Understanding Drug Therapy: Pharmacokinetics, Pharmacodynamics, and Rational Use

II- Processes Relevant to Drug Therapy: Pharma/PK/PD

Drug Phases:

• Phase 1 (Pharmaceutical Phase): Drug taken orally becomes soluble, allowing it to pass through biological membranes. This phase is absent in subcutaneous, IM, and IV administration.
• Phase 2 (Pharmacokinetic Phase): Involves absorption (primarily through the small intestine), distribution, metabolism (biotransformation, mainly in the liver), and excretion.
• Phase 3 (Pharmacodynamic Phase): Refers to the biological or physiological response to the drug.

Pharmaceutics Phase (Dissolution):

This is the initial stage of drug action and involves two steps:

• Disintegration: The breakdown of tablets into smaller particles.
• Dissolution: The dissolving of these smaller particles into gastrointestinal fluids before absorption.

Generally, drugs disintegrate and are absorbed better in acidic media than alkaline. Coated drugs resist disintegration in gastric acid and only break down in the alkaline environment of the small intestine.

PK Phase (Drug Movement):

This phase describes the movement of a drug within the body and can occur via:

• Passive diffusion
• Active transport
• Pinocytosis

Pharmacokinetics (PK) vs. Pharmacodynamics (PD):

PK factors influence drug movement:

• Absorption
• Distribution
• Metabolism
• Elimination

PD factors relate to the drug's effect:

• Target proteins
• Downstream messengers

The overall process can be visualized as:

(Dose Administered) → (Absorption) → [C] in systemic circulation → [C] site of action → Pharmacological effect (efficacy + toxicity)

(A) → [C] → (B) → X in tissue of distribution → (C) → Metabolism and/or Excretion!

Pharmacogenetics and Pharmacogenomics:

• Pharmacogenetics: Studies individual variations in DNA sequences related to drug absorption and disposition. This includes polymorphic variations in genes, transporters, metabolizing enzymes, and receptors.
• Pharmacogenomics: Studies variations in gene expression related to individual susceptibility to diseases and drug responses at cellular, tissue, and individual levels.

3- Principles of Rational Drug Use and Their Application:

Definition:

• Appropriate drug for clinical needs.
• Doses that meet individual requirements.
• Adequate duration of treatment.
• Lowest cost to the patient and community.

Principles:

1. Rely on accurate diagnosis in treatment planning.
2. Determine the right drug, right dose, right time, and correct method of application.
3. Assess treatment success, side effects, and compliance.
4. Predict interactions when using multiple drugs.
5. Assess the practicability and cost of treatment.

Application:

• Advertisement: Media, informative videos, newspapers.
• Training: Physicians, pharmacists, healthcare personnel.
• Guidelines: For diagnosis and treatment of diseases.
• Legislation: Regulation and promotional activities of medicinal products.
• Drug Boxes: Large font size on directions for use.
• Monitoring and Evaluation: Surveys for physicians, pharmacists, nurses, and the public.

5- Adverse Drug Reactions (ADRs): Epidemiology, Data, and Classification

Definition:

A response to a drug that is noxious and unintended, occurring at doses used in humans for prophylaxis, diagnosis, or treatment. Excludes treatment failures, overdose, drug abuse, and non-compliance.

Epidemiological Data:

• Substantial morbidity and mortality.
• Estimates of incidence vary by study methods and population.
• 4th to 6th leading cause of death among hospitalized patients.
• 6.7% incidence of serious ADRs.
• 0.3% to 7% of all hospital admissions are due to ADRs.
• 30% to 60% of ADRs are preventable.
• $3.5 billion spent annually on extra medical costs of Adverse Drug Events (ADEs).

Classification:

By Onset:

• Acute: Within 60 minutes (e.g., anaphylactic shock, bronchoconstriction).
• Subacute: 1-24 hours (e.g., rash, serum sickness).
• Latent: > 2 days (e.g., eczematous eruptions, dyskinesia).

By Severity:

• Mild: No change in treatment.
• Moderate: Requires change in treatment, additional therapy, or hospitalization (e.g., amphotericin B, hypokalemia).
• Severe: Disabling or life-threatening (e.g., QT interval prolongation, kidney failure).

By Type:

• Type A: Extension of pharmacological effect, predictable, dose-dependent.
• Type B: Idiosyncratic, immunological reaction, rare, unpredictable.

Surveillance:

• Subjective Report: Patient complaints.
• Objective Report: Direct observation, abnormal findings, physical exams, lab tests, diagnostic procedures.

Surveillance is related to the detection, assessment, understanding, and prevention of ADRs.

Aim of Pharmacovigilance:

• Improve patient care and safety.
• Improve public health and safety.
• Assess the benefit, harm, effectiveness, and risk of medicines.
• Promote education and clinical training.
• Promote effective communication to the public.
• Promote rational and safe use of medicines.

6- Drug Interactions: Epidemiological Data / Classification

Drug Interaction:

The effect of one drug is changed by the effect of another.

Epidemiological Data:

• Incidence of ADRs due to interactions is 30% in hospitalized patients.
• Incidence is 70% in ambulatory patients.
• Although the incidence of severe ADRs is <1%, it remains a significant problem and risk.

Classification:

• PK Interactions: Absorption, distribution, metabolism, or excretion of a drug is affected by another drug (e.g., renal excretion of digoxin altered by amiodarone).
• PD Interactions: Drugs may have additive, synergistic, or antagonistic effects (e.g., NSAIDs antagonizing antihypertensives like ACE inhibitors).
• Miscellaneous: Interactions with dietary supplements, food, and beverages (e.g., Vitamin K in leafy greens promoting clotting factors, counteracting anticoagulants).

Clinically Significant Drug Interactions:

Clinically Insignificant Drug Interactions:

• Grapefruit: Enzymatic inhibition → effect on CCBs/carbamazepine.
• Soy: Enzyme inhibition → effect on warfarin/haloperidol/olanzapine.
• Garlic: (+) antiplatelet activity → effect on anticoagulants/aspirin.

7- Drug Use in Children, Elderly, Kidney Injury, Liver Injury

Children:

• Drug response differs, especially in neonates.
• Doses must be calculated with care.
• Avoid IM injections due to pain.

Dosing:

• Based on body weight or age ranges (infants, 1-5 years, 6-12 years).

Elderly:

• Reduced renal clearance, taking longer to excrete drugs.
• Susceptible to nephrotoxic drugs.
• Acute illness can lead to decreased renal clearance.

Liver Impairment:

• Liver disease may affect metabolism.
• Drugs should be used minimally.
• Main problems: Ascites, evidence of encephalopathy.

Impaired Metabolism:

• Hypoproteinemia: Hypoalbuminemia in severe liver disease leads to decreased protein binding and increased toxicity of highly protein-bound drugs (e.g., phenytoin).
• ↓ Clotting: ↓ synthesis of clotting factors, prolonged prothrombin time. ↓ effect of oral anticoagulants (warfarin).
• Fluid Overload: Edema and ascites are worsened by certain drugs.
• Hepatotoxic Drugs: Dose-related or unpredictable. Should be avoided or used carefully.
• Renal Impairment: ↓ renal excretion of drugs, leading to increased serum levels even if elimination is normal. Many ADRs occur. Some drugs are effective only with low renal function.

