Pharmacology Intro Flashcards
What is Pharmacology?
The study of how drugs interact with living systems
T or F. Drug receptors are usually proteins and drugs can influence their function
T
Pharmacokinetics
- How drugs react with our body (before it reaches target receptor); absorption, distribution, metabolism, excretion (ADME)
- How drugs are dosed, administered, how frequently, how much
Detailed interaction of drugs with specific receptors
Pharmacodynamics
T or F. Pharmacology is very applied life science
T
Antihistamine used in the 1980s and 1990s
Seldane (Terfenadine - generic)
Terfenadine
- supposedly an H1 receptor antagonist (anti-histamine)
- blockbuster drug b/c did not cause drowsiness
- BUT actually, metabolized by liver into ACTIVE antihistamine form = fexofenadine
- thus, terfenadine is a PRODRUG
Terfenadine to Fexofenadine
Alkylated group on drug is oxidized by metabolism in liver
Receptors
- molecular target of drug
- actions of drugs is the result of their interaction with a target receptor
Prodrug
- not intrinsically active
- activated by some metabolic step after administration
Terfenadine is metabolized quickly in liver by
first pass metabolism
A ‘good’ pharmacokinetic profile
long lifetime in body; especially that it’s not eliminated extremely quickly
Off-target effect of terfenadine
- metabolism of terfenadine to fexofenadine is inhibited
- inactive form can go to heart and cause cardiac arrhythmias
- terfenadine is a very powerful blocker of certain proteins (hERG ion channels) that control electrical activity and beating of heart
‘Torsades de pointes’
off-target effect of terfenadine (runny nose medication)
- potentially lethal cardiac arrhythmia
- patients may be susceptible
Off-target effects
- drugs not usually perfect for just one receptor type
- sometimes they will influence closely related receptors (H1 vs H2)
- sometimes they will influence completely unrelated receptors (H1 vs potassium channels in the heart)
Adverse events
undesirable drug effects
On-target effects
adverse events that arise
- related to the mechanism of action of the drug
NNT vs NNH
numbers needed to treat vs numbers needed to harm
Some reasons for adverse events of Terfenadine
- substances that inhibit the activity of certain liver enzymes in drug metabolism (CYP3A4); diminished liver function, antibiotics (erythromycin) or antifungals + grapefruit juice (CYP3A4 inhibitor)
- some patients will carry mutated versions of the genes encoding susceptible ion channel ‘off-targets’ in the heart
Simple solution to adverse effects of Terfenadine
administer metabolite of terfenadine which does not have cardiotoxic effects – Allegra
Pharmacogenomics
the genetic background of a patient can significantly affect how they respond to a drug
Drug interactions
- very common for one drug/substance to adversely affect the response to another
- ingesting multiple drugs at once can have unexpected consequences
Intracellular receptors
- receptors inside cell (drug has to be membrane permeable - hydrophobic)
- drugs must be lipid soluble (or transport mechanism)
- steroid hormones and their analogs
- mode of action: bind to LBD of a receptor, leading to displacement of HSP or other chaperone, this exposes DNA recognition domain and leads to activation of transcription of target genes
- effects have slow onset; long-lasting (not rapidly reversible)
A large fraction of therapeutic drubs target this family of transmembrane receptors
GPCRs
G proteins are distinct from receptors
GPCR - G proteins activity
- at rest, G-alpha is bound to receptor and it is bound to GDP (nucleotide)
- ligand binds to receptor, that triggers GDP/GTP exchange; G-alpha releases GDP and binds to GTP coupled to dissociation of G-alpha from complex;
G beta gamma also dissociates and those can act as effectors in signalling pathways in the cell as they have downstream targets and vary depending on type of receptors activated - G-alpha while bound to GTP can also activate downstream signalling cascades
- Eventually, G-alpha has intrinsic GTPase activity where it will hydrolyze GTP back to GDP form; “molecular timer mechanism” – return system back to basal resting state when it re-binds to receptor
G-beta/gamma vs G-alpha
G beta gamma (act as a unit) usually stays tethered with the membrane and they can directly activate various downstream effectors ; generates some signals
G alpha subunits have initial affects on initial components of a cascade that have much more downstream effects that allow for amplification of a signal = target adenylate cyclase (AC), and phospholipase C (PLC) - activated when G alpha q are activated
How are GPCRs usually categorized?
based on the subtype of G-alpha that it is associated with
Adenylate cyclase (AC)
- an enzyme that will amplify signal by repeatedly causing ATP inside cell to move into a form called cAMP dependent protein kinases (biological signal) that will lead to activation of protein kinase A
Gs vs Gi
Gs trigger increased AC activity
Gi suppresses
** happens very quickly!
Activation of Phospholipase C
- Gq
- leads to production of IP3 (from breakdown of PIP2)
- IP3 triggers release of intracellular Ca 2+ stores (ER)
- (from PIP2) DAG activates protein kinase C and target substrates
- very quick!
