Physiology & Pathophysiology
LECTURE2 Core Concept 1 Cardiac Physiology
1. Public Health Impact of Cardiovascular Diseases (心血管疾病的公共卫生影响)
- Leading Causes of Premature Death:
- Premature death is defined as death before the age of 75.
- Two major categories of cardiovascular disease account for nearly 50% of all premature deaths in the UK:
- Ischaemic Heart Disease (IHD - 缺血性心脏病).
- Cerebrovascular Disease (CVD - 脑血管疾病).
- Demographic Differences:
- Males: Higher proportion of premature deaths caused by IHD compared to females.
- Females: Lower proportion of total deaths caused by cardiovascular disease compared to males.
- Role of Pharmacists:
- Increasing role in public health, particularly in monitoring blood pressure (血压).
- High blood pressure is often asymptomatic (“silent killer”) but leads to serious disease. Early detection and treatment are crucial.
2. Anatomy of the Cardiovascular System (心血管系统解剖)
- The Heart (心脏):
- Comprises four chambers:
- Right Atrium (右心房) and Left Atrium (左心房): Upper chambers.
- Right Ventricle (右心室) and Left Ventricle (左心室): Larger lower chambers.
- Orientation: The “Right” side of the heart corresponds to the person’s right side (which appears on the left when facing the person).
- Comprises four chambers:
- Blood Vessels (血管):
- Arteries (动脉): Large vessels carrying blood away from the heart.
- Arterioles (小动脉): Smaller branches of arteries.
- Capillaries (毛细血管): The smallest vessels where gas exchange ($O_2$ uptake, $CO_2$ removal) occurs at the tissue level.
- Venules (小静脉): Small veins collecting blood from capillaries.
- Veins (静脉): Large vessels returning blood to the heart.
- Circulation Path:
- Deoxygenated blood returns to the Right Atrium.
- Enters Right Ventricle and is pumped to the Lungs (肺) (via Pulmonary Artery).
- Gas exchange occurs in lungs ($CO_2$ released, $O_2$ taken up).
- Oxygenated blood returns to the Left Atrium.
- Enters Left Ventricle and is pumped out to the body/brain (via Aorta).
- The Kidneys (肾脏):
- Play a vital role in long-term homeostasis of the circulation.
- Regulate blood volume and blood osmolarity (渗透压).
3. The Heartbeat and Conduction System (心跳与传导系统)
- Function:
- Primary role: Supply cells with oxygen and remove metabolic waste.
- Performance: Beats ~70 times per minute; pumps ~7,000 liters of blood per day.
- Relies on coordinated contractions driven by spontaneous electrical impulses.
- Electrical Conduction Pathway:
- Sinoatrial Node (SA Node - 窦房结):
- The pacemaker of the heart.
- Small, banana-shaped tissue (~1.5 x 0.5 cm) in the right atrium.
- Generates spontaneous electrical impulses to initiate the heartbeat.
- Internodal Tract (结间束):
- Conducts electrical activity through the atria to the AV node.
- Atrioventricular Node (AV Node - 房室结):
- Located at the base of the right atrium.
- Key Function: Acts as a relay station to slow down conduction (delay of ~100 ms).
- Purpose of Delay: Ensures atria contract and empty blood into ventricles before the ventricles contract (coordination).
- Bundle of His (希氏束) and Bundle Branches:
- Conducts signals from the AV node to the septum and splits into left and right branches.
- Purkinje Fibers (浦肯野纤维):
- Conducting tissue that spreads signals to ventricular muscle cells.
- Ensures all ventricular muscle cells are excited simultaneously for a coordinated contraction.
- Sinoatrial Node (SA Node - 窦房结):
- Mechanism of Propagation:
- Electrical signals move from cell to cell via gap junctions (缝隙连接).
4. The Cardiac Cycle (心动周期)
- Definition: The sequence of events between one heartbeat and the next, consisting of contraction and relaxation phases.
- Heart Valves (心脏瓣膜):
- Passive structures (act like tendons) moved by muscle contraction/relaxation to ensure one-way blood flow.
- Tricuspid Valve (三尖瓣): Between right atrium and right ventricle.
- Mitral Valve (二尖瓣): Between left atrium and left ventricle.
- Pulmonary Valve (肺动脉瓣): Between right ventricle and pulmonary artery.
- Aortic Valve (主动脉瓣): Between left ventricle and aorta.
- Phases of the Cycle:
- Systole (收缩期):
- Ventricular muscle contracts.
- Peak contraction pressure.
- AV valves (Tricuspid/Mitral) close to prevent backflow into atria.
- Aortic and Pulmonary valves open to pump blood out to the body/lungs.
- Diastole (舒张期):
- Ventricular muscle relaxes.
- The heart spends more time in diastole (approx. 2/3 of the cycle) than systole.
- Pressure Dynamics:
- Ventricular pressure falls close to zero.
- Low ventricular pressure keeps Aortic/Pulmonary valves closed (maintaining high pressure in arteries and preventing backflow).
- AV valves open, allowing blood to flow from atria to ventricles.
- Filling:
- Blood only flows from veins into the heart during diastole when ventricular pressure is low.
- As ventricles fill, walls stretch, creating opposition that results in a volume plateau while pressure remains low.
- Systole (收缩期):
5. Systemic Blood Pressure (体循环血压)
- Mechanism: Pressure is created by the heart pumping and is necessary to push blood through circulation. It fluctuates during the cardiac cycle.
- Definitions:
- Systolic Pressure (SP - 收缩压): Maximum pressure in the arterial system (during ventricular contraction).
- Diastolic Pressure (DP - 舒张压): Minimum pressure in the arterial system (during ventricular relaxation).
- Pulse Pressure (脉压): $SP - DP$.
- Mean Arterial Pressure (MAP - 平均动脉压): Used clinically and in research.
- Formula: $MAP = DP + \frac{1}{3}(SP - DP)$
- Logic: It is diastolic pressure plus one-third of the pulse pressure because the heart spends ~2/3 of the cycle in diastole and ~1/3 in systole.
- British Hypertension Society Classification:
| Category | Systolic BP (mmHg) | Diastolic BP (mmHg) |
|---|---|---|
| Optimal | < 120 | < 80 |
| Normal | < 130 | < 85 |
| High-Normal | 130 – 139 | 85 – 89 |
| Grade 1 Hypertension (Mild) | 140 – 159 | 90 – 99 |
| Grade 2 Hypertension (Moderate) | 160 – 179 | 100 – 109 |
| Grade 3 Hypertension (Severe) | $\ge$ 180 | $\ge$ 110 |
- Isolated Systolic Hypertension:
- Occurs when systolic pressure is elevated but diastolic remains normal (<90 mmHg).
- Systolic pressure is mainly determined by the force of heart pumping.
- Diastolic pressure is mainly determined by the constriction/dilation of blood vessels.
6. Key Definitions and Equations
- Stroke Volume (SV - 每搏输出量):
- The volume of blood ejected with each heartbeat.
- Typical value: ~70 ml.
- Cardiac Output (CO - 心输出量):
- The flow of blood from one ventricle over time.
- Typical value (at rest): ~5 Liters/minute.
- Because the cardiovascular system is a closed loop, flow from the left and right ventricles is the same.
- Fundamental Equation:
$$\text{Cardiac Output} (CO) = \text{Heart Rate} (HR) \times \text{Stroke Volume} (SV)$$- This equation allows for calculation of physiological changes (e.g., if HR increases and SV stays constant, CO increases).
7. Measurement of Cardiac Function (心脏功能测量)
- Electrocardiogram (ECG - 心电图):
- Measures electrical activity in the heart via changes in electrical signals on the skin surface.
- Used clinically to detect heart rhythm problems (arrhythmias).
- Historical Evolution: Started with large machines using salt solution baths (1920s); evolved to portable clinical machines and personal devices (smartphones).
- Echocardiography (超声心动图):
- Uses ultrasound to image the heart.
- Allows visualization of blood flow (turbulence), valve structure/function, and wall defects (e.g., hole in the heart).
- Magnetic Resonance Imaging (MRI - 磁共振成像):
- Provides high-resolution images of structure and real-time monitoring of function.
- limitations: Requires large specialized equipment, patient must lie still for a long time, not used routinely (reserved for complex cases).
LECTURE4 Core Concept 3: Cardiac Physiology 2
1. Introduction to Haemodynamics
Haemodynamics (血液动力学) is defined as the dynamics of blood flow. The term is derived from “hemo” (blood) and “dynamics” (movement). The heart and blood vessels work as an integrated unit to regulate both blood flow and blood pressure throughout the body. It is critical to distinguish between these two concepts:
- Blood Pressure (血压): Usually refers to the global pressure within the entire vascular system, typically measured from the aorta.
- Blood Flow (血流): Can refer to the total output from the ventricles (Cardiac Output) or the localized flow within a specific organ or tissue area.
2. Core Learning Objectives
- Define Cardiac Output (心输出量) and explain its regulating factors.
- Understand the relationship between Heart Rate (心率), Stroke Volume (每搏输出量), and Cardiac Output.
- Identify Heart Valves (心脏瓣膜) and their roles in controlling flow.
- Describe the anatomy of circulation and the structures of different blood vessels.
- Understand pressure changes in arterial and venous systems during the Cardiac Cycle (心动周期).
- Distinguish between Preload (前负荷) and Afterload (后负荷).
- Define Compliance (顺应性), Resistance (阻力), and Total Peripheral Resistance (总外周阻力).
- Explain the significance of Poiseuille’s Law (泊肃叶定律) regarding flow through vessels.
- Describe homeostatic regulation of blood pressure via the Autonomic Nervous System (自主神经系统) and Humoral Systems (体液系统/激素调节).
- Distinguish between Functional Hyperaemia (功能性充血) and Reactive Hyperaemia (反应性充血).
3. Principles of Pressure and Resistance
The circulation is a dynamic and adjustable network. The heart provides a “head of pressure” to propel blood through vessels of varying diameters.