Guidelines:

• Avoid intramuscular injections in children due to pain.
• Children may require medicines not specifically licensed for pediatric use; medical acts do not prohibit unlicensed medicines.
• Informed use of unlicensed medicines or licensed medicines for unlicensed applications ('off-label' use) is often necessary in pediatric practice.

Doses are based on body weight for neonates, infants (up to one year), and children (1–5 years, 6–12 years).

Liver Impairment (Detailed):

• Impaired Drug Metabolism: Liver is the main route of elimination for many drugs. Liver disease must be severe before significant changes occur. Routine liver function tests are poor indicators. Some drugs (e.g., rifampicin, fusidic acid) excreted in bile can accumulate in obstructive jaundice.
• Hypoproteinemia: Hypoalbuminemia in severe liver disease reduces protein binding, increasing toxicity of highly protein-bound drugs (e.g., phenytoin, prednisolone).
• ↓ Clotting: Reduced hepatic synthesis of clotting factors (prolonged prothrombin time) increases sensitivity to oral anticoagulants (e.g., warfarin).
• Hepatic Encephalopathy: Many drugs can worsen cerebral function and precipitate encephalopathy (sedatives, opioid analgesics, diuretics causing hypokalemia, drugs causing constipation).
• Fluid Overload: Edema and ascites can be exacerbated by drugs causing fluid retention (e.g., NSAIDs, corticosteroids).
• Hepatotoxic Drugs: Dose-related or unpredictable. May cause toxicity at lower doses in hepatic impairment. Should be avoided or used carefully.

Renal Impairment:

• Reduced renal excretion can cause toxicity.
• Sensitivity to some drugs is increased even if elimination is unimpaired.
• Side effects are often poorly tolerated.
• Some drugs are not effective with reduced renal function.

Dose reduction or alternative drugs can avoid many problems.

8- Organic Nitrates: Pharmacokinetics and Differences

Organic nitrates are used for acute angina attacks and long-term prevention.

Short-Acting Nitrates:

• Rapid onset (1-3 minutes).
• Sublingual: Nitroglycerin for immediate angina treatment.
• IV Administration: For continuous titration in unstable angina/AHF.
• Slow-Releasing (Transdermal/Buccal): For angina prevention.

Long-Acting Nitrates:

• Usually taken orally for long-term angina management (6-8 hours duration).

Monitoring:

• Sublingual: Rapidly metabolized; effectiveness measured subjectively.
• IV: Continuous monitoring of BP, HR, SpO2 recommended.

Adverse Reactions:

• Dizziness
• Nausea
• Palpitations
• Vertigo
• Headache
• Diaphoresis
• Syncope
• Hypotension (adverse effect of nitroglycerin)

Tolerance:

• Physiological Tolerance: Due to sympathetic nervous system response and compensating mechanisms (e.g., Na, H2O retention). Long-acting (oral/transdermal) or IV can induce tolerance.
• Pharmacological Tolerance: To avoid tolerance, allow 10-12 hour nitrate-free intervals when possible.

PK:

The liver rapidly metabolizes organic nitrates. Oral bioavailability is low due to first-pass metabolism. Sublingual route avoids this, providing rapid therapeutic levels but with a brief duration (15-30 minutes). Oral preparations offer sustained systemic levels. Excretion is mainly via the kidneys as glucuronide derivatives.

Effectiveness:

• Venous Dilation: Reduces preload and heart workload.
• Coronary Vasodilation: Increases blood supply to the heart muscle.
• Decreases myocardial oxygen consumption due to reduced cardiac workload.

IV nitroglycerin is rapid but effects reverse quickly upon stopping infusion. Buccal and transdermal forms can lead to tolerance; nitrate-free periods are essential.

Toxicity and Tolerance:

9- Beta-Adrenoceptor Agonists (Beta Blockers)

Mechanism of Action (MOA):

Beta blockers antagonize the effects of catecholamines at beta-adrenoceptor sites by occupying beta receptors and competitively decreasing receptor occupancy.

Classification:

• First-generation: Nonselective β antagonists (e.g., propranolol, timolol, nadolol).
• Second-generation: Selective β1 antagonists (e.g., acebutolol, atenolol, metoprolol, esmolol).
• Third-generation: Selective (e.g., betaxolol) and nonselective (e.g., labetalol).

Properties:

• Receptor Blockage: Nonselective, selective β1, or beta and alpha blockage.
• Intrinsic Sympathomimetic Property (ISA).
• Membrane Stabilizing Action (e.g., propranolol).

Adverse Drug Reactions (ADRs):

Recommendations for Use:

Beta blockers can be used for:

• Hypertension
• Glaucoma
• Migraine
• Hyperthyroidism
• Angina pectoris
• Myocardial Infarction (MI)
• Congestive Heart Failure (CHF)

10- Calcium Channel Blockers (CCBs)

Classification:

Calcium channel blockers act selectively on cardiovascular tissues. Dihydropyridines are selective vasodilators, while non-dihydropyridines are equipotent on cardiac and vascular tissue.

Short & Long Acting Formulations:

Most have short half-lives, requiring 3x/day dosing. Amlodipine has a very long half-life.

Examples:

• Amlodipine 5 mg tablets
• Diltiazem 60 mg tablets
• Adizem-SR (diltiazem SR) 90 mg capsules
• Adizem-XL 120 mg capsules
• Nifedipine 5 mg capsules
• Adalat Retard (nifedipine retard) 10 mg tablets
• Adipine SR (nifedipine SR) 10 mg capsules

ADR:

• Constipation (10%)
• Dizziness, Headache, Nausea
• Peripheral edema
• Fatigue
• Verapamil is not for Congestive HF.
• Cardiac depression (at high doses).

Clinical Use:

• Cardiac: Hypertension (HTN), Supraventricular Tachycardia (SVT), Angina Pectoris (AP).
• Non-cardiac: Migraine, Raynaud's phenomenon, cluster headaches.

Nifedipine does not decrease atrioventricular conduction and can be used more safely than verapamil or diltiazem in patients with AV conduction abnormalities.

Angina: Immediate short-acting calcium channel blockers can increase the risk of cardiac events and are contraindicated.

11- Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs)

Adverse Reactions:

1. Severe Hypotension: After initial dose in hypovolemic patients (due to diuretics, salt restriction).
2. Acute Renal Failure: Particularly in patients with renal artery stenosis.
3. Hyperkalemia: More common in patients with renal insufficiency or diabetes.
4. Dry Cough: Less common with ARBs.
5. Fetal Toxicity: Anuria, hypotension, renal failure (contraindicated in 2nd and 3rd trimester).
6. Altered sense of taste, allergic skin rash.

Practical Recommendations for Use and Monitoring:

• Start with a very low dose.
• Be cautious if the patient is on diuretics (risk of hypotension).
• Wait 3-5 days for effect, then double the dose.
• Check K+ levels with each dose change.

12- Diuretics: Classification, Monitoring of Effectiveness and Safety

Classification:

1. Loop Diuretics: Bumetanide, Ethacrynic acid, Furosemide.
2. Thiazides: Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide.
3. K+-Sparing: Amiloride, Eplerenone, Triamterene.
4. Carbonic Anhydrase Inhibitors: Acetazolamide.
5. Osmotic Diuretics: Mannitol, Urea.

Monitoring for Effectiveness:

• Keep checking BP.
• Renal function (Creatinine, Urea).
• Electrolytes (Na+, K+, Ca2+).
• Weight (for fluid loss).

