Pharmacodynamics: Drug Action & Receptors

General Principles of Pharmacology: Pharmacodynamics

• Studies how drugs affect the body.
• Examines the influence of drug concentrations on their effects.

Definition of a Drug

• Any substance capable of altering biological functions through its chemical actions.
• Specifically targets receptors in the body.

Receptor Interactions

• Receptors are crucial cell components that interact with drugs, leading to various effects.
• Some drugs can exert effects without binding to receptors.

Drug-Receptor Interaction Specifics

• Receptors are located either outside or inside cells.
• Primarily proteins.
• This interaction is highly specific.

Lock and Key Model of Drug Action

• Receptors exist in either an inactive or active state.
• Receptors naturally tend toward an inactive state.
• Agonists activate receptors, leading to an active state.
• Antagonists bind to receptors, resulting in an inactive state.

Ligands and Their Function

• Ligands are molecules that bind to receptors, playing a key role in cellular signaling and function.
• Many drugs mimic or inhibit natural molecules that control ion flow across cell membranes.
• Upon binding, ligands can activate receptors, inhibit receptor activations, or induce partial activation.

Inert Binding Sites

• Molecules that bind to drugs but don't regulate.
• Do not produce detectable effects.
• Can influence drug distribution by altering the amount of free drug in circulation.

Non-Receptor-Dependent Drugs

• Antacids, such as those used to neutralize stomach acid for heartburn rely on non-receptor actions.
• Sodium bicarbonate treats metabolic acidosis.

Osmotic Agents

• Interact with water molecules to modify fluid balance from low to high concentration.
• Mannitol acts as an osmotic diuretic to draw water out of tissues for edema.
• Lactulose serves as an osmotic laxative to promote bowel movement.

Chemical Antagonists

• Interact directly with other drugs to negate their effects, instead of interacting with a receptor.
• Protamine neutralizes heparin by ionic binding.
• Deferoxamine treats iron overdose.
• Penicillamine treats copper toxicity.
• N-Acetylcysteine treats acetaminophen overdose.

GABAa Receptors and Chloride Ions

• GABAa receptors are linked to chloride ions, causing hyperpolarization.
• Chloride leads to GABAa-induced polarization.

G Protein-Coupled Receptors (GPCRs)

• Also known as metabotropic or 7-transmembrane receptors.
• Receptor polypeptide "snakes" across the plasma membrane seven times.
• A three-step signaling process: ligand binding, G protein activation, and triggering of cellular response.

G Protein Activation

• Activates intracellular second messengers like cAMP, IP3, and DAG.
• These second messengers facilitate reactions to initial signals.

Role of Gs Proteins

• Activates adenylyl cyclase to produce cAMP.
• cAMP mediates hormonal responses like increased heart rate and contraction, smooth muscle relaxation, glycogenolysis, lipolysis, water conservation, and calcium homeostasis.

Role of Gq Proteins

• Activates phospholipase C to produce IP3 and DAG.
• IP3 releases calcium ions.
• Calcium functions as a messenger in muscle contraction, cell growth/division, and other cellular processes.

Role of DAG

• Activates protein kinase C (PKC).
• PKC regulates gene expression, cell growth, and differentiation.

Role of Gi Proteins

• Inhibits adenylyl cyclase.
• Prevents cAMP production.

Ligand-Gated Ion Channels

• Referred to as "Ionotropic Receptors".
• Ions transit into/out of the cell via doors/gates.
• A ligand opens the doors.
• Nicotinic receptors associate with Sodium.
• Sodium causes Nicotine and also, Depolarization.

Enzyme-Linked Receptors

• Catalytic Receptors.
• Activation causes protein-adding (phosphorylation).
• Switch for proteinic function performance.

Catalytic Tyrosine Kinase

• Possess Tyrosine Kinase Acitivity as a structural component.
• Receptors self-phosphorylate and other proteins.
• Triggers cellular function cascades (growth, division, survival etc.).

