Drug Action

PRINCIPLES OF DRUG ACTION (PHARMACODYNAMICS)

OBJECTIVES OF THE UNIT

List different types of receptors at which drugs can act.
Identify concept of affinity and those factors that cause a drug to bind to a receptor.
State the concept of intrinsic activity.
Differentiate between full and partial agonists.
Definitions of potency and efficacy.
Agonist and Antagonist.

PHARMACODYNAMICS

Definition:
- This is the area concerned with the drugs' action on biological systems.
Drug Action:
- This refers to the effect of drugs on living systems.
Site of Drug Action:
- The receptor sites where a drug acts to initiate a group of functions; this can occur at:
- Extra cellular: Outside the cell.
- Cellular: On the cell surface.
- Intracellular: Inside the cell.

TYPES OF DRUG ACTION (TYPE OF RESPONSES)

Stimulation/Activation:
- Condition where a drug binds to a receptor, initiating a response or increasing the receptor's activities.
Inhibition/Depression:
- Action of a drug that leads to a decrease in the activities of a receptor or blocks the receptor.
Replacement:
- Example: Hormone replacement therapy (HRT).
Irritation:
- Actions that can lead to side effects or adverse effects.
Cytotoxic:
- Action of a drug that causes cell death.

MECHANISM OF DRUG ACTION IN MAN

Mode of Action:
- Types of effects produced by a drug, for example:
- Morphine:
  - Depresses the function of the cerebral cortex, hypothalamus, and medullar center to provide analgesia, heavy sedation (narcosis), and depressive effects on the cough center (antitussive effect).
Drug Action via Receptors:
- Receptors are macromolecules that endogenous or exogenous substances (such as drugs) can bind to, bringing about structural changes leading to specific physiological, pathological, or pharmacological effects.

LOCATION OF RECEPTORS

Cell membrane:
- Anchored or embedded in the phospholipid layer, majority of cellular receptors are proteinous (e.g., M1, M2, α1, α2, β1, β2).
Cytoplasm:
- Some receptor sites exist intracellularly (e.g., steroids).
Nucleus:
- Some receptors, such as steroid receptors, are located in the nucleus.

RECEPTOR SPECIFICITY AND FUNCTION

Specificity:
- Receptors interact with a limited number of structurally related molecules.
Drug Actions via Indirect Alteration of Effects of Endogenous Chemicals (Agonists):
- Physiological increases in endogenous release (e.g., insulin).
- Inhibition of endogenous re-uptake.
- Inhibition of endogenous metabolism.
- Prevention of endogenous release.

PROCESSES OF DRUG ACTION

Drugs carry out their actions through the following processes:
- Drug activation via the inhibition of transport processes.
- Drug action via enzyme inhibition.
- Drug action via enzyme activity activation.
- Miscellaneous drug actions:
- Examples include chelating, osmotic diuresis, volatile general anesthetics, and replacement drugs.

MAJOR CATEGORIES OF RECEPTORS

G-protein coupled receptors (GPCR).
Receptors with intrinsic ion channel.
Enzyme linked receptors.
Transcription factors (receptors for gene expression).

CLASSES OF DRUG–RECEPTOR INTERACTIONS

Ligand-activated ion channels:
- Example: Acetylcholine interacting with a nicotinic receptor, a non-specific Na+/K+ transmembrane ion channel.
G-protein–coupled receptors (GPCR):
- Comprise the largest class of receptors; interactions mediated by GTP-binding proteins.
Receptor-activated tyrosine kinases:
- Many growth-related signals (e.g., insulin) mediated via membrane receptors with intrinsic tyrosine kinase activity.
Intracellular nuclear receptors:
- Ligands (e.g., cortisol) diffuse rapidly through the plasma membrane due to their lipophilic nature.

DRUG-RECEPTOR INTERACTION

Selectivity:
- Degree of complementary correlation between drug and receptor.
- Example: Adrenaline’s selectivity for α and β receptors.
Affinity:
- The ability of a drug to bind to the receptor.
Intrinsic Activity (IA) or Efficacy:
- The ability of a drug to produce a pharmacological response after forming a drug-receptor complex.

FUNCTION OF RECEPTORS

Regulate signals from outside the cell to inside the effector cell (signals not permeable to the cell membrane).
Amplify the signal.
Integrate various intracellular and extracellular signals.
Adapt to short-term and long-term changes to maintain homeostasis.

