Pharmacodynamics (PD)

• PD


  Pharmacodynamics - the study of how drugs exert their effects on the body
• Pharmacodynamics

  Involves understanding the relationship between the concentration of a drug at its site of action and the resulting effect on the body
• 4 main types of drug targets

  • Receptors
  • Ion channels
  • Carriers/transporters
  • Enzymes
• Receptors

  Proteins on the surface or within cells that drugs bind to, triggering a response. Where the drug is received
• Receptors


  • Beta-adrenergic receptors targeted by beta-blockers like metoprolol for heart conditions
• Receptor types


  • Ligand gated ion channels
  • G protein-coupled receptors
  • Kinase-linked receptors
  • Nuclear receptors
• Ligand gated ion channels

  Drugs binds to the receptor which changes the polarisation of the cell which results in a cellular effect. Takes milliseconds
• G protein-coupled receptors

  When a drug binds to a receptor it activated G proteins which cause changes in ion channels or enzymes which leads to an effect in the cell. Seconds
• Kinase-linked receptors

  Binds to a receptor leads to protein synthesis and cellular effects. Hours
• Nuclear receptors


  Drug goes through the nucleus and then binds to a receptor which then leads to cellular effects. Hours
• Ion channels


  Proteins that regulate the flow of ions (e.g., sodium, potassium) across cell membranes
• Ion channels


  • Voltage-gated sodium channels targeted by local anesthetics like lidocaine to block pain signals
• Carriers/transporters


  Proteins that transport molecules across cell membranes
• Carriers/transporters


  • Solute carrier family (SLC) transporters targeted by antiviral drugs like valacyclovir to enter cells and inhibit viral replication
• Enzymes


  Proteins that catalyze biochemical reactions in the body
• Enzymes


  • Acetylcholinesterase targeted by acetylcholinesterase inhibitors like donepezil to increase acetylcholine levels in Alzheimer's disease
• Agonists


  Drugs that bind to receptor to produce a cellular response mimicking the action of an endogenous (produced within the body) ligands. Enhanced cellular activity (all receptors are activated)
• Affinity


  Ability to bind to the receptor
• Efficacy


  Ability to activate receptor once bound (response)
• Need both affinity and efficacy to cause an effect
• Partial agonists


  Drugs that are only partly effective as agonists
• Potency


  The amount of drug needed for a response. Higher potency = less drug needed for a response
• Selectivity


  • The degree to which a drug achieves an intended action relative to other actions
  • Describes the ability of a drug to affect a particular target population
  • No drug is 100% selective - trying to increase dose to increase selectivity is dangerous
  • Higher doses can lead to side effects and actions to take place in unintended areas
• Antagonists


  Drugs that bind to a receptor and prevent receptor activation by a natural ligand (e.g., beta blockers) blocks the receptor, blocked cellular activity. Good affinity but no efficacy = no response
• Reversible antagonists


  Reversible antagonists bind to receptors through non-covalent interactions, such as hydrogen bonds or Van der Waals forces. They compete with agonists for binding sites and can be displaced by increasing the concentration of the agonist
• Irreversible antagonists


  Irreversible antagonists form covalent bonds with receptors, creating a permanent or long-lasting bond that cannot be easily broken. Once bound, they cannot be displaced by increasing the concentration of the agonist
• Adverse drug event


  • Any injury resulting from medical intervention relating to a drug
  • Occurs when a person is taking the medication but is not necessarily due to the drug
  • Includes medication errors and adverse drug reactions
• Adverse drug reaction


  • Any response to a drug which is: Noxious (harmful), Unintended but expected (side effects), Occurs at doses normally and appropriately used in humans for prevention, diagnosis or treatment of a disease
  • Type A: Pharmacological effects that are predictable and dose dependent (e.g. side effect, toxicity, drug interactions)
  • Type B: Hypersensitivity reactions that are unpredictable and not dose dependent
• Types of ADRs


  • Allergy - adverse effects involving the immunological system
  • Side effect - any unintended effect occurring at doses normally used and is related to the pharmacological properties of the drug
  • Drug interaction - interaction with another medicine causing variation in its pharmacological effect. May increase or decrease a medicines effect.
  • Intolerance - a lower threshold to the normal pharmacological action of a drug
  • Toxicity/overdose - dose related, usually occurs by same mechanisms as therapeutic effect
• Types of drug interactions

  • Pharmaceutical interaction - compatibility (chemical interactions of drugs)
  • Pharmacokinetic interaction - absorption (normally food interactions), distribution (including protein binding), elimination (renal - competition for active efflux/tubular reabsorption), metabolism (cytochrome P450) of the drug
  • Pharmacodynamic interaction - antagonistic (reduced effectiveness; risk lack of effect, eg morphine and naloxond are used as an antidote), agonistic (increased effectiveness; risk of toxicity eg. Benzodiazepine and alcohol) direct/indirect
  • Physicochemical - drugs may not be compatible in intravenous mixtures, reduced solubility may prevent absorption, drugs may interact with inert excipients within a dose form, may de-stabilise dose forms, may render drug and dose form ineffective or possibly dangerous (e.g. particulate matter)
• Risk factors of ADRs and drug interactions

  • Age: Older adults may be more susceptible to ADRs due to changes in metabolism and organ function
  • Polypharmacy: Taking multiple medications increases the risk of interactions and adverse reactions
  • Underlying Health Conditions: Certain diseases or conditions can increase the risk of ADRs or interactions
  • Genetics: Genetic factors can affect how drugs are metabolized, leading to variability in response and risk of ADRs
  • Renal or Hepatic Impairment: Impaired kidney or liver function can affect drug metabolism and clearance, increasing the risk of ADRs
  • Drug Characteristics: Some drugs are more likely to cause ADRs or interactions due to their mechanism of action or side effect profile
  • Dose and Duration of Treatment: Higher doses or longer durations of treatment can increase the risk of ADRs
  • Patient Compliance: Non-adherence to medication regimens can lead to suboptimal treatment outcomes and increased risk of ADRs
  • Nutritional Status: Certain nutrients or dietary factors can interact with medications, affecting their efficacy or causing ADRs
  • Drug Formulation: Differences in drug formulations (e.g., extended-release vs. immediate-release) can affect drug absorption and metabolism, leading to variability in response and risk of ADRs