Lecture 1 - Sept 9 Flashcards
Pharmakon (ancient greek)
= drug, therefore study of drugs
What is a drug
a drug is a chmeical given to alter body function (so yes herbal medication and water (alters hydration state) count
Pharmacy
-pharmacy consists of preparation/dispensing/utilisation of drugs
Pharmacology (into 2 parts)
- pharmacodynamics (effect of drug on its site of action/body)
- pharmacokinetics (what the body does to drug to get it out of body)
drug receptor complex
-most drugs need to bind to a receptor to have effect
-receptor is a protein/glycoprotein that sits on a cell surface
Ligand
anything that binds to a receptor to elicit some sort of response
Affinity
strength of drug-receptor binding (how well a drug sits in a receptor, doesn’t tell you anything about what the drug does)
Affinity equation and Association/disosication Rate
-the binding of a drug to receptor occurs at a certain rate called the associate rate (K1)
-the rate of the drug letting go of its receptor is dissociation rate (K-1)
-affinity = K1/K-1
Drug-receptor complex
=a drug bound to its receptor
K1 vs K-1 Fast/Slow in relation to affinity
-high affinity = when a drug binds rapidly to a receptor and slowly dissosciates so K1 is fast, K-1 is slow
-low affinity = drug does not bind well to a receptro and dissosciates fast so K-1 is fast, K1 is slow
Drug/Receptor/Drug-Receptor Complex Equilibrium
-equilibrium between new drug binding and unbinding/dissosciating
-[D] + [R] <-> [DR]
Drugs with high rates of association and low rates of dissociation will have..
-lots of DR (drug-receptor complex)
-high affinity
Agonist
-agonist = drug that binds to its receptor and mimics effect as the natural ligand
-full agonist = drug elicits the full biological effect when bind to receptor (high efficacy)
-partial agonist = when a drug can only elicit part of the effect
Antagonist
-a drug that binds to a receptor and blocks it (prevents agonist from reaching its receptor)
-anatagonists bind to recpetors to block agonists, but antagonists are not activating the recpetor when they bind
Ligand vs Agonist
-ligand is any molecule that binds to a receptor
-an agonist is a type of ligand that activates the receptor to elicit a biological response
slide 24 pic
Drug Efficacy
-typically higher dose = greater effect
-drugs compete with bodys natural ligans for receptors so llikely more effective at high doses when drug outnumbers bodys ligans
minimal effective dose
-MED = smallest amount of drug given to produce effect (less side effects)
maximum doses
–highest amount of dose given wihout cause severe side effects
-adding more drug does not produce strongrt effect bceasue all receptors are occupied so no changes possible with higher dose
Desensitization
=continued presence of agonsit drug may reduce response to a drug
-prolonged adminsitration of oxytocin for augemntaion of labour may decrease response to oxytocin (increased risk of PPH)
-usually recpetors become less effective or fewer in number
Sensitization
continued presence of antagoisnt by increased number of receptors
-repeated exposure to drug = increased repsonse to it instead of diminsihed (like nicotine)
Withdrawal
group of symptoms that occur upon abrupt discontunitions of drug or rapid decrease in dose (infants born to drug users can have supressed breathing)
receptors changing
cell receptors are always being recyled and resynthesized so when a drug is given over a period of time, the number of receptors on cell surface can change in repsonse to the drug
The Dose Response Curve
describes acitivy of drug
-relationshup between drug dose and repsonse
-usually s shaped?
EC 50 (dose that gives half the maximal effect)
-determined in a laboratory
EC50
-effective concentration 50
-EC50 = drug concentration that gives half the maximal effect
Slide 29
A has highest affinity (least amount to get to EC50)
A has lowest EC50
A is the most potent (need less concentration on x axis to get high on y axis)
Potency
-get potency by comparing EC50s of drugs
-copares effective concentation of a drug in producing an effect with drugs acting in a simlar way
-potent drugs usually have a high affinity for the receptor (takes less drug to fill up the receptors because they bind well)
-more potent means less drug is needed for the same effect
slide 30
Potency vs Efficacy
-potency = amount of drug given to produce a certain efffect (comparison of EC50)
-efficacy = the maximum response (effect) produced by a drug
drug can be potent (requiring low doses to achieve an effect) but may not necessarily have high efficacy (not achieving a significant maximum effect) like a partial agonist
slide 31
-potentcy on x axis
efficacy on y axis
Antagonist examples
-antihistamines bind receptors and block natural histamines from binding (reduces allergic reaction)
-naloxone (NARCAN) blocks opioid receptros and reverse the actions of morphine sulfate, reducing respiratroy depression, analgesia, sedation
-beta blockers such as labetallol block actions of sympathic nervous system (reducs hypertension and increases bronchoconstrcition)
-beta blocker blocks epinephrine
slide 33 - agonsit has positive intrinsic activity and antagonsit has zero instrinsic activity (doesnt elicit response/theraputic effect and doesnt bind to receptor)
Types of antagonsim
- receptor based
-reversible (competitive or noncompetitive)
-irreveisble - physiological antagonism
Competitive Antagonism (receptor based)
-antagonist competes with other agonsits for receptor
-antagonist binds and unbinds from that receptor
[D] + [R] <–> [DR]
slide 35
non-competitive antagonism
-antagonist binds to a site other than the receptor but still keeps agonist from having an effect
-problem is that there isnt competition so treating an overdose is difficult
-ex. ketamin binds near N-methyl-D-aspartate glutamate receptors on nerve cells producing confusion and hallucinations