- Vessel Diameter and Flow:
- Wide Vessels: Offer low resistance, allowing blood to flow easily (e.g., the aorta).
- Narrow Vessels: Offer high resistance, restricting flow (e.g., capillaries).
- Pressure Relationship: Arteries provide the primary resistance to flow. When resistance is high (narrowed vessels), pressure increases. Conversely, widening an artery causes pressure to drop.
4. Pressures During the Cardiac Cycle
A Wiggers Diagram (威格斯图) is used to track pressure changes across one cardiac cycle (from the start of one systole to the next).
- Left Ventricle (左心室): Pressure is very low during diastole. At the start of systole, pressure rises steeply to a peak before falling.
- Aorta (主动脉): Pressure remains relatively high even during diastole (diastolic blood pressure, approx. 75–80 mmHg). Blood is only ejected when the pressure in the left ventricle exceeds the pressure in the aorta.
- Left Atrium (左心房): Pressure remains consistently low throughout the cycle. The mitral valve prevents the high pressure in the contracting ventricle from pushing blood back into the atrium.
- Venous Pressure: Unlike arterial pressure, venous pressure is usually close to zero.
5. Effects of Gravity on Blood Flow
Gravity pulls blood toward the lower extremities when standing. To ensure the brain receives a constant blood supply, the body uses physiological mechanisms—primarily blood pressure—to drive blood upward.
- Comparative Physiology: Different animals adapt to their environments. A Giraffe (长颈鹿) has a blood pressure more than double that of a human to overcome the gravitational pull of its long neck. Conversely, fish have very low blood pressure as their blood moves mostly horizontally.
6. Anatomy and Distribution of the Circulation
The circulation is divided into two main circuits:
- Systemic Circulation (体循环): Arteries carry oxygenated blood away from the heart to the body; veins return deoxygenated blood.
- Pulmonary Circulation (肺循环): Arteries carry deoxygenated blood to the lungs; veins return oxygenated blood to the heart.
- Vessel Hierarchy: Blood flows from the heart $\rightarrow$ Large Arteries $\rightarrow$ Arterioles (小动脉) $\rightarrow$ Capillaries (毛细血管) $\rightarrow$ Venules (小静脉) $\rightarrow$ Veins (静脉).
Blood Volume Distribution (At Rest):
Blood is not evenly distributed. The venous system holds the majority of the body’s blood volume.
- Resistance Vessels (阻力血管): Arteries (holding ~15% of blood) offer resistance to flow.
- Capacitance Vessels (容量血管): Veins (holding ~64% of blood) act as a reservoir.
| Part of Circulation | % Total Blood Volume |
|---|---|
| Heart | 7% |
| Pulmonary Vessels | 9% |
| Systemic Arteries (Large/Small/Arterioles) | 15% |
| Capillaries | 5% |
| Systemic Veins (Large/Small/Venules) | 64% |
7. Arterial Blood Pressure Homeostasis
Homeostasis (体内平衡) is the maintenance of a stable state. Blood pressure must be regulated within a narrow range:
- Too Low: Vessels may collapse, stopping blood flow.
- Too High: Causes damage to vessel walls and major organs (brain, kidneys, heart). Long-term hypertension is a “silent” condition leading to dementia, kidney disease, heart attacks, and strokes.
The Control System:
- Sensors: Detect Mean Arterial Pressure (MAP).
- Communication: Signal changes to the brain.
- Integration: The brain processes information from various sensors (mostly in large arteries near the heart).
- Instruction: The system sends signals to correct the change.
8. Time Scales of Blood Pressure Control
Different mechanisms respond to pressure changes over varying durations:
- Immediate (Seconds to Minutes):
- Baroreceptors (压力感受器): Sense stretch in vessel walls. Essential for immediate adjustments, such as when standing up.
- Chemoreceptors (化学感受器): Detect chemical changes in the blood.
- Medium Term (Minutes to Hours):
- Renin-Angiotensin-Aldosterone System (RAAS) (肾素-血管紧张素-醛固酮系统): A hormonal system where the kidneys sense flow changes and release renin to trigger a hormonal cascade.
- Long Term (Hours to Days):
- Fluid Shift (液体转移): Movement of fluid between interstitial spaces and blood vessels to adjust volume.
- Kidney Response (肾脏响应): Long-term renal adjustments to maintain pressure and flow.
9. Levels of Blood Flow Regulation
Blood flow can be controlled at three levels of specificity:
- Changing Cardiac Output: Increasing Heart Rate or Stroke Volume increases flow to all organs (e.g., during exercise).
- Changing Distribution: Redirecting blood from one organ to another without changing total Cardiac Output. For example, after eating, blood is directed to the Gastrointestinal Tract (胃肠道) while flow to muscles is reduced.
- Local Control: Changing flow to a single vessel or group of vessels within an organ. In the brain, blood flow is redirected to specific active regions depending on the task (reading vs. writing). Brain imaging (fMRI) actually measures these changes in local blood flow rather than direct neuronal activity.
10. Summary of Key Haemodynamic Terms
- Mean Arterial Pressure (MAP) (平均动脉压): The average pressure sensed by the vessels.
- Total Peripheral Resistance (TPR) (总外周阻力): Also known as Systemic Vascular Resistance (系统血管阻力); the sum of resistance offered by the entire vascular network.
- Preload: The load on the heart before it beats (determined by the volume of blood filling the heart).
- Afterload: The load the heart must pump against (the resistance in the circulation).
LECTURE6 Core Concept 5: Cardiac Physiology 3
1. Introduction to Blood (血液介绍)
1.1 Definition and Nature
- Fluid Tissue (流体组织): Blood is a component of the circulatory system described as a fluid tissue. It consists of a regulated mix of cells and proteins suspended in fluid, lacking a solid matrix.
- Extracellular Water (细胞外液):
- Blood contains approximately 20% of the body’s extracellular water.
- The remaining 80% is located in the interstitial tissues (between and within organs).
- Exchange with Interstitial Fluid (间质液):
- Circulating blood is separated from interstitial fluid by the capillary wall (semipermeable membrane/endothelial cells).
- Rapid Exchange: Small molecules (water, ions) cross the membrane easily, resulting in similar compositions of these substances in both blood and interstitial fluid.
- Barrier Function: Large molecules (proteins) and cells cannot easily cross the barrier. This maintains a distinct composition where blood has a much higher protein concentration than interstitial fluid.
2. Composition and Separation of Blood (血液的组成与分离)
2.1 Separation by Centrifugation (离心分离)
When fresh whole blood is prevented from clotting and centrifuged, it separates into three distinct layers based on density:
- Plasma (血浆): The top layer (straw-colored). Composed of water, ions, and proteins.
- Buffy Coat (白细胞层): A thin middle layer (<1% of volume). Composed of White Blood Cells (Leukocytes) and Platelets.
- Red Blood Cells (红细胞): The bottom layer (red). Accounts for approximately 40-45% of blood volume.
2.2 Plasma vs. Serum (血浆与血清)
- Plasma (血浆): Obtained from fresh blood that has been prevented from clotting. Contains all proteins, including clotting factors.
- Serum (血清): Obtained by allowing blood to clot first, then centrifuging.
- The clot (Thrombus) forms at the bottom.
- The fluid on top is serum.
- Key Difference: Serum lacks clotting proteins (like fibrinogen) because they have been consumed to form the clot.
3. Plasma Proteins (血浆蛋白)
- Total Protein Concentration: 55–80 g/L.
3.1 Albumin (白蛋白)
- Abundance: The most abundant single protein in plasma (approx. 28-55 g/L).
- Functions:
- Colloid Osmotic Pressure (胶体渗透压): Generates 22 mmHg of the total 28 mmHg pressure. This force pulls water into the circulatory system.
- Buffering: Helps buffer blood pH via ionizable groups.
- Transport: Acts as a carrier for lipophilic molecules with low solubility, small hormones, and drugs.
- Pharmacokinetics: Binding to albumin can prolong the life of drugs in plasma; drug interactions can occur if drugs displace each other from albumin binding sites.
3.2 Fibrinogen (纤维蛋白原)
- Function: The precursor material for blood clots.
- Mechanism: It is soluble in blood but is cleaved by clotting factors into Fibrin (纤维蛋白), which forms a mesh to trap cells.
- Concentration: 1.5–4 g/L.
3.3 Globulins (球蛋白)
- A broad class of proteins (approx. 28 g/L total).
- Transport:
- Lipoproteins (脂蛋白): Transport lipids (HDL, LDL).
- Transferrin (转铁蛋白): Transports iron.
- Enzymes: Clotting factors (e.g., Thrombin).
- Hormones: Protein hormones like Erythropoietin (促红细胞生成素).
- Immune Function: Immunoglobulins (免疫球蛋白) or antibodies.
3.4 Diagnostic Proteins
- Proteins that should not normally be in plasma can indicate tissue damage.
- Troponin (肌钙蛋白): An important contractile protein in the heart. Its presence in blood indicates cardiac muscle damage (e.g., Myocardial Infarction).
4. Blood Tests (血液检测)
Common routine tests and their significance:
4.1 Red Blood Cell Tests
- Hematocrit (红细胞压积/HCT): The percentage of blood volume occupied by red blood cells.
- Typical value: ~45% (Normal range: Females 37-48%, Males 42-52%).
- Erythrocyte Count (红细胞计数): ~5 million cells/mm³.
- Mean Corpuscular Volume (平均红细胞体积/MCV): The volume of a single erythrocyte. Typical value: 90 fL (femtoliters).
4.2 White Blood Cell (Leukocyte) Tests
- Leukocyte Count: ~7,000 cells/mm³.
- Cell Types:
- Neutrophils (中性粒细胞): ~60% (Most abundant).
- Lymphocytes (淋巴细胞): ~30%.
- Monocytes (单核细胞): ~5%.
- Eosinophils (嗜酸性粒细胞): ~5%.
- Basophils (嗜碱性粒细胞): ~1%.
- Polymorphonuclear Cells (多形核细胞/PMN): Refers to Neutrophils, Eosinophils, and Basophils, characterized by oddly shaped, multi-lobed nuclei.
