1. absorbed
2. metabolized in the liver
3. distributed to rest of the body
4. excreted in the kidney

• mediated by interaction with receptors
• non-receptor mediated effects

• antacids (chemical property)
• osmotic diuretics (physical diuretics)
• chelators (interaction with small molecule)
• some anticancer agents, replace or block normal metabolite

• form a drug receptor complex (DR), which allows it to have a response = protein + drug

• signal recognition- seletively binding of extracellular signal/drug
  • drug must be recognized by and bind to site on macromolecule (just like endogenous signals)
  • requires selectivity (distinguish signals at molecular level)
• signal transduction- transform binding into cellular changes
  • usually involves inh. of normal activity of macromolecular target
  • ex: drug acts at allosteric site, leading to alteration of activity of protein
  • only handful of different intracellular transduction mechanism

• endogenous signaling receptors
  • NT's, hormones, GF's, cytokines
• drug receptors (these proteins don't have endogenous EC signal that normally activates them)
  • enzymes
  • ion channels
  • transporters
  • DNA

• voltage gated sodium
• renal tubule sodium
• voltage gated calcium
• NMDA/Glu cation
• GABA gated Cl-
• K channels in pancreatic beta cells

USUALLY BLOCK ION FLUX THRU CHANNEL

• Na/K/2Cl cotransporter
• Na/K pump
• weak acid carrier (renal tubule)
• gastric proton pump

• biogenic amine vesicular uptake pump
• norepinephrine
• serotonin
• dopamine

• ion channels (usually inh.)
• ion pumps (usually inh.)
• inhibit enzymes
• block amine reuptake

• ability of receptors to distinguish subtle differences
• ex: distinguish catecholamines

• molecular level
  • drug + R = DR complex
• cellular level
  • biochemical or ionic changes
• organ/tissue level
  • physiological response
• whole body
  • integrated body response
• population level
  • varied response of individuals

• mass action
  • rate of formation of product (DR) is a function of the concentration of reactants
• reversible
  • no CB formed or broken
• equilibrium
  • allow reaction to reach steady stayte

• R_t = total receptors (free + bound receptors)
  • aka R + DR

DR/Rt = D/(D+Kd)

• K_d = conc. of drug that yields half occupancy of receptors aka k2/k1

• affinity- tightness of binding
  • measure by K_d
  • concentration units (lower K_d = higher affinity)
• capacity- population of receptors in system
  • measured by maximum binding (B_max = R_T

• shift to right = lower affinity
• shift to left = higher affinity

• direct control of ion channel (fastest R's)
  • ex: nicotinic R
• indirect (G protein) coupling via second messanger/ion channel (second fastest- seconds)
  • ex: muscarinic R
• direct control of effector enzyme (third fastests- minutes)
  • ex: insulin R using Tyr kinase R
• control of DNA transcription
  • ex: estrogen R

• amount of drug response proportional to amount of drug bound to target

• dose and time

Remember, drug disposition and pharmacokinetics are addressing the relationship between amount of drug and concentration of the drug at the site.

• relationship between concentration at site of action and response
  • learn dose-response (D-R) relationship

graded

quantal

• how much drug needed to yield response
• measured as EC₅₀ (dose that yields 50% effect)
  • low EC₅₀ means high potency
  • units are conc. (Molarity) or dose (mg/kg)

• activate R or system
  • endogenous signals are agonists
  • drugs that mimic endogenous signals

• measure of drugs effectiveness at producing a defined response
• on graded D-R curve, efficacy is determined by peak response
  • expressed as fraction or percent of maximal response

• drugs act via different mechanisms (ex: aspirin vs morphine)
• drugs act via same receptor system, but have different abilities to activate receptors in that system (ex: morphine vs. codeine)

• drug that inhibits/blocks effects of agonists
  • can be competitive or non competitive
  • endogenous antagonists are rare
• receptor efficacy is zero (but there is clinical efficacy)
  • effects of antagonist are only detected in the presence of an agonist

• decreased efficacy (seen on D-R curve as smaller slope)

• decreases potency (increase Kd)
• same efficacy

Can be overcome by increasing amounts of agonist. Most antagonists used clinically are competitive.

• drugs with efficacies greater than zero but less than one
• acts as agonist with a "ceiling effect"
• if in the presence of another agonist
  • partial agonist decrease effects of agonist, acting as competitive antagoist

• disposition
  • dose
  • time factors
  • physiological state
  • drug interactions
• receptor interactions (what happens when drugs reach target)
  • binding (higher binding affinity = higher potency)
  • intrinsic activity/receptor efficacy- ability of drug to activate receptor
• other
  • psyc.
  • pharmacogenetics
  • multiple receptors
  • receptor plasticity

• receptor subtypes
  • most NT's, hormones have many different R's
• drug selectivity (ex: antipsychotic drugs)
  • determines clinical profile, includes therapeutic effects and non-therapeutic effects (adverse/side effects)
  • most drugs act at many different R's as agonist or antagonists
  • different receptors can be coupled to different effector systems and be located in different tissues

• chronic overstimulation (continuous or repeated) leads to decrease response (desensitization)
  • tachyphylaxis- rapid occuring desensitization
  • tolerance- slower loss of response
• chronic understimulation leads to enhanced response (supersensitivity/sensitization)

• short term- nicotinic receptor
• long term- week long exposure to beta agonists

• down regulation- loss of receptors from the cell surface
  • can occur within minutes

• chronic exposure to beta antagonist (propranolol) causes upregulation of beta receptors
  • once antagonist gone from the system, enhanced response to endogenous agonist (can cause dangerous rebound)

• assess "all or none" responses
• determine selectivity of a drug for different responses
  • selectivity for multiple therapeutic responses
  • selectivity between the therapeutic response and a toxic response (margin of safety)
• valueable for showing biological variability of drug response
  • can yield info on genetic basis of drug mechanism

• determines receptor efficacy
  • assumes continuously variable response
• use in in vitro studies, isolated tissue

• dose required to produce a specified response in an individual
  • vary on individual sensitivity to drug
    • function of genetic differences in factors (ex: R function, met. enzymes)

• bell shaped curve
• shows variability in population drug sensitivity

• potency (same def. as with graded)
• safety margin
• biological variability and mechanism (steepness of curve and width of frequency)

• ratio between lethal and effective dose
  • ED₅₀- effective dose
  • LD₅₀- lethal
  • TD₅₀- toxic
• measured via therapeutic index
  • LD/ED (we want this to be high)

• steepness (cumulative  frequency distribution) and width (frequency distribution) of quantal DR curve
• slope varies dependent on molecular mechanism of drug effects caused by:
  • polymorphisms in expression and activity of various enzymes (ex: P450 enzymes)

• graph plotting those who responded at a given dose in addition to those who responded at lower doses