Monitoring (General):

Regular monitoring of Na, K, Glucose, and acid-base balance is needed, especially in patients with impaired renal function. Hypovolemia and electrolyte disturbances should be assessed.

Fixed Combinations:

• ACEI + Diuretics: Captopril-hydrochlorothiazide (useful for cough).
• ARBs + Diuretics: Losartan-hydrochlorothiazide.
• BB + Diuretics: Bisoprolol-hydrochlorothiazide.

Benefits of Fixed Dosage Combinations:

• Achieve BP control through different mechanisms of action.
• Enhance compliance with a single tablet (once or twice daily).
• Using low doses of two different agents minimizes clinical and metabolic effects, particularly in patients with target organ damage or severe initial hypertension.

13- Lipid-Lowering Drugs: Classification, Monitoring of Effectiveness

Classification (3 most common):

• Omega-3 Fatty Acids
• Fibrates

Monitoring for Effectiveness:

• Lipid Panel (Total Cholesterol, LDL, HDL, Triglycerides).
• ↓ BP.

Monitoring for Safety:

• Rhabdomyolysis: Monitor for myoglobinuria/serum CK.
• Liver Monitoring: AST, ALT, bilirubin, albumin.

Target Cholesterol Values in CVD Patients:

• Total Cholesterol < 5.2 mmol/L
• LDL < 1.8 mmol/L
• HDL > 1.6 mmol/L
• Triglycerides < 1.7 mmol/L

14- Algorithm for Hypertension (HTN)

(Graph image reference: https://www.evernote.com/shard/s320/res/cee9b6bc-5c41-46ee-b1c6-3e4ad122129b/1.PNG)

Diuretics, beta-blockers, ACEIs, and ARBs are suitable for initiation and maintenance of therapy. Choice depends on patient factors:

• Previous experience
• Cost
• Risk factors
• Target organ damage
• CVD
• CKD
• DM
• Lung disorder

Treatment:

• Can be started as monotherapy or combination therapy.
• A goal BP of 140/90 mmHg is appropriate for general prevention of CV events and CV risk reduction.
• Patients with diabetes are at high risk of CV events and are typically recommended ACEIs/ARBs, often in combination.

15- NSAID Drugs: MOA, ADRs

Mechanism of Action (MOA):

NSAIDs differ in their antipyretic, analgesic, and anti-inflammatory activity. They inhibit the cyclooxygenase (COX) enzyme, which catalyzes the first step of prostanoid biosynthesis, reducing prostaglandin (PG) synthesis with both beneficial and unwanted effects.

NSAID Actions:

1. Anti-inflammatory: By inhibiting COX, reducing PG formation.
2. Analgesic: Prostaglandin E2 (PGE2) sensitizes nerve endings to pain mediators. Decreasing PGE2 synthesis reduces pain sensation.
3. Antipyretic: Fever is caused by elevated thermoregulatory center set-point, potentially stimulated by PGE2. NSAIDs reduce PGE2 synthesis.
4. Respiratory Action: Increase alveolar ventilation. High doses can affect the respiratory center, causing hyperventilation.
5. Gastrointestinal Effect: Inhibition of prostanoid formation leads to increased gastric acid secretion and diminished mucus protection.
6. On Kidney: Inhibition of PGE2 and PGI2 synthesis, which maintain renal blood flow, can lead to sodium and water retention, edema, and hyperkalemia. Interstitial nephritis can occur.

ADRs:

1. GI: Epigastric distress, nausea, vomiting, ulcers.
2. Blood: Irreversible acetylation of platelet COX → ↓ platelet TXA2 level.
3. Respiration: High salicylate concentrations can cause respiratory depression.
4. Hypersensitivity: Urticaria, bronchoconstriction, angioedema, anaphylactic shock.

Classification by COX-1 and COX-II Inhibition:

1. Selective COX-1 inhibitors.
2. Non-selective COX inhibitors (e.g., Indomethacin, Diclofenac).
3. Relative COX-2 inhibitors (e.g., Meloxicam, Etodolac).
4. Selective COX-2 inhibitors (e.g., Celecoxib, Rofecoxib).

Rational Use:

• For mild pain, depending on comorbidities (CVD risk factors, GI risk, age, renal/hepatic function).
• Do not give to children (risk of Reye's syndrome).
• Paracetamol is effective for acute pain.
• Topical NSAIDs are good for acute/chronic local pain.
• NSAIDs are first-line for low back pain, but paracetamol can be used if NSAIDs are contraindicated.

16- Corticosteroids (CSDs): MOA, Comparison, Types of Therapy

Mechanism of Action (MOA):

Cortisol is the principal human glucocorticoid. Its effects include:

• Metabolic: Favor gluconeogenesis, stimulate protein catabolism (except in the liver), and lipolysis.
• ↑ Stress Resistance: Increase plasma glucose, providing energy for stress; modest ↑ BP via vasoconstriction.
• Effects on Blood Cells: ↓ Eosinophils, basophils, monocytes, lymphocytes; ↑ Hb, RBCs, platelets.
• Endocrine System: Negative feedback on corticotropin production; inhibition of further glucocorticoid synthesis; increased growth hormone production.

Comparison (Based on Duration of Action and Potency):

Type of Therapy:

Pulse therapy, high dose, medium dose, low dose therapy, alternate-day therapy, replacement therapy. Dosage regimens depend on disease severity, desired effect, and duration. For severe autoimmune conditions, aggressive treatment is needed. Alternate-day administration can minimize adverse effects.

ADRs and Prevention:

• Osteoporosis: Take with Vitamin D.
• Cushing-like Syndrome: Monitor and stop if needed.
• Cataract risk.
• Hypokalemia.
• Hyperglycemia: Monitor blood glucose levels.

17- Antiarrhythmic Drugs: Classification...

Class I - Na+ Channel Blockers:

• Block voltage-sensitive Na+ channels, slowing the rate of phase 0 depolarization, reducing excitability and conduction velocity.
• Class IA: Quinidine, Procainamide (atrial and ventricular arrhythmias).
• Class IB: Lidocaine, Mexiletine (acute ventricular arrhythmias, especially post-MI).
• Class IC: Propafenone, Flecainide (SVT, ventricular arrhythmias, prevention of paroxysmal AFib). Can provoke proarrhythmia.

Class II - Beta Blockers:

• ↓ slope of phase 4, prolong AC conduction, ↓ HR and contractility, ↓ SA and AV node activity.
• Clinical use: SVT, AFib, A flutter.
• Example: Metoprolol.

Class III - K+ Channel Blockers:

• Prolong the duration of the action potential.
• Examples: Amiodarone, Sotalol.
• Clinical use: AFib, A flutter, VT, severe refractory supraventricular arrhythmias.

Class IV - Ca2+ Channel Blockers:

• Decrease current carried by Ca2+, ↓ rate of spontaneous depolarization.
• Effective mainly for atrial arrhythmias.
• Examples: Verapamil, Diltiazem.
• ↓ conduction velocity, ↑ ERP, ↑ PR interval.
• Clinical use: SVT.

Goals of Antiarrhythmic Drugs:

• Discontinuation of arrhythmia.
• Prevention of recurrent arrhythmia.
• Controlling ventricular rate if recurrence cannot be prevented.

