FINAL Flashcards
pharmacopoeia
first list of medicinal drugs
(early drugs were plants)
first pharmacopoeia
De Materia Medica by Dioscorides
pharmacology
study of drugs
Langley
described the concept of a receptor
- hypothesized that chemical mediators released by nerves act on a receptive substance in order to achieve their effects
Thomas Elliott
concept of neurotransmission
- Adrenaline released by sympathetic nerves produces the effects in the sympathetic nervous system
Loewi’s frog heart experiment
expanded on concept of neurotransmission
- 2 frog hearts close to each other
- when he stimulated the vagus nerve, the first heart slowed - 2nd heart also slowed
- aCH travelled to second heart and slowed the heart rate there
discovery of insulin
- Banting and Best
- hypothesized that the pancreas releases a substance that metabolizes glucose
- treated dogs with modified pancreas extracts
the sandwich experiment
- aortic strip experiment: piece of aorta from an animal that is exposed to different drugs to either contract or relax the strip
- was trying to contract - kept relaxing
- strips were in close proximity - wondered if one strip was releasing a substance that was affecting the other
- 2 aortic strips - one of them was perfused with only krebs soln - the other was perfused with krebs soln + ACh
- strips were in close proximity to each other - first strip was also relaxing
- endothelial cells of blood vessels were releasing nitric oxide (called it EDRF - endothelial derived relaxing factor) which was causing the relaxation of the second strip too
discovery of penicillin
- Fleming
- area immediately around the mold is clear of staph
- ## Penicillium notatum
pharmacist
licensed professional who dispenses/manages medications
pharmacologist
studies how drugs work - can be engaged in drug discovery
pahrmacokinetics
what the body does to drugs (how is drug absorbed, distributed, metabolized, excreted - ADME processes)
pahrmacodynamics
study of what drugs do to the body
drug
substance that brings about a change in biological function through its chemical actions
drugs that are endogenous to the body are given at
superphysiological doses
drugs have three names
- chemical
- generic (suffixes of a given class usually match)
- brand
signal transduction
translation of the chemistry of a drug into a biological effect
receptor
a macromolecule whose biological function changes when a drug binds to it
- specific shape
- selective binding of drugs
strongest bonds
covalent bonds (can be irreversible)
weakest bonds
Van Der Waals
4 main types of receptors
(from fastest to slowest acting)
- Ion channel
- G-protein coupled
- Coupled to enzymes
- Intracellular
example of drug that does not need a receptor
Antacids that buffer acid in the stomach
Ion channel
- fastest acting
- receptor located on or associated with an ion channel
- drug binds to receptor and causes channel to open
- example of ligand: ACh
G-protein coupled
- receptor coupled to a G protein
- G proteins enhance or inhibit cell signalling
- involves intermediate steps
- examples of ligands: adrenergics like epinephrine
- G protein to 2nd messengers, leads to cell signalling
Coupled to enzymes
receptors dimerize once bound by ligand –> activates tyrosine kinases that phosphorylate tyrosine residues on signalling proteins, activating cell signalling
- examples of ligands: growth factors, insulin
- important in cancer (have to block these receptors)
Intracellular
- slowest-acting: receptors located within cells (sometimes on nucleus) - ligands have to be able to cross cell membrane
- once inside cell, if receptor is not on nucleus, a chaperone will escort the drug-receptor complex to the nucleus
- examples of ligands: steroid hormones like cortisol
types of ligands
- Agonist
- Antagonist (reversible/ irreversible)
- Partial agonist
- Others
affinity
The propensity of a ligand to bind to a receptor - attraction between drug/ receptor
- high affinity drug: binds readily to its receptor (holds on)
- low affinity: spends less time bound to a given receptor (binds only for a few secs)
- drugs can bind and release and bind again until they are eliminated
intrinsic activity
the action carried out by the ligand while it is bound to the receptor
(affinity is binding a drug to a receptor, intrinsic activity is what happens as a result of the binding)
agonist
has affinity + intrinsic activity at the receptor
- reversible rxn
- when an agonist like epinephrine binds to Beta-1 receptors on the heart, the heart rate increases (effect)
law of mass action
when more epinephrine is released (anxious), more receptors are bound - heart rate will increase further
- the more receptors that are bound in a tissue the greater the response you will see
affinity of a drug for a receptor is expressed as _____
dissociation constant or Kd (measures the propensity of a drug to release from a receptor)
Kd
dissociation constant
- measures the propensity of a drug to dissociate from a receptor
- concentration of a drug that occupies 50% of the receptors at equilibrium
- high Kd means the drug readily dissociates from its receptor
- low Kd means drug has high affinity for its receptor
high Kd
Drug readily dissociates from its receptor
- can be good cuz drug can bind just lone enough to produce the desired effect without causing excessive harm
Low Kd
drug has high affinity for its receptor
antagonist
has affinity for the receptor but no intrinsic activity at the receptor
- less receptors get bound by the agonist
- ex: reduces heart rate by preventing binding of epinephrine (endogenous agonist)
- typically elicit the opposite effect from the agonist
reversible antagonist
competitive antagonist
- bind to and release from a receptor - constant state of flux
if a patient were to overdose from a reversible antagonist
increase concentration of agonist
irreversible antagonist
