2022 MB

Explain the reasons why you may want to administer a drug to a patient
through a particular route of drug administration

Most drugs can be administered by a variety of routes. The choice of appropriate route in a given
situation depends both on drug as well as patient related factors. Mostly common sense
considerations, feasibility and convenience dictate the route to be used.

Factors governing choice of route

1. Physical and chemical properties of the drug (solid/liquid/gas; solubility, stability, pH, irritancy).

2. Site of desired action—localized and approachable or generalized and not approachable.

3. Rate and extent of absorption of the drug from different routes.

4. Effect of digestive juices and first pass metabolism on the drug.

5. Rapidity with which the response is desired (routine treatment or emergency).

6. Accuracy of dosage required (i.v. and inhalational can provide fine tuning).

7. Condition of the patient (unconscious, vomiting).

Explain the term “Area under Curve”

AREA UNDER CURVE (AUC): is a common measure of the extent of bioavailability of a drug given by a
particular route.

The total amount of drug in the systemic circulation is defined by the AUC.

AUC Oral vs I.V

The AUC is expressed as 1 when the drug is adminstered intravenuosly ( ie there is 100% absorption) but
the AUC is expressed as less than 100% when the drug is adminstered orally for two reasons which are :

incomplete absorption and first pass elimination

Incomplete absorption: orally adminstered drugs may be incompletely absorbed due to lack of
absorption through the gut wall, the drug being too hydrophilic or the drug being too lipophilic or due to
a reverse transporter associated with p- glycoprotein (this process pumps drugs out of the gut wall into
the gut lumen).

First pass metabolism: following absorption through the gut wall, the portal blood delivers the drug to
the liver before entering the systemic circulation. The liver now metabolizes the drug before it enters
into the cirulation. Also, the liver can excrete the drug into the bile. These processes will reduce the
bioavailability of the drug at the site of action. The drug can also be metabolized by the gut wall by
cytochrome enzymes (Cyp3A4 enzymes) found in the gut wall

Classify diuretic agents

2021 MB

1.
Classification of Oral Anti-Diabetic agents

Classes of Drugs used in treatment of Heart Failure

Clinical syndrome that can result from any structural or functional cardiac disorder that

impairs the abilty of the ventricle to fill with or eject blood.

INOTROPIC DRUGS

• Cardiac glycosides:

• Digoxin, digitoxin

• Sympathomimetic amines:
 • Dopamine , dobutamine

• Phosphodiesterase inhibitors:

• Amrinone , milrinone

VASODILATORS

Arteriolar: hydralazine , minoxidil, nicorandil

Venodilators: nitrates

Arteriolar and venodilators: ACE inhibitors, angiotensin receptor blockers

DIURETICS

Loop diuretics: furosemide, torsemide

Thiazide diuretics: hydrochlorthiazide

K+ Sparing diuretics: Spironolactone (Also is aldosterone antagonist), Amiloride

BETA BLOCKERS

Metoprolol, bisoprolol, carvedilol

• Acetazolamide
RELATIONSHIP BETWEEN FIRST PASS METABOLISM AND BIOAVAILABILIY

• 1) Drugs that are extensively metabolized have poor bioavailability after first pass metabolism.

• ˃ Eg Glyceryl trinitrate (nitroglycerin) which is used to treat angina. Because of its high first
pass metabolism, it is not effective when taken orally but has to be given sublingually. Therefore
larger doses of the drug has to be taken in other to increase the blood levels of such drug in the
system.

• 2) On the other hand, drugs with high first pass metabolism have very high bioavailability in the
blood in cases of liver diseases.

• ˃ eg in liver Cirrhosis:

• ↓ drug metabolism → ↑ bioavailability of drug in the system → ↑ Drug effect →toxicity.

 • EFFECT OF FOOD ON ORAL DRUG ABSORPTION: Food affects absorption and first pass
metabolism in opposite ways. While Food increases the (F) of drugs that are subject to high first
pass eg grapefruit, food usually decreases the (F) of drugs that are poorly absorbed. Food can
affect oral drug absorption in the following ways:

• › some drugs require acid environment to enhance absorption eg ketoconazole

• › Presence of fat or bile enhance absorption for some drugs eg carbamazepine

• › binding to fibre reduces absorption eg digoxin

• › binding to calcium (chelate) reduces absorption eg tetracyclines, quinolones.

• › poor acid stability : prolonged gastric exposure → degradation, therefore reducing absorption
in some drugs eg erythromycin , azithromycin.

• FIRST PASS METABOLISM OF ORAL DRUGS : This occurs in the liver and gut lumen.

• First pass metabolism in gut lumen:

• › Gastric acid inactivates benzylpenicillin

• › Proteolytic enzymes inactivate insulin.

• First pass metabolism in gut wall:

• Monamine oxidase → metabolises monoamine

• 1) CYP3A4:

• This enzyme in the gut wall can be blocked by grapefruit juice

• Also by some drug inducers, inhibitors, substrates.

• If 40mg simvastatin is adminstered with water, the extent of absorption will be low but if the
same drug is adminstered with grapefriut, then the extent of absorption will be high.

