Pharmacology - General Flashcards
What pharmacokinetic variables affect drug levels
-absorption:
route, nature of absorption surface, blood flow, drug solubility (small bowel abnormalities)
-distribution:
volume of distribution and bioavailability (reduced albumen)
-biotransformation:
metabolism in liver, lungs, kidneys, skin, intestine (reduced hepatic enzyme function in baby)
-elimination:
rate of clearance (impaired liver function)
What pharmacodynamic variables affect drug dosing
-therapeutic index:
ratio of TD50 to ED50
-tachyphylaxis:
response diminishes rapidly after administration
-bioaccumulation:
accumulation of substances in an organism
What factors contribute to the variation in drug response
age gender body mass disease states polypharmacy tachyphylaxis
What mechanisms are involved in variation of drug response
- alteration in concentration of drug that reaches receptor: absorption, clearance
- variation in concentration of endogenous receptor ligand: high levels of endogenous catecholamines
- alteration in number or function of receptors: downregulation or upregulation
- changes in response components distal to the receptor
What is the difference between a full and partial agonist
-full agonist:
can activate the receptor-effector system to the maximum effect
-partial agonist:
binds some receptors but does not evoke as great a response
When can a partial agonist act as an antagonist
in the presence of a full agonist (ex. buprenorphine)
What is EC50 and what are spare receptors
EC50 = the concentration of a drug required to produce 50% of the drugs maximal effect
spare receptor = maximal biological response is possible without full occupancy of all receptors
2 mechanisms:
temporal - prolonged effect after transient binding
numerical - limited substrate with excess receptors
What is an antagonist and give an example
- a drug that binds to a receptor, does not activate it and competes with binding of other molecules
- example: naloxone, flumazenil, beta-blockers
What is the difference between competitive and non-competitive antagonists and what type is naloxone
-non-competitive antagonist binds via covalent bonds or so tight that the receptor is not available to the agonist
-competitive antagonist has less affinity for the receptor than irreversible antagonists
at higher concentrations of agonist there will be a given effect
-naloxone is a competitive antagonist
Define potency, efficacy and dose response curves
-potency is the amount of drug required to produce 50% of maximum effect
ED50 = dose of a drug required to produce 50% maximum effect
EC50 = concentration of a drug required to produce 50% maximum effect
-efficacy is the maximum effect a drug can bring about
What factors affect a drugs efficacy
affinity of receptor for drug drug-receptor interaction route of administration absorption distribution clearance
What are the steps in activating a second messenger
- method of transmembrane signalling
- binding of extracellular ligand to G-protein-coupled receptor causes activation of cytosolic G-protein
- activation of GTP-binding protein leads to increase in 2nd messengers
- second messenger then produces an active intracellular element
-examples of second messengers:
cAMP - mobilises fats/carbs, conserves water in kidneys, increases HR/contractility, calcium regulation
cGMP - relaxes vascular smooth muscle
calcium/phosphoinositides - smooth muscle contraction
Discuss the events in cAMP activation
- ligand binds to G protein coupled receptor, activates cytosolic g proteins, activated GTP
- activated GTP in turn activates adenylyl cyclase, which in turn converts ATP to cAMP
- cAMP activates protein kinase A, which stimulates protein synthesis
What are some ligands that work via second messengers
adrenaline noradrenaline acetylcholine on muscarinic receptor opioids nitric oxide
What are some mechanisms of transmembrane signalling
- lipid-soluble ligand crossing membrane to act on intracellular receptors
(ex. steroids, thyroid hormones) - ligand-gated ion channel
(ex. GABA, acetylcholine on nicotinic receptors) - transmembrane receptor binding to intracellular protein tyrosine kinase
(ex. insulin) - voltage gated ion channel
(ex. verapamil) - second messenger
(ex. glucagon, dopamine, adrenaline, serotonin, acetylcholine on muscarinic, nitric oxide)
What influences the extent and rate by which a drug is absorbed
route of administration nature of absorbing surface blood flow drug solubility drug formulation
What routes of drug administration are there
sublingual, buccal, oral, rectal, subcutaneous, intramuscular, intravenous, intrathecal, epidural, inhalational, topical