PLC
- phospholipase C hydrolyzes phospholipids in the membrane
TKRs
- activation driven by dimerization of receptors in the presence of a ligand
- receptors autophosphorylate and become activated
- Receptor itself is a kinase (unlike GPCR where it relied on intermediates to phosphorylate)
Fastest mechanism of signalling in the body
Ion channels; depends on electrical signals generated by these channels
binds AAs or neurotransmitters
Ion channels
- allow ions to cross plasma membrane very rapidly
- changes in membrane voltage (underlies transmission of signals in the nervous system, beating of heart, etc.)
- different ion channel types are controlled by distinct stimuli (ligand binding or membrane voltage changes); drugs that target these alter their response to these stimuli, or block the flow of ions
Common drugs for psychiatric conditions target …
ligand-gated channels
Other varieties of drug targets
- structural proteins (microtubules)
- DNA replication machinery (foreign or native)
- membrane transport proteins
- enzymes
- foreign proteins (bacterial cell walls, bacterial DNA/RNA machinery)
Agonism
a substance/drug binds to a receptor and influences its activity
-> usually depicted as a concentration-response curve
EC50
effective concentration 50
- refers to the concentration of drug that yields a 50% maximal effect
Emax
maximal biological effect observed with the drug
Efficacy
term that refers to the maximal drug effect (Emax)
- biological response of some kind; effect size
Potency
term that refers to the concentration dependence (EC50)
- drug with strong potency has a low EC50 (only small concentration needed to generate a large effect)
High EC50 = weak
Drugs with different efficacy exhibit a difference in …
the maximal effect that can be achieved
T or F. Receptors can have multiple agonists with distinct actions on the receptor
T!
Drugs with different potency exhibit different…
concentrations required for a particular effect
Agonists are usually categorized based on their
efficacy
Different types of agonist and antagonist
full - can generate the maximal observed effect
partial - can generate a fractional effect
antagonist - cannot generate a biological effect on their own
inverse - cause suppression of basal activity
Why is pharmacokinetics important?
they define how often or how much of a drug you should be taking in order for the conctn of the drug to be at its optimal level in your body for an optimal amount of time
Important considerations for route of administration
- convenience: it is easy to take a medication orally (vs. injection/IV, other routes)
- bioavailability: different drugs may be absorbed with different efficiency from the gut
- processing: hepatic portal circulation is a major consideration; drugs absorbed from the gut first encounter the liver BEFORE entering systemic circulation so there can be significant processing/breakdown
Extraction ratio
clearance (liver)/blood flow
high extraction ratio = attractive property for prodrug but not for a drug delivered in active form, so cleared out and degraded quickly = low bioavailability
Inverse of extraction ratio
related to bioavailability; thus, inversely proportional
Routes of administration
- oral - most common; rate of absorption is slow and affected by intake of food; influenced by breakdown in the gut, processing in the liver (variable between indivs)
- intravenous - delivered directly into the systemic circulation; very rapid onset; inconvenient and requires expertise; high control over circulating level by controlling rate of infusion/amount injected
- intramuscular/subcutaneous - into muscle, or below skin; rate of absorption depends on blood flow to site; common use to “depot” preparations (slow dissolving for sustained releasE)
- inhalation - absorption is through epithelium in the lungs, and can be very rapid
- sublingual - rapid absorption route, also bypasses ‘first pass’ effects despite taking orally
- transdermal (ointment or patch) - convenient, slow absorption, and sustained exposure
Bioavailability
fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route
Distribution
in pharmacokinetics, refers to how a drug/substance is partitioned into different body ‘compartments’ after it is absorbed
-> can have a big influence on the effective concentration of a drug in the body, as well as the lifetime of the drug in the body
2 Key Factors of Distribution
- binding to plasma proteins (eg. albumin)
- drugs will circulate in an eq’m between ‘free’ and ‘bound’
- usually only the ‘free’ fraction is considered to be pharmacologically active
- some drugs are highly bound - drug accumulation in tissues
- accumulation is favoured for drugs that are lipophilic
- more highly perfused tissues can accumulate more readily than tissues with poor perfusion
- key parameter is VOD
VOD
Volume of distribution
total amount of drug in body/[drug] (in blood, plasma, serum, unbound, etc.)
