Pharmacodynamics: Drug Action & Mechanisms

Pharmacodynamics Definition

• Pharmacodynamics examines what drugs to do the body
• It studies the effects of drugs and their mechanisms of action within the body
• This is distinct from pharmacokinetics, which studies what the body does to the drug

Targets for Drug Action

• Drugs affect physiological function in a specific way
• Most drugs are effective because they bind to target proteins, including enzymes, carriers, ion channels, and receptors

Principles of Drug Action

• Stimulation involves increasing activity, like epinephrine increasing heart rate
• Depression involves reducing activity, like benzodiazepines depressing the central nervous system (CNS)
• Irritation involves causing irritation, like bitter substances increasing salivation and gastric irritation
• Replacement involves replacing a deficiency, such as insulin in diabetes mellitus (DM)
• Cytotoxic action involves being toxic to cells, such as drugs targeting microorganisms or cancer cells

Drug Mechanism of Action (MOA)

• Physical action examples includes bulk laxatives
• Chemical action examples include antacids such as Al(OH)3
• The mechanism of drugs involves mimicking or blocking endogenous agents that act on ion channels
• Enzymes mediate drug inhibition, this might be competitive or non-competitive eg neostigmine & AChE, or aspirin and cyclooxygenase
• The mechanism of action of drugs can also involve affecting receptors; epinephrine on beta receptors on the heart

How Drugs Work

• Drugs work by activating proteins, binding to receptors and eliciting a tissue response
• Other drugs work by antagonizing, blocking, or inhibiting proteins
• Some drugs work by binding to receptors without producing a tissue response, and preventing an agonist from binding
• Some drugs have unconventional mechanisms of action, such as partial agonists that offer a less than maximal response
• Drug receptor interaction is affected by a drugs affinity and efficacy

Receptors - Affinity

• Affinity is the degree to which a drug can bind and remain bound to a receptor
• High affinity means a drug binds well and remains long enough to activate the receptor
• Low affinity means a drug binds less well and may not remain long enough to activate the receptor

Receptors - Intrinsic Activity/Efficacy

• Intrinsic activity/efficacy relates to the extent the drug activates the receptor
• Drug + Receptor = Drug-Receptor Complex -> Response

Drug Classification

• Drugs that act on receptors may be agonists or antagonists
• Agonists initiate changes in cell function by producing effects of various types
• Antagonists bind to receptors without initiating such changes

Agonist Classification

• Full agonist has high affinity and high intrinsic activity, leading to maximal efficacy
• Partial agonist has high affinity but low intrinsic activity with effectiveness less than maximal
• Antagonist has high affinity but no intrinsic activity

Drug Potency

• Potency is the amount or dose of a drug required to produce an effect of a given intensity
• Agonist potency depends on affinity (tendency to bind to receptors) and efficacy (ability to initiate changes once bound)
• Highly potent drugs evoke a larger response at low doses, while lower potency drugs evoke a smaller response at low doses

Spare Receptors

• Potent agonists can produce the maximum response at drug concentrations that dont occupy all available receptors
• Remaining unoccupied receptors are spare receptors

How Drugs Work by Activating Endogenous Proteins

• Agonists of Cell Surface Receptors include alpha-agonists and morphine agonists
• Agonists of Nuclear Receptors include hormone replacement therapy (HRT) for menopause and steroids for inflammation
• Enzyme Activators include nitroglycerine (guanylyl cyclase) and pralidoxime
• Ion Channel Openers include minoxidil (K) and alprazolam (Cl)

Dose-Response Effects

• A series of agonists may bind to the same receptor to produce the same maximal response
• To achieve maximal effect, a potent drug requires a small concentration
• Using the concentrations and the response produced, a dose-response curve can be created
• Dose-Response Curves are useful for differentiating agonists based on their potency and determining the Emax and ED50/EC50 of a drug

How Drugs Work by Antagonizing Cell Surface Receptors

• Reversible antagonists can unbind from the receptor
• Irreversible antagonists cannot unbind from the receptor
• Competitive antagonists compete with agonists for receptor binding sites
• Non-competitive antagonists exert an antagonistic effect without competing for occupancy of the receptor

Competitive Antagonism

• Competitive antagonism concentration of an agonist can be increased in the presence of the antagonist, resulting in a response from the tissue
• The dose-response curve progressively shifts to the right without a change in slope
• There is a linear increase in dose ratio with the concentration of the antagonist

Non-Competitive Antagonism

• Drug binds to receptor at allosteric binding site and stays bound
• Irreversible: cannot be removed (covalent bond) from receptor
• Produces slight dextral shift in the agonist DR curve in the low concentration range
• However, as more and more receptors are bound the agonist drug becomes incapable of eliciting a maximal effect

Tachyphylaxis and Tolerance

• Tachyphylaxis is when a drug's effect diminishes rapidly after repeated administration, typically within minutes
• Tolerance is the gradual decrease in responsiveness to a drug, which develops over days and weeks
• Mechanisms include change in receptors, loss of receptors, exhaustion of mediators, increased metabolic degradation, and physiological adaptation

