102 · L2 Pharmacodynamics (Receptors & Dose-Response)

• Affinity = probability drug occupies receptor; Efficacy (intrinsic activity) = ability to activate once bound
• Agonist = affinity + efficacy; Antagonist = affinity, no efficacy
• Full agonist needs only 5–10% receptor occupancy; partial agonist needs 100% for submaximal response

Four receptor types

Pharmacodynamics & ligands

Pharmacodynamics studies dose-response relationships and how drugs alter physiological functions, initiated by drug interactions with molecular targets. Molecules (drugs, hormones, neurotransmitters) that bind a receptor are called ligands; the binding can be specific and reversible or irreversible (covalent). A ligand may activate or inactivate a receptor, and activation may increase or decrease a cell function.

Characteristics of membrane receptors

• Proteins, typical molecular weight 45–200 kDa, can be composed of subunits (α, β, γ).
• Binding is reversible/irreversible and stereo-selective; receptors are saturable (finite number available).
• Specific binding causes changes in ion flow / signal transduction to intracellular sites.
• May require more than one drug molecule to bind to generate a signal.
• Magnitude of signal depends on the number of receptors occupied (occupancy rate); signal can be amplified by intracellular mechanisms.
• Drugs are receptor modulators — they do NOT confer new properties on cells/tissues.
• Receptors must have recognition and transduction properties.
• Receptor populations can be upregulated, downregulated, or sequestered.

Desensitization vs down-regulation

Repeated administration of a ligand (especially high doses) can lead to a diminished effect at the same high dose — the receptor becomes desensitized.

Drug-receptor binding forces

Lock and Key & the conformational test

Receptors are responsible for the selectivity of drug action. The interaction shows a high degree of specificity — the Lock and Key phenomenon: size, shape, and charge distribution of the ligand determine which binding sites it can interact with; an extra or improperly placed atom (like an extra tooth on a key) can exclude binding.

Structure-Activity Relationship (SAR)

Affinity is determined by the chemical structure (and charges) of the ligand. Minor changes in the ligand molecule may produce MAJOR changes in pharmacological properties — and can dramatically increase or decrease affinities for different receptor classes, altering therapeutic and toxic effects.

Dose-response relationship

The dose-response curve graphs observed effect as a function of drug concentration at the receptor site. The underlying interaction is represented as:

[X] + [R] ↔ [XR] → E

where [X] = drug concentration at receptor, [R] = free receptor concentration, [XR] = drug-receptor complex, and E = pharmacological effect.

Pharmacological & chemical antagonism

Beyond physiological antagonism (already covered), two more types:

• Pharmacological antagonism — the antagonist inhibits the effect of an agonist (or partial agonist) by an action on the same pathway, though not necessarily the same receptor.
• Chemical antagonism — a chemical interaction between a drug and a chemical (or between two drugs) leading to loss of, or reduction in, response.

Potency — reading the curve

Agonists acting on the same receptor type all reach the same maximal response; the most potent produces E_max/2 at the lowest concentration. Potency is a comparative term, only meaningful between agonists sharing a receptor.

Signal transduction — three stages

When a drug binds its receptor, a transduction pathway follows attachment but precedes the response:

1. Signal reception — a ligand binds a receptor protein (cell-surface or internal). Internal receptors need no relay; cell-surface receptors pass the signal on.
2. Signal transduction — second messengers, enzymes, and activated proteins relay the signal in a chain reaction, converting extracellular to intracellular signals.
3. Cellular response — a specific cellular process is triggered (alters function, metabolism, shape, gene expression).

Four categories of chemical signalling

Therapeutic Index — definition

The Therapeutic Index is the ratio of the dose that elicits toxicity to the dose that produces a therapeutic effect:

T.I. = Toxic Dose (TD₅₀) / Effective Dose (ED₅₀)

Receptor naming convention — named for their BEST ligand

The card uses muscarinic and adrenergic receptors as examples but never states the naming rule the source gives:

Law of Mass Action — the quantitative basis of occupancy

The card discusses affinity and potency but omits the source's explicit foundational principle:

Spare receptors — the formal definition the card only implies

The card lists "spare receptors" in Key Terms ("full agonist needs only 5–10% occupancy") but never gives the source's formal statement:

ED₅₀, E_max and K_d — the three numbers that describe a drug

Two describe the response, one describes binding, and they do not point the same way.

ED₅₀ and E_max are read off the curve — ED₅₀ from the horizontal position, E_max from the height. K_d is not on the curve: it belongs to the binding reaction [X] + [R] ↔ [XR], before any response exists.