Administration of 40mg
Simvastatin with

◦ Water

• Grapefruit juice

• P- glycoprotein (enterocytes to gut lumen):

• Interactions between inhibitors (eg verapamil, macrolides) and substrates (eg digoxin).

• In the graph below, adminstering 0.75mg of digoxin with a placebo will decrease the rate of
absorption and adminstering with clarithromycin will increase the rate of absorption

• HEPATIC FIRST PASS METABOLISM: Hepatic first pass metabolism reduces the amount of parent
drug and forms metabolites

Administration of 0.75mg digoxin with

◦ placebo

• clarithromycin

WRITE SHORT NOTE ON 5a REDUCTASE INHIBITOR

4A. Uses of androgens:

• Male hypogonadism.

• Treatment of endometriosis.

• Management of breast engorgement.

• Management of anemia.

• Perfomance enhancer in sports.

• Growth stimulant in boys with delayed puberty

• Catabolic and wasting states.

• Angioedema.

• Male contraception.

B. 5α-reductase inhibitors

Finasteride

• Blocks the conversion of testosterone to DHT.

• Onset of action is about 8 hours and lasts for about 24 hours.

• Half-life is about 8 hours.

• Developed for treatment of BPH.

• Also approved for the treatment of male pattern baldness.

• Also effective for treatment of hirsutism.

• Impotence is an important side effect of its use.

5. CLASSIFICATION OF NEUROMUSCULAR BLOCKERS

Based on the mode of action, these drugs are classified basically into two, namely:

Depolarizing and non-depolarizing neuromuscular blockers.

Depolarizing neuromuscular blockers E.g-Suxamethonium (succinylcholine), Decamethonium

Non-Depolarizing Neuromuscular blockers

There are two groups of non-depolarizing neuromuscular blockers; benzylisoquinolinium compounds

and aminosteroid compounds.

Benzylisoquinolinium Compounds-1

Examples include tubocurarine, atracurium, cisatracurium and mivacurium

Aminosteroid Compounds-1

 Examples include pancuronium, Vecuronium and Rocuronium.

Mode of action of suxamethonium

 It binds to the postsynaptic nicotinic receptor at the neuromuscular junction, mimicking

acetylcholine action and resulting in persistent membrane depolarization.

 Depolarization causes muscle contraction, which occurs rapidly and is observed clinically as
muscle fasciculation.

 However, persistent depolarization leads to neuromuscular impairment and a state of flaccid

paralysis occurs.

 Suxamethonium results in a Phase I block, characterised by absence of fade and post-tetanic

facilitation on peripheral nerve stimulation.

Therapeutic Indication of Suxamethonium

 It the drug of choice for anaesthesia when a rapid sequence induction is used for patients at
risk of aspiration,

 or when rapid tracheal intubation is required in an emergency situation.

 It is also indicated when rapid recovery of neuromuscular function may be needed.

1. DRUGS USED IN TREATMENT OF HYPERTENSION
Diuretics:
a. Thiazides: Hydrochlorothiazide, chlorthalidone
b. High ceiling: Furosemide
c. K+ sparing: Spironolactone, triamterene and amiloride
MOA: Acts on Kidneys to increase excretion of Na and H2O – decrease in blood volume –
decreased BP
 Angiotensin-converting Enzyme (ACE) inhibitors:
◦ Captopril, lisinopril., enalapril, ramipril
MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral resistance and blood volume
 Angiotensin (AT1) blockers:
◦ Losartan, candesartan, valsartan and telmisartan
MOA: Blocks binding of Angiotensin II to its receptors
• Centrally acting:
• Clonidine, α-Methyldopa
MOA: Act on central α2A receptors to decrease sympathetic outflow – fall in BP
• ß-adrenergic blockers:
• Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)
• Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)
MOA: Bind to beta adrenergic receptors and blocks the activity
• ß and α – adrenergic blockers:
• Labetolol – used in hypertensive emergencies
• α – adrenergic blockers:
• Prazosin, terazosin, doxazosin, phenoxybenzamine and phentolamine
MOA: Blocking of alpha adrenergic receptors in smooth muscles - vasodilatation
• Calcium Channel Blockers (CCB):
• Verapamil, diltiazem, nifedipine, felodipine, amlodipine, nimodipine
MOA: Blocks influx of Ca++ in smooth muscle cells – relaxation of SMCs – decrease BP
• K+ Channel activators:
• Diazoxide, minoxidil, pinacidil
MOA: Leaking of K+ due to opening – hyper polarization of SMCs – relaxation of SMCs
• Vasodilators:
• Arteriolar – Hydralazine (also CCBs and K+ channel activators)
• Arterio-venular: Sodium Nitroprusside
2. ADVERSE EFFECTS OF INSULIN THERAPY
 Hypoglycaemia
 Modest weight gain
 Allergic reactions to recombinant human insulin or because of sensitivity to a
component added to insulin in its formulation e.g protamine, zinc
 Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy)
 Enlargement of subcutaneous fat depots (lipohypertrophy)
THERAPEUTIC USES OF GONADOTROPINS

THYROID STORM

• A sudden exacerbation of symptoms of thyrotoxicosis, characterized by fever, sweating,

tachycardia, extreme nervous excitability, and pulmonary edema. It is a life-threatening
emergency
• Precipitated by infection, trauma, toxemia of pregnancy

• It is treated by iv propranolol, propylthiouracil and steroids (hydrocortisone/prednisolone)

rG-CSF (filgrastim)

• 175 aa glycoprotein produced in E. coli.