Other Antiarrhythmic Drugs:

• Adenosine: Drug of choice for abolishing acute supraventricular tachycardia (SVT). Extremely short duration of action (~15 sec). Can provoke proarrhythmia.
• Digoxin: Used to control ventricular rate in atrial fibrillation and flutter. Slows AV nodal conduction. Therapeutic use: HF, AFib, atrial tachycardia.

18- Antiarrhythmics for Acute Atrial Fibrillation (AF) Prophylaxis

Acute AF (<48 hours):

• Without signs of HF:
  1. Propafenone: For conversion of atrial fib to sinus rhythm. Effectiveness varies; requires ECG and BP control. Contraindicated in significant structural heart disease, recent MI, uncontrolled CHF, severe bradycardia, BBB.
  2. Amiodarone: Loading doses PO or IV. Monitor for edema, pulmonary toxicity, electrolytes.
  3. Metoprolol: Monitor ECG and BP. Contraindicated in AV block, CHF, bradycardia, asthma, hypotension, COPD.
• With signs of HF: Amiodarone, Digoxin.

Prolonged AF (>48 hours):

• Anticoagulation therapy: Vitamin K antagonists (therapeutic range for 3 weeks prior to cardioversion).
• Amiodarone, beta-blockers, verapamil, digoxin: Slowing of ventricular rate.

Monitoring:

• Propafenone: ECG, BP, pulse.
• Quinidine: Cardiac monitor during IV administration; CBC, liver/renal function tests during long-term use.
• Metoprolol: Monitor ECG and BP.
• Amiodarone: BP, HR, ECG, rhythm; assess for lethargy, edema, weight loss, pulmonary toxicity (baseline PFTs, chest X-ray annually).
• Digoxin: Monitor serum concentrations (narrow therapeutic range); draw levels at least 6-8 hours after the last dose.

Adverse Reactions:

• Quinidine: Proarrhythmia, hypotension, hepatotoxicity, GI symptoms, cinchonism, autoimmune syndromes.
• Propafenone: Conduction abnormalities, proarrhythmia, hepatitis, depression, alopecia, CHF.
• Metoprolol: Bradycardia, cold extremities, fatigue, nightmares, depression, CHF, impotence.
• Amiodarone: Hypothyroidism, hyperthyroidism, corneal microdeposits, pulmonary fibrosis, GI intolerance, neuropathy, sinus node dysfunction.
• Digoxin: Concentration-dependent; loss of appetite, nausea, vomiting, diarrhea, blurred vision, drowsiness, dizziness, depression.

20- Unfractionated Heparin (UFH): Indications, Administration, Bleeding Management

Mechanism of Action (MOA):

Heparin binds to antithrombin III, forming a complex that inactivates thrombin and clotting factors IX, X, XI, XII.

Indications:

• Deep venous thrombosis (DVT)
• Acute pulmonary embolism (PE)
• Acute MI
• Unstable angina
• Prophylaxis against postoperative venous thrombosis.

Methods of Administration:

• IV: Rapid absorption, preferred for immediate anticoagulant effect.
• Subcutaneous.

Dosage: Initial dose: 80 IU/kg (bolus); Continuous infusion: 18 IU/kg/h (average 20,000-40,000 IU/d).

Monitoring of Effectiveness:

1. Dosage is adequate when aPTT reaches the therapeutic range (1.5–2 times baseline).
2. Normal aPTT: 24-40 seconds.
3. Therapeutic aPTT: 1.5–2 times baseline.
4. aPTT should be determined every 4 hours initially.
5. Heparin should be administered until INR is within the therapeutic range (INR 2–3) if transitioning to warfarin.

Monitoring of Safety:

• Hb, Hct.
• Signs of bleeding.
• Fecal occult blood test.
• aPTT.
• Platelet counts.

Be cautious of thrombocytopenia, osteoporosis, hyperkalemia, and bleeding.

Use of Antidote in Case of Overdose/Bleeding:

• Discontinue heparin.
• If bleeding occurs, administer protamine sulfate (specific antagonist). 1 mg protamine sulfate IV for every 100 IU of heparin remaining. Rate of infusion should not exceed 50 mg in 10 minutes. Avoid excess protamine.

21- Low Molecular Weight Heparin (LMWH)

• Drugs: Enoxaparin, Nadroparin, Dalteparin, Certoparin.
• MOA: Preferentially inhibit Factor Xa over thrombin.

Differences from Unfractionated Heparin:

Indications:

• Deep venous thrombosis (DVT)
• Acute pulmonary embolism (PE)
• Acute MI
• Unstable angina

Adverse Reactions:

• Bleeding: Elderly, renal/hepatic insufficiency, alcoholics are more prone. Careful monitoring of bleeding time is required.
• Hypersensitivity Reactions: Chills, fever, urticaria, anaphylactic shock (heparin is of animal origin).
• Osteoporosis: Long-term therapy (≥ 6 months) associated with osteoporosis and fractures.
• Heparin-Induced Thrombocytopenia (HIT): Lower risk with LMWH.

LMWH is administered subcutaneously once every 12-24 hours. Monitoring is usually not required except in patients with kidney problems, burn patients, or those at risk of bleeding. Anti-Xa activity monitoring is more sensitive but not routinely used; samples drawn 4 hours post-dosing.

Transitioning:

Warfarin should be started concomitantly with LMWH for 4-5 days. When INR reaches ≥ 2, heparin can be stopped while warfarin continues.

22- Vitamin K Antagonists (e.g., Warfarin)

Indications:

• Primary/secondary prophylaxis of Arterial Thromboembolism (DVT/PE, Cerebrovascular disease, Cardiac disorders, AFib, Heart valve replacement).

Dosage:

• Depends on INR value.
• Starts from 5-10 mg, adjusted by 0.5-3 mg.
• Therapeutic range INR: 2-3.

Monitoring of Effectiveness and Safety:

• Prothrombin time, hematocrit; INR (frequency varies).
• INR: Normal <1.18; therapeutic 2.0–3.5.
• Prothrombin index (PI): Normal 70-130%; therapeutic 15–25%.
• Monitoring frequency: Weekly during the first month, then monthly.

Pharmacotherapy for Overdose and Bleeding:

• INR above therapeutic range but < 5 (no bleeding): Reduce or omit dose, resume at lower dose.
• INR 5-9 (no bleeding): Omit 1-2 doses, resume at lower dose when INR normalizes.
• INR 9-20 (no bleeding): Omit warfarin. Vitamin K 3-5 mg PO. Monitor INR, repeat Vitamin K as needed.
• INR > 20 or serious bleeding: Omit warfarin. Vitamin K 10 mg slow IV infusion. FFP transfusion, Prothrombin Complex Concentrate (PCC).

23- Warfarin Use Before Surgery

• In patients with previous arterial embolism, withhold warfarin for 4 days preoperatively. Measure INR the day before surgery; a small dose of Vitamin K may be needed.
• After acute venous thromboembolism, defer surgery for at least 1 month, preferably 3 months, of anticoagulation.

Achieving Acceptable INR for Surgery:

• Surgery/Procedure < 24 hours: Discontinue warfarin, administer IV Vitamin K. If surgery within 6 hours, Octaplex is recommended. Check INR immediately post-infusion and pre-surgery. Repeat Octaplex if INR not corrected.
• Surgery/Procedure 23-96 hours: Discontinue warfarin, administer IV or PO Vitamin K. Check INR in 24 hours. If not corrected, give another dose of IV Vitamin K and recheck INR in 12 hours.
• Elective Surgery (Planned Reversal): Stop warfarin 5-6 days prior. Consider LMWH bridging therapy.