non-competitive antagonist
- bind to receptor and don’t let go
if a patient were to overdose from a irreversible antagonist
effects cant be overcome by adding agonist
- have to wait till new receptors are made
Emax
maximum effect from a drug
spare receptors
extra receptors
- if Emax (maximum effect of a drug) occurs before all receptors are bound, there are spare receptors
- increase sensitivity of a tissue to a given drug (so if you can achieve max effect from a drug while binding to a lower number of receptors - means you probably have more sensitive tissue)
- can be used to overcome effects of an irreversible antagonist
allosteric binding
alternative binding sites
- agonist and antagonist bind at different sites on the same receptor
- antagonist binding to allosteric site changes receptor conformation so that agonist cannot bind
- can also potentiate effects of an agonist (make it easier for agonist to bind - increasing its power)
example of drug that binds to allosteric binding site and potentiates effects of an agonist
benzodiazepine binds to allowsterics site to facilitate binding of GABA
partial agonist
has affinity for the receptor but lacks the full intrinsic activity of an agonist
- fine tunes: stimulates when understimulated + can prevent overstimulation by reducing stimulation
inverse agonist
binds to a constitutively active receptor and shuts it off
- does the opposite of what an agonist does (agonist turns on an inactive receptor - inverse agonist turns oFF an active receptor)
tolerance
- Behavioural: Adjusting behaviour to the intoxicating effects of alcohol (acting like drug is not affecting them as much)
– Pharmacokinetic: Body becomes more efficient at eliminating a drug
– Pharmacodynamic: receptor downregulation/ desensitization
Pharmacodynamic tolerance
- overstimulating tissue so it DOWNREGULATES receptors (pulls receptors into the cell) - fewer receptors available for the drug to bind
- overstimulated receptors’ signals reduce (desensitization)
both mechanisms result in reduced effect from the drug
upregulation
constantly blocking receptors with an antagonist results in an increased number of receptors
rebound effect
stopped taking antagonist - more receptors on tissue cuz of upregulation - exaggerated effect
hwo to minimize rebound effect
- reduce dose of drug slowly (tapering)
- giving tissue time to reset its receptors
- also means some of the receptors will still be blocked
side effects
unintended effects of drug therapy
side effects arise from
1) continuation of drug action (drug helping you sleep - still sleepy in the morning - can give drug with short half life so its gone from teh system by morning)
2) bind correct receptor, but wrong region (off target receptors)
3) bind other receptors (binding to receptors it’s not supposed to bind to - can design a more selective drug)
what impact does dose have on the risk of side effects
the more drug you give to patient the more they will experience side effects
- dose-response curves tell you how much drug to give to patient
2 types of dose-response curves
- graded
- quantal
point of maximum efficacy (Emax)
plateau in the dose response curve - increasing [ ] doe snot increase response anymore
dose repsonse curve
- plot dose as log [dose] on x-axis
- plot response on y-axis
- Emax is the max response a drug can ellicit
- EC50 is the dose that elicits 50% of the maximal response (50% of Emax)
efficacy
response produced by a drug (Emax)
potency
how much drug is required to elicit a response (EC50)
why a more potent drug can be better
lower dose required to reach the same efficacy - lower dose required means less drug available to bind to off target receptors
effect of adding a reversible antagonist on a dose response curve
shifts to right - as more drug will be required to elicit the same response (have to outcompete drug B for the receptor)
- EC50 increases
effect of adding a irreversible antagonist on a dose response curve
sigmoidal curve goes DOWN - Emax decreased
- the higher the dose of the irreversible antagonist, the more the Emax will reduce
effect of adding an allosteric antagonist on a dose response curve
curve goes DOWN again - cuz no competition between agonist and antagonist since the binding site is different so adding more agonist is gonna do nothing
- Emax reduced
- same as irreversible anatgonist
effect of adding a partial agonist on a dose response curve
- ## reduced Emax (binds with full affinity but response is less)
quantal dose response curves
measure an all or none response - useful for predicting relative efficacy and toxicity in a population
- life or death (outcome is mortality)
- pain or no pain
- nausea or no nausea
Cumulative plotting in quantal DRC
at each dose, we plot a cumulative frequency of responses (how many total patients have responded up to and including that dose) - sigmoidal curve
ED50
(quantal)
median effective dose - dose that was effective in 50% of the population
TD50
(quantal)
median toxic dose - dose that was toxic in 50% of the population
LD50
lethal dose: dose that kills 50% of the test population
therapeutic index
ratio of TD50: ED50
- wanna maximize gap between ED50 and TD50
therapeutic window
range of safe/effective concentrations of drug in plasma - expressed at the level of an individual patient
- plotting time (x-axis) vs plasma concentration of drug (y-axis)
- below a certain threshold, drug does nothing (sub-therapeutic)
- above a certain threshold, drug is toxic
- therapeutic window: amount of time drug spends above sub-therapeutic range and below toxic range
- wanna keep it in therapeutic window as long as possible
- duration of action: time spent in the therapeutic range
pharmacokinetics
What the body does to drugs
- delivering drug to its site of action
- metabolizing and excreting drug
ADME
- Absorption: How does a drug get into the body?