- not meant to represent a real volume; just a concept
- high VOD = longer lifetime
T or F. The rate of elimination depends on the concentration of drug
T, reservoir of drug in the tissues can prolong the lifetime of the drug in the body
Biotransformation
key mechanisms leading to elimination
- metabolism in liver (phase 1 and 2)
- excretion (kidney/gut)
**biotransformation refers to when the liver modifies a drug for excretion and it also describe the process when a liver modifies a prodrug into an active drug for example
Metabolism in liver phases
1 - mixed function oxidase system (CYP family enzymes) generates oxidative modifications of drugs (hydroxylation, dehydrogenation, etc.)
2 - conjugation of parent compound, or phase 1 product with large polar adducts to make the product more prone to excretion
How is a drug eventually excreted?
- bile/feces:
- biotransformed drugs in the liver are incorporated into bile and secreted into the gut
- modifications (large polar adducts) make these drugs more polar and less prone to be reabsorbed in the digestive tract - urine:
- drug passes through glomerular filtration, or is actively secreted in to the renal tubule, and excreted in urine
Why is drug elimination typically described by a half-life?
enzymes and systems mediating drug elimination are not saturated; exponential decay equation can be used to describe elimination
In a few notable cases, especially ethanol, elimination is capacity limited
bc ethanol concentrations are much higher than the affinity of a key enzyme involved in their elimination
-> capacity-limited elimination
How is safety or efficacy studied/surveilled?
- Controlled human studies = after considerable pre-clinical development, optimization, animal testing = to assess dosage, administration, safety, efficacy
- Phase 1: small scale (Dozens of subjects), testing for tolerable dosing ranges, bioavailability, excretion
- Phase 2: intermediate scale (hundreds), testing for efficacy (sometimes different dosages), monitoring for safety in greater numbers of patients
- Phase 3: large scale, randomized, double-blinded trial, compared against a placebo or current accepted treatment
Systematic reviews, meta-analysis
gold standard; approach to combine data from multiple trials, often after a drug has been approved; help guide future policy
Forest plots provide data on:
- # of trials
- size of each trial (size of symbol)
- outcomes of trials (not always consistent)
- overall summary of all trials
- OR (odds ratio): ratio of event rate in treatment vs control (which one is favoured in individual trials, vs overall)
Therapeutic index
ratio of the median toxic dose and effective dose
- TD50/ED50
- the bigger the difference (ED50 and TD50) the better bc it gives you a much bigger window with patients who are not responding a slightly higher dose to see if they respond before they begin to have adverse outcomes
In patient studies, effect or toxicity is often described using a…
quantal dose-response curve
Relative risk reduction
- 1 - (event rate on treatment group/control group)
- event = defined in whatever study you are reading; ex: death by any means, etc.
- reporting relative risk reduction while de-emphasizing other important info is misleading
Absolute risk reduction
- more descriptive way to report the benefit of taking a drug
- described absolute number of cases that are prevented by taking a drug (rather than a percentage relative to baseline)
- = event rate in control - event rate in treatment group
- policymakers will use this to determine if rate of benefits are good enough for the public health to fund this
Number needed to treat
- another way to think about absolute risk, or population-level benefit of a drug
- = 1/ARR
- x ppl need to take drug in order for 1 to see beneficial effect
Key points to consider about NNT
- low NNT is good; NNT = 1 means just about everybody taking drug will receive desired benefit
- high NNT not good
- NNH ; low NNH is bad and high is good!
- some drugs are given with a high NNT bc the potential outcome they are preventing are very very severe like death or so on.. Falls on judgement of regulators to decide whether the benefit to a population outweighs the potential risk to a population
What does a negative absolute risk mean?
means that an event has a higher rate in the experimental group so 1/ARR = number needed to harm
