Principles of Pharmacology Flashcards
Definitions
pharmacology
- study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes
pharmacokinetics
- what the body does to the drug
- measurement and formal interpretation of changes with time of drug concentrations in one or more different regions of the body in relation to dosing
pharmacodynamics
- what the drug does to the body
- study of the interaction between a drug and its molecular target and of the pharmacological response
pharmacokinetics
PK focuses on concentrations of drug in blood plasma
- crucial in drug development and toxicology
- used to adjust dose regimes to target concentrations
therapeutic drug monitoring (TDM)
- plasma conc used to individualism dosage to target therapeutic range for an individual patient
- used mostly in drugs
- narrow therapeutic window
- slient pharmacodynamics (no obvious physiological response to therapy eg antibiotics)
Key terms
Clearance (CL) - volume of blood cleared irreversibly of drug per unit of time (volume/time), important for maintenance dosing
Volume of distribution Vd - defined as volume in which the amount of drug in the body would need to be uniformly distributed to produce the observed concentration in the blood, important for loading doses
Half life (t1/2) - time taken for blood plasma or drug conc to fall by one-half
Steady state (Css) - concentration of a drug at steady state, rate of drug administration = rate of drug elimination and plasma conc remains constant
Cmax - max conc of the drug following administration
Tmax - time taken to achieve Cmax
area under the curve (AUC) - describes the conc of drug in systemic circulation as a function of time post dose
first-order kinetics - constant proportion of drug is eliminated per unit of time
zero-order kinetics - elimination rate does not inc in proportion to dose and conc. clearance and half life are no longer constant
ADME
ADME
- absorption (from site of administration)
- distribution (within the body)
- metabolism
- excretion
important pharmacokinetic parameters that describe the passage of a drug through the body
absorption
- all routes of administration require drug absorption (exception IV route, drug directly administered into systemic circulation)
- before a drug can be distributed to its site of action, must be absorbed into systemic circulation
- drug formulation important factor
- drugs need to cross biological membranes and enter blood vessels on other other side to be able to be absorbed
- when free to move to their site of action, drug molecules are transferred from one body compartment to another via blood
- movement can be limited as membrane enclose various sites
- passive dissusion carrier-mediated transport allow movement of drugs through the body
variables that affect drug absorption
nature of cell membrane
- larger absorbing surface, greater drug absorption, more rapid effects
blood flow
- rich blood supply enhances absorption
solubility
- drug must be in solution to be absorbed
- more soluble, more rapid absorption
ionistation
- many drugs are weak acids or bases
- ionised form usually water soluble, does not diffuse readily through membranes
- unionised form more lipid solume, more capable of membrane diffusion
- extenent of ionisation is dependent of pH of environment
formulation
- drug formulations can be manipulated to achieve desirable absorption characteristics
- eg slow release or enteric formulations
route of administration
can affect both onset and magnitude of drug action
drug can enter systemic circulation by being injects (IV), or absorbed from extravscular sites including:
- oral (enteral)
- parental (SC, IM, IV, intrathecal or epidermal)
- inhalation
- topical
- rectal
oral absorption
most common route of admin
- safe, convenient and economical
small intestine - major site of absorption
factors that affect gastrointestinal absorption
- gut content (fed, fasted) and motility
- blood flow
- particle size and formulation of drug
- physicochemical factors including some drug interactions
first-pass metabolism
- orally administered drugs that are absorbed travel through portal system and liver before entering systemic circulation
- if % of drug is metabolised by liver, only remained of drug will be able to enter systemic circulation to exer tits effect (reduced bioavailability, requires much larger dose orally rather than parentally
bioavailability (F)
- proportion of administered dose that reaches systemic circulation intact
intravenous absorption
- administered directly into systemic circulation
- 100% bioavailability (no loss during absorption process)
- administration may be a single dose, or continuous infusion
other routes of absorption
parenteral
- intravenous
- subcutaneous
- intramuscular
- intrathecal/epidural
- intraosseous
- intraarticular
inhalation
rectal
topical
- skin
- eyes/ears
- mucous membranes
distribution
after drug enters systemic circulation, can be distributed to various compartments of the body
- blood
- bone
- fat
- total body water
- extracellular water
distribution
- process of reversible transfer of a drug between one location and another (usllay blood ) in the body
some drugs remain exclusively in the blood
plasma protein binding in disrtibution
- when drug enters systemic circulation, proportion of free drug molecules bind reversibly to proteins and lipoproteins to form drug-protein complexes
