An oral drug travels gut to portal vein to liver to circulation to kidney or bile. Intravenous dosing skips the early steps, which is why it is the 100% baseline, while oral drugs lose bioavailability to first-pass metabolism in the gut wall and liver.
Protein binding limits the drug. The bound form is large in volume and cannot cross capillary walls, so only the free fraction is active, crosses the blood-brain barrier, and is filtered by the glomerulus.
層 4 執行
綁定之後怎麼執行
代謝分兩階段。Phase I 由 CYP450 主導，多數不改變活性，但藥物之間的交互作用主要發生在這裡，因為酵素的誘導或抑制會改變藥物濃度。Phase II 做結合反應，把產物變成水溶性以便排泄。
Metabolism has two phases. Phase I is driven by CYP450 and usually preserves activity, but it is where most drug interactions occur because enzyme induction or inhibition changes drug levels. Phase II conjugates the product so it becomes water-soluble for excretion.
Weak acids and weak bases are handled in opposite directions. A weak acid is unionised in acidic urine and lipid-soluble, so it is reabsorbed, which means alkalinising the urine speeds its removal. Weak bases need the opposite treatment.
Route of administration is the intervention. Sublingual dosing bypasses first-pass metabolism, which would otherwise destroy the drug before it reached circulation. Structural design also intervenes, as removing the catechol ring lets a drug escape enzymatic degradation.
層 7 代價
阻斷的代價
分子量決定了唯一的出口。約 300 Da 以下的藥物走尿液，超過 500 Da 走膽汁，因此中間分子量的藥物需要代謝轉換才能排泄。與 Probenecid 併用會抑制主動分泌，讓 Penicillin 濃度升高。
Molecular weight decides the only available exit. Drugs under about 300 daltons leave through urine and those over 500 through bile, so mid-range drugs must be metabolised first. Co-administration with probenecid also inhibits active secretion and raises penicillin levels.
Pharmacodynamics converts drug-receptor binding into effect, built on a reversible equilibrium. Because it is reversible, raising concentration can occupy every receptor, and an antagonist can only push the effect back.
The core equation is free drug plus free receptor forming a complex that produces effect. Free rather than total concentration is what matters, so protein binding reduces the amount actually available.
Receptors fall into four families. Ion channels such as the nicotinic receptor are the most direct; GPCRs come in three couplings; nuclear receptors sit inside the cell and act slowly but durably; receptor tyrosine kinases such as insulin complete the list.
層 4 執行
綁定之後怎麼執行
G 蛋白的亞型決定了第二傳訊者，而第二傳訊者決定方向。Gq 走 IP₃ 與 DAG 並升高鈣離子；Gi 降低 cAMP；Gs 升高 cAMP。口訣是 QISS。
The G-protein subtype determines the second messenger, and the second messenger determines direction. Gq raises calcium through IP₃ and DAG, Gi lowers cAMP, and Gs raises cAMP.
Kd does not equal ED₅₀ because one describes binding and the other describes effect, and the effect also depends on receptor reserve and signal amplification. Potency and efficacy are likewise independent.
Agonists and antagonists differ in intrinsic activity. A full agonist has an intrinsic activity of 1 and a partial agonist has less. Antagonists are competitive or non-competitive: competitive binds the same site, non-competitive binds elsewhere or blocks the channel.
層 7 代價
阻斷的代價
長期使用致效劑會讓受體下降調節，而下降有兩種方式。去敏感化是磷酸化使受體與 G 蛋白脫鉤，快速可逆且受體數量不變；下調是受體被內吞降解，緩慢且受體數量真的減少。
Chronic agonist use causes downregulation, and there are two forms. Desensitisation is phosphorylation that uncouples the receptor from the G protein, fast and reversible with receptor numbers unchanged. Downregulation is internalisation and degradation, slow, with receptor numbers actually falling.
This is a two-node signalling system in which sympathetic and parasympathetic control the same effectors in opposite directions. Sympathetic handles emergencies, parasympathetic restores and stores, and the enteric system can run independently.