AGONISTS AND ANTAGONISTS

Agonists:
- Drugs or chemicals that bind to and activate a receptor producing a response.
- Defined as ligands that, upon binding, produce a necessary conformational change to initiate a signal coupled to a biological response.
- When all available receptors are occupied, a maximal response is produced.
Examples of receptor systems:
- Adrenergic: Agonist - salbutamol; Antagonist - atenolol.
- Dopaminergic: Agonist - dopamine; Antagonist - haloperidol.
- Cholinergic: Agonist - bethanechol; Antagonist - atropine.

DRUG-RECEPTOR RESPONSE

Agonists (Types)

Agonist:
- Binds to a receptor and creates a biological response. May mimic or elicit a different response than the endogenous ligand's.
Full Agonists:
- Produce a maximal biological response mimicking the endogenous ligand (e.g., phenylephrine at α-adrenoceptors).
Partial Agonists:
- Have efficacies greater than zero but less than that of a full agonist. Cannot produce an Emax equal to that of a full agonist even when all receptors are occupied (e.g., aripiprazole for treating schizophrenia). Partial agonists may act as antagonists under appropriate conditions.
Inverse Agonists:
- Some receptors show spontaneous conversion from the inactive (R) to the active state (R*) in the absence of agonist.
- These receptors exhibit constitutive activity, forming a baseline response without drugs. Inverse agonists stabilize the inactive R form and are categorized similarly to antagonists.

### LOGIC REPRESENTATION OF RECEPTOR ACTIVITY
**Complete Activation: Full Agonist**
- High drug concentrations result in 100% receptor activation.

**Complete Response Below Baseline: Inverse Agonist**
- Produces a response below the baseline measured in the absence of the drug.

| Drug Type                | Receptor Activation   |
|------------------------- |----------------------|
| Full Agonist            | 100% Activation       |
| Partial Agonist         | < 100% Activation     |
| Inverse Agonist         | Response Below Baseline|

FULL AGONIST, PARTIAL AGONIST, AND INVERSE AGONIST

Full Agonist:
- Binds to a receptor, resulting in maximal response.
Partial Agonist:
- Binds to a receptor but cannot initiate a maximal response regardless of concentration.
Inverse Agonist:
- Binds tightly to a receptor but has intrinsic activity of zero or less, producing an effect opposite to that of the agonist (e.g., β-Carboline as an inverse agonist for benzodiazepine receptors).

ANTAGONIST

Definition:
- A ligand that binds to a receptor but does not produce the conformational change necessary to initiate an intracellular signal; thus, blocks the action of an agonist or endogenous substance.
Occupation of Receptors by Antagonists:
- Prevents the binding of any other ligand.
Types of Antagonism:
- Chemical antagonism: e.g., Heparin (−) and protamine (+); Chelating agents.
- Physiological/Functional antagonism.
- Pharmacokinetic antagonism.
- Pharmacological antagonism:
- Competitive (Reversible)
- Noncompetitive (Irreversible)

POTENCY OF A DRUG

Definition:
- A relative measure of the amount of a drug required to produce a specified level of response (e.g., 50%) in comparison with other drugs that produce the same effect through the same receptor mechanism.
Determining Factors:
- The potency is influenced by both the affinity of the drug for its receptor and the administered drug's reach to the receptor.

EFFICACY

Definition:
- The extent to which a drug produces a response when all available receptors or binding sites are occupied (i.e., Emax on the dose-response curve).
Comparison of Efficiencies:
- When comparing drugs acting at the same receptor, a full agonist has the greatest efficacy and can achieve the maximum possible response from the receptor.

THERAPEUTIC INDEX OR THERAPEUTIC WINDOW

Definition:
- This is the margin of safety which depends upon doses producing a desirable effect (ED50) and those eliciting a toxic effect (TD50 or LD50).
- Formulation:
- Therapeutic window = $ rac{TD{50} ext{ or } LD{50}}{ED_{50}}$.
- Where:
  - TD50 or LD50: The dose that causes 50% death in the population.
  - ED50: The dose that produces half-maximal response; the threshold dose produces the first noticeable effect.

INTRINSIC ACTIVITY

Definition:
- The ability of a drug, once bound to activate the receptor.
Antagonists:
- Bind to the receptor but do not initiate a response; they block the action of an agonist or endogenous substances that operate via the receptor.
Types of Antagonists:
- Competitive antagonists: Bind at the same site as the agonist.
- Noncompetitive antagonists: Bind to other sites on the receptor.

SUMMARY ON POTENCY AND EFFICACY

Potency of a Drug:
- A relative measure of the amount of a drug required to achieve a specific level of response (e.g., 50%) compared to other drugs with similar effects.
Efficacy of a Drug:
- The ability of a drug to elicit a pharmacologic response completely.

