pharmacology Flashcards
physiochemical
react with each other
- adsorption
- chelation
- precipitation
- neutralisation
e.g. paracetamol overdose treated with activated charcoal as it sticks to the paracetamol
pharmacodynamics
the effect a drug has on the body
effects of drugs and mechanism of their action
types of drug interactions
summative= addition of drugs together is the same as just one of the drugs at the same dose
synergistic= two drugs together and overall effect is greater than the individual effect of one at the same dose ( 1+1>2)
antagonism= drugs oppose each other (morphine and naloxone)
potentiation= two drugs and only one makes the other more powerful
pharmacodynamic mechanisms
receptor based
signal transduction
physiological systems
Receptors and drug interaction
agonists
partial agonists
antagonists (competitive and non-competitive)
physiological systems
different drugs that effect different receptors but in same physiological system
Ca channel antagonist and beta blocker
ACE I and NSAID
pharmacokinetics
what the body does to a drug
absorption
distribution
metabolism
excretion
absorption
motility=decrease in motility will decrease absorption
acidity= balance between ionised and unionised particles of a drug. Ionised particles can’t pass through membranes but unionised can. Changing acidity changes balance between these particles
solubility
complex formation
direct action on enterocytes
bioavailability
distribution
protein binding- wont have clinical effect
travel to other tissues- such as fatty tissue
travel to effect site
if two drugs are highly protein bound, the clinical effect of both drugs will increase as less of the drug will bind so more drugs are free in the blood
metabolism
CYP450
inhibition
induction
CYP450 (metabolism)
haemoproteins
metabolise many substrates - endo/exogenous
class 1,2,3 are most important
inhibition (metabolism)
enzyme inhibitors
e.g. metronidazole slows down CYP450 pathway
induction (metabolism)
enzyme induction can cause a drug interaction
e.g. morphine- CYP450- morpine6glucuride (becomes more potent)
excretion
renal:
- ph dependant
- weak bases= cleared faster if urine is acidic
- weak acids= cleared faster if urine is basic
biliary (minor)
drug interactions
protein binding
enzyme induction and inhibition
acute kidney injury
grapefruit juice
risk factors- patient
polypharmacy
old age
genetics
hepatic disease
renal disease
risk factors- drug
narrow therapeutic index
steep dose/response curve
saturable metabolism
how to avoid interactions
prescribe rationally
BNF
ward pharmacist
product information leaflet
drug definition
a medicine or other substance that has a physiological effect when ingested or otherwise introduced into the body
drugability
the ability of a protein target to bind to small molecules with high affinity
sometimes called ligandability
types of drug targets
receptors
enzymes
transporters
ion channels
mainly proteins
receptor definition
component of a cell that interacts with a specific ligand and initiates a change of biochemical events, leading to observed effects
ligands can be exogenous (drugs) or endogenous (hormones, neurotransmitters)
types of receptors
ligand-gated ion channels, e.g. nicotinic ACh receptor
G protein coupled receptor, e.g. beta-adrenoceptors
kinase linked receptors, e.g. receptors for growth factors
cytosolic/nuclear receptors, e.g. steroid receptors
ligand gated ion channels
outside the cell is the receptor
ligand binds to it and a constitutional change occurs, opening the channel
G protein coupled receptor
largest and most diverse, make up about 4% of genes
ligands include light energy, peptides, lipids, sugars, proteins
act as a molecular switch
interact with PLC or adenylyl cyclase
kinase linked receptors
interaction with ligand causes conformational change in phosphorylation state
initiates signalling cascade
nuclear receptors
present in cytoplasm
ligand binds to receptor activating receptor
this then binds to DNA and modifies gene transcription
agonist
compound that binds to a receptor and activates it
antagonist
reduces the effect of an agonist
ligand
molecule that binds to another molecule
agonist response curve
as agonist conc. increases so does the response
until response reaches 100% and then it will plateau
when plotted as a log(agonist) there is a sigmoid curve
potency
EC50- concentration that gives half the maximal response
full agonists
drugs that have full efficacy at receptor
partial agonists