- extent of binding dependent on affinity of drug for protein, relative concentrations of drug and protein, number of drug binding sites on protein
- saturable process
- when administering multiple drugs that bind to plasma proteins, they can compete for binding sites and amount of free drug in circulation may be altered (can alter therapeutic action of drugs)
- free fraction responsible for drug action
tissue binding in distribution
adipose tissue
- lipid soluble drugs have a high affinity for adipose tissue
- prone to accumulation (prolong half life of the drug)
- low blood supply to adipose tissue (drugs delivered there at a slower rate)
bone
- some drugs have an affinity for bone
- eg tetracycline
tissue specific barriers to drug distribution
blood brain barrier
- endothelial cells of brain capillaries joined via tight junctions
- allows passage of lipid soluble drugs
- additional protection of membrane transporters protect the brain
placental barrier
- separates blood vessels of mother and fetus to work as a protective barrier
- lipophilic drugs can readily cross
volume of distribution
- theoretical volume in which the amount of drug in the body would need to be uniformly distributed to produce the same conc in blood
- indication of accumulation of drugs in tissues compartments (used to calculate loading doses)
- if drug is highly plasma protein bound and hydrophilic, remains within circulatory system (Vd = low, similar to blood volume)
- if drug is lipophilic and moves out of circulation and binds to other sites (Vd = larger than blood volume)
- larger Vd, more widespread the drug is within the body
- loading dose = Css x Vd
single compartment model
- simplified model of a human being
- volume of distribution links the total amount of drug in body to plasma conc, body is a single compartment in which the drug is distributed
other kinetic models
exist to recognize the complexity of the human body
- brain, adipose tissue and muscle will all have variable blood supply, different permeability to drugs
two compartment model
- drugs can enter and leave a peripheral compartment only through a central compartment
metabolism
- process of chemical modification of a drug
- mainly via enzymes
- liver primary site of metabolism
other sites
- kidneys
- lungs
- intestines
prodrugs
- drugs that require activation (metabolism) to elicit a therapeutic action
- for majority of drugs, metabolism results in formation of a more water-soluble compound or metabolite that can be readily excreted
- clears parent compound from circulation and promotes excretion
drugs can be
- excreted unchanged
- undergo functionalization and be directly excreted
- undergo conjugation and be directly excreted
- undergo functionalization then conjugation prior to excretion
functionalisation reactions (phase 1) in metabolism
unmask a polar functional grou[ in drug molecule to produce a more water-soluble metabolite
- dealkylation
- hydrolysis
- hydroxylation
- oxidation
cytochrome P450
- CYP enzymes found in smooth ER
- abundant in hepatocytes
- more than 50 varieties
conjugation reactions (phase 2) in metabolism
involve joining a suitable functional group in a drug molecule with a polar group of an endogenous substance in the body
- enhances urinary excretion
often results in inactive products
- glucuronyl, sulphate, methyl, or acetyl
saturation kinetics (zero order kinetics)
- relevant to hepatically cleared drugs
- some drugs (ethanol, phenytoin) do not follow models discussed
- saturation of carrier or enzyme, drug conc inc
- changes in dose lead to disproportionate changes in plasma concs (relationship between dose and steady state is unpredictable)
eg
- rate of clearance of ethanol from plasma is constant at approximately 4mmol/L/hr irrespective of dose or plasma conc (saturation of alcohol dehydrogenase)
clearance
- drug elimination
- volume of plasma from which a substance is completely removed from body per unit time
- expressed as volume/time (mL/min or L/h)
- steady state (Css) is point where rate of input of drug is = rate of elimination
dose = Css x CL
renal clearance
net effect of
- glomurelar filtration
- active secretion
- passive reabsorption
only unbound drug is filtered at glomerulus
some drugs require dose adjustment in renal impairment (dec in dose/dosing freq)
hepatic clearance (CLh)
hepatic extraction ratio (Eh)
- fraction of drug entering liver in blood that is irreversibly removed by metabolism on each pass through liver (0.7 = 70% removed)
low extraction
- clearance capacity limited by liver enzymes to clear drug
high extraction
- clearance capacity limited by delivery of drug to liver (blood flow)
half life
distribution and clearnace influence half life
- changes will alter half life
used to determine duration of action of a drug after a single dose
t1/2 = 0.693 x Vd / CL
single compartment model and t1/2
clearance of drug can be described by t1/2 of drug
- after one half life, conc of drug plasma dec to half its initial conc
- longer half life, longer it stays in body
steady state achieved after 3-5 half lives of drug
- loading dose may be given to speed up process
- size of loading dose determined by volume of distribution (Vd)
pregnancy
physiological changes during pregnancy alter pharmacokinetics of drugs
- delayed gastric emptying
- changes to body mass, plasma volume, body fat and fluid distribution can alter Vd
- altered metabolism
- somedrugs can cross placenta and enter fetal blood circulation