4.3 Platelet Tests
- Platelet Count: ~250,000/mm³.
- Also known as Thrombocytes.
5. Blood Cell Characteristics (血细胞特征)
5.1 Erythrocytes (Red Blood Cells)
- Structure: No nucleus (in mammals), biconcave disc shape (7.5 µm diameter, 2 µm thick).
- Lack of nucleus prevents the cell from bulging, allowing passage through narrow capillaries.
- Content:
- High intracellular Hemoglobin (血红蛋白) concentration (~35 g/100mL).
- Packaging hemoglobin in cells prevents high blood viscosity (粘度). If hemoglobin were free in plasma, blood would be too thick to flow (Poiseuille’s Law).
- Metabolism: Retain enzymes for glycolysis and carbonic anhydrase (for CO2 transport) but cannot synthesize new proteins.
- Lifespan & Destruction:
- Lifespan: ~120 days.
- Fragile due to mechanical/chemical stress.
- Damaged cells become rigid and get trapped in the Spleen (脾脏) capillaries.
- Recycled by tissue macrophages (Reticuloendothelial system).
5.2 Platelets (Thrombocytes)
- Structure: Small cell fragments (not true cells), no nucleus.
- Lifespan: ~10 days.
- Function: Crucial for hemostasis (stopping bleeding).
6. Hematopoiesis (造血作用)
6.1 Origin
- All blood cells originate from Pluripotent Hematopoietic Stem Cells (多能造血干细胞) in the Bone Marrow (骨髓).
- Active Marrow Locations:
- Birth to age 5: All bones.
- Adult (>20 years): Sternum, vertebrae, ribs, and pelvis.
6.2 Lineages
The stem cell differentiates into two progenitors:
- Lymphoid Progenitor: Develops into Lymphoblasts $\rightarrow$ Lymphocytes.
- Myeloid Progenitor: Develops into:
- Erythrocytes (Red Blood Cells).
- Megakaryocytes (巨核细胞): Massive cells that shed fragments to become Platelets.
- Myeloblasts: Differentiate into Basophils, Neutrophils, Eosinophils, and Monocytes.
6.3 Regulation
- Differentiation is driven by specific Growth Factors (生长因子) depending on the body’s needs.
7. Erythropoiesis (红细胞生成)
- Definition: The specific production of red blood cells.
- Sensing Mechanism:
- The Kidney (not bone marrow) senses Hypoxemia (low oxygen levels).
- Hormonal Control:
- The kidney secretes Erythropoietin (EPO/促红细胞生成素).
- EPO circulates to the bone marrow and stimulates erythrocyte production.
- Capacity: Production rate can increase 6-8 times in response to hypoxia (e.g., high altitude).
8. Hemostasis (止血)
Definition: The maintenance of a steady state in blood, specifically preventing blood loss upon vessel damage. It involves four main stages:
8.1 Vascular Spasm (血管痉挛)
- Reflex constriction of blood vessels to reduce blood flow.
- Triggered by vasoconstrictors released by damaged tissue and activated platelets.
8.2 Platelet Plug Formation (血小板栓子形成)
- Adhesion: Platelets stick to the exposed vessel wall and to each other.
- Activation:
- Resting platelets are smooth discs.
- Activated platelets extend pseudopods (filopodia), spread out (resembling a “fried egg”), and aggregate to plug the hole.
8.3 Blood Coagulation (血液凝固)
- Formation of a clot (thrombus).
- Involves the polymerization of soluble Fibrinogen into an insoluble Fibrin mesh.
- The fibrin mesh traps cells and strengthens the plug.
8.4 Fibrous Tissue Formation (纤维组织形成)
- Permanent repair and healing.
- Repair cells synthesize collagen fibers to replace the clot with scar tissue.
9. Coagulation Cascade (凝血级联反应)
A complex series of enzymatic reactions leading to a fibrin clot.
9.1 Pathways
- Extrinsic Pathway (外源性途径):
- Initiated by Trauma to the blood vessel and surrounding tissue.
- Release of Tissue Factor (Factor III).
- Explosive/Fast response; initiates coagulation.
- Intrinsic Pathway (内源性途径):
- Triggered by damage within the vessel (e.g., exposed endothelium).
- Slower; thought to sustain coagulation.
9.2 Common Pathway
Both pathways converge to activate Factor X (Factor 10).
- Step 1: Generation of Prothrombin Activators (Activated Factor X + Factor V).
- Step 2: Conversion of Prothrombin (凝血酶原) $\rightarrow$ Thrombin (凝血酶).
- Step 3: Thrombin effects (Positive Feedback loop):
- Converts Fibrinogen $\rightarrow$ Fibrin.
- Activates Factor XIII to cross-link fibrin strands (stabilizing the clot).
- Stimulates intrinsic pathway activators (more prothrombin activation).
9.3 Key Requirements
- Calcium (Ca2+): Essential for several steps in the cascade.
- Blood collection tubes often use Citrate to bind calcium and prevent clotting in the tube.
10. Prevention of Harmful Clotting (防止有害凝血)
The body has mechanisms to limit coagulation to the site of injury:
10.1 Natural Mechanisms
- Flow: Blood flow dilutes soluble activated factors.
- Liver Clearance: Kupffer cells in the liver remove activated factors.
- Endothelial Factors (Released by healthy vessels):
- Prostacyclin & Nitric Oxide: Inhibit platelet activation.
- TFPI (Tissue Factor Pathway Inhibitor): Blocks the extrinsic pathway.
- Thrombomodulin: Binds thrombin.
- Heparin: Present on endothelial membranes.
10.2 Pharmacological Interventions
Two distinct classes of drugs (non-overlapping functions):
- Anti-platelet drugs (抗血小板药): Prevent platelet activation (e.g., Aspirin, Clopidogrel).
- Anticoagulants (抗凝药): Interfere with the clotting cascade/fibrin formation.
LECTURE7 Core Concept 6: Anaemia
1. Anaemia Overview and Definition
1.1 Definition
- Anaemia (贫血) is defined as a decrease in the oxygen-carrying capacity of the blood arising as a result of a decreased quantity of haemoglobin (血红蛋白) in the blood.
- Reference: It is recommended to consult the BNF summaries for “Anaemias” before initiating treatment to determine the specific type present.
1.2 Formation of Red Blood Cells (Erythropoiesis)
- Site: The principal site of production is the Bone Marrow (骨髓).
- Timeline:
- Erythropoiesis (红细胞生成) takes approximately 8 days.
- Lifespan: The lifespan of an erythrocyte is approximately 120 days.
- Maturation Stages:
- Erythroblasts (成红细胞)
- Normoblasts (幼红细胞)
- Reticulocytes (网织红细胞): These are immature red blood cells released from the bone marrow into circulation.
- Clinical Significance: When treating anaemia, the first sign of a response is an increase in reticulocytes (up to 2% or higher), as the marrow releases them first.
- Erythrocytes (红细胞)
- Control: Regulated by cytokines and Erythropoietin (促红细胞生成素, EPO).
1.3 Key Symptoms and Presentation
- Common Symptoms:
- Fatigue (疲劳): Getting tired easily.
- Breathlessness (呼吸急促): Difficulty breathing, especially during exertion.
- Reduced exercise tolerance (运动耐量降低).
- Other Symptoms:
- Dizziness, headache, insomnia.
- Palpitations (心悸) and Tachycardia (心动过速): The heart beats faster to circulate blood more quickly to compensate for low oxygen.
- Systolic murmurs.
- Physical Presentation:
- Pallor (苍白): Pale skin due to reduced haemoglobin, which normally contributes to skin colour.
- Complications:
- Angina (心绞痛): In patients with existing Coronary Heart Disease (CHD), anaemia can precipitate angina due to restricted oxygen flow to the heart.
2. Classification and Causes of Anaemia
2.1 Essential Requirements for Red Blood Cell Production
Deficiencies in these substances lead to specific types of anaemia:
- Iron (铁): Required for haemoglobin formation.
- Vitamin B12 (维生素 B12): Required for DNA synthesis, fatty acid metabolism, and amino acid metabolism. (Deficiency affects nerve myelin sheaths).
- Folic Acid (叶酸): Required for DNA synthesis.
2.2 Classification by Cell Size
- Macrocytic (大细胞性):
- Large red blood cells.
- Cause: Typically Megaloblastic anaemia (巨幼细胞性贫血) due to Vitamin B12 or Folic acid deficiency.
- Microcytic (小细胞性):
- Small red blood cells.
- Cause: Iron deficiency anaemia (缺铁性贫血).
- Normocytic (正细胞性):
- Normal-sized red blood cells.
- Cause: Blood loss (acute or chronic). The cells are normal, but there are not enough of them.
2.3 General Causes of Anaemia
- Reduced Red Cell Production:
- Deficiency (Iron, B12, Folate).
- Sideroblastic anaemia.
- Aplastic anaemia.
- Renal failure (lack of EPO).
- Increased Requirements:
- Pregnancy and Lactation.
- Excessive Red Cell Destruction (Haemolysis):
- G6PD deficiency (葡萄糖-6-磷酸脱氢酶缺乏症).
- Sickle cell anaemia.
- Blood Loss:
- Acute: Trauma.
- Chronic: Gastrointestinal (GI) blood loss (e.g., ulcers, tumours).
3. Iron Deficiency Anaemia (IDA)
3.1 Causes of IDA
- Reduced Intake: Poor diet or impaired absorption (e.g., Coeliac disease, Crohn’s disease, post-GI surgery).
- Increased Requirements: Pregnancy, lactation.
- Blood Loss: Trauma, menstruation, or GI bleed (often chronic and asymptomatic).
3.2 Management and Assessment (BSG Guidelines)
- Diagnosis:
- Take a detailed history.
- Confirm diagnosis: Must confirm anaemia is due to iron deficiency (check Serum Ferritin) before treating to avoid iron overload.
- Note: IDA is the most common cause, but it must not be assumed.