Irreversible Antagonism
-irreversible antagonist binds to a receptor and does not let go
-rate of breakdown at drug-rrecptr complex = 0
-its disscosication contant, k-1 = 0
-Kd is very low
-affinity is very higj
-example = carbon monoxide
-example = acetylsalicylic acid (ASA/APIRIIN) blocks COX enzyme irrevirable in platelts so decreased clotting for several days until new platelets are made, dont give aspirin week before birth of PPH
Physiological antagonism
-nothing to do with receptor site
-when one drug is take to counteract effects of another
-take coffee after drinking alcohol (caffeien wakes you up, ethanol reduces level of alertness)
-anaphylactic reaction is treated with both physiological and competitive antagonism (receptro based):
-epinephrine (adrenergic drug) to counter effects of histamine
-fast acting antihistamins given too
epinephrine
-activates beta 2 adrenegric receptors for bronchodilation
-activaes alpha adrenegric repceots to cause vasoconstriction (so less swelling and blood presure doesnt drop)
-reduces histamine release from mast cells and basophils
-increases heart rate and cardiac output
Dose response curve - quantal effects
-many repsonse to drugs are quantal - yes or no if headache is gone
-helpful in determining if drug has significant effect
-dose response currve constucted using the sums of those responding to treatment at increasing doses
-curve allows us to estimate ED50
ED50
-estimated dose 50%
-dose at which 50% of population will expereince effect
-from middle of dose response curve
ec50 vs ed50
-EC50 is lab setting
-ED50 is population setting
slide 42
side effects - dose response curves
-want to deliver therapeutic effect with least amount of toxicity
-dose response curves are not just for desired effects but also measure unwanted effects
-TD50 = dose required to produce a toxic effect in 50% of population
-td50 is in middle of curve
TD50
TD50 = dose required to produce toxic effect in 50% population
slide 44-45
fluoxetine is more effective becasue smalle dose is needed
-drugs are equally effacous
Theraputic window
-difference between dose of drug that is effective and the dose that causes unacceptable effect is important
-LD50 = dose of a drug is lethal to 50% of population
-difference between ED50 and LD50 is the therapeutic window for a drug (margin of safety)
-theraputic window = LD50-ED50
review slide 46-47
therapeutic index
-calculated by LD50-ED50 = therapeutic index
-the larger the TI, the safer the drug
-the TI isn’t a useful measure as we want to know when toxic effects occur, not just when drug is lethal
-drugs with low TI (same a a narrow therapeutic window) have only a small range of doses at which there are therapeutic effects without potentially fatal complications
theraputic index examples
most antibiotics have large TI (safe)
-vacomycin has low TI - neurotoxic and ototoxic (last choice for GBS)
-most antibiotics such as b-lactams, macrolides, and quinolones have a high TI and therefore do not require therapeutic drug monitoring
-BUT vancomycin has low TI as do the aminoglycoside antibiotics (gentamicin, tobramycin, etc)
-major form of toxicity: neurocity (usually reversible) and ototoxicity (often irreversible)
-vancomycin: last line of intrapartum GBS prophylaxis for GBS positive people with allergies to beta-lactams and resistance to clindamycin
-gentamicin: can be used to treat chorioamnionitis in mother and signs of infection in infant (align with ampicillin)
potency vs efficacy
Potency = how much you hate to give (dose/concentrations)
Efficacy = how well it can do the thing (turn on all the lights or half)
beta receptors
→ a beta-adrenoreceptor agonist stimulates beta receptors
→ a beta-adrenoreceptor blocker blocks the beta-adrenoreceptor
a receptor isn’t always on a cell surface
-newest NSAID such as rofecoxib (VIOXX) and celecoxib (celebrex) inhibit COX-2 but not COX-1 so would work better for inflation cause by arthritis
-a receptor isn’t always on a cell surface like adrenoreceptors are → instead drugs can work on transported molecules or enzymes
-ex. the enzyme cyclooxygenase (COX) is essential for production of prostaglandins, including those that mediate inflammation. To decrease inflammation, COX inhibitors are developed
-2 COX isoforms (similar protein but different amino acid sequence): COX-1 is constitutive and active in physoli response, whereas COX2 is induced by inflammatory stimuli
COX production is inhibited by NSAIDS nonsteroidal anti-inflammatory drugs
-Aspirin mainly inhibits COX-1 → this inhibition of constitutive prostaglandin explains why Aspirin increases clotting time, since prostaglandins are necessary for platelet aggregation
-prostaglandin = lipid from arachnoid acid that body makes at sites of tissue damage or infection
drug nomenclature
Drugs can be named by:
-chemical name IUPAC International Union of Pure and Applied Chemistry
-USAN United States Adopted Name
-BAN British Approved Name
-INN International Nonproprietary Name (designated by WHO World Health Org..)
-In canada, INN is typically used but sometimes USAN
-All terms are correct, different countries use different names
Examples:
-acetaminophen (USAN), paracetamol = INN and BAN
-cephalexin (USAN), cefalexin, cephalexin as INN or Canadian
-Acyclovir USAN), aciclovir = INN
-epinephrine (USAN and INN), adrenaline = BAN
-pethidine (INN, BAN), or meperidine/demerol in Canada
Dissosciation constant KD
-the ratio of the rate of breakdown (K-1) to the rate of formation (K1) is called the dissociation constant (KD)
-KD = K-1/K1
-drugs with a high rate of dissociation and a low rate of formation will have a high dissociation constant → this means drug DOES NOT bind well to receptor
-drugs with a high rate of formation and a low rate of dissociate have a low dissociation constant → this means the drug’s binding to the receptor is strong.
