Lecture 1 - Sept 9

Question 1

Pharmakon (ancient greek)

Answer 1

= drug, therefore study of drugs

Question 2

What is a drug

Answer 2

a drug is a chmeical given to alter body function (so yes herbal medication and water (alters hydration state) count

Question 3

Pharmacy

Answer 3

-pharmacy consists of preparation/dispensing/utilisation of drugs

Question 4

Pharmacology (into 2 parts)

Answer 4

1. pharmacodynamics (effect of drug on its site of action/body)
2. pharmacokinetics (what the body does to drug to get it out of body)

Question 5

drug receptor complex

Answer 5

-most drugs need to bind to a receptor to have effect
-receptor is a protein/glycoprotein that sits on a cell surface

Question 6

Ligand

Answer 6

anything that binds to a receptor to elicit some sort of response

Question 7

Affinity

Answer 7

strength of drug-receptor binding (how well a drug sits in a receptor, doesn’t tell you anything about what the drug does)

Question 8

Affinity equation and Association/disosication Rate

Answer 8

-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

Question 9

Drug-receptor complex

Answer 9

=a drug bound to its receptor

Question 10

K1 vs K-1 Fast/Slow in relation to affinity

Answer 10

-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

Question 11

Drug/Receptor/Drug-Receptor Complex Equilibrium

Answer 11

-equilibrium between new drug binding and unbinding/dissosciating

-[D] + [R] <-> [DR]

Question 12

Drugs with high rates of association and low rates of dissociation will have..

Answer 12

-lots of DR (drug-receptor complex)
-high affinity

Question 13

Agonist

Answer 13

-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

Question 14

Antagonist

Answer 14

-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

Question 15

Ligand vs Agonist

Answer 15

-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

Question 16

slide 24 pic

Question 17

Drug Efficacy

Answer 17

-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

Question 18

minimal effective dose

Answer 18

-MED = smallest amount of drug given to produce effect (less side effects)

Question 19

maximum doses

Answer 19

–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

Question 20

Desensitization

Answer 20

=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

Question 21

Sensitization

Answer 21

continued presence of antagoisnt by increased number of receptors
-repeated exposure to drug = increased repsonse to it instead of diminsihed (like nicotine)

Question 22

Withdrawal

Answer 22

group of symptoms that occur upon abrupt discontunitions of drug or rapid decrease in dose (infants born to drug users can have supressed breathing)

Question 23

receptors changing

Answer 23

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

Question 24

The Dose Response Curve

Answer 24

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

Question 25

EC50

Answer 25

-effective concentration 50 -EC50 = drug concentration that gives half the maximal effect

Question 26

Slide 29

Answer 26

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)

Question 27

Potency

Answer 27

-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

Question 28

slide 30

Question 29

Potency vs Efficacy

Answer 29

-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

Question 30

slide 31

Answer 30

-potentcy on x axis efficacy on y axis

Question 31

Antagonist examples

Answer 31

-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

Question 32

slide 33 - agonsit has positive intrinsic activity and antagonsit has zero instrinsic activity (doesnt elicit response/theraputic effect and doesnt bind to receptor)

Question 33

Types of antagonsim

Answer 33

1. receptor based -reversible (competitive or noncompetitive) -irreveisble 2. physiological antagonism

Question 34

Competitive Antagonism (receptor based)

Answer 34

-antagonist competes with other agonsits for receptor -antagonist binds and unbinds from that receptor [D] + [R] <--> [DR]

Question 35

slide 35

Question 36

non-competitive antagonism

Answer 36

-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

Question 37

Irreversible Antagonism

Answer 37

-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

Question 38

Physiological antagonism

Answer 38

-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

Question 39

epinephrine

Answer 39

-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

Question 40

Dose response curve - quantal effects

Answer 40

-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

Question 41

ED50

Answer 41

-estimated dose 50% -dose at which 50% of population will expereince effect -from middle of dose response curve

Question 42

ec50 vs ed50

Answer 42

-EC50 is lab setting -ED50 is population setting

Question 43

slide 42

Question 44

side effects - dose response curves

Answer 44

-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

Question 45

TD50

Answer 45

TD50 = dose required to produce toxic effect in 50% population

Question 46

slide 44-45

Answer 46

fluoxetine is more effective becasue smalle dose is needed -drugs are equally effacous

Question 47

Theraputic window

Answer 47

-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

Question 48

review slide 46-47

Question 49

therapeutic index

Answer 49

-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

Question 50

theraputic index examples

Answer 50

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)

Question 51

potency vs efficacy

Answer 51

Potency = how much you hate to give (dose/concentrations) Efficacy = how well it can do the thing (turn on all the lights or half)

Question 52

beta receptors

Answer 52

→ a beta-adrenoreceptor agonist stimulates beta receptors → a beta-adrenoreceptor blocker blocks the beta-adrenoreceptor

Question 53

a receptor isn't always on a cell surface

Answer 53

-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

Question 54

drug nomenclature

Answer 54

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

Question 55

Dissosciation constant KD

Answer 55

-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.