Dose Range Loading doses are no longer recommended.

Start patient on expected daily dose or as a compromise give four (4) times expected daily dose on day one and the daily dose on each subsequent day (the latter regime takes into account the half-time of warfarin). The daily dose varies depending on body weight, sex, age, diseases and other drugs. Thus a 90 kg six foot tall man of fifty may require 12.5 mg per day while a five foot, 50 kg elderly lady may require only 2 mg.

Cardiac Glycosides

These have a positive inotropic effect and reduce the size of a failing dilated heart leading to increased cardiac output and increased efficiency. They increase myocardial excit-ability and automaticity, depress conducting tissue and increase vagal activity. Digoxin’s half-life is more than 24 hours. The therapeutic blood level is 0.8 to 2.0mg/ml.

General Indications

(Digoxin)

Cardiac failure, atrial fibrillation, atrial flutter, paroxysmal atrial tachcardia.

Cautions/Side Effects

(Digoxin)

These usually occur at toxic serum levels above 2.0 mg/ml, but may do so in the therapeutic range especially in the elderly. Fatigue, anorexia,

nausea, visual disturbances, muscle weakness, psychic symptoms, abdominal pain, dizziness, vomiting, cardiacdisturbance - heart block,cardiac arrhythmias. Tocicity most likely with hypokalemia. Treat digoxin - induced heart block with atropine; PVC’s and ventricular tachycardia with i.v. phenytoin. These drugs must be used with caution:

(1) following acute myocar-dial infarction;

(2) within 14 days of previous treatment with cardiac glycosides;

(3) in the presence of Quinidine treatment;

(4) in the presence of severe potassium imbalance;

(5) in renal insufficiency and in the elderly (most of whom have some renal impairment).

These drugs may act at any combination of the following sites:

1. The vessel wall unrelated to nerve ending e.g. diazoxide, hydrallazine, nitrates, nitrities.
2. The sympathetic receptor - Beta blockers, e.g. propranolol, metoprolol.
3. The post ganglionic sympathetic nerve endings e.g. guanethidine, reserpine.
4. Sympathetic autonomic ganglia.
5. The CNS (the brain stem) e.g. reserpine, methyl-dopa.
6. Blood volume.

TREATMENT PROTOCOL ANGIOTENSIN CONVERTING ENZYME INHIBITORS

Angiotensin - converting enzyme inhibitors inhibit the conversion of angiotensin I to angiotensin II therapy causing peripheral vasodilation. They also block the production of aldosterone resulting in sodium and water excretion and the retention of potassium. They should be used when thiazides and beta-blockers are contraindicated or where they fail as first line therapy.

ACEIs may cause a rapid fall in blood pressure in some patients on thiazides, therefore discontinue thiazides 3 days before starting therapy with an ACEI. Even though ACEIs have greater activity in patients with high renin levels, low doses of ACEIs and thiazides produce a similar effect in patients with low renin levels.

ACEIs have been shown to reduce mortality in heart failure. May cause some regression of left ventricular hypertrophy. Use with caution in patients with renal disease as ACEIs may occasionally cause impairment of renal function.

ACEIs may cause fetal or neonatal death or injury when used during the second or third trimester of pregnancy. When pregnancy is detected discontinue the ACEI as soon as possible.

DRUG INTERACTIONS

1. Loop and Thiazide Diuretics: Postural hypo-tension.
2. Potassium Sparing Diuretics\Potassium Supplements|Trimetho-prim: hyperkalemia. Monitor potassium level. Caution patients against use of potassium containing salt substitutes or diet supplements.
3. Allopurinol: Steven Johnson’s Syn-drome, skin erup-tions, anaphylactic coronary spasm. Monitor patients for hypersentivityreac-tions e.g. pruritus, chest pain, hypoten-sion or broncho-spasm

Calcium Channel Blockers interfere with the inward displacement of calcium ions through the slow channels of active cell membranes. They influence the myocardial cells, the cells within the specialized conducting system of the heart, and the cells in vascular smooth muscle.

There are important differences between the types of calcium channel blockers available as exhibited by a phenylalkylamine (verapamil), the dihydropyridines (nifedi-pine, amlodipine, felodipine, lacidipine, isradipine) and benzothiazepine (diltiazem). Verapamil is used for the treat-ment of angina, hypertension and arrhythmias. Nifedipine has more activity on the smooth muscles and blood vessels than on the myocardium. Hence it is used for angina and hypertension. Isradipine has a similar action to nifedipine but is only indicated for mild to moderate hypertension.

Diltiazem 60mg is for the prophylaxis and treatment of angina. Calcium Channel Blockers have greater activity in patients with low rennin levels. Verapamil should be used with extreme caution in combination with beta-blockers. Though gingival hyperplasia is a rare side effect, patients on long term Calcium Channel Blockers should have a good dental hygiene program. DIAZOXIDE:- A thiazide without diuretic actions; potent antihypertensive which acts by decreasing arteriole peripheral resistance with little effect on veins. Used chiefly to obtain immediate control of severe hypertension and must be given rapidly i.v. as it is so extensively bound to plasma proteins. HYDRALAZINE:-Used in severe hypertension and as a vasodilator afterload in intractable heart failure. It reduces peripheral resistance by relaxing arterioles with little effect on veins. The compensatory sympathetic discharge induced by the hypotension causes reflex tachycardia and increased cardiac output. It must therefore be used with a beta blocker and a diuretic in treating hypertension. This does not occur in the case of the failing heart.