- Investigation: Once confirmed, do not delay treatment. Concurrent investigations for the underlying cause (e.g., gastroscopy, colonoscopy for GI bleeds) may be needed.
- Treatment Guidelines:
- Start Oral Iron (口服铁剂) immediately.
- Monitor response in the first 4 weeks.
- Continue treatment for 3 months after levels normalize to replenish stores.
3.3 Oral Iron Therapy
- Formulation: Ferrous salts (亚铁盐, Fe2+) are better absorbed than Ferric salts (Fe3+) due to solubility at intestinal pH.
- Dosing Regimen:
- Current recommendation: One tablet per day.
- Alternative: Every other day (alternate days) if not tolerated. This allows the body to recover and may reduce side effects while maintaining absorption efficacy.
- Absorption:
- Greatest absorption occurs before food (on an empty stomach) in the duodenum.
- Taking with food reduces absorption but is often recommended to manage side effects.
3.4 Side Effects and Management
- Common Side Effects: Constipation, diarrhoea, GI discomfort, nausea.
- Dark Stools (黑便):
- Iron causes stools to turn black.
- Patient Counselling Point: Warn patients about this, as it resembles the presentation of a GI bleed (melena). Patients with a history of GI bleeds may think their condition has returned.
- Managing Side Effects:
- Take with food (reduces absorption but improves tolerability).
- Change the salt/formulation (reduce the amount of elemental iron).
- Switch to alternate-day dosing.
3.5 Iron Salts and Elemental Iron Content
Different salts contain varying amounts of Elemental Iron (元素铁). If a patient experiences side effects, switching to a salt with lower elemental iron may help.
- Ferrous Fumarate (富马酸亚铁): 210mg tablet ≈ 69mg iron (High).
- Ferrous Sulphate (硫酸亚铁): 200mg dried tablet ≈ 65mg iron.
- Ferrous Gluconate (葡萄糖酸亚铁): 300mg tablet ≈ 35mg iron (Lower iron content, often better tolerated).
- Sodium Feredetate: 190mg/5mL ≈ 27.5mg iron.
3.6 Other Oral Formulations
- Modified Release (缓瑞制剂):
- Status: Not recommended by the BNF.
- Reason: They release iron slowly, carrying it past the duodenum (primary absorption site). Fewer side effects likely result from poor absorption rather than safer formulation. Expensive with no therapeutic advantage.
- Combination Products:
- Iron + Vitamin C: Not recommended; the amount of ascorbic acid is usually insufficient to significantly aid absorption.
- Iron + B Vitamins: Not recommended.
- Iron + Folic Acid: Only recommended for prophylaxis in pregnancy for high-risk mothers.
- Ferric Maltol (麦芽酚铁):
- Mechanism: A chelate where maltol prevents ferric iron precipitation. It releases ferric iron in the small intestine, which converts to ferrous for absorption.
- Pros: High bioavailability, low GI side effects.
- Cons: Significant cost (approx. £50 vs <£1 for sulphate).
- Use: 3rd line option; alternative to parenteral iron.
3.7 Paediatric Ferrous Sulphate Mixture (Historical/Compounding Note)
- Contains Ferrous Sulphate and Ascorbic Acid.
- Compounding Rule: Ascorbic acid (Vitamin C) must be added to the water before the Ferrous Sulphate.
- Reason: Prevents the oxidation of Ferrous iron (Fe2+) to Ferric iron (Fe3+). If mixed incorrectly, the solution turns brown (oxidized) instead of pale blue-green.
3.8 Parenteral Iron Therapy (IV Iron)
- Indications (Restricted Use):
- Unable to tolerate oral iron.
- Continuing severe blood loss.
- Malabsorption.
- Chronic renal failure (often used alongside Erythropoietin/EPO to support rapid red cell production).
- Efficacy: Generally not quicker than oral therapy because the rate-limiting step is the biological time to produce red cells (8-10 days).
- Risks/Problems:
- Painful injections.
- Permanent skin staining.
- Risk of Anaphylaxis (过敏性休克) (Requires monitoring; previous tolerance does not guarantee future safety).
4. Macrocytic Anaemias (Megaloblastic)
4.1 Folic Acid Deficiency
- Metabolism: Polyglutamate (diet) $\rightarrow$ Monoglutamate (gut) $\rightarrow$ Dihydrofolate $\rightarrow$ Tetrahydrofolate (四氢叶酸) (active form for DNA synthesis).
- Causes:
- Poor diet (e.g., alcoholics).
- Malabsorption.
- Pregnancy (increased need).
- Drugs: Phenytoin, Barbiturates, Ethanol (alcohol), Methotrexate, Trimethoprim.
- Treatment:
- Deficiency: Oral Folic Acid 5mg daily for 4 months.
- Prophylaxis (Neural Tube Defects): 0.4mg daily (standard) or 5mg daily (high-risk mothers). Note: The 0.4mg dose is for fetal protection, not anaemia treatment.
4.2 Vitamin B12 Deficiency
- Physiological Role: Essential for DNA synthesis and the formation of Myelin Sheaths (髓鞘) around nerve fibres.
- Symptoms:
- Standard anaemia symptoms plus Peripheral Neuropathy (周围神经病变).
- Warning: Neuropathy can be irreversible if deficiency is prolonged.
- Causes:
- Pernicious Anaemia (恶性贫血): Lack of Intrinsic Factor (内因子) (secreted in the gut), preventing B12 absorption. Requires lifelong injections.
- Strict Veganism (纯素食主义): B12 is found in animal products. Vegans require yeast-derived supplements.
- GI Surgery, bacterial overgrowth, tapeworms.
- Treatment:
- Hydroxycobalamin (羟钴胺) Injection (IM).
- Regimen: 1mg alternate days initially (to replenish stores), then 1mg every 3 months for life.
5. Haemolytic Anaemia: G6PD Deficiency
5.1 Mechanism
- Glucose-6-phosphate dehydrogenase (G6PD) is involved in producing Glutathione (谷胱甘肽).
- Glutathione protects red blood cells from oxidising agents.
- In G6PD deficiency, red cells lack protection and are destroyed (haemolysed) when exposed to oxidative stress.
5.2 Risk Factors and Triggers
- Prevalence: More common in populations from Africa, Asia, Oceania, and Southern Europe.
- Triggers:
- Fava beans (蚕豆).
- Drugs: Sulphonamides (e.g., Co-trimoxazole), Nitrofurantoin, Primaquine, Quinolones (e.g., Ciprofloxacin). (See BNF for full list).
- Note: Susceptibility varies between individuals; drugs are not routinely tested in deficient patients.
5.3 Management
- Identify and stop the oxidising agent/drug.
- Keep the patient well hydrated.
- Blood transfusion (only in severe cases).
6. Laboratory Monitoring and Diagnostics
6.1 Key Parameters
- Transferrin (转铁蛋白): The protein that transports iron in plasma. Normally 1/3 saturated.
- Total Iron Binding Capacity (TIBC, 总铁结合力): Serum iron + unsaturated iron binding sites. Represents the total capacity of plasma to carry iron.
- Ferritin (铁蛋白): The protein that stores iron.
6.2 Diagnostic Patterns
| Test | Microcytic (Iron Deficiency) | Macrocytic (B12/Folate Deficiency) | Normocytic (Blood Loss) |
|---|---|---|---|
| MCV (Mean Cell Volume) | $\downarrow$ (Low) | $\uparrow$ (High) | Normal |
| Haemoglobin (Hb) | $\downarrow$ | $\downarrow$ | $\downarrow$ |
| Ferritin | $\downarrow$ (Depleted stores) | Normal | Normal or $\downarrow$ |
| Serum Iron | $\downarrow$ | Normal | $\downarrow$ |
| TIBC | $\uparrow$ (Body compensates) | Normal | $\uparrow$ |
| Reticulocyte Count | $\downarrow$ | Normal | $\downarrow$ |
6.3 Differential Tests for Megaloblastic Anaemia
- Folate Assessment:
- Serum Folate: Affected by recent diet (can appear high after a meal).
- Red Cell Folate: Less affected by diet; a better indicator of tissue stores but harder to measure.
- Vitamin B12 Assessment:
- Total B12: May not always be low even in deficiency.
- Active B12: Better indication but harder to measure.
- Methylmalonic Acid (MMA, 甲基丙二酸): Rises ($\uparrow$) specifically with B12 deficiency (metabolic byproduct).
LECTURE19 Core Concept 18: Cardiac Physiology 4
LECTURE36 Core Concept 35: Atrial Fibrillation
Pharmacology & Therapeutics
LECTURE17 Core Concept 16: Pharmacology of antihypertensive drugs
LECTURE20 Core Concept 19: Heart failure therapeutics
LECTURE27 Core Concept 26: Organic nitrates and phosphodiesterase inhibitors
LECTURE28 Core Concept 27: Drugs affecting blood coagulation
LECTURE30 Core Concept 29: Lipid Lowering drugs
Pharmaceutics
LECTURE3 Core Concept 2: Pharmaceutics 1
1. Introduction to Solid Dosage Forms
- Prevalence: Solid dosage forms constitute approximately 70-80% of dosage forms in pharmacies (historically up to 90%).
- Examples: Tablets (片剂), capsules (胶囊), granules (颗粒剂), powders (散剂).
- Role of Excipients (辅料):
- In solid dosage forms, excipients are added not only for drug stability or release but significantly for the purpose of manufacturing (生产).
- Functions include improving powder flow (粉体流动性) to prevent weight variation in tablets and ensuring smooth tableting processes.
- Definition of Solid vs. Liquid:
- Solid (固体): Has a specific 3D structure/dimension (e.g., length, diameter).
- Liquid (液体): Takes the shape of its container; no specific 3D shape.
- Semi-solid (半固体): Has no specific shape, does not flow like liquid, and does not hold a 3D structure like a solid (e.g., creams).
2. Classification of Solid-State Substances
Solid-state substances are classified based on their molecular packing (分子堆积):
- Crystalline (结晶):
- Molecules have an orderly arrangement (3D structure).