Potency and efficacy are independent axes — the three worked comparisons

Potency asks how much drug is needed; efficacy asks how much effect it can generate.

Row 1: both reach 100%, so both have the same E_max — equal efficacy. But A needs 0.3 nM to reach 50% of it while B needs 300 nM, so A is 1000× more potent and sits to the left.

Reading the curve — hyperbola on a linear axis, sigmoid on a log axis

Full agonist, partial agonist, antagonist — three characteristic curves

The source's height ladder: full agonist 100% > partial agonist A 80% > B 40% > C 10% > antagonist D 0%. All may engage the same receptor — only the intrinsic activity differs, so the ceiling is set by the drug, not the receptor.

The partial agonist's double life — agonist alone, antagonist in company

• Alone: occupies receptors and produces a sub-maximal response — weaker than a full agonist, stronger than an antagonist.
• Beside a full agonist: low intrinsic activity drags the full agonist's maximum down — it now behaves as an antagonist.

Competitive antagonism — parallel right shift, E_max unchanged

1. Antagonist and agonist compete for the same binding site, and binding is reversible — higher concentration occupies more receptors.
2. The curve shifts parallel right: ED₅₀ rises, apparent potency falls.
3. Maximum unchanged — enough agonist out-competes the antagonist.

Non-competitive antagonism — right shift plus a lower ceiling

1. The antagonist binds irreversibly, or acts at an allosteric site, so the receptor stays permanently or long-term occupied.
2. The curve shifts right, the maximum falls, and the slope may fall too.
3. More agonist cannot restore the maximum — fewer usable receptors remain.

Competitive versus non-competitive — the full comparison

Binding strength predicts reversibility — reversibility predicts curve shape

The ladder runs van der Waals < hydrogen < ionic < covalent, and only the covalent rung is irreversible under biological conditions. Reversible bonding → competitive block (right shift, surmountable); covalent bonding → non-competitive (maximum falls, not restorable). The ladder is why the curve has its shape.

K_d is not ED₅₀ — binding is not response

K_d says how tightly the drug binds; ED₅₀ says how much drug gives half the maximal response. They coincide only when response tracks occupancy one-for-one. With spare receptors the tissue reaches its maximum while most receptors are empty, so ED₅₀ sits well left of K_d.

Where amplification happens — three stages mapped onto the curve

The transduction stage is a chain reaction of second messengers and enzymes, and the signal is amplified intracellularly — which is why a small occupancy can produce a full response. Reception sets occupancy, transduction decouples ED₅₀ from occupancy, the cellular response sets E_max.

One-line summary: the dose-response relationship says how strong and how safe a drug is; the agonist–antagonist interaction says how it is blocked and whether the block can be reversed.

102 · L4 Cardiovascular System

BP = Cardiac Output × Peripheral Vascular Resistance (CO = HR × SV)

MAP = DBP + ⅓(SBP − DBP). Normal <120/80; Stage 1 HTN 130–139/80–89; Stage 2 ≥140/90 (2017 ACC/AHA).

Antihypertensives — "ABCD"

Cardiovascular system — anatomy & physiology

The cardiovascular system has three basic components: the heart (the "pump" — in adults ~255–310 g / 9–11 oz, the size of your fist, propelling >6,000 L of blood daily, beating >40 million times/year and >3 billion times over a lifetime), the blood vessels (arteries, arterioles, veins, venules, capillaries — a closed tube network ~60,000 miles / 96,500 km long, >2× the Earth's equator), and the blood (~8% of body weight; ~5.6 L in an average man, ~4.5 L in a woman).

Cardiovascular diseases — causes & types

There are > 60 cardiovascular diseases; some congenital, most develop over a lifetime. Major risk factors / causes:

• Smoking; overweight / obese; lack of physical activity
• Too much salt, alcohol and cholesterol in the diet
• Emotional stress; older age / gender / personality type
• Family history of high blood pressure; kidney disease
• Adrenal and thyroid disorders

Blood pressure variables & measurement

BP is recorded as two numbers, e.g. 120/80 mmHg: the SBP (120, pressure when the heart contracts) and the DBP (80, pressure when the heart relaxes and refills). Other variables are Pulse Pressure (PP) and MAP = DBP + ⅓(SBP − DBP). Diagnosis needs 3 separate sphygmomanometer measurements at one-month intervals — not a single reading.

Why hypertension is dangerous

Hypertension makes the heart work harder against resistance and drives arteriosclerosis and heart failure. In ~90–95% of patients the cause is unknown — primary / essential hypertension; the remainder is secondary hypertension (known cause). The AHA estimates HTN costs the US US$131–198 billion/year (care + medicines + lost productivity).