- fetus has immature liver drug-metabolising enzymes, so metabolism is different to adults
- excretion increases may require dose adjustment
need to consider potential drug exposure to developing fetus
breastfeeding
need to consider potential drug exposure to child
drugs have capacity to cross mammary gland epithelium and excreted in breastmilk
drugs likely to cross have certain characteristics
- basic compounds
- low plasma protein binding capacity
- high lipid solubility
neonates
lack many protective mechanisms of older children and adults
- thin permeable skin
- lack stomach acid
- lungs lack mucous barrier
- poor body temp regulation (easily dehydrated
delayed maturation of liver metabolism enzymes
infants and children
from 1 year old absorption, disrtibution and excretion are similar to adult
metabolism varies depending on age
requires weight based drug dosing
concentration-response relationship
how much of an effect a drug will have and how much drug is required to have an effect
potency
- measure of how much drug is required to have an effect
efficacy
- how much of an effect will the drug have when all targets are occupied
drug specificity, selectivity and affinity
specificity
- number of effects a drug produces
selectivity
- number of molecular targets that a drug interacts with
affinity
- strength of interaction between a drug and molecular target
most drugs show some selectivity but lack specificity
- in many cases, inc dose cause it to affect targets other than the principal one, = side effects
ideal drug interacts with a single molecular target at a single site to cause one effect
factors that alter drug efficacy
tachyphylaxis
- effect of drug diminished when it is given continuously or repeatedly
tolerance
- develops over time (hours, days, weeks, months)
- gradual decrease in responsiveness of a drug
drug resistance
- loss of effectiveness that can be a result of many different mechanisms
- change in receptors
- translocation of receptors
exhaustion of mediators
- inc metabolic degradation of the drug
- physiological adaption
- active extrusion of drug from cells
molecular drug targets
majority of drugs cause their effect by acting on one of four main types of protein targets
- regulatory proteins
- 4 types
- transporters, ion channels, enzymes, receptors
in addition to primary targets, many drugs bind to plasma proteins and other tissue proteins without producing a physiological effect
transporters
required to allow passage across cell membranes when passive diffusion is not possible
- eg not lipid soluble enough to cross
transport across cell membranes can still be passive
- carrier-mediated diffusion
most common form of transport is active
- hydrolysis of ATP forms energy to actively pump substance across a membrane against an electrochemical gradient
secondary active transporters
some transporters have an organic molecule coupled to transport of an ion
symporter
- a transporter that moves both molecules across the membrane in the same direction
antiporter
- molecules move across the membrane in opposite directions
ion channels
- proteins embedded in cell membrane that control the flow of ions into and out of the cell
- ions can only pass down their electrochemical gradient from a compartment of higher to lower conc
- the rate of flow through the channel is very high
- drugs target ion channels (eg amiloride, diuretic. verapamil, calcium channel blocker)
enzymes
biological catalysts that control biochemical reactions within the cell
drugs can either activate or inhibit enzyme activity to alter a physiological response
- eg warfarin inhibits the enzyme vitamin K epoxide reductase, prevents activation of vitamin K1, blocks production of vitamin K1-dependent clotting factors
drugs that interact with enzymes often resemble substrate structure of the enzyme
receptors
- signalling proteins that recognise and respond to chemical messengers (hormones, neurotransmitters)
- coordinate functions of all the different cells in the body
- change function with a cell
- largest and most diverse type of molecular target
- drugs act as agonists or antagonist on receptors
can be divided into 4 superfamilies based on differences in structure and coupling mechanisms
- ligand gates ion channels
- g protein coupled receptors
- kinase receptors
(located in cell membrane, have a ligant binding site, respond to extracellular messengers)
- nuclear receptors - affect gene subscription
ligand gated ion channels (ionotropic receptors)
ions enter, cause hyperpolarisation or depolarisation, causing cellular effects
- milliseconds
- nictonic ACh receptor
G-protein coupled receptors (metabotropic)
ione enter, change in excitability, second messengers cause Ca2+ release, protein phosphorylation, and other effects which cause cellular effects
- seconds
- muscarinic ACh receptor
kinase linked receptors
protein phosphorlyation causes gene transcription, protein synthesis and cellular effects
- hours
- cytokine receptors
nuclear receptors
gene transcription causes protein synthesis and cellular effects
- hours
- oestrogen receptor
drug target interactions - agonists
binding of a drug to receptor causes a functional response
response determined by drugs affinity to receptor
full/partial agonist depending of capacity to cause a response
- partial agonists bind to and activate receptors but are unable to elicit the same maximal response as and endogenous ligand even when all receptors are occupied