- Distribution: Where does a drug go in the body?
- Metabolism: How does the body change a drug?
- Excretion: By what route does a drug leave?
Routes of administration of a drug
ABSORPTION
- oral (most common)
- sublingual (blood vessels underneath your drug - absorption directly into bloodstream)
- injection (intravenous - direct access to circulation; subcutaneous - pinch up skin and inject; intramuscular)
- inhalation (includes intranasal) - asthma and COPD - localized effect to lungs usually
- transdermal - through skin
- topical - local effect around skin - not aiming of drug to be absorbed systemically)
- rectal: lower GI or if you cant access oral route if they keep puking
absorption goal
have drug reach systemic circulation (want drug to get into bloodstream and to the heart so the heart can circulate drug all over the body so it can reach its target receptors)
bioavailability (F)
fraction of administered drug that reaches the systemic circulation
- amount of drug in systemic circulation/ amount of drug administered
What would be the bioavailability of a drug that is administered by intravenous injection
100% (all of it gets into systemic circulation)
absorption of orally administered drugs
- ## main site of absorption: small intestine (drug first enters enterocyte then bloodstream)
Factors influencing oral absorption:
- molecular size/composition of drug
- gastric emptying time: controls rate of absorption
- intestinal transporters
- hepatic metabolism
effects of molecular size/ composition of drug on absorption
- smaller and lipophilic drug easier to absorb/get across the membrane (transcellular transport); for paracellular transport: doesn’t have to be lipophilic but still small
- polar (ionized) molecules harder to get across - charge makes the molecule bigger
weakly acidic drugs will _____ in an acidic environment
remain un-ionized
weakly basic drugs will _____ in an acidic environment
become ionized
- becomes charged and bigger - becomes difficult to absorb
ion trapping
drug becomes trapped as it moves between two compartments, moving from a non-ionized to an ionized state
- mother’s plasma more basic than fetal plasma - so if pregnant mother takes a weakly basic drug it will remain un-ionized in her circulation and be able to readily cross the placenta - but once it is in the fetal circulation it becomes ionized due to the acidic environment and is unable to move back into the maternal circulation and gets trapped there
stomach
controls rate of absorption of drug since it squirts drug into small intestine
- slowing down peristalsis (with an anticholinergic) slows down rate of absorption by reducing speed at which stomach releases drug into SI
- altering gastric emptying time can alter the rate of absorption
food and gastric emptying
- gastric emptying delayed by food - slows down the rate of absorption
- minerals (calcium, iron, magnesium, aluminum) bind to drugs - mineral-drug complex reduces absorption of both minerals and drugs
acid-labile drugs
sensitive to acid - want them to get through stomach as fast as possible - take them on an empty stomach - or coat the drug so that the protective coating only gets dissolved in the ph of the SI
how would you protect the stomach from a drug if it is corrosive to the stomach
take drug with food - or coat the drug (aspirin has a coating since it is corrosive to the stomach)
intestinal trasnporters
- P-glycoprotein (P-gp) transporters are EFFLUX pumps that push drug from the enterocyte back into the lumen of the intestine (will then get excreted)
- not all drugs are substrates for P-gp but the ones that are may be prone to DDI’s
- some drugs can either induce or inhibit Pgp (consequences of increasing or decreasing pgp)
hepatic metabolism
drug goes to liver after being absorbed into circulation from SI - takes a ‘first pass’ through the liver before reaching the systemic circulation - some drug molecules get metabolized and inactivated by liver before they reach the systemic circulation
barrier summary
1) molecules too big or got ionized - cant cross enterocyte
2) pgp causes efflex and excretion
3) remaining gets into portal circulation and goes to liver - first pass metabolism in the liver inactivates - by metabolic enzymes
4) finally into the systemic circulation - here we calculate bioavailability (approx 30%)
how do we choose which route of administration is best
- properties of the drug: some drugs can’t be given orally (peptides like insulin (get broken down by stomach))
- target: systemic/local?
