2. Agonists/Antagonists Flashcards
Agonist
Promote normal cell signaling process by mimicking natural chemical and enhance cellular activity
Antagonists
Most drugs
Interact at same site as natural chemical and inhibits signaling pathway
Agonists Actions
Activates receptors in physiological systems so the drug mimics physiological activation
Epinephrine
Agonist
Activates beta receptors in the heart causing increase in HR and force contractions
Also has an affinity for alpha receptors in the SNS causing vasoconstriction in large arterial smooth muscle resulting in increase BP
Epi - non-selective effect on SNS alpha and beta receptors
Antagonist actions
Block receptors or enzymes in physiological systems
Drug effects are in the OPPOSITE direction of normal physiological response
Metoprolol
Beta receptor antagonist in SNS so effects are decrease HR
Does not allow norepinephrine to bind at its normal receptor
Norepinephrine normally causes increase HR
Atropine
Acetylcholine antagonist - inhibiting an inhibitory process
Will bump acetylcholine off acetylcholine receptors that normally do not let signal proceed- decrease HR
Through bumping them off signaling pathway continues:
Cause Increase HR
Benzodiazepines
GABA agonist
More neuron inhibition
Feel relaxed and sleepy
Flumazeneil
Used for benzodiazepine overdose
GABA Antagonist - does not let chloride enter the cell, therefore nerve fires and wakes people up
Net effect: increase neuron firing, wakes people up
Can cause seizures
Antagonist Actions not always “net negative effect”
Some physiological systems when activated results in a decrease in end organ effects
Antagonist to an inhibitory process: Inhibiting an inhibitory process causes other processes to up regulate -increase HR
Ex: in PNS acetylcholine is naturally occurring agonist
Atropine is an acetylcholine antagonist so it would cause:
Acetylcholine is a naturally occurring agonist-inhibit signaling pathways in heart leading to decrease HR
So atropine is Inhibiting an inhibitory process to up regulate other processes
Increase HR
GABA Receptors in the Brain
Inhibitory signaling pathway - when receptors are activated they inhibit signaling processes
When enzyme binds to GABA receptors causes hyperpolarization - more Cl- into the cell and inhibiting nerve from firing (net negative nerve firing)
Ex: alcohol, benzodiazepines (agonist with net negative effect)
Enzyme Inhibition
Drug that binds to enzyme site and prevents physiologic process
Angiotensin
NORMAL :Substrate binds to Angiotensin Converting enzyme to convert angiotensin I to angiotensin II
DRUG: Lisinopril - binds to angiotensin converting enzyme in the same was angiotensin I would bind, preventing angiotensin I from binding and now Angiotensin I is not converted to Angiotensin II- lower BP
Non-Competitve Inhibiton
target site on enzyme that changes conformation of enzyme and now less likely substrate will want to bind
Competitive Inhibiton
Lisinopril example with Angiotensin
Interferes with active site so substrate cannot bind
Stereochemistry
Orientation of drugs and how they fit into receptor site determines how likely they will bind- usually 50/50 mixture
S-Left side
R-Right
S-Omeprizol = one enantiomer more effective/potent
Full agonist
The more drug you give the greater the effect until you reach a plateau - full effect
Narcotics = more drug higher response
Partial Agonist
Interact at same receptor site as full agonists, but do not give same effect as other medications in that class would even as drug concentration increases
Buprinorphine - used to treat pain, causes decreased effect (saboxone) used to treat opioid addiction. If people take it they do not get same high as oxycodone (full agonist)
Mg-mg of full and partial agonists the effects are much less in partial agonists
Can stay at receptor and prevents other opioids from binding
Sensitization or Up-Regulation of Receptors
- Prolonged or continued use of receptor antagonist
More receptors pop up on cell and increase receptors for natural compounds/medication
- Can develop over months to a year
Desensitization or Down-regulation of Receptors
- Prolonged or continuous use of receptor agonist
Receptors become internalized because of the prolonged stimulation
“Medication not working well anymore”
2 can develop over months to a year
Drug Tolerance
Risk of tolerance depends on drug, potency, dose, chronicity of use, individual variability and physiological system involved
Drug Tolerance in Agonists