direct or allosteric agonist depending on binding site
allosteric modulators
indirectly alter function of a receptor
can be allosteric agonist or antagonist
bind to a distinctly different site from the orthostatic site resulting in
- activating the receptor to cause a different biological response to the agonist
- altering the binding affinity of the receptor agonist
- changing the efficacy of receptor activation by the agonist
antagonists
bind to receptor without eliciting a response and preventing binding of an agonist preventing activation f receptor
reversible competitive antagonists
- interfere with binding of endogenous agonists, compete for receptor sites
irreversible competitive antagonists
- limited therapeutic use
- permanently make receptor unavailable to bind to
non-competitive antagonists
- block response to an agonist at some point within the cascade of intracellular events
- dec maximal response of agonst
receptors
receptors can undergo many changes including
- loss if responsiveness
- change in number of receptors
tachyphylaxis
- diminished response of receptor after repeated exposure to the same concentration of drug
desnsitisation
- decreased response of the receptor-second messenger system
downregulation
- decrease in the number of receptors
- can contribute to desensitiation and loss of response
upregulation
- increase in receptor number
- can cause receptor hypersensitivity
- often occurs after chronic use of drugs that block receptors, drug removed, patient experiences inc response to stimuli
inter-individual variation
variation in response to some drugs can occur as a result of
- environmental factors
- genetic variations
genes influence pharmacokinetics by altering expression of proteins involved in ADME
genes influence pharmacodynamics with differences in enzyme or immune mechanisms
pharmacogenetics
- the study of the role of genetics in drug response
- relates to the inheritance of genes that define an individual’s variability in drug exposure and response
genetic variation in humans can occur as a result of mutations that
- occur in our own cells
- inherited genes from our ancestors
genetic polymorphisms
- changes in DNA sequence that occurs at an allele frequency of at least 1% of the population
single nucleotide polymorphisms
- arise from substituition of one nucleotide for another
- if it occurs in a coding region of a gene, it can result in proteins being altered in structure, stability, activity, ligand-binding properties
examples of drug-metabolising enzymes that exhibit genetic polymorphisms
- CYP enzymes (responsible for hepatic metabolism of many drugs)
- N-acetyltransferase
- glutathione-S-transferases
- thiopurine methyltransferase (TPMT)
- UDP glucuronosyltransferases
ethnicity
- eg chinese patients ablity to metabolise ethanol differs to European patients (inc in acteylaldehyde plasma conc, flushing and palpitations)
CYP2D6 can have many genetic variations
- responsible for metabolism of drugs including codiene
- poor metaboliser phenotype variations
- 7-10% in caucasians
- 1-2% in north asian populations
- ultra rapid metaboliser phenotype variations
- 2-3% in caucasians
- up to 25% in north African populations
single gene pharmacokinetic disorders
mutation that disrupts gene function
aminoglycoside ototoxicity
- inc susceptibility to hearing loss post exposure to antibiotics
- inherited maternally
- mutation of mitochondrial DNA
pharmacogenetic testing
when testing is performed to optimise drug dosing, it is generally based on phenotype using either
- measurement of a metabolic ratio
- mteabolite:drug ratio in blood or urine
- direct measurement of enzyme activity
potential consequences of polymorphic drug-metabolising enzymes
- inc plasma drug conc and duration of action
- dec plasma drug conc and therapeutic failure
- adverse drug reactions/toxicity
- failure to activate a prodrug
- drug metabolism via alternative pathways
- exacerbation of drug interactions
HER2
- expression important in guiding treating decision for breast cancer patients
- trastuzumab targets HER2, efficiency based on HER2 expression
CYP2D6
- analgesic effects of codeine result from its conversion to morphine
- approx 10% codeine dose converted by CYP2D6
- polymorphisms in CYP2D6 can result in patients either:
- responding poorly to codeine (poor metabolisers)
- opioid toxicity (ultra rapid metabolisers)
thiopurines and TPMT
thiopurines use for immunosupression
TMPT metabolises these drugs
large inherited variations in TPMT activity
- low TPMT activity = inc toxicity risk
- high TPMT activity = dec efficacy
before starting treatment, can test
- phenotyping (TPMT activity)
- genotyping (TPMT alleles, TPMT3A, TPMT)
individualising drug dosing
various strategies can be applied to guide dose selection on basis of exposure, response or toxicity including
- initial dose selection based on a predicted capacity to eliminate the drug (genotyping, phenotyping)
- dose adaption in order to tailor the drug effect or respond to a change in circumstance
therapeutic drug monitoring
- commonly used approach to guide dosing decisions based on drug exposure
- considers PK parameters of medications and PD targets
PK/PD optimisation of antimicrobial dosing
time dependent (f T>mic)
- inc frequency of dosing to optimise efficacy
conc dependent (Cmax/MIC)
- inc dose to optimise efficacy
- conc-dependent with time dependence (AUC/MIC)
- inc dose and freq to optimise efficacy