- Includes Polymorphs (多晶型), Hydrates (水合物), Solvates (溶剂合物), and Co-crystals (共晶).
- Amorphous (无定形):
- Random arrangement of molecules (no long-range order).
- Described as a “pile of molecules/powder.”
3. Crystallisation (结晶过程)
- Purpose:
- To separate the drug from impurities or solvents.
- To obtain a pure solid (纯固体).
- Methods:
- Evaporative crystallisation (蒸发结晶).
- Cooling crystallisation (冷却结晶): Creating a saturated/super-saturated solution and cooling slowly.
- Precipitation (沉淀): Adding a solvent in which the drug is insoluble (anti-solvent).
- Control Parameters:
- Supersaturation state (过饱和状态).
- Seeding (晶种): Adding specific crystals to induce nucleation and control crystal type.
- Rate of cooling: Slow cooling is preferred to produce uniform crystals; fast cooling may produce random/amorphous forms.
4. Polymorphism (多晶型现象)
Definition: The phenomenon whereby molecules arrange themselves in more than one pattern within a crystal, while chemically remaining the same compound. Approximately 36% of drugs exhibit polymorphism.
Impact of Polymorphism:
Different polymorphs have identical chemical properties (spectra) but different physical properties:
- Melting point (熔点)
- Solubility (溶解度)
- Dissolution rate (溶出速率)
- Bioavailability (生物利用度)
- Powder flow (粉体流动性)
- Compressibility (可压性)
Stability vs. Solubility Rule:
- Stable Polymorph (稳定晶型):
- Stronger intermolecular interactions.
- Higher melting point.
- Lower solubility and dissolution rate.
- Metastable Polymorph (亚稳态晶型):
- Weaker interactions.
- Lower melting point.
- Higher solubility and dissolution rate.
- Note: Metastable forms tend to convert to the stable form over time (influenced by humidity/temperature).
Key Examples:
-
Paracetamol (对乙酰氨基酚):
- Form I (Stable): “Zigzag” structure. Hard to compress, causes capping (顶裂) (tablet splits into layers).
- Form II (Metastable): Layered structure. Good compressibility (可压性) (deforms plastically), but converts back to Form I over time.
- Industry implication: Granulation is often required for Form I to improve compressibility.
-
Olanzapine (奥氮平):
- Form IV (Metastable): Dissolves rapidly.
- Form I (Stable): Dissolves slowly.
- Clinical significance: Different dissolution rates affect absorption.
-
Chloramphenicol Palmitate (氯霉素棕榈酸酯):
- $\alpha$-polymorph (Stable): Low absorption, low blood serum levels.
- $\beta$-polymorph (Metastable): Much higher rate of absorption and bioavailability.
- Formulation must control the ratio to ensure therapeutic efficacy.
5. Solvates and Hydrates (溶剂合物与水合物)
- Definitions:
- Solvates: Crystal lattice includes solvent molecules.
- Hydrates: Crystal lattice includes water molecules (e.g., Amoxicillin Trihydrate).
- Efflorescence (风化): Hydrates lose water of crystallisation to the atmosphere, potentially becoming sticky or turning into powder.
- Solubility Differences:
- General Rule: Anhydrous (无水物) forms are usually more rapidly soluble than Hydrates.
- Reason: Hydrates already have water interactions, lowering the thermodynamic drive to dissolve.
- Example: Theophylline (茶碱). Anhydrous form peaks at supersaturation before precipitating; Monohydrate dissolves slowly to equilibrium.
- Exception: Erythromycin (红霉素). Dihydrate is more soluble than the anhydrous form (Anhydrous < Monohydrate < Dihydrate).
- Conclusion: Physical analysis is required for every drug; rules are not absolute.
- General Rule: Anhydrous (无水物) forms are usually more rapidly soluble than Hydrates.
6. Crystal Habit (晶习)
- Definition: The outer shape of the crystal (e.g., cubic, needle, plate, blade).
- Importance: Affects flowability (流动性).
- Regular shapes (Cubic/Spherical): Better flow.
- Needle/Blade shapes: Poor flow (entangle with each other).
- Controlled by: Solvent type, impurities, temperature, and seeding.
7. Co-crystals (共晶)
- Definition: Crystals composed of an Active Pharmaceutical Ingredient (API) and a Coformer (共晶形成物) in a stoichiometric ratio, held together by hydrogen bonds.
- Coformer: Must be non-toxic and safe. Can be another drug or an excipient.
- Purpose: To modify physical properties (stability, solubility, hygroscopicity) without changing the chemical structure of the API.
- Examples:
- Escitalopram Oxalate (草酸艾司西酞普兰): Improves stability.
- Chloral Hydrate (水合氯醛) + Betaine: Forms Chloral-betaine. Improves taste and reduces gastric irritation compared to volatile/irritant chloral hydrate.
- Sodium Valproate + Valproic Acid: Forms a solid co-crystal from a liquid (valproic acid) and handles deliquescence (潮解) issues of the salt, improving stability.
8. Hygroscopicity and Deliquescence (引湿性与潮解)
- Hygroscopicity: Substance absorbs water vapor from the atmosphere.
- Deliquescence: Substance absorbs enough water to dissolve in it, turning into a liquid (e.g., Sodium Hydroxide).
- Cause: Often due to polar surface groups or impurities (e.g., alkali metal residues).
- Management: Requires airtight packaging or conversion to stable forms (salts/co-crystals).
9. Amorphous Solids (无定形固体)
- Characteristics:
- No orderly arrangement (random).
- No sharp melting point; exhibits a Glass Transition Temperature (玻璃化转变温度).
- Advantages: Higher solubility and bioavailability (due to high internal energy and surface area).
- Disadvantages: Thermodynamically unstable (tends to crystallize), chemically unstable, hygroscopic.
- Example: Itraconazole (伊曲康唑) capsules use amorphous beads to enhance solubility of this poorly soluble drug.
Solid Dispersions (固体分散体):
- Method: Dispersing the drug in a polymer matrix to stabilize the amorphous state or improve solubility.
- Types:
- Solid Dispersion: Drug particles dispersed in polymer (like a solid suspension).
- Solid Solution (固体溶液): Drug molecularly dissolved in the polymer.
- Case Study: Ritonavir (利托那韦)
- Originally marketed as semi-solid capsules.
- Failure: The drug converted from a soluble form to a stable, insoluble crystal form (polymorph conversion) upon storage, leading to therapeutic failure.
- Solution: Reformulated as a Solid Dispersion (using Copovidone polymer) to “shield” the drug and maintain it in a stable, soluble state.
10. Drug Salts (药物盐)
- Rationale: Most drugs are weak acids or bases. They are converted to salts (reacting with strong base/acid) to ensure ionization.
- Advantages:
- Significantly enhanced solubility (e.g., Penicillin vs. Potassium Penicillin).
- Improved dissolution rate.
- Higher melting point.
- Disadvantages:
- Decreased percentage of active ingredient: The salt counterion adds weight (e.g., 500mg of salt $\neq$ 500mg of active base).
- Increased hygroscopicity.
- Potential for corrosion or decreased chemical stability.
- Non-equivalence: Different salts of the same drug (e.g., Diclofenac Sodium vs. Diclofenac Potassium) have different physical properties and bioavailabilities; they are not automatically interchangeable.
LECTURE8 Core Concept 7: Pharmaceutics 2
1. Introduction to Solid Dosage Forms and Particle Science
-
Significance of Solid Dosage Forms:
- Solid dosage forms (e.g., tablets, capsules) are a long-life process in pharmaceutical education and practice. Knowledge about them is essential for the entire educational process and professional practice.
- Fillers (填充剂): Lactose is one of the most common fillers used in the pharmaceutical industry.
-
Importance of Particle Size (颗粒大小):
- Different dosage forms require specific particle sizes.
- Macrophages (巨噬细胞): Currently under research for IV injection (immunotherapy for cancer). They require specific sizes (0.5 - 1 µm).
- Pulmonary Drug Delivery (肺部给药): Powders for inhalers typically require a particle size of 1 to 5 µm for aerodynamic reasons.
- Granules (颗粒): Can be up to 1-2 mm depending on the dosage form.
- Needle Size: Larger needles (e.g., 2 mm) are used for specific reasons, such as delivering oily injections (e.g., depot injections for hormones) or treating babies/patients who cannot tolerate standard needles, though primarily large needles are for viscous fluids that cannot pass through small gauges.
2. Milling (研磨) - Particle Size Reduction
Definition: Mechanical energy is applied to physically break down coarse particles into finer ones. It is regarded as a “top-down” approach (自上而下的方法).
-
Purpose/Applications:
- Dissolution and Bioavailability (溶解度和生物利用度): Reducing particle size increases surface area, thereby improving dissolution rates and bioavailability.
- Surface Modification (表面改性): Important for flowability.
- Pulmonary Drug Delivery: Achieving the necessary aerodynamic diameter.
- Synthesis constraints: When powders are synthesized, size cannot always be controlled, so post-synthesis optimization (milling) is required.
-
Energy Requirement:
- Reducing particle size requires significant energy input (similar to emulsification).
2.1 Mechanisms of Particle Size Reduction
- Compression (压缩): Applying pressure to crush materials (e.g., squishing a cucumber). Used in Roller mills.
- Impact and Attrition (撞击和磨损): Hammering or collision. Used in Hammer mills and Vibration ball mills.
- Cutting or Shearing (切割或剪切): Using blades or high-speed rotation. Used in Cutter mills.
- Liquid Shear (液体剪切): Used in wet milling.
2.2 Dry Milling (干法研磨)
-
Concept: Grinding powder without liquid (Analogy: Grinding coffee beans).
-
Advantages:
- No solvent incompatibility issues.
- Lower cost.
- Less complex (no drying stage required).
-
Disadvantages:
- Powder Agglomeration (粉末团聚): Fine particles may form clumps due to electrostatic interactions or heat.
- Heat Generation (产热): Dissipated energy produces heat, which can degrade thermosensitive drugs or cause melting.