The signal passes through three stages: pre-ganglionic fibre, ganglion, post-ganglionic fibre, then effector. Pre-ganglionic transmission is fixed because the two divisions cannot be distinguished at the ganglion, so the same transmitter is used and identity only emerges after the ganglion.
層 3 綁定
綁什麼 — 這是 Q1 的核心
所有節前纖維都是 ACh 作用在菸鹼型受體。節後副交感仍是 ACh 但改用毒蕈鹼型受體，節後交感改用正腎上腺素作用在腎上腺素受體。唯一例外是汗腺，交感節後纖維釋放 ACh 而非 NE。 藥物分類為四象限：擬交感（Epi、Salbutamol）、抗交感（Metoprolol、Phentolamine）、擬副交感（Bethanechol、Neostigmine）、抗副交感（Atropine、Ipratropium）。
All pre-ganglionic fibres use acetylcholine on nicotinic receptors. Post-ganglionic parasympathetic fibres keep acetylcholine but switch to muscarinic receptors, while post-ganglionic sympathetic fibres switch to norepinephrine on adrenoceptors. The single exception is the sweat gland, where sympathetic fibres release acetylcholine.
The adrenoceptor subtype determines everything. α1 uses Gq to raise calcium and constrict vessels, α2 uses Gi to inhibit norepinephrine release, β1 uses Gs to speed the heart, β2 uses Gs to relax smooth muscle, and β3 uses Gs to relax the bladder. Among muscarinic receptors the odd numbers are Gq and the even numbers are Gi, while nicotinic receptors are ion channels and therefore fastest.
The same Gs chain runs in opposite directions in different effectors, contracting cardiac muscle but relaxing smooth muscle. Cardiac muscle contracts because calcium rises, while smooth muscle relaxes because cAMP activates MLCP and removes the phosphate groups needed for binding.
There are three modes of intervention. Direct agents bind the receptor themselves. Indirect agents raise existing norepinephrine by mobilising vesicular stores, blocking reuptake, or blocking metabolism. Mixed agents do both. Structurally, non-catecholamines lack the catechol ring, escape COMT and MAO, and so become orally viable with a longer half-life.
The cost of blockade equals what the blocked receptor normally does. Blocking β2 prevents bronchial relaxation and causes spasm, so non-selective beta blockers are contraindicated in asthma. Blocking α2 removes presynaptic negative feedback, so norepinephrine release increases and blood pressure rises instead of falling.
The cardiovascular system is a pump, a set of pipes and a regulator. Blood pressure equals cardiac output times systemic vascular resistance, so there are only three ways to lower it: reduce output, reduce resistance, or both.
Three systems deliver regulatory signals: the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the baroreceptor reflex. The first two raise blood pressure while the third reflexively slows the heart when pressure is high, so hypertension often comes with bradycardia.
層 3 綁定
綁什麼 — ABCD 四個作用點
降血壓藥物有四個作用點。腎上腺素受體作用在血管與心臟，鈣離子通道阻斷劑分血管選擇與心臟選擇兩類，腎素血管張力素系統靠 ACE 與 Ang II 受體，利尿劑作用在腎臟的再吸收位置。 診斷需非同日三次血壓均偏高；分期有三套標準，答題必須寫明引用哪一套。
Antihypertensives act at four points. Adrenoceptors act on vessels and heart, calcium channel blockers split into vessel-selective and heart-selective, the renin-angiotensin system is targeted through ACE and the angiotensin receptor, and diuretics act on renal reabsorption sites.
層 4 執行
綁定之後怎麼執行
四個槓桿各有用不同的訊號機制。ACEI 阻斷 Ang I 轉成 Ang II 並減少醛固酮。β1 阻斷劑降低心率與腎素。Dihydropyridine 類阻斷血管的鈣內流。利尿劑阻斷鈉的再吸收而讓鈉從尿中排出。
Each lever uses a different mechanism. ACE inhibitors block the conversion of angiotensin I and reduce aldosterone. Beta-1 blockers lower heart rate and renin. Dihydropyridine calcium channel blockers block calcium entry into vessels. Diuretics block sodium reabsorption so sodium leaves through urine.