What factors affect rate of absorption from the small intestine
-ionisation status:
alkaline pH favours absorption of un-ionised basic drugs
-intestinal motility:
increased motility leads to reduced transit time and less absorption
-gut surface area, blood flow, formulation or drug
Why is aspirin absorption enhanced by low pH in the stomach
aspirin is acidic and is more in the uncharged and lipid soluble state at acidic pH
How does the ionisation of a drug affect its solubility
- drugs exist as acids or bases in the body
- ionised (charged, polar) drugs are water soluble and do not cross membranes easily
- unionised (uncharged, nonpolar) drugs are lipid soluble and cross membrane easily
What is first pass metabolism
-when drugs are metabolised before they enter the systemic circulation
-after administration of an orally ingested drug, the portal system delivers the drug to the liver
metabolised in gut wall, portal blood, liver or excreted into bile before reaching systemic circulation
-reduces bioavailability of the drug
What administration routes bypass the first pass effect
all injections
gtn patches/spray, transdermal
rectal (partially reduces)
What are the disadvantages of rectal drug administration
erratic absorption due to rectal contents
local drug irritation
uncertainty of drug retention
How can you increase the bioavailability of a drug
-different route of administration: iv, im, sc, sl, pr (50% bypasses the liver), inhalation, transdermal
-alter properties of drug:
local anaesthetic better absorbed in alkaline pH
give as prodrug
given levodopa with carbidopa to reduce breakdown
What is bioavailability and what factors affect it and what is the bioavailability of ibuprofen
-bioavailability is the fraction of unchanged drug reaching the systemic circulation
-it is determined by:
absorption - depends on route, absorptive surface, charge of molecule, blood flow
first pass elimination - depends on route of administration and liver function
-ibuprofen has high bioavailability: weak organic acid, rapid absorption, minimal first pass effect
What is biotransformation and describe phase 1 and phase 2 reactions
- biotransformation is the alteration of a substance within the body
- main sites: liver (in smooth er), lungs, skin, kidneys, brain, intestine
-phase 1 reactions: converts a parent drug to a more polar metabolite by unmasking or introducing a polar group
types of reactions - oxidation, reduction, hydrolysis, deamination, desulfuration
-phase 2 reactions: covalent attachment of a hydrophilic molecule to form a hydrophilic water-soluble compound
types of reactions - conjugation (glucuronidation, acetylation, glutathione conjugation, sulfation)
What is the role of the cytochrome p450 enzyme system
- enzymes involved in phase 1 oxidation reactions, located on smooth er
- transfers activated oxygen to a drug to form the oxidised metabolite
- makes molecules more polar and thus easier to excrete
What is meant by cp450 induction and give an example
- some drugs cause increased activity of cp450 enzymes, thus increasing metabolism of various drugs
- examples: carbamazepine, rifampicin, alcohol, phenobarbital, griseofulvin, phenytoin, sulphonylurea
How is suxamethonium metabolised
- rapid phase 1 hydrolysis by butylcholinesterase in plasma and liver
- some people are genetically deficient in butylcholinesterase and have slowed metabolism
What factors are responsible for differences in drug metabolism between individuals
- genetics: differences in enzyme levels
- diet: induces/inhibits enzymes (grapefruit juice is an enzyme inhibitor)
- environment: exposure to inducers/inhibitors
- age: decreased enzyme activity
- gender: increased metabolic rates in males
- drug-drug interactions: enzyme inhibitors/inducers
- disease states: hepatic, renal, pulmonary, cardiac, thyroid disease
Give an example of a drug-drug interaction
- enzyme inducers - rifampicin causes treatment failure with ocp
- enzyme inhibitors - amiodarone causes increased concentration of statins, digoxin and warfarin
- protein binding - valproate displaces phenytoin from plasma proteins
- renal clearance
What is meant by hepatic induction
- repeated administration of a substrate brings about enhanced enzyme synthesis or reduced enzyme degradation
- causes increased metabolism of the substrate
Does biotransformation result in more or less active substances
- both, but less active is more common
- less active: nsaid are metabolised to less active metabolites
- more active: codeine is metabolised to more active morphine