24- Warfarin Interactions

Transition from LMWH to Warfarin:

Start warfarin concomitantly with LMWH for 4-5 days. When INR reaches ≥ 2, stop LMWH while continuing warfarin.

25/26 - New Oral Anticoagulants (NOACs): Dabigatran, Rivaroxaban

Indications:

• Reduction of stroke and systemic embolism risk in non-valvular atrial fibrillation.
• Treatment of DVT and PE (after 5-10 days of parenteral anticoagulant).
• Reduction in the risk of DVT and PE recurrence.

Effectiveness Monitoring:

aPTT and PTT are used. Thrombin time (TCT) is more sensitive but not routinely used. For Dabigatran, aPTT is sensitive but insensitive at higher doses. Normal TT is not useful for dose adjustment.

Safety:

• Assess renal function (CrCl < 30 ml/min: discontinue; 30-50 ml/min: reduce dose).

Interactions:

• With P-glycoprotein (P-gp) inducers/inhibitors (e.g., ketoconazole, cyclosporine, verapamil, amiodarone, rifampicin).
• NSAIDs: Monitor for bleeding risk, especially with long half-life NSAIDs (e.g., naproxen). Short half-life NSAIDs (e.g., ibuprofen) show less increased bleeding risk.
• P-gp Inhibitors: Avoid combinations that increase dabigatran levels (azoles, calcium channel blockers, immunosuppressants, macrolides, protease inhibitors).

27- Antiplatelet Drugs (Aspirin, Clopidogrel, Ticagrelor): Indications, Dual Therapy, Monitoring

Hemostasis is a defense mechanism to prevent blood loss after injury, involving blood flow dynamics, vessel wall components, platelets, and plasma proteins.

Optimal time for aspirin before surgery is 5 days.

Antiplatelet Drugs:

1. COX-1 Inhibitors (NSAIDs).
2. Membrane Receptor Antagonists (Serotonin, Alpha 2 adrenergic).
3. Thromboxane Receptor Antagonists.
4. Receptor Antagonists GP IIb/IIIa.
5. PDE Inhibitors.
6. PGI2.

Indications:

• Primary prevention in patients with numerous risk factors.
• Patients with AFib.
• Prior Ischemic Heart Disease.
• Acute MI.
• Acute Coronary Syndrome.
• Coronary Stenting.
• Prevention of thrombotic stroke events.

Aspirin also has antipyretic, analgesic, and anti-inflammatory effects.

Side Effects:

• Diarrhea.
• Bleeding.
• Agranulocytosis (rare).

Interactions:

• Aspirin + NSAIDs (e.g., ibuprofen): Ibuprofen can reduce aspirin's antiplatelet effect.
• Ticlopidine and Clopidogrel: Prodrugs requiring metabolic activation, with different activation mechanisms.

Effectiveness:

Measured by PT and INR. Five days is the optimal time without aspirin treatment before surgery.

28- Thrombolytics: Comparison of Commonly Used Agents

Thrombolytic agents convert plasminogen to plasmin, which lyses fibrin clots.

Types:

• Streptokinase
• Alteplase (tPA)
• Anistreplase

Indications:

• Pulmonary embolism with hemodynamic instability.
• DVT.
• Ascending thrombophlebitis.
• Peripheral vascular disease.
• Myocardial infarction.
• Ischemic stroke (<3 hours, Alteplase only).

Monitoring of Efficacy and Safety:

• Efficacy: Pain relief and ST-segment normalization predict reperfusion. Rapid CK elevation indicates reperfusion. For stroke, assess motor/sensory function.
• Safety: Constant monitoring of physical state, signs of bleeding, BP, CBC due to hemorrhage risk. Streptokinase is antigenic; monitor for allergic reactions.

Comparison:

• Alteplase is fibrin-specific, superior for older clots, and has a shorter half-life (5 min) than streptokinase.
• Streptokinase causes a systemic fibrinolytic state due to poor specificity.

29- Treatment of Bronchial Obstruction: Sympathomimetics / Anticholinergics

Sympathomimetic Agents (Beta-Adrenoceptor Agonists):

• MOA: Bind to β receptors on airway smooth muscle, stimulating adenylyl cyclase, increasing intracellular cAMP, relaxing smooth muscle, and inhibiting bronchoconstricting mediators. Best delivered by inhalation for local effect and minimal systemic toxicity.
• Epinephrine: Rapidly acting bronchodilator (injected or inhaled). ADRs: tachycardia, arrhythmias, worsening angina.
• Isoproterenol: Potent nonselective β1 and β2 bronchodilator. Rarely used due to cardiac stimulation.
• Ephedrine: Longer duration, oral activity, lower potency. Infrequently used now.
• Beta2-Selective Drugs: Widely used first-line for asthma bronchoconstriction (e.g., Albuterol, Terbutaline, Metaproterenol, Pirbuterol). Available as metered-dose inhalers (MDIs); bronchodilation within 15 minutes, lasts 3-4 hours.
• Long-Acting Beta2 Agonists (LABAs): Salmeterol, Formoterol. Provide 12+ hours of action. Used with inhaled corticosteroids; not for monotherapy.

Methylxanthines:

• Theophylline, Theobromine, Caffeine.
• Used for acute asthma attacks (especially nocturnal) and long-term control.
• Theophylline is a potent bronchodilator but requires plasma level monitoring due to narrow therapeutic index and potential toxicity.
• Clinical use has declined with the advent of safer and more effective agents.

Antimuscarinic Drugs:

• Ipratropium bromide, Tiotropium bromide.
• Produce a slower response than sympathomimetics; better for regular prophylactic use.
• Combination with beta2 agonists provides longer bronchodilation.
• Effective in COPD with partially reversible obstruction.

Effectiveness:

• Decrease in symptoms.
• Improvement in pulmonary function tests (PFTs).
• Theophylline serum levels.

Interactions:

• Methylxanthines: Antagonize propranolol, potentiate sympathomimetics, additive effects with diuretics and antibiotics.
• Antimuscarinic Drugs: Decrease gut motility, delay gastric emptying, potentially increasing absorption of other medications. Side effects exacerbated by antihistamines, antiparkinsonian drugs, MAOIs, TCAs.

30- Treatment of Bronchial Obstruction: Drugs for Inflammation

Causes of bronchial obstruction include asthma and COPD.

Adrenoreceptor Agonists:

Stimulate β receptors in airway smooth muscle, increasing cAMP, relaxing smooth muscle, and inhibiting mast cell mediators. Best delivered by inhalation.

Beta2-Selective Adrenoreceptor Agonists:

Particularly Albuterol, are widely used for asthma bronchoconstriction. Effective via inhalation or oral administration. Inhalation technique: Aerosolized powder with spacer, Metered Dose Inhalers (MDIs). Nebulized therapy reserved for patients unable to coordinate MDI use.

Methylxanthine Drugs:

Theophylline, Theobromine, Caffeine. High concentrations inhibit phosphodiesterases, affecting cAMP and cGMP. Used for asthma control, but require monitoring due to narrow therapeutic index and toxicity.

Antimuscarinic Agents:

Effective bronchodilators, with less systemic absorption and toxicity when inhaled (e.g., Ipratropium bromide). Greater bronchodilation with less toxicity achieved with selective quaternary ammonium derivatives.