Prolonged use of agonists leading to a down-regulation of receptors result in a DECREASED effect of the agonist drug at the chronic dose
Drug tolerance in Antagonists
Prolonged use of antagonists leading to up-regulation of receptors result in DECREASED effect of the antagonist drug at the chronic dose
Cross-Tolerance
Occurs with drugs that affect similar receptors
EX: benzo and alcohol bind to same receptors so it benzos have decrease effect
Drug Withdrawal
Abrupt cessation of drugs to which tolerance has developed
Withdrawal effects are the opposite of the original effects of the drug in the system due to receptor adaptation (down/up regulation)
Different from addiction - addiction is seeking the drug based on euphoric feeling
Not all tolerance = addiction, tolerance occurs over months addiction usually faster
Withdrawal after down regulation (agonist)
Benzodiazepine on GABA receptor in brain:
Benzodiazepine is overstimulating the receptors so some will become internalized and the patient does not get same relaxed feeling and has other regulatory molecules dominating exciting other neurons
Causes: anxious feelings
Withdrawal after up regulation (antagonist)
NORMALLY: Metoprolol wants to lower HR - binds to beta-receptors on heart blocking epinephrine from binding - inhibiting physiological pathway
After time body does not like HR being that low and will up regulate more receptors and now more places for epinephrine to bind and allow physiological process to move forward and HR increases
Drug Dose-Response Relationships
Drug response is logarithmic so as you increase the dose it effects will eventually plateau - there are only so many receptors for drug to bind
increasing dose will not increase efficacy could cause adverse side effects and toxicity
Therapeutic Effects
Pharmacological effect of drugs used to treat disease state
Side effects
Pharmacological effects other than intended to treat disease
EX: dihareia from metformin
Adverse Drug Reactions
Side effects significant enough to warrant a change in dose or discontinuation of medication
Lisinopril - constant cough
Toxic Effects
Predicative side effects that are severe and indicative of too high a dose or concentration of the dug
Narcotics- stop breathing
Idiosyncratic Side effecrs
Generally unpredictable, non-dose related and related to an immune system response
EX: skin rash, anaphylaxis
Hydralazine (antihypertensive medication) causing Lupus
Solution: discontinue medication and document as an allergy
What determines drug dose?
Looking to optimize the effect based on 50% of targets bound
Balancing efficacy and side effecrs
Drugs lose selectivity at higher concentrations
More drug acting at different sites cause unintended side effects
Potency
Used to describe concentration of the drug (in relation to other drugs or the endogenous conmpound) to achieve the same effect
Higher the potency = lower the drug dose
Potency is influenced by molecular chemistry and bond interactions
Therapeutic Indec
Drug Safety!
TI = 50% therapeutic effect/ 50% toxic effect
Large TI= monitor less frequently, safer
Small TI= monitor more frequently
Drug-Drug Interactions
Effects of two drugs or more that increase or decrease the actions of one or another
Pharmacokinetics Drug-drug Interactions
One drug inhibits the breakdown of another medication
More common
Pharmacodynamic Drug-drug interactions
Stimulate same receptors
Ex: benzo and alcohol
Ace inhibitor
Alpha blocker = net benefit of decreasing BP, but do not work on same mechanism
Additive effects of drugs
(1+1=2)
Give 2 blood pressure lowering medications
Synergistic Effects of Drugs
(1+1=4)
more pronounced effect from medication
2 antibiotics that work together - more drug killing when given together than if were given individually
Drugs that antagonize each other
Some medications when given together cause effects that mitigate each other or decrease effectiveness of other drugs
Pharmacodynamics response, not at the same receptor- multiple signaling molecules or receptor cause the same physiologic response
Pseudoephedrine and patients taking BP lowering medications
Drugs that antagonize each other
pseudoephedrine - increases BP and HR
With patients taking BP lowering medication who take pseudoephedrine their BP and HR will increase
Causes of variability in Drug Response
- Body weight and size
- Age and sex
- Genetics- pharmacogeneitics
- Conditions of health
- Placebo effect
Causes of variability in drug response (pharmacokinetics)
- Dose formulation, route of administration
- Drug tolerance from repeated administration
- Drug interactions
