LECTURE 2

12 things to ascertain about a drug

Whenever you are introduced to a drug make it a habit to ascertain the following parameters about the drug.

1] Generic or chemical name & Proprietary or brand name(s)

2] Chemical structure

3] Mechanism of action

4] Adsorption, Distribution, Metabolism & Excretion of the drug [A D M E]

5] Onset of action.

6] Duration of action

7] Half life (ti/2

8] Its effects

9] Indications or clinical uses

10) Side effects or adverse reactions

11] Contraindications

12] Drug Interactions

13] Dosage/Preparations

14] Advantages Or Disadvantages When ever we discuss a drug together we will try to use this format.

IN THIS DISCUSSION WE WILL BE STRESSING

PRINCIPLES.

Examples will be given to support the argument.

Try not to miss the beauty of “the woods as a whole”

because you are concentrating on the “details of the

trees.”

Get the principles first.

The facts and the details will fit into the puzzle

gradually as the information is gradually presented to

you, and you get a more complete grasp of

Pharmacology.

• 1- Every drug has a generic or chemical name, which

often tells us some thing about the chemistry of the drug.

In addition, the generic name of a drug allows physicians,

pharmacologists and other health professionals to have a

universal nomenclature for a specific chemical formulation.

For example paracetamol, or acetamenophen is the name

of a commonly used non steroidal anti inflammatory drug.

These names allow us to identify this chemical compound

anywhere we go in the world.

Generic names are used universally and allow for

international discussion on pharmaceuticals.

Structure of paracetamol

(acetamenophen).

Proprietary or brand name(s). • Drugs also have Proprietary or brand name(s). This is a name or

identification given by drug manufacturers to isolate their product from other similar chemical formulations.

• A Proprietary or brand name is a name used to sell, prevent copying and label drugs.”

• For example in the Caribbean and British Commonwealth, paracetamol (acetamenophen) is available as Calpol, Panadol, Cetamol, Paramol.

• In the USA, acetamenophen is marketed as Tylenol among others.

• You will pick up information on proprietary or brand names for your area when you see visiting drug representatives, and in publications like MIMS, or Physicians Desk Reference etc.

• It is not easy to keep up with all the brand names of a particular drug but it is helpful to be aware of those that are available in your, community, state, country etc. as is most relevant to you.

• GENERALLY WE DISCUSS DRUGS BY THEIR GENERIC OR CHEMICAL NAMES

2) Chemical Structure

The chemical structure of a drug allows us predict the drugs

physical and chemical properties and behavior, and allows us to

determine how we should proceed to make improvements, or add

to drugs in this class.

Look at the structures of the drugs below.

What do they have in common?

Do you think these drugs are all in the same class?

Why do you think so?

Here are some structures of some common oral hypoglycaemic

agents all in the same class. We call them the sulphonyl ureas.

The structure of some popular beta blockers or beta adrenergic receptor

antagonists appears below.

• Beta adrenergic antagonists or beta blockers are indicated in the treatment of

• hypertension,

• prophylaxis of angina pectoris,

• prophylaxis of supraventricular and ventricular arrhythmias,

• long term prophylaxis of patients who have had a myocardial infarction and are at high risk for infarction or sudden death,

• prophylaxis of migraine headaches,

• management of hypertrophic obstructive cardiomyopathies to reduce the force of cardiac contractions,

• management of hyperthyroidism and anxiety states to decrease the heart rate.

• Some common beta blockers are propranolol (Inderal), atenolol (Tenormin), metoprolol (Lopressor), nadolol (Corgard), and timolol (Blocadren), betaxolol (Betoptic), cartelol (Ocupress), and timolol (Timoptic), labetalol (Normodyne), Pindolol

• The Structure of Angiotensin-converting enzyme (ACE) inhibitors.

• Accupril, Captopril, Enalapril, Lisinopril,Quinapril are the names of some commonly used Angiotensin-converting enzyme (ACE) inhibitors.

• These drugs are used inter alia for management of hypertention, as first line therapy for CHF, as well as to increase the survival rate among patients with moderate to severe CHF, post myocardial infarction to lessen the progressive enlargement of the left ventricle.

• ACE inhibitor therapy appears to be the most promising approach to slowing the development and progression of nephropathy in patients with type 2 diabetes (formerly known as non-insulin-dependent diabetes).

Structure of the Histamine H 2 -receptor antagonists. I love

to call them the “tidines.” Note the similarities, and the

differences in their structures.