1. UNDERSTANDING PHARMACODYNAMICS

Simple Definition: If Pharmacokinetics is "what the body does to the drug," Pharmacodynamics is "what the drug does to the body." It explores how drugs interact with cells to produce a therapeutic effect.
Drug Action vs. Effect:
- Action: The initial chemical interaction (e.g., binding to a receptor).
- Effect: The physical result of that action (e.g., lower blood pressure).
Where does it happen? (Sites of Action):
- Extracellular: Outside the cell (e.g., neutralizing stomach acid).
- Cellular: On the cell surface (e.g., binding to a gateway).
- Intracellular: Deep inside the cell or within the nucleus (e.g., affecting DNA or proteins).

2. TYPES OF DRUG RESPONSES

Stimulation/Activation: The drug "switches on" a process or speeds it up.
Inhibition/Depression: The drug "switches off" a process or slows it down.
Replacement: Adding something the body is missing, like using Insulin for diabetes or Hormone Replacement Therapy (HRT).
Irritation: A rough effect on the tissue, often leading to side effects.
Cytotoxic Action: Intentionally killing cells (common in cancer treatments or antibiotics).

3. THE RECEPTOR CONCEPT: THE LOCK AND KEY

Receptors are large molecules (mostly proteins) that act as "locks." Drugs are the "keys." Only the right key can fit into the lock to produce a change.

Receptor Locations:
- Cell Membrane: Most common; they sit on the "skin" of the cell.
- Cytoplasm: Inside the fluid of the cell.
- Nucleus: Deep inside, where genetic instructions are kept (common for steroids).
How Drugs Indirectly Change Things:
- They can stop the body from breaking down its own natural chemicals, making those chemicals last longer.
- They can block the body from recycling chemicals, keeping more of them available for use.

4. MAJOR CATEGORIES OF RECEPTORS

G-Protein Coupled Receptors (GPCR): The largest family. They act like a relay race; once the drug binds, a G-protein carries the message further inside the cell.
Ion Channel Receptors: When the drug binds, a gate opens to let ions like $Na^{+}$ or $K^{+}$ flow through, changing the cell's electrical charge.
Enzyme-Linked Receptors: Binding to these directly activates an enzyme inside the cell (e.g., the Insulin receptor).
Transcription Factors: These interact with the nucleus to turn genes on or off, changing which proteins the cell makes.

5. KEY DEFINITIONS IN DRUG BINDING

Selectivity: How specific a drug is. A highly selective drug only fits one specific lock, meaning fewer side effects.
Affinity: The "stickiness." It describes how strongly a drug is attracted to a receptor.
Intrinsic Activity (Efficacy): The "power." Once the drug is stuck to the receptor, how well can it actually flip the switch and create a response?

6. AGONISTS VS. ANTAGONISTS

Agonists (The Helpers): Both bind to the receptor and activate it.
- Full Agonist: Produces the maximum possible response ( $100\%$ ).
- Partial Agonist: Produces a response, but even at high doses, it can't reach the maximum effect. It can actually block a full agonist from working if they compete for the same spot.
- Inverse Agonist: Some receptors are "on" even without drugs. An inverse agonist turns them below their normal baseline level.
Antagonists (The Blockers): They bind to the receptor but do nothing to activate it. They just "jam the lock" so the body's natural chemicals (or other drugs) can't get in.
- Competitive: Fights with the agonist for the exact same spot. If you add more agonist, you can "out-compete" the blocker.
- Noncompetitive: Attaches to a different part of the receptor, changing the shape of the lock so the key no longer fits. Adding more agonist won't help here.

7. MEASURING DRUG PERFORMANCE

Potency: How much do you need? If Drug A works at $5$ mg and Drug B works at $500$ mg, Drug A is more potent. It is measured by the $ED_{50}$ (the dose required for a $50\%$ response).
Efficacy: How well does it work? This is the maximum effect ( $E_{max}$ ) a drug can produce, regardless of how much you give.
Note: High efficacy is usually more important than high potency.

8. THE MARGIN OF SAFETY (THERAPEUTIC INDEX)

We want to know how far the "helpful dose" is from the "deadly dose."

The Formula:
$\text{Therapeutic Index (TI)} = \frac{TD<em>{50} \text{ or } LD</em>{50}}{ED_{50}}$
Interpretation:
- $ED_{50}$ : Effective Dose for $50\%$ of people.
- $TD<em>{50} / LD</em>{50}$ : Toxic or Lethal Dose for $50\%$ of people.
- A Large TI is safe (it takes a huge mistake to cause harm).
- A Small TI is dangerous (the dose that heals is very close to the dose that kills).