Hypertension — lifestyle modification (no drugs)

For patients without end-organ damage (BP <140/90 mmHg), the first step is lifestyle change:

Diuretics — sites of action & mechanisms

All three diuretic groups interfere directly with specific transport proteins in the nephron. Less total fluid volume → lower intravascular pressure.

Sympathetic tone & β1-blockers

Activation of β1 adrenergic receptors on the heart → ↑ heart rate and contractility → ↑ BP. β1-blockers (Atenolol, Metoprolol) blunt this sympathetic drive — the "B" in ABCD (see card).

Renin–Angiotensin–Aldosterone System (RAAS)

The RAAS cascade raises BP two ways — vasoconstriction and volume expansion:

ACE inhibitors (Lisinopril, Captopril, Enalapril, Perindopril, Ramipril) cut Ang II → vasodilation + lower volume. ARBs block the AT₁ receptor (AT₁ activation → vasoconstriction; AT₂ → vasodilation) for ACEI-intolerant patients: Losartan, Candesartan, Irbesartan, Telmisartan, Valsartan.

Calcium channel blockers — vasodilator mechanism

Vascular smooth-muscle contraction needs extracellular Ca²⁺ influx. CCBs block this influx, so less Ca²⁺ is available for excitation–contraction coupling → arteriole dilation. Examples: Verapamil, Diltiazem, Nifedipine (the "C" in ABCD).

Cardiac arrhythmias — origins & the ECG

The SA node is the origin of the heartbeat; normal electrical synchrony = normal sinus rhythm. Any deviation is an arrhythmia, and arrhythmias are the major cause of death after myocardial infarction. The ECG is the most important non-invasive diagnostic tool — an arrhythmia shows as a deviation in rate, regularity, or activation pattern.

Cardiac action potential phases

Antiarrhythmics — Vaughan Williams in detail

The four classes (summary on the card) split further, and the lecture stresses use-dependent block (higher affinity for OPEN / INACTIVATED channels; resting channels are non-conducting).

Heart failure — pathophysiology & management

Heart failure is a syndrome, not a disease: cardiac output is inadequate for the body's demands (congestive HF = fluid build-up / oedema, esp. lower limbs). Case numbers rose over two decades via population aging and better MI survival.

In HF, ↓ CO → ↓ GFR → ↑ salt/water retention → ↑ workload. Loop diuretics (Frusemide) inhibit Na⁺ reabsorption in Henle → massive diuresis → ↓ ECF volume → ↓ wall tension → ↓ myocardial demand.

Heart failure — management goals (the "5 aims")

Heart failure — chest X-ray as a bedside sign

Mean arterial pressure — what the formula is doing

MAP = DBP + ⅓(SBP − DBP)

• Diastolic pressure carries the larger weight in the formula, which is why mean arterial pressure is not a plain average of the two numbers.
• At about 70 beats per minute each cardiac cycle lasts under a second, and most of that time is relaxation, so diastole occupies the larger share of the cycle.
• Organs do not respond to the peak pressure; perfusion depends on the pressure sustained across the whole cycle, which is why one mean value is used rather than two numbers.

Primary versus secondary hypertension — and where the damage lands

90–95% of patients have no identifiable cause → primary / essential hypertension. The rest is secondary, with a known cause (kidney disease, adrenal or thyroid disorders) — and removing it can improve the pressure.

• The brain has delicate vessels and sees roughly 30% less pressure than the systemic reading, so it is the organ most vulnerable to rupture and stroke. The heart must pump against higher resistance, so the myocardium thickens and its oxygen demand rises, ending in myocardial infarction or heart failure.
• The kidney is the one target organ whose failure makes the cause worse: fine vessels are damaged, sodium and water excretion is impaired, volume rises, pressure rises further, and the kidney is damaged again — a vicious cycle.
• In the eyes the damage shows up as retinopathy and problems with intraocular pressure, and can end in blindness.

The RAAS cascade — the aldosterone arm and the AT₁ receptor

The card's table stops at Angiotensin II. The system is named renin–angiotensin–aldosterone: the source runs Angiotensin II → AT₁ receptor → vasoconstriction + aldosterone → Na⁺/H₂O retention → BP ↑. Vasoconstriction raises the resistance term, the aldosterone arm the volume term.

The cardiac action potential — the plateau and the long duration

The card lists phases 0–4 and their ions but not the purpose of the plateau. Phase 2 holds Ca²⁺ influx balanced against K⁺ efflux, and that is what stretches the action potential to several hundred milliseconds — far longer than a nerve impulse.