• Histamine H 2 -receptor antagonists, also known

as H 2 -blockers, are used to treat duodenal ulcers

and prevent their return.

• They are also used to treat gastric ulcers and for

some conditions, such as Zollinger-Ellison

disease, in which the stomach produces too much

acid.

• In over-the-counter (OTC) strengths, these

medicines are used to relieve and/or prevent

heartburn, acid indigestion, and sour stomach.

• Clearly we will not go around committing to memory

the chemical structures of all the preparations we

use.

• But it helps when some one presents to us with

some vials of medication, and the labels state ****lol

or ****tidine or ***pril.

• We immediately realize that the patient is taking

respectively, a Beta blocker, an H2 antagonist for a

stomach ailment, or an ACE inhibitor.

• Clearly too, you can see that this simple information

can give us valuable information in our history

tasking efforts.

• We will learn more about the chemical structure of

drugs and their significance as we continue our

studies

• 3. The Mechanism of action tells us HOW the drug works.

• It is the mechanism or way by which a drug exerts is effect

• This is very important information because it allows us to make intelligent decisions for employing the drug from a physiological perspective.

• For example, Enalapril (an ACE inhibitor) competes with the natural substrate, angiotensin I, thereby inhibiting its conversion to angiotensin II.

• Beta agonists activate the beta receptors of the smooth muscle of the bronchi, linked by an activating enzyme GS, to result in stimulation of adenyl cyclase and increased camp in these muscle cells. The increase in cAMP results in a powerful bronchodilator response.

• The Methylxanthines produce bronchodilatation by inhibiting phosphodiesterase(PDE), the enzyme that degrades camp to AMP.

• Ipratropium competitively blocks muscarinic receptors in the respiratory airway to effectively prevent the bronchoconstriction mediated by vagal discharge.

• Disodium cromoglycolate (Cromolyn) appears to decrease the release of mediators such as leukotrienes and histamine from mast cells in order to prevent bronchoconstriction in the airways (its effect).

• By binding to intracellular receptors glucocorticoids activate glucocorticoid response elements (GREs) in the nucleus, resulting in synthesis of substances that prevent the full expression of inflammation and allergy.

• Zafirlukast is an antagonist at the LTD4 and LTE4 leukotriene receptor sites.

• NOW ALL OF THESE DRUG CLASSES ARE USED TO

OVERCOME BRONCHOCONSTRICTION IN

ASTHMATICS…………

• BUT ALL OF THEM WORK BY DIFFERENT MECHANISMS

OF ACTION

• We must try to distinguish mechanism of action from the effects of the drug- although these often seem to be the same.

• For example, Beta agonists stimulate the beta receptors in the bronchioles (its mechanism of action) to cause bronchodilataton(its effect).

• Similarly, Cisapride is indicated for the treatment of gastroesophageal reflux disease (GERD).

• With respect to its mechanism of action, Cisapride promotes acetylcholine release from postganglionic nerve endings in the myenteric plexus- longitudinal muscles of the GI tract, thereby indirectly improving gastrointestinal motility.

• The exact mechanism by which cisapride exerts its prokinetic effects is not known. It has been shown that it acts as both an agonist and antagonist at serotonin receptors throughout the GI tract. Cisapride is an agonist at type 4 serotonin (5-HTA) receptors and is an antagonist at type 3 serotonin (5-HTA) receptors. It is believed that the prokinetic effects of cisapride are due more to actions at the 5-HTA receptor.

• The resultant clinical effects seen with cisapride therapy which contribute to the relief of symptoms and the healing of lesions associated with reflux disease include

• decreased exposure of the esophagus to gastric acid,

• increased lower esophageal sphincter pressure and esophageal motility,

• accelerated gastric emptying of both liquids and solids, and

• decreased colonic transit time.

• 4. Adsorption, Distribution, Metabolism & Excretion of the drug [A D M E]

• Knowledge of the method of adsorption ( the method by which the drugs gets into the circulation to exert an effect) allows us to use the appropriate route of administration of the drug to achieve our particular immediate aim.

• Knowledge of the method of the drugs distribution and thus its concentration or drug levels in the circulation at any point in time, allows us to decide the drug effectively, and specifically.

• For example, if an antibiotic seems to have an affinity for adsorption or distribution in the brain, and tends to concentrate there we would choose that drug preferentially in treating infections of the brain tissue.

• If a drug is concentrated in the bone, it would facilitate treatment of bone conditions for which the drug might be indicated.

• Knowledge of the drugs metabolism allows us to chose the drug preferentially above others in a particular indication.