Corticosteroids:

• Do not directly relax airway smooth muscle but reduce bronchial hyperreactivity.
• Inhibit infiltration of inflammatory cells (lymphocytes, eosinophils, mast cells).
• Inhaled corticosteroids (ICS) are most effective for avoiding systemic side effects (e.g., Beclomethasone, Budesonide, Fluticasone).
• Potential side effects: Cough, hoarseness, sore throat, thrush. Rinsing mouth after use can prevent these.

Treatment of COPD:

• Characterized by airflow limitation not fully reversible.
• Treatment approaches are similar to asthma but with less expected benefit.
• Acute symptoms: Short-acting β agonist, anticholinergic, or combination.
• Persistent symptoms: Long-acting bronchodilator (LABA or long-acting anticholinergic like Tiotropium).
• Severe obstruction/exacerbations: Inhaled corticosteroids reduce exacerbation frequency.
• Theophylline may improve diaphragmatic function.
• Antibiotics are routinely used for COPD exacerbations due to frequent bacterial infections.

Interactions:

• Oral beta-2 agonists may interact with certain antidepressants, thyroid drugs, and other bronchodilators.
• Methylxanthines can potentiate sympathomimetics and antagonize propranolol.
• Beta blockers can decrease the effect of beta-agonists.
• Antimuscarinic agents may delay absorption of other medications and interact with MAOIs, disopyramide, etc.

Extras:

• Corticosteroids are used in severe cases.
• Leukotriene antagonists are indicated for prophylactic therapy of mild to moderate asthma as an alternative to ICS. Side effects include headache and rash.
• Mast cell stabilizers (e.g., Cromolyn) administered via MDI for long-term prophylaxis. Inhalation can cause cough, throat irritation, or oropharyngeal candidiasis. Rinse mouth after use.

31- Antihistamines: Classification, Comparison...

Classification:

1. H1 Antihistamines:
   • 1st Generation: Ethanolamines (e.g., Carbinoxamine), Piperazines (e.g., Hydroxyzine), Alkylamines (e.g., Brompheniramine), Phenothiazine derivatives (e.g., Promethazine). High lipid solubility, cross BBB, cause sedation.
   • 2nd Generation: Piperidines (e.g., Fexofenadine). Less sedative effect as they cross BBB less readily. Used for allergic/inflammatory conditions, motion sickness, nausea.
2. H2 Receptor Antagonists: Clinically used for gastric ulcers and heartburn (e.g., Ranitidine).
3. H3, H4 Receptor Antagonists.

Comparison:

• 1st Gen (Sedating): High lipid solubility, cross BBB, antagonize CNS and PNS H1 receptors, cause sedation and cognitive impairment. Used for sleep disturbances (e.g., Alimemazine, Promethazine are most sedating).
• 2nd Gen (Non-sedating): Newer, larger molecules, less likely to cross BBB.

ADRs:

• Drowsiness, Headache, Psychomotor impairment.
• Antimuscarinic effects (urinary retention, dry mouth, blurred vision).
• Rare: Hypotension, palpitations, arrhythmias, extrapyramidal effects.

Interactions:

• TCAs: Additive antimuscarinic and sedative effects.
• Antifungal imidazoles (Ketoconazole) & Macrolide antibiotics (Erythromycin): Avoid co-administration as they increase plasma concentrations of 2nd-gen antihistamines, potentially causing lethal ventricular arrhythmias (blockade of HERG potassium channels).
• Concurrent use with other CNS depressants is contraindicated while driving or operating machinery.

32- Antidepressants: Classification, Comparison...

Indication:

Moderate to severe depression.

Classification:

Comparison:

• SSRIs selectively inhibit serotonin reuptake.
• SSRIs and SNRIs have minimal effects on alpha-adrenergic, muscarinic, and H1 receptors.
• TCAs and SNRIs inhibit both serotonin and norepinephrine reuptake.

ADRs:

Interactions:

• SSRI + MAOI: Serotonin Syndrome.
• TCA: Combination with MAOIs can cause hypertensive crisis, hyperpyrexia, convulsions, coma. Combination with CNS depressants causes toxic sedation.

Rational Management of Depression:

Choice depends on indication, efficacy, cost, availability, side effects, drug interactions, patient history, preference, age, gender, and medical status. SSRIs are commonly prescribed first-line due to ease of use, tolerability, and safety in overdose. TCAs have similar efficacy but more side effects and toxicity in overdose. Sertraline is considered safe in patients with unstable angina or recent MI.

Duration of Treatment:

At least 4 weeks to see effects. Treatment typically continues for at least 6 months post-remission. Maintenance therapy for 2 years may be needed for recurrent depression.

32- Antipsychotics

MOA:

Block dopamine (D2) and serotonin (5-HT2A) receptors. Atypical antipsychotics also act on adrenergic, cholinergic, and histamine receptors.

ADRs:

• Antidopaminergic: Extrapyramidal symptoms (EPS) - Parkinsonism, dystonia, akathisia; Hyperprolactinemia.
• Anti-HAM effects (Anticholinergic, Antihistaminic, Anti-alpha-adrenergic).
• Weight gain.
• Elevated liver enzymes, jaundice.
• Seizures.
• Tardive Dyskinesia (TD).
• Neuroleptic Malignant Syndrome (NMS).

Comparison:

• Atypical antipsychotics generally have fewer side effects (especially EPS) than traditional ones and are often considered first-line.
• High-potency traditional antipsychotics have greater dopamine receptor affinity but more EPS. Low-potency traditional antipsychotics have more anti-HAM effects.

Indications:

• Acute and chronic psychosis, schizophrenia.
• Acute agitation, anxiety.
• Nausea and vomiting (e.g., Haloperidol).
• Tourette's syndrome.

Monitoring:

• Antipsychotic scales, clinical symptoms.
• Monitor for EPS, weight gain, metabolic parameters.
• Plasma drug concentrations (especially on monotherapy).
• ECG (QT interval), CBC, liver enzymes, BP, pulse, temperature before and periodically during treatment.

Rational Pharmacotherapy of Psychosis:

1. For first episode, start with atypical antipsychotics. If no response, consider typical low potency, then typical high potency.
2. Monotherapy is generally more effective than combination therapy.
3. High doses should be used for short durations and reviewed regularly.
4. Consider risk factors (obesity, age - caution in elderly >70 yrs).
5. ECG monitoring is crucial; adjust dose if QT is prolonged.
6. If no improvement after 3 months, reassess treatment.

Interactions:

Combining antipsychotics is generally not recommended due to increased side effect risk.

Conversion to Long-Acting Formulations:

Requires careful titration. Injections given at intervals of 1 to 4 weeks. Start with a test dose to assess side effects.

34- Benzodiazepines

Classification and Comparison (by Duration of Action):

PK/PD:

• Metabolized by CYP450 (except oxazepam, lorazepam, temazepam).
• PD: Potentiate GABAergic inhibition by increasing Cl- channel opening frequency, leading to hyperpolarization.
• Antidote: Flumazenil.
• Avoid with alcohol, opioids, or barbiturates.

Indications:

• Anxiety disorders (panic disorder, GAD, social anxiety, PTSD, OCD).
• Muscular disorders (skeletal muscle spasms, spasticity).
• Amnesia (premedication for procedures).
• Seizures (Clonazepam, Diazepam, Lorazepam).
• Hypnotics.
• Alcohol withdrawal symptoms.
• Centrally acting muscle relaxants.