• Not glycosylated.

• Stimulates of CFU-G to increase neutrophil production.

• Also enhances the phagocytic and cytotoxic functions of neutrophils.

Uses:

• Treatment of severe neutropenia after autologous hematopoietic stem cell transplantation and
high-dose cancer chemotherapy.

• Treatment of severe congenital neutropenias.

• Myelodysplasia or marrow damage.

• AIDS.

• Mobilization of CD34-positive progenitor cells for peripheral blood stem cell collection for
transplantation after myeloablative chemotherapy.

• Administration is by intravenous infusion or subcutaneous injection of 1-20μg/kg/day (over 30

minutes for iv infusion).

• T1/2 is 3.5 hrs.

Side effects

• Bone pain

• Skin reactions.

• Granulocytosis.

• Splenomegaly.

Pegylated recombinant human G-CSF (pegfilgrastim).

• Minimal glomerular filteration.

• Longer half life than filgrastim.

• Dose is 6mg s/c.

Advantages of oral route of drug administration
1. It is the simplest, most convenient, and safest means of drug administration.
 2. It is convenient for repeated and prolonged use.

3. It can be self-administered and pain-free.

4. It is economical since it does not involve the patient in extra cost. Where the drug is a
solid e.g., tablet and capsule, the patient needs just one or two cups of water, which in
most cases is freely available. If the drug is in liquid form, nothing is needed except a
measuring tool that comes with the drug in most cases.

5. No sterile precautions needed.

6. Danger of acute drug reaction is minimal

Disadvantages of oral route of drug administration

1. It is not suitable for emergency as onset of action of orally administered drugs is
relatively slow.

2. It can only be used in conscious patients and those patients who can swallow.

3. It requires patient’s cooperation or compliance, especially outpatients.

4. It is not suitable for:

a. unpalatable and highly irritant drugs

b. drugs that are destroyed by gastric acid and digestive juices (e.g., insulin)
c. drugs with extensive first-pass metabolism (e.g. lignocaine, imipramine)
d. patients with severe vomiting and diarrhea.

5. Oral route of drug administration is sometimes inefficient as absorption is in most

cases irregular and incomplete.

6. Changes in drug solubility can result from reactions with other materials present in
the gastrointestinal tract e.g., the interference of absorption of tetracyclines through the
formation of insoluble complexes with calcium, which can be available from dairy
products or formulation additives.
CARBONIC ANHYDRASE INHIBITORS

• Carbonic anhydrase is present in many nephron sites, but the predominant location of this
enzyme is the luminal membrane of the proximal tubule cells , where it catalyzes the
dehydration of H2CO3, a critical step in the reabsorption of bicarbonate.

• By blocking carbonic anhydrase, inhibitors block sodium bicarbonate reabsorption and cause
diuresis.

• The carbonic anhydrase inhibitors were the forerunners of modern diuretics

PHARMACOKINETICS

• The carbonic anhydrase inhibitors are well absorbed after oral administration.

• An increase in urine pH from the bicarbonate diuresis is apparent within 30 minutes, maximal at
2 hours, and persists for 12 hours after a single dose.

• Excretion of the drug is by secretion in the proximal tubule segment.

• Therefore, dosing must be reduced in renal insufficiency

PHARMACODYNAMICS

• Inhibition of carbonic anhydrase activity profoundly depresses bicarbonate reabsorption in the

proximal tubule.

• At its maximal safely administered dosage, 85% of the bicarbonate reabsorptive capacity of the
superficial proximal tubule is inhibited.

• Some bicarbonate can still be absorbed at other nephron sites by carbonic anhydrase–
independent mechanisms, and the overall effect of maximal acetazolamide dosage is about 45%
inhibition of whole kidney bicarbonate reabsorption.

• Nevertheless, carbonic anhydrase inhibition causes significant bicarbonate losses and

hyperchloremic metabolic acidosis.

• Because of this and the fact that HCO3 - depletion leads to enhanced NaCl reabsorption by the
remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with
use over several days

EXAMPLES

• Acetazolamide

• Dichlorphenamide

• Methazolamide
INDICATION

• Glaucoma

• Urinary Alkalinization

• Metabolic Alkalosis

• Acute Mountain Sickness

• Renal Potassium Wasting

CONTRAINDICATION

• Carbonic anhydrase inhibitor-induced alkalinization of the urine will decrease urinary excretion
of NH4+ and may contribute to the development of hyperammonemia and hepatic
encephalopathy in patients with cirrhosis
7a. Organophosphate

b. Cholinesterase inhibitor
FEMALE CONTRACEPTION

ORAL

 Combined pill
 Phased regimens
 Minipill (Pregestin Only Pill)
 Postcoital (emergency) contraception (Levenorgestrel, Mifepristone)

INJECTABLE

MALE CONTRACEPTION