• We would not exhibit drugs that are metabolized preferentially in the liver, if the patient has a liver ailment, nor would we use drugs that are metabolized preferentially in the kidney, if the patient has a kidney problem.

• Knowledge of the drugs excretion (the route in which the drug is cleared form the body ) allows us to make an intelligent choice about drugs in a particular drug class for a specific patient.

• If the drug is excreted by the kidney and the patient has a renal problem, we might chose preferentially its competitor in the same class which is not excreted via the kidneys mainly.

• On the other hand we might use a drug that is excreted exclusively by the kidney into the urine for a bladder condition.

• 5- The Onset of action of a drug is the amount of time it takes a drug to begin working.

• The onset of action of a drug may be influenced by its route of administration.

• Drugs given intravenously generally have a more rapid onset than drugs taken orally, since oral agents must be absorbed and pass through the gut before entering the blood stream.

• 6) The Duration of action of a drug is the length of time for which the drug has its therapeutic effect.

• The duration of action usually corresponds to the half life of the drug [except when the drug binds irreversibly to its receptor] and is dependent on metabolism and excretion of the drug.

• The duration of Drug Action

• - can continue just until an agonist leaves or is removed from a receptor

• - or can continue after an agonist leaves or is removed, when a coupled effector is still active in the cell

• - in the case of covalently bound drug/receptor complexes or combinations, may be required to be destroyed before the action stops

•

• 7) The half life of a drug (t1/2) is an expression used to describe the rate at which a drug is removed from the body.

• It is the time it takes half of the drug to be cleared by the body metabolizing the drug.

• The half life of a drug is the time taken for the amount of drug in the body [or the blood or plasma concentration] to decline to half its value, and is related to the elimination rate constant by tl/2 0.693/k.

• The half life provides an estimate of the time required to reduce by one half the quantity of drug present in a particular body compartment (e.g. the plasma).

• Not only is a knowledge of the half life of a drug valuable in allowing a comparison between the elimination rates of several drugs, it is also useful in establishing dosage schedules within its therapeutic range.

• The half life of a drug depends simultaneously on both the clearance rate (inversely) and the volume of distribution (directly). Thus if the clearance rate is large the half life is shortened; if the volume of distribution is large, the half life is longer.

• 8) The effects of a drug describes WHAT the drug does -its actions.

• For example Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity.

• Thus, when enalapril lowers angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases. In addition, baroreceptor reflex mechanisms are stimulated in response to the fall in blood pressure.

• ACE-inhibiting drugs can act locally to reduce vascular tone by decreasing local angiotensin II-induced sympathetic and/or vasoconstrictive activity.

• ACE inhibitors also can inhibit presynaptic norepinephrine release and postsynaptic adrenergic receptor activity, decreasing vascular sensitivity to vasopressor activity even though this action may not be clinically evident at usual doses. Decreases in plasma angiotensin II levels also reduce aldosterone secretion, with a subsequent decrease in sodium and water retention.

• Enalapril causes arterial dilation, thereby lowering total peripheral vascular resistance. In hypertensive patients, blood pressure is decreased with little or no change in heart rate, stroke volume, or cardiac output.

• However, in patients with heart failure, enalapril increases cardiac output, cardiac index, stroke volume, and exercise tolerance. The drug also decreases pulmonary wedge pressure, pulmonary vascular resistance, and mean arterial and right atrial pressures in these patients.

• 9) The Indications or clinical uses of a drug are the purposes for which the drug is prescribed or used.

• For example, Enalapril is an oral and parenteral angiotensin- converting enzyme (ACE) inhibitor used ( or indicated) in the treatment of hypertension and congestive heart failure

• Metranidazole (Flagyl), is indicated in the treatment of T. Vaginalis, amebiasis, leishmaniasis, and in infections caused by anaerobic bacteria such as Bacteroides, clostridia, some streptococci, and in the therapy of pseudomonas colitis, a clostridial infection sometimes associated with antibiotic therapy.

• 10 Adverse reactions or side effects are actions or effects of a drug that are unpleasant, often causing the drug to be discontinued or which might lead to poor compliance in the use of the drug.

• For example, common adverse reactions associated with cisapride therapy are headache, nausea/vomiting, abdominal pain, rhinitis, diarrhea, and constipation, flatulence, dyspepsia, sinusitis, coughing, viral infection, upper respiratory tract infection, pain, fever, urinary tract infection, urinary frequency, insomnia, anxiety, nervousness, rash, pruritus, arthralgia, abnormal vision, vaginitis, dizziness, vomiting, pharyngitis, angina, fatigue, back pain, depression, dehydration, and myalgia.