ADRs:

• Drowsiness, confusion, ataxia (common).
• Cognitive impairment, decreased skills.
• Anterograde amnesia.
• Cardiovascular depression.

Use cautiously in patients with liver disease; avoid in patients with severe liver disease.

Termination of Therapy and Withdrawal Symptoms:

Abrupt withdrawal can cause severe, life-threatening symptoms: restlessness, anxiety, weakness, orthostatic hypotension, hyperactive reflexes, generalized seizures. Symptoms are more severe with short half-life drugs. Cross-dependence is marked among sedative-hypnotics.

Factors making withdrawal difficult:

• High daily dose.
• Shorter half-life.
• Longer duration of prior benzodiazepine treatment.
• Alcohol or substance abuse.

35- Antiepileptic Drugs (AEDs)

Definition: Chronic brain disorder characterized by recurrent epileptic seizures.

AED Classification:

Based on MOA or seizure type. Monotherapy is preferred; combination therapy used for refractory cases or different seizure types.

MOA:

Prevent the spread of abnormal electrical discharge by:

• Blocking Na+/Ca2+ channels.
• Increasing inhibitory GABAergic impulses.
• Interfering with excitatory glutamate transmission.

Mechanisms:

• Na+ Channel Blockers: Carbamazepine (check for hyponatremia), Phenytoin (check liver enzymes), Oxcarbazepine (similar to carbamazepine, induces hepatic enzymes).
• Ca2+ Channel Blockers: Ethosuximide, Lamotrigine, Gabapentin, Pregabalin.
• GABA Receptor Agonists: Clobazam, Clonazepam, Phenobarbital, Primidone.
• GABA Reuptake Inhibitors: Tiagabine.
• GABA Transaminase Inhibitors: Vigabatrin.
• AEDs with potential GABA MOA: Gabapentin, Pregabalin, Valproate.
• Glutamate Blockers: Felbamate, Topiramate.
• K+ Channel Openers: Retigabine.

Interactions:

Complex, involving hepatic enzyme induction or inhibition. Can increase toxicity without increasing efficacy.

• Carbamazepine ↓ plasma concentration of lamotrigine.
• Ethosuximide ↑ plasma concentration of phenytoin.
• Lamotrigine ↑ plasma concentration of carbamazepine's active metabolite.

Comparison:

AEDs modify neuronal excitability to prevent seizures. Actions include Na+/Ca2+ channel blockade, GABA potentiation, glutamate blockade.

Indications:

1. Partial Seizures: Simple partial, Complex partial.
2. Generalized Seizures: Tonic-clonic seizures, Status epilepticus.

ADRs:

• Increased risk of suicidal behavior.
• Nausea, vomiting, drowsiness, ataxia, rash.
• Hyponatremia, weight changes.
• Teratogenicity.
• Osteoporosis.

Driving Restrictions:

Patients must be seizure-free for 1 year to drive. Drowsiness necessitates avoidance of driving. First seizure requires a 6-month driving ban.

Pregnancy:

• AEDs increase teratogenicity risk. Valproate is associated with congenital malformations and should be avoided if safer alternatives exist. Phenytoin, primidone, phenobarbital, lamotrigine have lower teratogenic risk.
• Folic acid supplementation is recommended. Vitamin K at birth minimizes neonatal hemorrhage risk. Breastfeeding is generally safe at normal doses, except for barbiturates.

Rational Pharmacotherapy of Epilepsy:

1. Goal: Prevent seizures with effective dosage.
2. Choice of AED depends on seizure type, concurrent medications.
3. Dosage frequency based on plasma half-life and concentration.
4. Change of AEDs should be gradual.
5. Concurrent AEDs increase ADR risk.

Status Epilepticus Therapy:

1. Immediate measures: Position patient safely, support respiration, maintain BP, correct hypoglycemia.
2. Parenteral thiamine considered.
3. Urgent treatment with IV Lorazepam (repeat once after 10 min). Clonazepam can be an alternative.

36- Parkinson's Disease

Classification:

1. Levodopa and Carbidopa.
2. Monoamine Oxidase Inhibitors (MAOIs): Selegiline, Rasagiline.
3. Catechol-O-Methyltransferase (COMT) Inhibitors: Tolcapone, Entacapone.
4. Dopamine Receptor Agonists: Bromocriptine, Apomorphine.
5. Amantadine.
6. Antimuscarinic Agents: Benztropine, Trihexyphenidyl, Procyclidine, Biperiden.

Choice of Treatment:

• Medication does not prevent disease progression.
• Referral to a specialist for diagnosis confirmation is recommended.
• Review every 6-12 months.
• Treatment initiated when symptoms significantly disrupt daily activities.
• Levodopa or non-ergot dopamine receptor agonists are often initial choices.
• Combination therapy may be necessary.
• Elderly patients require low doses with gradual increases.

Interactions:

• Vitamin B6 (Pyridoxine): Increases peripheral breakdown of Levodopa, reducing efficacy.
• Levodopa + MAOIs: Can cause hypertensive crisis due to increased catecholamine production.
• Antimuscarinic agents can increase intraocular pressure (contraindicated in glaucoma).
• Can cause arrhythmias in cardiac patients.
• Antipsychotic drugs are contraindicated in Parkinsonism.

Levodopa and Carbidopa:

Levodopa, a precursor to dopamine, crosses the blood-brain barrier (BBB) to replenish dopamine deficiency in Parkinson's disease. Carbidopa inhibits peripheral levodopa breakdown.

ADRs:

COMT Inhibitor ADRs:

Diarrhea, postural hypotension, hepatic necrosis, dyskinesia, sleep disorder.

Dopamine Receptor Agonist ADRs:

Sedation, hallucinations, confusion, anorexia, nausea, vomiting, postural hypotension, dyskinesia.

Antimuscarinic Agent ADRs:

Mood changes, dry mouth, visual problems, pupillary dilation, confusion, hallucinations, sinus tachycardia, urinary retention, constipation.

Migraine

ADRs:

Triptans: Dizziness, muscle weakness, neck pain.

Interactions:

• Triptans + Ergot Derivatives: Increased risk of coronary artery vasoconstriction and hypertensive effects.
• Triptans + Propranolol: Increased triptan concentration.
• Ergot Derivatives: Increased risk of ergotism (vasoconstriction, convulsions, GI effects) with Macrolides, Tetracyclines, Imidazoles, Triazoles, Antivirals.

Diabetes Mellitus (DM) Goals

Blood Sugar Control:

• Goal: Keep blood sugar levels normal or near-normal to prevent long-term complications.
• Levels: Fasting < 7 mmol/L; Postprandial < 9 mmol/L.
• Home Blood Sugar Monitoring (SMBG) is helpful for detecting high/low glucose levels, adjusting A1C, confirming hypo/hyperglycemia, patient education, and motivation.
• Normal fasting blood sugar: < 5.6 mmol/L (100 mg/dL).

Cardiovascular (CVD) Risk Reduction (DM Type II):

• Most common complication of DM II.
• Risk reduced by: Quitting smoking, BP < 130/80 mmHg, Lipids (Cholesterol < 5 mmol/L, Triglycerides < 1.7 mmol/L, HDL > 1.6 mmol/L, LDL < 1.8 mmol/L).

A1C Goal:

For most people, A1C < 7%.

