pharmacodynamics I-II

• 1. histamine receptors-excess production of the agonist histamine caused JL's symptoms which stimulated this family of receptors; adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors
• 2. overstimulation of receptors or pathways--excess of histamine in JL's case
• 3. binds to adrenergic receptors?
• 4. competitive antagonist?
• 5. adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors

• biological macromolecules that reside in the plasma membrane, or intracellular compartment
• a receptor activates a particular pathway, enzyme, or protein within the cell, when it senses a signal
• histamine receptors--excess production of the agonists histamine cause JL's symptoms, which stimulated this family of receptors
• Adrenergic receptors--the "D" in JL's fexofenadine D acted via these receptors
• the signal molecule is generally called a ligand or agonist

the signal molecule

is a system, pathway, enzyme, or molecule that is activated in response to receptor binding, and intiates a response witin a cell

• activates calcium channels
• activates adenyl cyclase
• increases cAMP

• activates potassium channels
• inhibits adenyl cyclase
• decreases cAMP

inhibits calcium channels

• activates phospholipase C
• raises IP3 levels in the cells
• increases intracellular free calcium
• increases DAG
• activates PKC

interacts with many different ion transporters

• Receptors and signaling pathways:
• neurotransmitters (glutamate, serotonin)
• insulin and other growth factors
• histamine
• hormones (glucocorticoids, estrogen)
• adernegic receptors
• opiod receptors
• Enzymes:
• cholinesterase
• cyclooxygenase
• monoamine oxidase
• DNA topoisomerase
• other macromolecules:
• transport proteins
• membrane lipids
• nucleic acids
• antibodies
• new generation drugs
• ion channels:
• calcium channels
• potassium channels
• sodium channels
• water channels

• drugs exert their effects by interacting with endogenous receptors and/or target molecules
• receptor interactions
• receptor interactions coordinate cell/organ/system function, using endogenous ligands
• many drugs interat with these receptors as their mechanism of action
• there are no specific "drug receptors"--receptors bind endogenous ligands
• drugs utilize these receptors and "mimic" endogenous ligands to exert their pharmacologic effects
• in some cases (opiods, anadamide) we knew about the drug before we knew what the endogeous ligand was !
• some classes of drugs interact with target molecules that are not receptors, per se. (i.e. antacids, enzyme inhibitors, others)

• activation of specific ion channels change ion gradients, which is used to alter diverse body functions
• contraction/relaxation of vascular smooth muscle to regulate blood pressure
• contraction of skeletal muscle
• secretion of insulin by the pancreas
• ion channels are classified by how they are gated (regulated)
• activation by ligand binding-ligand gated ion channels
• activation by voltage changes across the membrane--voltage gated ion channels
• activation by second messenger systems--second messenger gated ion channels
• ion channels are generally specific for a given ion

• many drugs have enzymes as their targets
• drug either activates or inhibits the enzyme
• examples:
• cyclooxygenase--synthesizes inflammatory mediators, inhibited by aspirin
• monoamine oxidase--degrades amine neurotransmitters, target of the antidepressent seligilene
• cholinesterase--degreades acetylcholine at the synapses, target of the AD drug, donepezil
• DNA topoisomerase-target of the antibiotic ciproflaxcin

• drug targets may include structural proteins, such as tubulin the target for antineoplastic drugs
• drug targets may include circulating proteins, such as Omalizumab, an antibody to IgE
• drug targets may include molecular transporters, such serotonin reuptake systems, the targets of some of the new antidepressants
• new drug targets are being found every day
• the science or target identification and validation
• currently sought after targets include
• new targets for alzheimer's
• new targets for parkinson's disease
• new targets for cancer
• nanopharmaceuticals

• interaction of drugs with targets can have a testing impact on a cell due to innate cellular mechanisms that prevent overstimulation
• tachyphylaxis:
• drug effects diminshes with time
• homologous--only 1 type of receptor affected
• heterologous--multiple receptor types are affected, possibly due to converging second mesenger or effector systems
• receptor inactivation
• receptor looses ability to respond to stimulation
• beta adrenegic receptor is phosphorylated and inactivated after repeated stimulation
• down regulation
• decrease in the number of receptors, increase in degradation rate, decrease in synthesis
• the beta adrenergic receptor is also down regulated with repeated stimulation
• refractory receptors
• after a receptor is stimulated, a period of time is required before the next interaction can produce an effect
• voltage-gated sodium channels in neurons have a refractory period

• a single ligand/receptor complex can "turn on" many G proteins
• multiplies original signal
• a single activated G protein can persist in activated state, often for a longer time period than the ligand is bound to the receptor
• because of this prolongation and amplification, only a fraction of the total number of receptors for a specific ligand need to be occupied to produce a maximal effect in a cell
• the pool of receptors that are unstimulated are "spare receptors"
• insulin receptor--99% of a given cell's insulin receptors are spare
• only 1% required for maximal response
• large functional reserve to ensure that adequate amounts of glucose enter the cell
• the heart--only 5-10% of the beta adrenergic receptors are spare
• 90-95% are used for maximal response
• almost all receptors need binding for maximum contractility
• little functional reserve here, important for the failing heart

is the concentration of ligand that causes 50% receptor occupancy

a measurement of the amount of drug necessary to produce an effect of a given magnitude

potent

the "effective concentration needed to achieve a 50% maximal response

the maximum achievable response to a drug

is the drug dose which 50% of the patients exhibit a response, and 50% of the patients do not exhibit the response

lethal dose 50 the drug dose that kills 50% of patients

toxic dose 50 the drug dose that causes toxicity in 50% of patients note,, there may be series of TD50 for a single drug, one for each different toxic response

a range of doses (concentrations) of a drug that elicit a therapeutic response, without unacceptable side effects (toxicity)

therapeutic window is quantified by this

• binds reversibly to the active site of a receptor or drug target, and inhibits agonist binding
• an antagonist does not produce the conformational change necessary for receptor activation
• an antagonist maintains the receptor in the inactive state
• the presence of a competitive antagonist reduces the potency of an agonist
• the efficacy is not affected (antagonist can always be "competeted away" by more agonist)
• competitive antagonists shift the dose response curve to the right
• ex. antihistamine and pravastin

• may bind to active site or allosteric site
• binding is strong--may be irreversible and with high affinity
• cannot be "competed" away with high concentrations of agonist
• the presence of a competitive antagonist reduces the efficacy of an agonist
• noncompetitive agonists remove receptors from the available pool, hence the reduction in efficacy
• ex. aspirin and clopidogrel (plavix)

• binds to a receptor at the active site, but produces only a partial response
• in the presence of a full agonist (or endogenous agonist) the partial agonist reduces the maximum response
• acts somewhat like a competitive antagonist
• aka partial antagonists or mixed agonist/antagonist
• butyl and hexyl are full agonists with different potencies
• heptyl and octyl are partial agonists
• ex. pindolol