- Cohesive Powder: Can block the machine outlet, decreasing yield.
- Environmental Limitation: Generation of fine dust/particles can contaminate the environment and pose health risks to workers.
-
Equipment:
- Cutter Mill: Uses cutting and shearing (rotating blades). Good for fibrous materials.
- Hammer Mill: Uses impact and attrition.
- Vibration Ball Mill: Uses impact and attrition. Balls rotate and drop/collide to grind powder; also makes particles more spherical (attrition).
- Roller Mill: Uses compression. Powder passes through wheels to gradually reduce size.
2.3 Wet Milling (Slurry Milling) (湿法研磨)
-
Concept: Solid particles are suspended in a liquid medium (Analogy: Making a smoothie).
-
Solvent Selection: The liquid must be a non-solvent (the drug must not be soluble in it), otherwise the drug will dissolve rather than being milled.
-
Advantages:
- Suitable for Heat-labile (热不稳定) drugs (thermal control is easier).
- Suitable for Potent drugs (高效能药物): Prevents dust generation, protecting the environment and workers (e.g., narcotics like pethidine).
- Can achieve smaller particle sizes.
-
Disadvantages:
- Need to recover and dry the powder.
- Ostwald Ripening (奥斯特瓦尔德熟化): Even in “non-solvents,” there is minute solubility. Very fine particles may dissolve and precipitate onto larger particles, causing the large particles to grow. This leads to instability in suspensions.
-
Equipment:
- Toothed Rotor-Stator: Jacket cooling possible. High-speed rotation creates shearing forces (smoothing stones in a river analogy).
- Media (Bead) Mills: Uses beads for impaction and shearing within a liquid.
3. Screening (筛分) - Size Separation
Milling produces a range of particle sizes (non-uniform distribution). Screening is necessary to select the desired size range.
- Sifting (using Sieves):
- Particles pass through mesh depending on size and shape.
- Mechanical Agitation: Used in R&D. Stacked sieves with largest mesh on top and finest on bottom (Pan).
- Centrifugal Screening (离心筛分):
- Used for mass production in industry.
- Separation is based on mass (not just size/shape) due to centrifugal forces.
- Larger/heavier particles move to the outside/bottom; lighter/smaller ones stay top/center.
4. Mixing (混合)
- Definition: A process to obtain a uniform mixture with a homogeneous distribution of active ingredients.
- Nature of Process:
- Static/Non-spontaneous: Solids do not mix themselves (unlike liquids with Brownian motion).
- Energy: Requires energy input.
- Segregation (偏析): The opposite of mixing; particles tend to separate.
- Mix Quality:
- Ideal Mix: Every particle is adjacent to a different particle type (Perfect checkerboard). Impossible in reality.
- Random Mix: The practical goal.
- Scale of Scrutiny: Assessment involves taking samples (e.g., 20 tablets) to ensure the active component does not deviate by more than 5%.
4.1 Mechanisms of Mixing
- Convection (对流): Macroscopic mixing. Movement of large groups of particles from one region of the powder bed to another. Fast but coarse.
- Shear (剪切): Layers of material flow over one another at different speeds. Breaks down agglomerates.
- Diffusion (扩散): True random mixing. Movement of individual particles into empty spaces (increasing the “bed” volume).
- Equipment: V-Mixer (V-Blender) or tumbling mixers. Commonly used for tablet preparation in R&D to achieve microscopic mixing.
4.2 Segregation (Demixing)
Separation of the mix components, leading to content variation and batch failure.
- Causes/Factors:
- Particle Size: The most significant cause. Smaller particles fall through voids between larger particles (percolation).
- Particle Density: Heavier particles move to the bottom; lighter particles rise.
- Particle Shape: Spherical particles flow/segregate easily; irregular/interlocking particles may resist segregation but are harder to mix initially.
4.3 Advanced Mixing Techniques
- Ordered Mixing (有序混合):
- Used for potent drugs or inhalers.
- Small drug particles (fines) are adsorbed/coated onto the surface of larger carrier particles (coarse powder).
- Prevents segregation by using adhesion forces.
- Eutectic Mixtures (共晶混合物):
- Mixing two solids results in a mixture with a lower melting point than either individual component, often turning into a liquid at room temperature.
- Analogy: Salt on ice (melts the ice).
- Pharmaceutical Example: EMLA cream (Lidocaine + Prilocaine). They form an oil when mixed, which is then emulsified into a cream, avoiding the need for grinding.
5. Powder Flow (粉末流动性)
Significance: Critical for manufacturing. Powders must flow freely into molds, dyes, and machine hoppers. Poor flow leads to weight variation and batch failure.
5.1 Forces Affecting Flow
The balance between Driving Forces (Gravity, Mechanical) and Drag Forces (Adhesion, Cohesion).
- Adhesion (黏附): Attraction between a particle and a different surface (e.g., container wall).
- Cohesion (内聚): Attraction between like particles (same component).
- Van der Waals Forces: Increase as particle size decreases.
- Electrostatic Forces: From friction/contact.
- Surface Tension: From adsorbed liquid layers (moisture).
5.2 Factors Influencing Flowability
- Particle Size:
- Fine powders (< 125 µm): Generally have poor flow due to high Van der Waals forces and surface area. Ideally should be limited (5-10%).
- Coarse powders: Generally flow better.
- Particle Shape:
- Spherical: Minimum contact area = Good flow.
- Irregular/Flakes/Dendritic: High surface-to-volume ratio or Mechanical Interlocking (机械互锁) = Poor flow.
- Density: Higher density generally aids flow (gravity).
- Moisture (Relative Humidity):
- Powders are rarely 100% dry; bound water exists.
- Too much moisture increases cohesion (liquid bridges); too little can increase electrostatic charging. A balance is needed.
- Process Conditions (Hoppers):
- Hopper Design: The angle and width affect flow.
- Mass Flow vs. Funnel Flow: Design aims for mass flow where the whole bed moves, preventing “rat-holing” or stagnation.
5.3 Particle Analysis Methods
- Size: Sieving, Laser Diffraction (light scattering).
- Shape: Optical Microscopy, Scanning Electron Microscopy (SEM). SEM allows visualization of surface texture and shape (spherical vs. irregular).
5.4 Density Measurements
- Bulk Density (堆密度): Mass / Volume of the powder “as poured” (includes inter-particle voids).
- Tapped Density (振实密度): Mass / Volume after mechanical tapping. Tapping removes some air but not all.
- True Density (真密度): Density of the solid material itself, excluding all pores and voids. Measured using inert gas displacement. Constant for a material, whereas bulk/tapped densities vary by batch and packing.
- Porosity: The volume of void space within the powder bed.
5.5 Improving Flow
- Alter particle size (remove fines, granulation).
- Alter shape (make spherical).
- Add flow activators (glidants).
- Optimize hopper design or use vibration/force feeders.
LECTURE10 Core Concept 9: Quality and stability of drugs and medicines
LECTURE14 Core Concept 13: Pharmaceutics 3
LECTURE18 Core Concept 17: Pharmaceutics 4
LECTURE22 Core Concept 21: Pharmaceutics 5
LECTURE25 Core Concept 24: Quantitative Assessment of API degradation
LECTURE26 Core Concept 25: Pharmaceutics 6
LECTURE35 Core Concept 34: Pharmaceutics 7
LECTURE37 Core Concept 36: Pharmaceutics 8
LECTURE38 Core Concept 37: Pharmaceutics 9 Bioequivalance
LECTURE39 Core Concept 38: Modified release
LECTURE40 Core Concept 39: Pharmaceutics 10
DMPK (Drug Metabolism & Pharmacokinetics)
LECTURE5 DMPK Absorption Supporting Info
1. Introduction to Absorption
Absorption (吸收) is defined as the movement of a drug from the site of administration into the blood or lymph, usually across a biological membrane. In pharmacokinetics, absorption is considered an “input” process that determines the drug’s systemic exposure.
- Vascular vs. Lymphatic Absorption: While drugs can enter through the lymphatic system, pharmacokinetic studies focus primarily on absorption into the blood (vascular absorption) because blood flow is significantly greater than lymphatic flow.
- Measurement: The most common site of measurement is a blood sample, from which plasma is derived. This allows clinicians to infer the drug’s concentration and its ability to circulate to target organs to produce a pharmacological effect.
- Therapeutic Importance: Achieving an optimal plasma concentration is crucial for ensuring the drug reaches the site of action (作用位点) at a concentration sufficient for the desired therapeutic effect.
2. Routes of Drug Administration
The relevance of absorption depends entirely on the route of administration:
- Intravascular (血管内给药): Includes intravenous (IV) or intra-arterial routes. Since the drug is placed directly into the blood, there is no absorption step, and bioavailability is considered complete (100%). This serves as the “gold standard” reference.
- Extravascular (血管外给药): Includes oral, sublingual, subcutaneous, intramuscular, and rectal routes. For these routes, systemic absorption is a prerequisite for efficacy.
- Local vs. Systemic Effect: Most extravascular drugs are intended for systemic effects. However, if a drug is intended for a local effect (e.g., eye drops, topical creams), systemic absorption is actually a safety concern rather than a goal.
3. Drug Absorption After Oral Administration
Oral administration follows a specific anatomical sequence:
- Disintegration and Dissolution: The solid dosage form (e.g., tablet/capsule) must dissolve in the gastrointestinal (GI) lumen.
- Gut Wall Permeation: The dissolved drug moves across the epithelial cells (enterocytes) of the intestinal wall.
- First-Pass Metabolism: The drug passes through the liver via the portal vein before reaching the systemic circulation. During this passage, the drug may be lost due to metabolism or excretion.
The Small Intestine (小肠) is the major site of drug absorption due to:
- Large Surface Area: Created by circular folds, villi (finger-like projections), and microvilli (on the surface of enterocytes).
- High Permeability: A thin single layer of epithelial cells facilitates movement.
- High Blood Flow: Maintains a concentration gradient (sink condition) to drive passive diffusion.