• Often adverse reactions are dose related. For example, the side effects described for cisapride occur more frequently in patients receiving 20 mg of cisapride than in those receiving 10 mg.

• It is important to instruct our patients to call the doctor as soon as they can for appropriate advice if they get any side effects.

• Patients must be instructed to look out for known adverse effects of the drugs we prescribe, and to let their doctor know about these side effects if they do not go away or if they annoy them..

• 11) Contraindications/Precautions:

• Contraindications of a drug are “the areas in which using the drug put the patient at risk for an adverse effect.”

• Many drugs must not be used in pregnancy as they can be deleterious to the fetus.

• It has been known that external agents can affect foetal development since about 1920, when it was discovered that X irradiation during pregnancy could cause foetal malformation or death,

• Nearly 20 years later the importance of rubella infection was recognised, but it was not until 1960 that drugs were implicated as causative agents in teratogenesis: the shocking experience with thalidomide led to a widespread reappraisal of many other drugs in clinical use, and led to the setting up of drug regulatory bodies in many countries.

• The majority of birth defects (about 70%) occur with no recognizable causative factor.

• Drug or chemical exposure during pregnancy are believed to account for only about I% of all foetal malformations. While this percentage may appear small, the total numbers are substantial and result in appalling suffering as well as major social and economic effects on families and the community.

• I therefore, urge you to see that the axiom in medicine that : "All women of childbearing age are pregnant until proven otherwise" is very relevant to us all when prescribing as well.

• Some drugs are therefore not given to pregnant mothers at all, and some are given only when clearly needed (e.g. cisapride).

• Some drugs are not given to lactating mothers because these are drugs are found to be excreted into breast milk. For example, since cisapride is excreted into breast milk at a concentration of about one twentieth that found in maternal plasma, caution is advised in prescribing cisapride to breast-feeding women.

• Some drugs are not given (they are contraindicated) because they may harm the patient. For example, the use of cisapride in patients in whom increased gastrointestinal motility can be harmful is not recommended. These patients include those with GI bleeding, GI obstruction, or GI perforation.

• Some drugs are not given (they are contraindicated) because the patients have a known sensitivity or intolerance to the drug. Cisapride is an example of such a drug.A careful patient history should therefore be taken to determine previous cisapride intolerance or sensitivity.

• Some drugs are given with great care because of reported adverse reactions with the preparation. For example, since rare cases of cardiac arrhythmias have been reported, Cisapride should be used with caution in patients with conditions associated with QT prolongation, such as congenital prolonged QT syndrome, uncorrected electrolyte imbalance, or patients taking medications known to prolong QT intervals.

• 12) Dosage/Preparations

The term preparation refers to the way a drug is

prepared to deliver the most effective dose at a

safe therapeutic level.

• Drug manufacturers usually indicate the dosages

for which the drug ought to be given, as well as

their available preparations of the drug. For

example Panadol is available as a syrup or elixir for

children, and as tablets of strength 250 mgs, or 500

mgs etc.

• Some preparations are available in a slow release

form, or as suppositories, or are packaged in

ampoules ready prepared, or in a form that needs

to be constituted for injection.

• 13) Drug Interactions

• Note (and patients often enquire) that certain medicines should not be used together at all, because drug interaction might either increase, or decrease the efficacy of a drug. For example, when prescribing drugs to folk receiving H 2 -blockers it is especially important that we, as health care professional know if the patient is taking any of the following:

• Aminophylline (e.g., Somophyllin) or Anticoagulants (blood thinners) or Caffeine (e.g., NoDoz) or beta blockers (e.g., Lopressor) or Oxtriphylline (e.g., Choledyl) or Phenytoin (e.g., Dilantin) or Propranolol (e.g., Inderal) or Theophylline (e.g., Somophyllin-T) or Tricyclic antidepressants (amitriptyline [e.g., Elavil], amoxapine [e.g., Asendin], clomipramine [e.g., Anafranil], desipramine [e.g., Pertofrane], doxepin [e.g., Sinequan], imipramine [e.g., Tofranil], nortriptyline [e.g., Aventyl], protriptyline [e.g., Vivactil], trimipramine [e.g., Surmontil])—

• Use of these medicines with cimetidine has been shown to increase the effects of cimetidine. This is less of a problem with ranitidine and has not been reported for famotidine or nizatidine. However, all of the H 2 -blockers are similar, so drug interactions may occur with any of them

• Itraconazole (e.g., Sporanox) or Ketoconazole (e.g., Nizoral)--H 2 -blockers may decrease the effects of itraconazole or ketoconazole; H 2 -blockers should be taken at least 2 hours after these medicines.

