Receptor Pharmacology & Dose-Response Principles

Two-state receptor theory
- Receptors oscillate between an inactive (R) and active (R*) conformation.
- "Constitutive activity": a basal fraction of receptors (e.g., 15 out of 100) spontaneously reside in R* and generate a measurable effect (e.g., increased heart rate).
- Only receptors that show constitutive activity can display inverse agonism.
Practical implications
- Basal heart contractility or tone can exist even in absence of exogenous ligand.
- Drugs that force all receptors into the R state will suppress that baseline activity (e.g., inverse agonist → bradycardia/cardiac arrest if the receptor normally raises HR).

Full agonist
- High efficacy; shifts essentially all receptors to R*.
Partial agonist
- Intermediate efficacy; even at saturating doses some receptors remain in R.
- Ceiling effect visible as a plateau in the dose–response curve.
Inverse agonist
- Binds preferentially to constitutively active R*, stabilises R, and produces the opposite effect to an agonist.
Antagonist
- Has affinity but no intrinsic activity (no change in R⇌R* equilibrium).
- Occupies receptor and blocks other ligands.

Buprenorphine = partial μ-opioid agonist
- Ceiling on euphoria/respiratory depression → safer for opioid use disorder.
Nicotine replacement: partial stimulation of nicotinic receptors → cravings satisfied without full tobacco toxicity.

Efficacy (E_{max}) – maximal achievable effect of a drug.
- Relative measure: must compare ≥2 agents.
- Indicates how well a drug activates the receptor ➔ governs clinical utility.
Potency – dose or concentration required to reach a predefined effect (usually $ED<em>{50}$ or $EC</em>{50}$ ).
- Leftward position in semi-log plot = higher potency (lower dose needed).
- Clinically less important than efficacy unless linked to cost, toxicity, or therapeutic window.
Key graph interpretations
- Same E_{max}, different $ED_{50}$ → equal efficacy, differing potency.
- Different E_{max}, same $ED_{50}$ → differing efficacy, equal potency.
- A partial agonist can be more potent yet less efficacious than a full agonist.

If two agents are equally efficacious, potency alone rarely justifies choosing the costlier drug.
Narrow therapeutic window + high potency may increase overdose risk, but the relation is not absolute.

Competitive (reversible)
- Antagonist and agonist vie for same site.
- Surmountable: ↑agonist concentration restores E_{max}.
- Graph: parallel right shift (↑ $EC_{50}$ ), unchanged E_{max}.
Non-competitive / pseudo-irreversible
- Antagonist binds active site but dissociates very slowly.
- Insurmountable in short term: ↓E_{max} plus right shift of $EC_{50}$ .
Allosteric inhibition
- Antagonist binds distinct site → conformational change lowers agonist affinity/efficacy.
- Graph resembles non-competitive (↓E_{max}, ↑ $EC_{50}$ ).
Allosteric potentiation
- Positive modulator enhances agonist binding or signaling.
- Left shift ± higher E_{max}.

Diphenhydramine (Benadryl) competes with histamine at H1 receptors.
- Mild urticaria may resolve with standard dose; severe hives require ↑dose to out-compete massive local histamine.

Definition: $TI = \dfrac{TD<em>{50}}{ED</em>{50}}$ (or $LD_{50}$ in animals).
- $TD_{50}$ = dose causing toxicity in 50 % of population.
- Larger TI ⇒ safer drug.
A single drug can have multiple TIs (one per adverse effect).

Desirable-effect curve vs toxicity curves plotted together.
- Wide separation → high safety margin (e.g., penicillin).
- Overlap → narrow margin (e.g., warfarin anticoagulation vs bleeding).
Digoxin example
- $0.25\,\text{mg}$ : 25 % achieve HR ≤ 85 bpm, 0 % GI toxicity.
- $1.5\,\text{mg}$ : 100 % achieve control but ~70 % vomit.
- Clinical practice: start low and titrate—aim for therapeutic effect with minimal toxicity.

CNS depression levels (ascending):
1. Anxiolysis / Mild sedation
2. Hypnosis (sleep induction)
3. Surgical anesthesia
4. Medullary depression (respiratory arrest → fatal)
Drug class contrasts
- Benzodiazepines
- Dose–response has a ceiling: cannot easily reach medullary depression.
- OD on diazepam alone → prolonged sleep, not fatal; risk skyrockets if combined with other depressants (e.g., ethanol).
- Barbiturates & Ethanol
- Near-linear curve; no plateau before respiratory arrest.
- High fatality risk in overdose.
Clinical takeaway: prefer benzos over barbiturates for anxiety/insomnia due to wider safety margin.

Opioid analgesics
- Meperidine (full agonist) vs pentazocine (partial)
- Meperidine: ↑efficacy & potency.
- Pentazocine: lower E_{max} → adequate for mild pain; less respiratory depression risk.
- Meperidine vs morphine
- Equal E_{max}; morphine more potent.
Buprenorphine: partial agonist at μ receptors; ceiling on euphoria → addiction therapy utility.
Warfarin vs penicillin (TI illustration)
- Warfarin: narrow TI; monitoring INR essential.
- Penicillin: wide TI; dosing flexible.

Marketing often touts “higher potency” though efficacy and safety dictate therapeutic value.
Drug cost vs potency debate: If efficacy equal and toxicity manageable, cheaper agent may suffice (e.g., generic vs branded antihypertensive).
High potency agents with narrow TI require enhanced patient education, monitoring, and caution with poly-pharmacy (e.g., warfarin, digoxin).

Anticipate dose–response graphs requiring identification of: agonist class, potency shifts, E_{max} changes.
Master verbal definitions and graphical signatures.
Remember $TI$ formula and qualitative interpretation.
Inverse agonism question cue: “constitutive activity present?” — If no, inverse agonism impossible.