4. Bioavailability and Bioequivalence
4.1 Bioavailability (F) (生物利用度)
Bioavailability refers to the fraction or percentage of an administered dose of intact drug that reaches the systemic circulation.
- Absolute Bioavailability: Measured by comparing the extravascular dose to an intravenous dose.
- Relative Bioavailability: A comparison between two different formulations or routes (excluding IV), often used when IV data is unavailable due to stability or solubility issues.
4.2 Bioequivalence (生物等效性)
Bioequivalence refers to formulations containing the same dose of the same chemical entity in the same dosage form that are intended to be interchangeable.
- Assessment: Conducted via a randomized crossover study (随机交叉研究) with a washout period (清洗期) between formulations to ensure the drug from the first phase is eliminated before the second phase begins.
- Parameters:
- AUC (Area Under Curve): Represents the extent of absorption.
- Cmax (Maximum Concentration): Represents the rate of absorption.
- Tmax: The time at which Cmax is reached.
- Regulatory Criteria (FDA): Two products are bioequivalent if the 90% confidence intervals of the geometric means of the AUC and Cmax ratios are within the 80-125% range. Bioequivalent products are generally considered therapeutically equivalent.
5. Mechanisms of Membrane Transport
Drugs move across the enterocyte membrane through several processes:
5.1 Transcellular Transport (胞穿转运)
Movement through the cell itself.
- Passive Diffusion (被动扩散): Follows the concentration gradient until equilibrium is reached. It depends on:
- Lipophilicity: Higher lipophilicity generally increases permeability.
- Molecular Size: Larger molecules have lower permeability.
- Ionization: Charged molecules move more slowly.
- Carrier-Mediated Transport: Includes active transport (requiring energy, e.g., PEPT1, OATP2B1) or facilitated transport.
5.2 Paracellular Transport (旁细胞转运)
Movement between epithelial cells through tight junctions (紧密连接). This is a passive process primarily important for small, polar, hydrophilic drugs (e.g., Metformin). It is limited by the density and size of the junctions and the available surface area.
6. Role of Intestinal Transporters and Enzymes
The “Loss” of a drug during the absorption process is often mediated by the interplay of transporters and enzymes.
- Efflux Transporters: Proteins like P-glycoprotein (P-gp/P-糖蛋白) and BCRP (Breast Cancer Resistance Protein) are located on the apical membrane. They pump drugs back into the intestinal lumen, decreasing bioavailability.
- Metabolic Enzymes: CYP3A4 and UGTs are expressed in enterocytes.
- P-gp and CYP3A4 Interplay: P-gp can cause the “recirculation” of a drug by pumping it back into the lumen, where it is re-absorbed. This increases the drug’s exposure to CYP3A4 enzymes, leading to significant intestinal first-pass metabolism (肠道首过效应) and low bioavailability (e.g., Saquinavir, Atorvastatin).
7. Variability in Absorption
Drug absorption varies between individuals due to:
- Physiological Factors: GI transit time, stomach emptying, and blood flow.
- Expression Levels: The expression of CYP3A4 and P-gp varies along the length of the GI tract (e.g., CYP3A4 is higher in the proximal region, while P-gp increases distally) and between different patients.
- Drug Properties: LogP, pKa, solubility, and particle size.
Modern drug development utilizes Physiologically-Based Pharmacokinetic (PBPK) models (e.g., Simcyp) to simulate these complex interactions and predict inter-individual variability.
LECTURE5 Core Concept 4: DMPK Absorption
1. Introduction to Pharmacokinetics (药物代谢动力学)
Pharmacokinetics (PK) involves several key processes summarized under the ADME umbrella, which covers the movement and fate of a drug within the body:
- Absorption (A) (吸收): The movement of the drug from the site of administration into the blood (or lymph), usually across a membrane.
- Distribution (D) (分布): The movement of the drug from the blood to various organs and tissues.
- Elimination (消除): The irreversible removal of the drug from the body, consisting of:
- Metabolism (M) (代谢)
- Excretion (E) (排泄)
Absorption is the first process that allows a drug to reach the systemic circulation (体循环). While drugs given intravenously (IV) enter the blood directly (making absorption complete or irrelevant), absorption is a critical factor for all extravascular routes, most commonly the oral route.
2. Rate Limiting Steps for Oral Drug Absorption (口服药物吸收的限速步骤)
Absorption from a pharmacokinetic perspective is not just the movement across a membrane; it is a complex multi-step process. Any of these steps can be a “rate-limiting step” (限速步骤), meaning it is the slowest part of the process that determines the overall speed of absorption. Potential sites of loss or delay include:
- Disintegration (崩解): The breakdown of a solid dosage form (like a tablet) into granules and fine particles.
- Dissolution (溶解): The drug must be in a solution to start the absorption process.
- Gastric Emptying and Intestinal Transit (胃排空与肠道转运): The movement of the drug through the GI tract.
- Movement through Membranes (跨膜转运): Limited by either perfusion or permeability.
- First-pass Metabolism (首过效应/首过代谢): Loss of drug in the gut wall or liver before reaching systemic circulation.
3. Gastric Emptying (胃排空)
The small intestine is the major site of drug absorption due to its large surface area (villi and microvilli), excellent blood supply (perfusion), and thin, permeable single-layer epithelium. Therefore, the rate at which the stomach empties its contents into the small intestine—Gastric Emptying—controls the delivery of the drug to its primary absorption site.
3.1 Factors Affecting Gastric Emptying
- Co-administration of other drugs:
- Metoclopramide (甲氧氯普胺): Enhances/fastens gastric emptying. This leads to faster absorption, resulting in a higher peak plasma concentration ($C_{max}$) and a shorter time to reach that peak ($T_{max}$).
- Anticholinergic drugs (抗胆碱能药物): Relax smooth muscles of the stomach wall and delay gastric emptying. This results in slower absorption, a lower $C_{max}$, and a longer $T_{max}$.
- Note: In these cases, the extent of absorption (Area Under the Curve, AUC) usually remains comparable; only the rate changes.
- Food:
- Fasted State (空腹状态): Generally results in quick gastric emptying (around 1 hour). This is favorable for Enteric Coated (肠溶衣) formulations to prevent the coating from degrading in the stomach’s acidic environment.
- Fed State (进食状态): Food, especially heavy or fatty meals, delays gastric emptying significantly (potentially up to 10 hours). Poorly soluble drugs are often recommended to be taken with food to prolong dissolution time and increase the chance of the drug entering the solution.
- Age: Physiological changes in elderly individuals cause delayed gastric emptying compared to younger people.
4. Movement Through Membranes: Perfusion vs. Permeability
Once a drug is in solution, its movement across the intestinal membrane depends on both the membrane properties and the molecule’s physical-chemical properties.
4.1 Perfusion Limited Absorption (灌注限速吸收)
- Definition: The membrane offers no effective barrier. The drug crosses the membrane so easily that the blood flow (perfusion) taking the drug away to the systemic circulation becomes the slowest step.
- Drug Types: Small lipophilic (脂溶性) molecules and very small hydrophilic (水溶性) molecules like water.
- Sensitivity: Absorption rate varies with changes in intestinal blood flow.
4.2 Permeability Limited Absorption (渗透限速吸收)
- Definition: The molecule has difficulty passing across the membrane. Even though the membrane is thin, the properties of the molecule make it a barrier.
- Drug Types: Large, polar, or ionized (离子化) molecules. Many newly developed drugs fall into this category.
- Sensitivity: Absorption is insensitive to changes in blood flow because the crossing of the membrane itself is the bottleneck.
- Ionization Consideration: For acids and bases, the unionized form is generally more lipophilic and permeable. Ionization depends on the pH of the different regions of the small intestine.
5. Drug Release from Formulation
When drugs are administered as solid formulations, the release of the drug can limit absorption.
5.1 Release/Dissolution Rate-Limited Absorption
- If dissolution is slow (shallower decrease in solid form over time), the absorption is limited by the release of the drug from the formulation.
- Modified/Controlled Release (MR/CR) (缓控释制剂): These are designed to delay or adjust the rate of release.
- Benefits: Reduces fluctuations between maximum ($C_{max}$) and minimum ($C_{min}$) concentrations.
- Patient Compliance: Allows for longer dosing intervals (e.g., once or twice daily), which improves adherence compared to immediate-release (IR) formulations.
6. First-Pass Metabolism and Bioavailability (首过代谢与生物利用度)
Bioavailability (F) (生物利用度) is the fraction of the administered dose that reaches the systemic circulation in an unchanged form. It is the product of three factors:
$$F = f_a \times F_G \times F_H$$
- $f_a$: Fraction absorbed across the epithelium cells.
- $F_G$: Fraction escaping intestinal first-pass metabolism (gut wall).
- $F_H$: Fraction escaping hepatic first-pass metabolism (liver).
6.1 Intestinal First-Pass and Transporters
- Metabolic Enzymes: The gut wall contains enzymes like CYP3A4, which can metabolize drugs during absorption. A low $F_G$ value (close to 0) indicates extensive intestinal metabolism.
- Efflux Transporters (外排转运体): Proteins like P-glycoprotein (P-gp) (P-糖蛋白) pump drugs from the cell back into the intestinal lumen, further reducing bioavailability.
6.2 Drug-Food Interactions: Grapefruit Juice
- Grapefruit juice contains furanocoumarins (呋喃香豆素), which are irreversible inhibitors of intestinal CYP3A4.
- Effect: It inhibits the metabolism of CYP3A4 substrates in the intestine (not the liver at standard doses), leading to increased plasma concentrations and risks of toxicity (e.g., muscle pain/myopathy with statins).
7. Impact of Disease and Surgery
- Coeliac Disease (乳糜泻): Reduced expression of intestinal CYP3A4 (to about 15-50%), affecting the bioavailability of substrates.
- Crohn’s Disease (克罗恩病): Reduced expression of CYP3A4 and many other enzymes.
- Liver Cirrhosis (肝硬化): Reduced activity of metabolic enzymes and transporters, depending on the severity (Child-Pugh score).