• Similarly, the concurrent use of cisapride with anticholinergics is not recommended.

• The antimotility effects of drugs with anticholinergic activity will antagonize the beneficial GI effects of cisapride. Drugs with antimotility activity that should be avoided during therapy with cisapride include antispasmodic anticholinergics such as atropine, dicyclomine, and propantheline; certain HA-blockers; opiate agonists; and certain tricyclic antidepressants.

• When cisapride is administered concurrently with either cimetidine or ranitidine, the gastrointestinal absorption of cimetidine or ranitidine is increased. Also, cisapride's peak plasma levels and AUC are increased when coadministered with cimetidine, but not with ranitidine.

• 14) Advantages Or Disadvantages • Use this heading for comparing features of drugs in the same

class, or if the drug is new or in a new sub class and offers benefits over older drugs which may or may not have become obsolete.

• When a drug representative visits you with a new preparation of a drug in any class, how will you decide if to use this drug?

• I review the parameters discussed above to see what advantages can be achieved over the drugs in that class which I am already accustomed. I want to decide what disadvantages they might be that might influence patient compliance, or the patient’s health.

• Use this heading for comparing features of drugs in a new sub class of drugs. For example, in the late seventies when Cimetidine [Tagamet] came into vogue, because of its superiority, it replaced biogastrone and licorice etc.

• So then we compared the benefits of H2 antagonists like Cimetidine [Tagamet] over the drugs which it superceded.

• Since then Ranitidine Famotidine and Nizatidine are all preparations which are currently available in this drug class, and which all have particular advantages over Cimetidine.

• In my 25 + years as a physician we have seen the introduction of subclasses for the treatment of hypertension and other cardiac conditions such as the ACE inhibitors, the calcium channel blockers

• Captopril was the first drug in this class. Enalapril is longer-acting than captopril but shorter-acting than other ACE inhibitors and is usually dosed twice daily when given orally. Neither enalapril nor enalaprilat contains a sulfhydryl group. This has implications regarding the drug's adverse reaction profile, and might influence us whether we use it or not.

• Cisapride is indicated for the treatment of gastroesophageal reflux disease (GERD). Cisapride is not only chemically similar to metoclopramide, and as effective as this agents, but cisapride lacks the central nervous system-depressant and antidopaminergic effects that can occur with metoclopramide. We might therefore prefer Cisapride over metoclopramide.

• The local anaesthetic Marcaine has both a longer

onset and duration of action than Lignocaine.

Consequently, whereas lignocaine might be

preferred in procedures where a short onset and a

short duration is required marcaine is preferred

for longer procedures , simply because though

marcaine has a longer onset of action than

lignocaine (20 mins for marcaine compared to 5

mins for lignocaine), the longer duration of action

of marcaine (hours compared to minutes for

lignocaine) makes marcaine the preferred agent

for longer surgical procedures.

• Here again we see the benefits of appreciating the

concept of both onset of action, and duration of action.

• It is noteworthy that the presence of other medical

problems may affect the use of a particular drug. We must

therefore try to ascertain from the patient if they have other

medical problems.

• For example in the case of H 2 –blockers, in…Kidney disease

or Liver disease--The H 2 -blocker may build up in the

bloodstream, which may increase the risk of side effects

• Phenylketonuria (PKU)--Some H 2 -blockers preparations

contain aspartame. Aspartame is converted to phenylalanine in

the body and must be used with caution in patients with PKU.

• The Pepcid AC brand of famotidine chewable tablets contains

1.4 mg of phenylalanine per 10-mg dose. The Pepcid RPD

brand of famotidine oral dispersible tablets contains 1.05 mg of

phenylalanaine per 20-mg dose. The Zantac brand of ranitidine

EFFERdose tablets and EFFERdose granules contain 16.84

mg of phenylalanine per 150-mg dose

• To avoid giving drugs concomitantly with other illnesses we must think of, and ask the patient if they have any of these conditions

• autoimmune disease, or suppressed immune function

• collagen-vascular disease (such as lupus)

• heart or blood vessel disease

• high blood levels of potassium

• liver disease

• low blood levels of sodium

• low blood pressure

• kidney disease

• an unusual or allergic reaction to any drugs, foods, dyes, or preservatives

• pregnant or trying to get pregnant

• breast-feeding