Pharmacodynamics: Drug Effects and Mechanisms

Pharmacodynamics

• Pharmacodynamics refers to the effects of a drug on the body
• This involves the drug's mechanism of action, affecting receptors or non-receptors
• Pharmacological effects can be intended (therapeutic uses/indications) or unintended (adverse effects)
• Example: Drug A lowers heart rate and blood pressure
  • Therapeutic uses include treating hypertension and tachycardia
  • Adverse effects can include hypotension and bradycardia

Drug Receptor Interaction

• Drugs interact with receptors as full agonists, antagonists, partial agonists, or inverse agonists

Full Agonist

• A full agonist interacts with a receptor with both affinity and efficacy, leading to a pharmacologic effect
• Norepinephrine binds and activates beta-1 adrenergic receptors, increasing heart rate, as an example

Signaling Mechanisms for Receptors

• After a drug binds to a receptor, a signal transduction cascade occurs, leading to a cellular response

Types of Signaling Mechanisms

• Ligand-gated ion channels
  • Cause very fast responses
  • Involve ions like Na+ influx causing depolarization, or Cl- influx/K+ efflux causing hyperpolarization
• G protein-coupled receptors
  • Cause fast responses
  • Use cAMP, PLC as a second messenger
• Enzyme-linked receptors use protein phosphorylation for slow responses
• Intracellular receptors
  • Cause very slow responses
  • Directly alter gene expression

Graded Dose Response Curve (Quantitative)

• This curve illustrates the degree of response to an agonist in relation to the log of the dose
• Efficacy (Emax) is the maximal effect a drug can produce
• Potency is assessed by ED50 (EC50), the dose that produces 50% of the maximal response
• A lower ED50 indicates a more potent drug, but potency does not always mean effectiveness
• Efficacy is generally more important in clinical situations
• A graded dose response curve is quantitative

All/None Dose-Response Curve (Qualitative)

• This curve shows the percentage of patients who respond to a drug versus the log of the dose
• ED50 in this context is the dose that cures 50% of cases
• LD50 is the lethal dose that kills 50% of animals
• The therapeutic index (TI) is calculated as LD50/ED50
• A larger therapeutic index indicates a safer drug
• Drugs with a narrow therapeutic index include aminoglycosides, anticoagulants, hypoglycemic agents, lithium, theophylline, and tricyclic antidepressants (TCAs)
• An all/none dose-response curve is qualitative

Antagonists

• Antagonists interact with receptors without activating them
• They inhibit the action of endogenous agonists and have affinity without efficacy
• Most drugs are antagonists
• Types of antagonists: pharmacological, chemical, and physiological (functional)

Pharmacological Antagonists

• Competitive antagonists compete with the agonist for the same recognition site
• Duration of antagonism depends on the relative plasma concentrations of agonist and antagonist
• Causes a parallel shift to the right in the log dose-response curve
• No change in Emax
• ↑EC50 of agonist (i.e.↓ potency of agonist)
• Noncompetitive antagonists bind irreversibly to the recognition site or allosteric site
• Duration of antagonism depends on the rate of turnover of the receptor molecules
• Causes a downward shift in log dose-response curve with ↓ in Emax (up to complete loss)
• Treatment for toxicity of competitive antagonists can include high doses of agonists
• Treatment for toxicity of noncompetitive antagonists can NOT include high doses of agonists

Chemical Antagonists

• Chemical antagonists work through direct chemical interactions
• Negative charges on heparin are neutralized by positive charges on protamine sulfate (heparin antidote)
• Antacids neutralize HCL in the stomach

Physiological Antagonists (Functional)

• One drug antagonizes the effect of another by acting on a different receptor to induce the opposite action
• 2-bronchodilator and alpha vasoconstrictor effects of epinephrine can antagonize H1-bronchconstrictor and vasodilator effects of histamine

Partial Agonists (Agonist-Antagonists)

• Affinity can be greater than, less than, or equivalent to that of a full agonist
• In absence of the full agonist: it activates the empty receptor, but with lower efficacy than that of a full agonist
• In the presence of the full agonist, it acts as an antagonist [↓Emax of full agonist]
• Buprenorphine is a partial agonist for opioid receptors:
  • Alone: it has analgesic effects but less than morphine (full Agonist)
  • In the presence of morphine it reduces morphine's analgesic effect [antagonist]

Inverse Agonist

• Inverse agonists produce a response opposite to the pharmacological effect of the agonist
• Some anti-histamines are and example

Receptor Cycling (Turnover) and Desensitization

• The number of receptors is not constant but the receptors are cycling (turnover)
• Chronic use of an agonist leads to increased receptor internalization and a decrease in the number of receptors (down-regulation)
• Chronic use of an antagonist leads to an increase in the number of receptors (up-regulation)

Non-Receptor Mediated Mechanisms

• Some drugs act on enzymes, like monoamine oxidase inhibitors (MAOIs) that prevent the destruction of biogenic amines (e.g. norepinephrine)
• Some drugs act on plasmatic membranes: Cardiac glycosides inhibit membrane-bound ATPase
• Some drugs act on subcellular structures: Microtubules: Colchicine disrupts microtubules inhibiting mitosis
• Some drugs act on the genetic apparatus: Anticancer drugs affect DNA synthesis or function.

Drugs Acting by Chemical Action

• Antacids neutralize HCL in peptic ulcers
• Citrates interact with calcium to inhibit blood coagulation
• Protamine neutralizes heparin by its positive charge in treatment of heparin overdose
• Chelation: capacity of organic compounds to form complexes with metals (chelates)
  • The chelate may become more water-soluble and easily excreted.
  • It is useful in treatment of heavy metal poisoning:

Examples of Chelators

• Ethylene diamine tetra acetic acid (EDTA) chelates lead & calcium.
• Dimercaprol (BAL) chelates arsenic, gold & copper.
• Penicillamine chelates copper in Wilson's disease.
• Desferrioxamine chelates iron and is used in iron toxicity.