- Gastric Bypass Surgery (胃旁路手术): Procedures like Roux-en-Y bypass the main areas of absorption (duodenum and proximal jejunum). This can lead to either increased or decreased bioavailability depending on the drug.
8. Formulation-Metabolism Interplay
The distribution of enzymes like CYP3A4 is not uniform; abundance is highest in the proximal regions (duodenum) and decreases along the length of the gut.
- Immediate Release (IR): Released in the proximal region where enzyme levels are high, leading to extensive metabolism.
- Modified Release (MR): Can be designed to release the drug in distal regions (like the ileum or colon) where enzyme abundance is lower, potentially increasing bioavailability (e.g., Oxybutynin).
LECTURE9 Core Concept 8: DMPK Drug Disposition
1. Introduction to Drug Distribution
Distribution (分布) involves the reversible transfer of a drug between the blood and other tissues within the body.
- Distinction from Absorption:
- Absorption (吸收): The input of the drug into the blood. For IV administration, absorption is complete/instantaneous.
- Distribution (分布): The movement of the drug from the blood into the tissue.
- Process:
- The drug circulates via the blood to reach the site of pharmacological effect (target) and organs involved in elimination (metabolism and excretion).
- The process involves crossing one or multiple membranes.
2. Rate of Drug Distribution
The rate at which a drug distributes depends on physiological factors and the physicochemical properties of the drug.
2.1 Factors Affecting Distribution Rate
- Tissue Perfusion (组织灌注): The delivery of the drug to the tissue via blood flow.
- Membrane Permeability (膜渗透性): The ability of the drug to cross tissue membranes.
- Physicochemical Properties (理化性质):
- Lipophilicity (亲脂性): Small, lipophilic molecules cross membranes easily.
- Ionization (离子化): Ionized, polar molecules have difficulty crossing membranes.
- Plasma Protein Binding (血浆蛋白结合): Only the unbound drug (游离药物) can cross membranes.
2.2 Perfusion-Limited Distribution (灌注限速分布)
This occurs when the tissue or cell membrane does not represent a barrier to drug distribution.
- Applicability: Typically applies to small, lipophilic molecules that cross membranes very easily.
- Limiting Step: The rate-limiting step is the blood flow (perfusion) to the tissue, not the diffusion across the membrane.
- Mechanism:
- The drug follows the concentration gradient from blood to tissue until distribution equilibrium (分布平衡) is reached.
- Since the drug crosses the membrane easily, the speed depends entirely on how much blood reaches the organ.
- Tissue Classification by Perfusion:
- Highly Perfused Tissues (Vessel Rich): Lungs, kidneys, liver, brain.
- Receive a high percentage of cardiac output.
- Equilibrium is reached very quickly.
- Poorly Perfused Tissues: Skin, adipose (fat), inactive muscle.
- Lower blood supply per gram of tissue.
- Distribution is much slower.
- Highly Perfused Tissues (Vessel Rich): Lungs, kidneys, liver, brain.
- Example Case (IV Bolus of a Lipophilic Drug):
- Blood: Concentration declines rapidly as the drug distributes to tissues.
- Well-perfused organs: Drug appears rapidly.
- Muscle/Adipose: Drug appearance is delayed. Even though a lipophilic drug has a high affinity for adipose tissue, accumulation is slow due to low blood flow.
- Redistribution: Once equilibrium is reached and plasma concentration drops (due to elimination), the drug will move back from tissues (like adipose) into the blood.
Perfusion Data Reference:
- Lungs: Receive 100% of cardiac output (highest perfusion rate).
- Kidneys: Very high perfusion rate (~4 mL/min/g tissue).
- Adipose/Resting Muscle: Very low perfusion rate (~0.025 mL/min/g tissue).
2.3 Permeability-Limited Distribution (渗透限速分布)
This occurs when the movement of the drug across the membrane is the slowest step.
- Applicability:
- Polar, ionized molecules (极性、离子化分子).
- Large molecules.
- Tissues with tight membranes (impermeable barriers).
- Limiting Step: The permeability of the membrane is the rate-limiting step, not the blood flow.
- Membrane Barriers:
- Blood-Brain Barrier (BBB) (血脑屏障): Capillaries have tight junctions (紧密连接) and glial cells, creating a physical barrier. Only lipophilic drugs cross easily; others may require active transporters (主动转运体).
- Muscle Capillaries: Possess pores/gaps, allowing some polar molecules to cross the capillary wall, though entering the cell itself might still be difficult.
- Example - CSF to Plasma Ratio:
- Thiopental (Lipophilic): Rapidly crosses the BBB; reaches equilibrium (ratio = 1) quickly.
- Salicylic Acid (Polar/Ionized): Crosses very slowly; the ratio remains low and equilibrium takes a long time or is not reached efficiently.
3. Extent of Distribution: Volume of Distribution ($V_d$)
The Apparent Volume of Distribution (表观分布容积), often abbreviated as $V$ or $V_d$, describes the extent of drug distribution.
3.1 Definition and Concept
- Definition: A parameter relating the measured plasma (or blood) drug concentration to the total amount of drug in the body at equilibrium.
- Formula:
$$V_d = \frac{Amount\ of\ drug\ in\ the\ body\ (A)}{Plasma\ drug\ concentration\ ©}$$ - “Apparent” Nature:
- It is not a physical volume. It represents the “dilution space” (稀释空间) required to account for the observed plasma concentration.
- Values can range from ~3L (minimum, plasma volume) to >10,000L (far exceeding total body volume).
3.2 Interpreting $V_d$ Values
- Low $V_d$ (e.g., 3-10 L):
- Indicates the drug is confined primarily to the plasma or blood.
- Characteristics: Often acidic drugs (e.g., Warfarin) which bind highly to plasma proteins (albumin), or large molecules (e.g., Monoclonal antibodies).
- Physical Reference: Plasma water is ~3L.
- Medium $V_d$ (e.g., ~40 L):
- May correspond to Total Body Water (体液总量).
- Note: Caution is needed. Digitoxin has a $V_d$ ~40L, but it is not just in body water; it binds to specific tissues.
- High $V_d$ (e.g., >100 L to 20,000 L):
- Indicates extensive distribution into tissues.
- Characteristics: Often basic drugs (e.g., Fluoxetine) and lipophilic drugs.
- Mechanism: These drugs bind extensively to tissue components (e.g., acidic phospholipids, proteins in tissues), removing them from plasma and keeping plasma concentration ($C$) low. A low denominator ($C$) results in a high $V_d$.
3.3 Calculation of Fraction in Plasma
Using $V_d$, one can estimate the fraction of the drug remaining in the plasma vs. the rest of the body.
- Plasma Volume ($V_p$): Approximately 3 Liters.
- Fraction in Plasma:
$$Fraction\ in\ Plasma = \frac{V_p}{V_d} \approx \frac{3}{V_d}$$ - Example: If $V_d = 100\ L$, then $3/100 = 3%$ of the drug is in the plasma.
3.4 Impact of Reference Fluid
The calculated $V_d$ depends on which fluid is measured:
- Plasma ($C$): Contains proteins and water (most common).
- Blood ($C_b$): Contains plasma + cells (erythrocytes).
- Plasma Water ($C_u$): Unbound drug only.
- Relationship: At equilibrium, the total amount ($A$) is consistent, so:
$$A = V_d \cdot C = V_{d,blood} \cdot C_b = V_{d,unbound} \cdot C_u$$
3.5 Clinical Relevance: Loading Dose (负荷剂量)
$V_d$ is critical for determining the Loading Dose, which is an initial higher dose given to achieve therapeutic concentrations rapidly.
- Formula:
$$Loading\ Dose = \frac{V_{ss} \times C_{ss}}{F}$$- $V_{ss}$: Volume of distribution at steady state.
- $C_{ss}$: Desired target concentration.
- $F$: Bioavailability.
4. Plasma Protein Binding (血浆蛋白结合)
Drugs in the plasma exist in equilibrium between a bound form and an unbound form.
4.1 Key Plasma Proteins
- Albumin (白蛋白): Most abundant. Binds primarily acidic (e.g., Warfarin) and neutral drugs.
- Alpha-1 Acid Glycoprotein (AAG) ($\alpha_1$-酸性糖蛋白): Binds primarily basic drugs.
- Globulins (球蛋白): Bind specific endogenous substances like steroids.
4.2 Characteristics of Binding
- Reversible: The Drug-Protein complex forms and dissociates rapidly.
$$Drug + Protein \leftrightarrow Drug-Protein\ Complex$$ - Importance of Unbound Drug ($f_u$):
- Only the unbound (free) drug is able to:
- Cross membranes (distribute to tissues).
- Bind to receptors (pharmacological effect).
- Be eliminated (metabolism/excretion).
- Only the unbound (free) drug is able to:
- Fraction Unbound ($f_u$):
$$f_u = \frac{C_u (Unbound\ concentration)}{C (Total\ plasma\ concentration)}$$- Values vary widely (from <1% to 100%).
4.3 Measurement and Challenges
- Experimental Measurement: Clinical trials typically measure Total Plasma Concentration ($C$) because measuring unbound concentration ($C_u$) is technically difficult.
- Correction: If $f_u$ is known and constant, $C_u$ can be calculated:
$$C_u = f_u \times C_{total}$$ - Variability: $f_u$ can change in specific populations (e.g., pregnancy, liver cirrhosis, renal impairment). In these cases, using a standard $f_u$ value derived from healthy volunteers to calculate unbound concentration may be inaccurate.
5. Concept Application: Propofol Case Study
- Scenario: Propofol is a lipophilic, non-polar drug.
- Observation: It distributes into the brain much more rapidly than into adipose tissue, despite being highly lipophilic (and thus having high affinity for fat).
- Explanation:
- This is a perfusion-limited distribution scenario.
- The brain is a highly perfused organ (receives high blood flow).
- Adipose tissue is poorly perfused (low blood flow).
- Although the drug “likes” adipose tissue, it takes a long time for the blood to deliver sufficient drug to the fat. Therefore, brain concentrations rise rapidly, while adipose concentrations rise slowly.
