This document describes a case study of a 64-year-old male patient with heart failure who was prescribed digoxin. After initial improvement, he later developed side effects from high digoxin levels due to renal failure. His digoxin dose was adjusted and he stabilized. The document also covers key concepts about drug transport across membranes, ionization, and using the Henderson-Hasselbalch equation to understand how drug properties impact absorption and excretion.

1. Cardiovascular System-Theme 1
Dr. Fahad Azam
Pharmacology and Therapeutics

2. THEME 1: BREATHLESSNESS AND
SWELLING (CCF)
• CASE 1
• A 64 years old male with heart failure was put on digoxin therapy in tablet form, formulated by XYZ
pharmaceutical. Initially he was given 0.5mg 8 hourly for three days followed by 0.125mg/day.
Simultaneously he was suffering from severe cough, fever and malaise, the physician after
thorough investigations diagnosed him as a case of lower respiratory tract infection and prescribed
100mgday doxycycline initially for one week which was further extended to 10 days. The patient
suffered from diarrhea, doxycycline was discontinued, a course of metronidazole was given and
patient got cured.
•
• After few days patient presented with complaints of nausea, vomiting, fatigue, palpitations. The
dose of digoxin was increased to 0.25 mg/day and he felt better.
•
• After few years he was diagnosed for chronic renal failure, blood urea and creatinine were raised.
He developed heart sinking and palpitation. On examination, the patient had an irregular pulse.
ECG showed pulses bigeminy. Serum digoxin was 2.8 ng/ml. Digoxin therapy was stopped for three
days. KCI was administered for few days. The plasma level was now repeated and was 1ng/ml. The
dose of digoxin was adjusted to 0.125 mg /day. The patient became stable in a week.

3. LEARNING OBJECTIVES
1. Describe general principles of pharmacology, sources of drugs, routes of drug
administration, Essential Drugs concept.
2. Describe drug transport across biological membranes.
3. Relate concepts of half life of drug, plasma protein binding drug and volume of
distribution of drugs to its bioavailability.
4. Describe loading dose, steady state concentration, target concentration and
maintenance concentration and bioequivalence of drugs.
5. Describe drug excretion, clearance, zero and first order kinetic of drugs.
6. Relate drug metabolism, factors affecting drug metabolism and its clinical
significance.
7. Relate drug receptor concepts, antagonism, synergism, drug-receptor interaction
and signaling mechanism of drugs.
8. Define relation between drug concentration and response and define drug
response curves (graded and quantal).
9. Describe dose response curves, pharmacokinetic and pharmacodynamic drug
interactions, drug toxicity, therapeutic index and therapeutic window.

5. Modes of Transport Across Biological Membranes
Mechanism Direction Energy Required Carrier Saturable
Passive diffusion Down gradient No No No
Facilitated Down gradient No Yes Yes
diffusion
Active transport Against gradient Yes Yes Yes
(concentration/electrical)

6. Drug permeation is dependent on:
• Fick’s law of Diffusion:
– Solubility
– Concentration gradient
– Surface area
– Vascularity
– Thickness

7. Henderson-Hasselbalch equation
[protonated]
log ______________ = pKa -pH
[unprotonated ]

8. • Drugs are either weak bases or weak acids
(depending on their pKa) and can exist in
either ionized or non ionized form (depending
on their pKa and pH of the environment)
• Ionized = water soluble
• Non ionized = lipid soluble

9. • pKa is the intrinsic value of a drug, it does not
change
• pKa is the pH at which the drug or molecule is
50% ionized and 50 % non ionized

10. Clinical Application of Henderson-Hasselbalch
Equation
• Ionization increases renal clearance of Drugs
• Only free, unbound drug is filtered
• Both ionized and nonionized forms of drug are filtered
• Non ionized forms are reabsobred whereas ionized
forms are non absorbed as they have a charge and
cannot pass through lipid membranes (lipid insoluble)
• Ionized forms of drugs are “trapped” in the filtrate

11. Clinical Application of Henderson-Hasselbalch
Equation
• Both ionized and nonionized forms of drug are filtered
• Non ionized forms are reabsobred whereas ionized
forms are non absorbed as they have a charge and
cannot pass through lipid membranes (lipid insoluble)
• Ionized forms of drugs are “trapped” in the filtrate
• Acidification of urine increases ionization of weak
bases  increases renal elimination
• Alkalinization of urine  increases ionization of weak
acids  increases renal elimination

12. To Change Urinary pH
• Acidify: NH4Cl, Vitamin C, Cranberry juice
• Alkalinize: NaHCO3, Acetazolamide