Loop diuretics block sodium and with it the passive reabsorption of calcium, causing hypocalcaemia, whereas thiazides leave calcium transport intact and cause hypercalcaemia. Non-dihydropyridine calcium channel blockers act on the heart rather than vessels.
Antiarrhythmics are grouped by mechanism into four classes blocking sodium channels, beta receptors, potassium channels and calcium channels in turn. Class one shows use-dependence because it binds the inactivated state of the sodium channel, so a faster rate means more inactivated channels and stronger blockade.
層 7 代價
阻斷的代價
阻斷的代價包括乾咳與高血鉀。ACE 也分解 Bradykinin，所以抑制 ACE 會讓 Bradykinin 累積而刺激呼吸道產生乾咳；Ang II 下降使醛固酮減少，腎臟排鉀減少而高血鉀。雙側腎動脈狹窄時禁用 ACEI，因為腎灌流壓正靠 Ang II 維持。 Digoxin 改善症狀與住院率但不改善生存；β 阻斷劑改善生存，但需低劑量起始、約三個月才完整生效。
The costs of blockade include cough and hyperkalaemia. ACE also degrades bradykinin, so inhibiting it lets bradykinin accumulate and stimulate the airway, causing dry cough. Falling angiotensin II reduces aldosterone, so the kidney excretes less potassium and potassium rises. ACE inhibitors are contraindicated in bilateral renal artery stenosis because glomerular filtration pressure depends on angiotensin II.
The respiratory system has two independent problems: airway tone and airway inflammation. Bronchodilation handles only the first and anti-inflammatory drugs handle the second, so neither alone is sufficient.
Bronchial smooth muscle is under both sympathetic and parasympathetic control. Sympathetic β2 relaxes it while parasympathetic M3 contracts it, so asthma is a breakdown of that balance.
Three bronchodilator classes target three different things: beta-2 agonists bind β2 receptors, antimuscarinics block M3, and theophylline inhibits phosphodiesterase to maintain cAMP. Four anti-inflammatory classes act on mediator generation, the receptor, the synthesis enzyme, cell degranulation, and the breakdown enzyme.
β2 uses Gs to raise cAMP, and cAMP activates MLCP so the myosin light chain loses its phosphate groups and cannot bind actin, which relaxes smooth muscle. Bronchodilation is the result of this chain.
層 5 相反
哪裡方向相反
緩解藥與控制藥的時間方向相反。控制藥（吸入類固醇）作用在生成端，需要誘導新蛋白質合成，所以要數小時至數天；緩解藥（SABA）直接作用在效應端的肌肉上，所以是分鐘級。急性發作時控制藥來不及。 另一處：哮喘是發炎為主所以必須用類固醇，慢性阻塞性肺病是擴張為主所以用 LAMA 與 LABA，類固醇效果較差。
Controllers such as inhaled steroids act on the generation side and require new protein synthesis, taking hours to days, while relievers such as short-acting beta-2 agonists act directly on the effector muscle within minutes. During an acute attack the controller arrives too late.
層 6 介入
藥物怎麼介入 — 兩條階梯
兩條治療階梯方向相反。哮喘階梯往上是加抗發炎藥，核心是吸入類固醇；慢性阻塞性肺病階梯往上是加支氣管擴張藥，核心是 LAMA 與 LABA。 LABA 不能單獨用於哮喘，因為它只舒張支氣管卻不控制發炎，會掩蓋症狀而讓發炎繼續累積。
The two treatment ladders run in opposite directions. The asthma ladder adds anti-inflammatory therapy upward with inhaled steroids at its core, while the COPD ladder adds bronchodilation upward with LAMA and LABA at its core.