- onset of action (fastest to slowest: IV > intramuscular > subcutaneous > oral)
- patient characteristics: is the oral route available/convenient
- patient compliance: oral route gold standard, but depending on adherence, can also give depot injection (extended release formulation –> sits under skin and releases slowly over time)
onset of action oral vs IV
- IV: immediate spike in levels of drug in circulation, get max effect immediately, predictable pharmacokinetics of IV drugs let you get close to toxic dose (better prediction)
- oral: delay before you see any drug in the circulation - gradual increase as it gets absorbed
amount of time each drugs spends in therapeutic range is not very diff - IV just allows max effect immediately oral is more gradual
Which route would provide the fastest onset of action?
intravenous injection
distribution
reversible movement of drug between body compartments
- how it gets from circulation into tissue to act at receptors, and how it redistributes back from the tissues into the circulation so you can start to eliminate the drug
distribution depends on
- blood flow
- capillary permeability
- protein binding
- tissue binding
how distribution depends on blood flow
- critical organs in terms of blood flow receive drug first and in the largest amount –> skeletal muscle –> fat
- anesthetics (lipophilic): distributes to brain immediately –> redistribution of drug to adipose cuz they are lipophilic (leads to offset - drug wears off) –> obese ppl with high proportion of fat (have to keep giving them anesthetic) –> eventually adipose fills up and becomes saturated so drug leeches out of adipose and also no longer offset cuz drug has nowhere to go from the brain so it accumulates in the brain –> overdose
how distribution depends on capillary permeability
blood vessel composition determines how freely a drug can move from blood to tissue
- liver: more spacing between endothelial cells allows passage of drug from blood to tissues - key drug metabolism site
- brain: less spacing between endothelial cells - doesn’t allow passage of drug from blood to tissue - blood brain barrier - to pass, drug has to either be lipophilic and go through transcellular transport or it has to have a transporter - a lot of psychiatry drugs are lipophilic
how distribution depends on protein binding
liver produces plasma proteins - some drugs may bind to them a lot, reducing diffusion into tissue
how distribution depends on tissue binding
- drugs can bind tissues such as fat (highly lipophilic drugs distribute into fat)
- drugs can also bind protein in muscle
Volume of Distribution (Vd)
- theoretical volume in which total amount of administered drug should be uniformly distributed to account for its plasma concentration
- indicates how widely distributed a drug is
- dose administered/ plasma concentration
- average person has about 40L of water in their body
- drug with Vd larger than total body water –> being stored in fat tissue
If the plasma concentration of a drug is relatively small compared to the dose administered, what does this tell you about distribution?