What is drug clearance and what affects it
- clearance is the ability of the body to eliminate a drug
- clearance = rate of elimination/drug concentration
- systemic clearance (total body clearance) = CL kidney + CL liver + CL other
- affected by: concentration, bioavailability and elimination rate
What is the difference between first order and zero order kinetics
-first order kinetics (flow dependent elimination) = most drugs
elimination rate is proportional to the amount of drug in the body
there is a constant proportion of drug eliminated per unit time
elimination process is not saturated
-zero order kinetics (capacity limited elimination) = ethanol, aspirin, warfarin, heparin, phenytoin
elimination rate is independent of total drug concentration
constant amount of drug is eliminated per unit time
elimination process is saturated
What factors effect renal clearance
renal function
renal blood flow
plasma protein binding
ionization
Name some drugs mainly cleared by the kidneys
UNCHANGED
gentamicin, vancomycin, lithium, sotalol, metformin, sugammadex
Name some drugs that have high hepatic clearance and why is this important
- lignocaine, morphine, propranolol
- such drugs may have low bioavailability and may influence route of administration
What is drug half life and why is it important clinically
- half life is the time required to change the amount of a drug in the body by half
- t1/2 = 0.7 x VOD / CL
- helps to determine drug dosing regimens, indicates time to reach steady state
What is the relationship between clearance and dosing frequency
- goal in therapeutics is to achieve a maintenance dose (reach a steady state) where rate in = rate out
- clearance rate will determine this
- maintenance dose need to be adjusted for disease states
Give an example of a drug requiring dose adjustment for impaired clearance
gentamicin maintenance dose must be adjusted in renal failure
What is volume of distribution and give an example of a drug with high and low vod
- vod is a measure of the apparent space in the body available to contain a drug
- vod = amount of drug in body / blood concentration
- high vod = chloroquine, morphine, digoxin, fluoxetine, TCA
- low vod = aspirin, gentamicin, amoxicillin, lithium
If a drug is distributed in the total body water, what is its vod
TBW = 42L/70kg
What factors affect vod
patient factors = age, gender, disease state, fat distribution
drug properties = lipid solubility, protein binding
How is it possible to have a vod of 2500L in an adult
a drug that has higher concentrations in extravascular tissues than in blood
example: lipid soluble drugs
What is the importance of a drug with high vod in overdose
drugs with high vod cannot be dialysed
What are the changes in elderly that influence pharmacokinetic properties of drugs
- absorption: generally not changed
- distribution: decreased body water, decreased lean body mass, increased body fat, decreased serum albumin
- metabolism: greatest change in phase 1, decreased hepatic blood flow
- elimination: reduced creatinine clearance with age
What changes would you make to the dose of iv morphine in an elderly patient and why
- reduce the initial dose and increase the dosing interval
- elderly patients are more sensitive to the respiratory effects of morphine due to changes in respiratory function
- there is increased distribution time to the cns due to reduced cardiac output
- elimination half life is increased
What are some drugs that need dose adjusting in the elderly
- opioids: sensitivity to respiratory effect
- benzodiazepines: reduced hepatic clearance (except lorazepam and oxazepam)
- nsaid: renal issues
- gentamicin: reduced renal excretion increases half life
- anticoagulants: falls risk
Give examples of drugs with hepatic clearance that do not change in the elderly
lorazepam oxazepam warfarin ethanol lignocaine prazosin
What are the changes in children that influence pharmacokinetic properties of drugs
- absorption: neonates have lower gastric acidity and prolonged gastric emptying
- distribution: neonates have higher percentage total body water, lower body fat and lower albumin
- metabolism: activity of liver enzymes is lower, reduced clearance rates, increased elimination half life
- excretion: GFR is lower in newborns
What affects placental drug transfer
lipid solubility
molecular size
placental transporters
protein binding
What is fetal therapeutics and give examples
- drug administration to a pregnant women with the fetus as the target
- examples: steroids for lung maturation, antiretrovirals to reduced HIV transmission, antiarrhythmics