Treatment of DM Type II: Oral Hypoglycemics and Incretins

I- Insulin Secretagogues:

• Sulfonylureas: Stimulate insulin secretion by closing K+ channels in pancreatic β-cells. 1st Gen (older, more side effects), 2nd Gen (commonly used: Glyburide, Glipizide).
• Meglitinides: Modulate insulin release by regulating K+ channels.
• D-Phenylalanine Derivatives: Newer agents, stimulate insulin release.

II- Biguanides:

• Metformin (500 mg - 2.55 g/d).
• MOA not fully understood; slows glucose absorption from GIT, increases glycolysis.

III- Thiazolidinediones (TZDs):

• Pioglitazone (15-45 mg/d), Rosiglitazone (2-8 mg/d).
• ↓ Insulin resistance by acting as ligands for PPAR-gamma nuclear receptors, modulating gene expression involved in lipid and glucose metabolism.

IV- Alpha-Glucosidase Inhibitors:

• Acarbose, Miglitol. Delay starch digestion and absorption, reducing post-meal glucose excursions.

V- Incretins:

• Pramlintide: Synthetic amylin analog, injectable, modulates postprandial glucose. Administered with insulin.
• Exenatide: Synthetic glucagon-like peptide-1 analog, injectable, reduces body weight, approved as adjunct therapy for DM II with metformin.
• Sitagliptin: DPP-4 inhibitor, increases GLP-1 and GIP levels, decreases postprandial glucose excursions.

Insulin Therapy

• Rapid Acting: Insulin lispro, aspart, glulisine; inhaled human insulin. Onset 3-5 H.
• Short Acting (Regular): Identical to human insulin. Onset 30 min, peak 2-3 H, duration 5-8 H. Administer 30-45 min before meals.
• Intermediate Acting (NPH): Insulin + protamine. Onset 2-5 H, duration 4-12 H.
• Long Acting: Glargine (onset 1-1.5 H, peak 4-5 H, duration 11-24 H), Detemir (onset 1-2 H, duration >24 H).

Regimens:

• Split/Mixed: NPH with rapid or regular insulin before breakfast.
• Multiple Daily Injections (MDI): Long-acting once daily + rapid-acting before meals.
• Continuous Subcutaneous Insulin Infusion (CSII): Rapid-acting insulin via pump, 24/7.

Antithyroid Drugs

I- Thiomides:

• Methimazole, Propylthiouracil (PTU).
• Efficacy: Prevent hormone synthesis by inhibiting thyroid peroxidase. Block iodine oxidation, incorporation into tyrosine, and coupling of T3/T4. Do not block iodine uptake. Slow onset as they affect synthesis, not release. PTU also blocks peripheral T4 to T3 conversion.
• Safety: ADRs include hepatitis (monitor liver enzymes) and agranulocytosis (rare but fatal).

II- Anion Inhibitors:

• Perchlorate, Pertechnetate, Thiocyanate.
• Efficacy: Block iodine uptake by the gland via competitive inhibition of the iodine transport mechanism.

III- Iodides:

• Efficacy: Decrease organification and hormone release; decrease size and vascularity of hyperplastic gland.
• Safety: Increase intraglandular iodine storage, delaying thiomide onset. Should not be used alone as the gland can escape the iodide block. Avoid in pregnancy.

IV- Radioactive Iodine (131I):

• Efficacy: Destroys thyroid parenchyma over weeks.
• Safety: Contraindicated in pregnancy and nursing mothers. May lead to hypothyroidism (monitor T4/TSH; treat with levothyroxine if needed).

V- Adrenoreceptor Blocking Agents:

• Beta blockers (Metoprolol, Propranolol, Atenolol).
• Efficacy: Effective adjuncts in thyrotoxicosis management, improving symptoms. High doses of propranolol reduce T3 levels.

Rational Treatment of Thyrotoxicosis:

Goals: Decrease synthesis or release of thyroid hormone. Methods: Surgery, blocking hormone synthesis (thiomides), blocking release (iodides), destroying gland (radioactive iodine).

Clinical Aspects of Hypothyroidism

Inefficacy of Antibiotics (Ax)

When patients show inadequate clinical or microbiological response to antibiotics, systemic investigation is needed.

Potential Causes:

1. Errors in susceptibility testing (repeat test).
2. Incorrect antibiotic dosage or absorption (measure serum levels).
3. Abnormalities in the immune system.
4. Development of infection or superinfection (follow-up cultures).

Antibiotic therapy must be adjusted based on findings.

Pharmacotherapy of Diarrhea and Constipation

I- Diarrhea:

• Treatment: Address the cause (antibiotics/antiparasitics). Diarrhea is a symptom; management includes hydration and, if necessary, pharmacological agents.
• Loperamide: 2-4 mg every 4 hours PRN.
• Codeine Phosphate: 15-30 mg every 2-6 hours.
• Correct electrolyte disturbances.
• Bloody diarrhea may indicate C. difficile infection. Antidiarrheal agents can increase the risk of hemolytic uremic syndrome.

Chronic Diarrhea:

• Treat underlying disease.
• Loperamide, Anticholinergic agents.

Replacement Therapy:

Mainly lipase, used in exocrine pancreatic enzyme deficiency to prevent malabsorption and palliate pain.

II- Constipation (Pharmacotherapy):

• Osmotic Laxatives: Sorbitol (oral), Lactulose (10-20 mg/day), Sodium Phosphate (10 g/day), Polyethylene Glycol (17 g/day).
• Emollients: Glycerin suppositories (2-3 g/day), Mineral oil (15-45 mL/day), Docusate Sodium (100 mg 2-3x/day).
• Stimulants: Bisacodyl (10 mg suppositories up to 3x/week), Tegaserod (6 mg 2x/day).

Clinical Pharmacology of Antimicrobial Drugs: Rational Use

Antibiotics are crucial for treating infections but are often overprescribed, leading to resistance. Resistance limits treatment options and can be life-threatening.

Key Questions for Antibiotic Therapy:

• Is antibiotic therapy indicated based on clinical findings?
• Have appropriate microbiological tests been performed?
• What are the likely etiological agents?
• How can transmission be prevented?
• Is there evidence that antibiotics will not be beneficial?

Further Steps:

• Can a narrow-spectrum antibiotic substitute empirical therapy?
• Is one antibiotic or combination therapy needed?
• What is the optimal dose, route, and duration?
• What adjuvant therapy is needed (e.g., surgery, drainage, local antibiotic infusion)?

Risk of Bacterial Resistance to Antibiotics and Management

Resistance can be inherent or acquired via genes. Resistance genes transfer through transformation, transduction, and conjugation.

Antibiotics eliminate susceptible bacteria, increasing the proportion of resistant ones. They also affect normal flora. To prevent resistance, use antibiotics only when necessary, with the narrowest possible spectrum.

Eradication of H. pylori

• Requires combination therapy (2-3 antibiotics + acid suppression).
• Triple Therapy (14 days): PPI + Clarithromycin + Metronidazole or Amoxicillin (2x/day).
• Quadruple Therapy (14 days): PPI (2x/day) + Metronidazole + Bismuth + Tetracycline (4x/day).

Gastroesophageal Reflux Disease (GERD)

• Lifestyle Changes: Weight loss, elevate head of bed, small frequent meals.
• Pharmacological: PPIs (e.g., Omeprazole), H2 blockers (e.g., Cimetidine, Ranitidine), Antacids.