Intracellular Receptors

• Gene transcription linked.
• Exists in cytoplasm/nucleus.
• Ligand requires lipid solubility.
• Include Steroid and Thyroid hormones.
• DNA transcribes to RNA.
• RNA translates to Proteins.
• Examples: Glucocorticoids, Mineralocorticoids, Androgen, Estrogen, Progesterone, Vitamin D, Thyroid Hormone.

Receptor Regulation

• Downregulation decreases receptor numbers
• Continuous cell exposure to signaling molecule i.e. drug/hormone
• Protect over-stimulation.
• Receptors get destroyed, may lead to tolerance.
• Examples:
  • Opioid continuous use leads to downreglation requires a higher dose.
  • Agonist is over-exposed.
  • Reduced response/Desensitized
• Upregulation increases receptors numbers.
• Low exposure to the antagonist.
• More receptors on the membrane.
• Cells become sensitive to a drug and resistant to antagonists.

Graded Dose-Response Relationship

• Shows the relationship between dose and effect until all receptors are occupied.
• Increasing the dose does not increase the effect.
• EC50 is the effective concentration.
• Lower EC50 indicated a more potent drug.

Drug Efficacy

Efficacy reflects effect strength when bound to a receptor. Complexes are formed by drugs interacting with receptors.

Maximum Efficacy

All receptors are occupied. No additional increase in response with high concentrations.

Affinity and Intrinsic Activity

Affinity denotes the ability to bind. The ability to generate Biologic/Biochemical events leads to an effect.

Functional Agonists

Producing a strong mimic maximal responses.

Partial Agonists

• Drugs that bind to a receptor, but effect isn't maximal.
• Agonist of the full agonist is antagonized.

Inverse Agonists

• Binds to cause inverse effects
• Stabilize inactive receptors, active to inactive.

Antagonists

Does not affect receptors. Prevents Agonists from binding. Does not affect a receptor in the absent of an agonist.

Competitive Antagonists

Reversible manner of both antagonist, and agonists. Overcome inhibition with higher agonist concentrations, has higher EC50.

Irreversible Antagonists

Agonists don't counteract effects in Non-competitive.

Allosteric Antagonists

Alters the receptor site to change the agonist binding site. Decreases receptor efficacy/Emax despite being bound by an agonist.

Functional Antagonists

Antagonists act on a separate receptor, creating an opposing effect of the agonist. Example: Epinephrine inhibits Histamine Bronchoconstrictor.

Quantal-Dose Response Relationships

• Quantal events follow an all-or-none response.
• Dose-response relates between drug and proportions that respond.
• Curves determine doses for the populations.
• ED50 reflects therapeutic responses in populations.
• Potency relies on effects in settings that are controlled.

Therapeutic Index

Like a safety zone to determine if too much medicine. Therapeutic index describes dose produces toxicity/desired response.

Nervous Systems

• The Brain & Spinal cords
• Activity Integrates, Responsivity initiates, and individuals are made.

Peripheral Nervous System

• Neurons exists outside and inside of the spinal cord/brain.
• They are involved in sending, receiving, and relaying.
• Can be either Sensory (afferent picks up) or motor.
• Motor systems include somatic (skeletal) and Autonomic- Involuntary (digestion, heart beating etc.).
• Parasympathetic/Sympathetic are Autonomic.

Neuron Anatomy

• Axons transmit impulses, while dendrites will receive these among others.
• End structures release neurotransmitters.
• Synapses are a junction

Synapse

• Point where two neurons come face to face.
• Neurotransmitters (i.e. Dopamine & Serotonin etc) are transmitted (NT:s)
• Presynaptic membranes contain Synaptic Vesicles, and presynaptic receptors that are inhibitory and linked to Gi; Vesicles store Neuro Synaptic Transmitters (NTSs).
• Presynaptic Synapses transmit signals, NTSs are metabolise, and receptors are present in both.
• Vesicles are released by exocytosis upon activation by Calcium.
• Calcium can cause Action potentials through release of NTS.
• In addition, Synaptic receptors can recycle them with reuptake, and use enzyme degradation, creating small gaps.

Ganglia

• Cell cluster with traffic lights, serves as a hub station to process NTSs
• Cell transmits, relays and is intermediaries, it regulates functions like digestion etc. and co-ordinates communication.