Mechanisms of Tachyphylaxis and Tolerance

• Change in receptors involves those directly coupled to ion channels and second messengers, potentially through phosphorylation
• Loss of receptors involves receptors on cell surface becoming down-regulated and internalized through endocytosis
• Exhaustion of mediators involves depletion of essential immediate substances
• Increased metabolic degradation involves repeated drug administration causing lowered plasma concentrations
• Physiological adaptation is when homeostatic responses nullify a drug's effect

Effectiveness, Toxicity, and Lethality

• ED50 (Median Effective Dose 50): The dose at which 50% of the sampled population shows a given effect
• TD50 (Median Toxic Dose 50): The dose at which 50% of the population manifests a given toxic effect
• LD50 (Median Lethal Dose 50): The dose that is lethal to 50% of the tested subjects

Quantification of Drug Safety

• Therapeutic Index (TI) = TD50/ED50
• Therapeutic Index (TI) = LD50/ED50
• The higher the TI, the better the drug's safety profile because it indicates a larger margin between effectiveness and toxicity

Four Types of Receptors

• Receptors linked to ion channels, e.g. Nicotinic receptor
• Receptors coupled to G-proteins, e.g. Beta adrenoceptor
• Receptors linked to tyrosine kinase, e.g. Insulin receptor
• Intracellular or nuclear receptors, e.g. steroid receptor
• The rate at which drugs act depends on the type of receptor
• Each receptor type is unique based on its molecular structure, coupling, and effector components

Channel-Linked Receptors

• Also known as ionotropic receptors as they have similar structure to ion channels
• Involved mainly in fast synaptic transmission with ligand binding and channel opening occurring on a millisecond timescale
• Mainly found in the extracellular domain (cell membrane)
• Examples include nACh, GABAA, 5-HT3 receptors, Glutamate

Function of Channel-Linked Receptors

• Channel-linked receptors control the fastest synaptic events in the nervous system
• Receptors convert the binding of neurotransmitters into an electrical signal
• Binding of a neurotransmitter opens a pore for the NA+ or K+ ions to pass into cells
• Depolarization of the cell leads to the generation of an action potential
• There is a direct coupling between the receptor and the ion channel

G-Protein-Coupled Receptors

• G-protein-coupled receptors are also known as metabotropic receptors
• All comprise seven membrane-spanning segments (heptahelical)
• They are membrane receptors coupled to an intracellular effector system through a G-Protein
• G-proteins comprised of alpha, beta, and gamma subunits, where the alpha-subunit possessing GTPase activity
• Examples include mAChR, adrenoceptors, neuropeptide receptors, and chemokine receptors

G-Protein-Coupled Receptors - Second Messengers

• Cyclic Adenosine Phosphate (cAMP) and Inositol Triphosphate (IP3) are the principal second messengers
  • cAMP - binds results in activation or inhibition of adenylate cyclase, which catalyze cAMP to ATP
  • IP3 - controls the release of Ca2+ from intracellular stores
• Other second messengers include cGMP, Diacylglycerol (DAG), and Calcium ions (Ca2+)

Kinase-Linked Receptors

• These are receptors for various hormones like insulin and growth factors
• They have an intracellular domain that binds and activates tyrosine kinase when the receptor is occupied
• Kinase-linked receptors are mainly involved in cell growth, differentiation, and act indirectly by regulating gene transcription
• Signal transduction involves dimerization of receptors, followed by auto phosphorylation of tyrosine residues

Kinase-Linked Receptor Pathways

• Ras/Raf/MAP kinase pathway is important in cell division, growth, and differentiation
• Jak/Stat pathway is activated by cytokines and controls the synthesis and release of inflammatory mediators

Insulin Receptor Function

• Insulin receptor autophosphorylates
• Phosphorylated residues serve as docking sites for other proteins
  • IRS-1 binds, becomes phosphorylated, and recruits a kinase
• Recruited kinase (PI3 kinase) phosphorylates a lipid-soluble target PIP2, generating PIP3

Intracellular/Nuclear Receptors

• These receptors are located in the nucleus
• Ligands must first enter cells, because it only works with lipophilic compounds
  • Steroid hormones, thyroid hormones, vitamin D, and retinoic acid
• Receptors consist of a conserved DNA binding domain attached to variable ligand-binding and transcriptional control domains
• DNA-binding domains recognize specific base sequences, that promote or repress particular genes
• Effects are produced because of altered protein synthesis

Intracellular/Nuclear Receptor Structure

• Contains two loops of about 15 residues each (zinc fingers), knotted together by a cluster of 4 cysteine residues surrounding a zinc atom
• Hormone-binding domains lie downstream of the central region, with the upstream containing variable regions responsible for gene transcription
• Initiates patterns of protein synthesis and physiological effects

Pharmacogenomics

• Pharmacogenomics is the study of influence of an individual's genetic makeup on their response to therapeutic drugs
• This includes the role of genes on drug response