drug is widely distributed throughout the body
low Vd (10L)
drug is mostly intravascular (stays in blood vessel - high plasma protein binding)
drugs with high Vd (like amiodarone - 100L/kg)
distributes widely - long half life
2 main purposes of metabolism
1) make drug more hydrophilic to facilitate excretion
2) change activity of a drug - usually inactivate it
metabolism carried out by
liver enzymes
prodrug
a drug that is activated by metabolism
- usually drugs inactivated by metabolism - these are the exception
- ex: codeine converted to morphine (more potent) in the body
2 types of enzymatic reactions involved in metabolism
Phase I) oxidation/reduction - make drug more polar/soluble
Phase II) conjugation
phase 1
(oxidation/reduction)
- transfer electrons from NADPH to an oxygen molecule (oxidize drugs)
- enzymes located in the ER
- wide range of drugs
- usually inactivate drug
- involve CYP450 (enzymes associated with drug metabolism)
- CYP3A4 makes the biggest contribution to drug metabolism
phase 2
(conjugation)
addition of a chemical group to the drug - results in polar inactive molecule ready to be excreted
- glucouronic acid
clearance
volume of blood from which a drug is irreversibly removed per unit of time
- expressed in mL/min
excretion
irreversible loss of drug from the body
routes of excretion
- urine
- feces
- breast milk
- sweat
processes that impact renal excretion
- filtration: kidney only filters free drug not bound to plasma protein
- secretion at proximal tubule uses uses transporters - if there rae two drugs that are both secreted - compete with each other for transporter and interfere with each other’s excretion
- reabsorption (recovery of drug) unless drug is very polar
net drug removed
filtered + secreted - reabsorbed
first order elimination kinetics
- Constant fraction of drug is eliminated per unit of time
- Rate of elimination is proportional to plasma concentration
- Blood concentration declines in linear fashion
zero order elimination
- Constant amount of drug eliminated per unit of time
- Metabolism is saturated at therapeutic doses
- Only seen with a few drugs
- increases in dose can lead to big changes in plasma concentrations
why is pharmacokinetics important
- dosing
- variability between patients: drug interactions, impact of age, genetics (can be cause of impaired or enhanced function of kidneys an liver)
elimination half-life
the amount of time it takes for 50% of the drug to be eliminated form the body
- Drugs with short half-lives need to be dosed more frequently
- takes ~5 half-lives to reduce drug levels to negligible amounts
Advantage of a drug with a short t1/2?
Drug leaves the body quickly
- hypnotics to help u sleep
Advantage of a drug with a long t1/2?
Reduces the number of doses that need to be given - better adherence
wanna know how long it will take before drug is essentially gone from system. The t1/2 is 6 hours.
6 x 5 = 30 hrs
Major reason why doses of injectable drugs are generally lower than their oral forms
first pass through the liver (Bioavailability of an oral drug is always gonna be less than a 100%
most common reasons for drug interactions
metabolic - usually involve CYP450 enzymes (either inhibited or induced –> DI)
- competitive inhibition
- allosteric inhibition
- allosteric induction
- enterohepatic recycling
competitive inhibition (DI)
2 drugs both using CYP3A4 as their major metabolic route of elimination - one drug (X) binds more avidly to the enzyme - other drug (A) gets displaced - decreased metabolism of drug A so increased levels in the body leading to toxicity
in case of prodrug: enzyme inhibitor inhibits activation of drug
allosteric inhibition (DI)
drug (X) inhibiting enzyme that it isn’t even a substrate for - A is
- decreased metabolism of A - increased levels in the body leading to toxicity
in case of prodrug: enzyme inhibitor inhibits activation of drug
Allosteric induction (DI)
X binds elsewhere to induce 3A4 (not substrate for it itself) - increased metabolism of drug A - decreased levels in the body
- incase of prodrug, enzyme inducer induces activation of drug
enterohepatic recycling
- Liver inactivates (metabolizes) drug
- Drug moves to the intestine, and is reactivated by enteric bacteria
- If these bacteria are killed by an antibiotic, then the drug will not be recycled and instead will be lost in feces
impact of age as a source of variability between patients
Young
absorption:
- reduced peristalsis (reduced rate of absorption)
- increased gastric pH (may impact absorption of drugs affected by pH)
distribution:
- reduced plasma proteins produced by liver (more free drug to cross membranes and act at receptors)
metabolism:
- metabolic enzymes not fully developed (reduced ability to eliminate drugs through the liver)
excretion:
- renal function is impaired (reduced ability to eliminate drugs through the kidneys)
impact of age as a source of variability between patients
Old
absorption:
- Reduced peristalsis (reduced rate of absorption)
- Reduced blood flow (may reduce rate/extent of absorption
- Increased gastric pH (may impact absorption of drugs affected by pH)
distribution:
- We dry out with age, and have a higher proportion of fat
- distribution of hydrophillic drugs will be reduced
- distribution of lipophillic drugs will be increased
Metabolism
Impaired hepatic metabolism due to:
- Reduced blood flow
- Reduced liver size
- Reduced liver enzymes
Excretion
- Renal function declines with age (reduced ability to eliminate drugs through the kidneys)
The greatest currently known source for Pgen variation is from __________
pharmacokinetics - polymorphisms in metabolic enzymes
- CYP 2D6 is the most common isozyme for genetic variability
Poor metabolizers of 2D6
- Low/no CYP450 2D6, etc
- Drug eliminated by that isozyme accumulates
- potential for toxicity
- if Drug A were a prodrug –> Therapeutic failure (cuz less activation)
ultra rapid metabolizers of 2D6
Extra copies of CYP450 2D6, etc
– Drug depleted –> therapeutic failure
- prodrug: excessive activation –> toxicity