層 7 代價
阻斷的代價
第一代抗組織胺阻斷 M 受體但脂溶性高能通過血腦屏障，所以產生嗜睡——而嗜睡正好可用來治暈車。去充血劑阻斷 α1 讓鼻黏膜血管收縮而消腫，但長期使用使受體下調，產生反彈性充血。Theophylline 治療窗窄，需監測血中濃度。
The cost of blockade shows in the side effects. First-generation antihistamines block muscarinic receptors but are lipid-soluble enough to cross the blood-brain barrier, so they sedate. Decongestants block α1 to shrink nasal vessels, but long-term use downregulates receptors and causes rebound congestion.
The central nervous system is a control centre protected by the blood-brain barrier, so whether a drug can enter is the first question. Only after entry does mechanism matter.
Signals travel along neurons and finally act through neurotransmitters on receptors. Most neurotransmitters are amines or peptides, and many drugs either mimic or block them.
To cross the blood-brain barrier a drug must be small, lipid-soluble and unionised. Only after entry does it act on a specific receptor, such as the mu receptor for opioids, GABA or AMPA receptors for antiepileptics, and serotonin or NK1 receptors for antiemetics.
Antiepileptics use two opposite strategies. Those enhancing GABA increase inhibition, with barbiturates lengthening chloride channel opening and benzodiazepines increasing its frequency. The other group cuts off excitatory transmission, with perampanel blocking AMPA receptors and ezogabine opening potassium channels to hyperpolarise the cell. Both aim to make the neuron harder to bring to threshold.
COX-1 handles daily housekeeping such as gastric protection and platelet production, while COX-2 is induced only at inflamed tissue and produces swelling, pain and heat. Selective COX-2 inhibitors cause fewer gastrointestinal problems but carry higher cardiovascular risk.
Drugs act either directly on receptors, as opioids do, or indirectly by raising existing transmitters, as acetylcholinesterase inhibitors do by letting acetylcholine accumulate. Antiemetics are chosen by trigger rather than severity.
Blocking mu receptors with an opioid also suppresses the respiratory centre, which is the main cause of death. Chronic benzodiazepine use downregulates GABA receptors, producing tolerance and dependence, which is why long-term anxiety treatment uses SSRIs instead. Cholinesterase inhibitors improve symptoms only, because Alzheimer's is caused by neuronal degeneration.
08跨系統對照換系統不用重讀的真正用法
同一個底層陷阱，在六科換了不同外觀。看到左欄應該能填出右欄。
底層陷阱
L3 ANS
L4 CVS
L5 Resp
L6 CNS
L1 PK
同一機制 方向相反
Gs 在心肌收縮、平滑肌舒張
環利尿劑低血鈣、Thiazide 高血鈣
緩解藥分鐘級、控制藥天級
COX-1 維持、COX-2 發炎
弱酸鹼化、弱鹼酸化
阻斷 產生代償
阻斷 α2 使 NE↑
阻斷 α1 使 GFR↓
去充血劑長期致反彈性充血
阻斷 μ 致呼吸抑制
結合率高則游離低
分佈決定 副作用
β2 在肺、β1 在心
α1 在血管、β1 在腎
M3 在腺體與平滑肌
μ 在呼吸中樞
結合態不能過膜
酵素決定 能不能口服
非兒茶酚胺可口服
—
LABA 不能單獨用
一代抗組織胺過 BBB
首渡代謝破壞藥物
量與競爭
阻斷 β2 需加量競爭
使用依賴性
LABA 掩蓋發炎
部分致效劑變拮抗劑
抑制分泌可被競爭
09筆答格式
每一層寫 1–3 句完整句子，不要用 bullet point。以下示範 L3 層 3。
All pre-ganglionic fibres use acetylcholine on nicotinic receptors, because sympathetic and parasympathetic fibres cannot be distinguished at the ganglion. Post-ganglionic parasympathetic fibres continue to use acetylcholine but switch to muscarinic receptors, whereas post-ganglionic sympathetic fibres switch to norepinephrine on adrenoceptors. The single exception is the sweat gland, where sympathetic post-ganglionic fibres release acetylcholine rather than norepinephrine.