drugs bind and activate receptor but only have partial efficacy relative to a full agonist
efficacy
maximum response achievable from a dose
intrinsic activity
= maximum efficacy for partial agonist ÷ efficacy of full agonist
antagonists and receptors
they do not activate receptors
reverse affects of agonists
competitive shift curve to right
non-competitive shift curve right and down
cholinergic receptors
muscarinic- mAChR
nicotinic- nAChR
muscarinic
agonist=muscarine
antagonist= atropine
nicotinic
agonist=nicotine
antagonist= curare
histamine H2 receptors
agonist= histamine:
- contracts ileum
- acid secretion from parietal cells
antagonist= mepyramine:
- reverse contraction of ileum
- no affect on acid secretion
factors governing drug action
receptor related= affinity and efficacy
tissue related= receptor number and signal amplification
affinity
described how well a ligand binds to a receptor
a property shown by both agonists and antagonists
influence of receptor number
the number of receptors influences the response of agonists and antagonists
as you increase antagonist conc. the number of receptor available for agonists decreases
receptor reserve
spare receptors
holds for a full agonist in a given tissue
no receptor reserve for partial agonists
signal transduction
transmission of a molecular signal from a cells exterior to its interior
signalling cascade that passes through many different pathways
different pathways can be interfered with to affect the response
signal amplification
changes in signal transduction can amplify the response even when the receptor and agonist are the same
allosteric modulation
substances that indirectly influence/modulate the effects of a primary ligand (which directly activates or deactivates the function of a target protein)
allosteric ligand affects signalling cascade causing a modified response
inverse agonism
agent binds to same receptor as agonist but induces a pharmacological response opposite of that agonist
causes down regulation of response rather than an antagonist preventing agonistic effect
tolerance
reduction in a drug effect over time
continuously, repeatedly high concentrations
desensitiastion
uncoupled
internalised
degraded
specificity
no compound is every truly specific
selectivity
better term to describe drug activity, over specificity
enzyme inhibitor
molecule that binds to an enzyme and decreases its activity
prevents substrate from entering active site so prevents the enzyme from catalysing the reaction
types of enzyme inhibitor
irreversible inhibitor:
-usually reacts with enzyme and changes it chemically
reversible inhibitor:
- binds non-covalently and different types of inhibition are produced
- depends on whether inhibitor binds to enzyme, enzyme-substrate complex or both
statins
HMG-CoA reductase inhibitors
block rate limiting step in cholesterol pathway
class of lipid lowering medications, reducing CVD
parkinson’s treatment
L-DOPA: produced from the amino acid L-tyrosine, as a precursor for neurotransmitter biosynthesis
peripheral COMT inhibitor: prevents LDOPA breakdown, generating more for CNS pathway
central dopamine receptor agonists: agonise dopamine receptors, not enzyme inhibitors
drug and ion transport
passive:
- symporter (Na/K/Cl, NaCl)
- channels (Na,Ca,K,Cl)
active:
-ATPases (Na/K, K/H)
protein ports
uniporters: use energy from ATP to pull molecules in
symporters: use movement in of one molecule to pull in another molecule against a conc. gradient
antiporters: one substance moves against its gradient, using energy from a second substance moving down its gradient
example of symporters
Na/K/Cl cotransporter
moves ions in same direction
functions in organs that secrete fluids
causes ion loss in urine
ion channels
epithelial sodium- heart failure
voltage gated calcium or sodium- nerve, arrhythmia
metabolic potassium- diabetes
receptor activated chloride- epilepsy
voltage gated calcium channels
found in membranes of excitable cells
at resting potential they are closed, and opened when the membrane is depolarised
calcium ions enter cell resulting in activation of calcium sensitive potassium channels, muscular contraction and excitation of neurones
voltage gated calcium inhibition
amlodipine is a calcium channel blocker, inhibiting movement of calcium into vascular smooth muscle cells and cardiac muscle cells
causes vasodilation and reduction in peripheral vascular resistance- lowering BP
epithelial sodium channel
apical membrane bound ion channel, only permeable to sodium ions
causes reabsorption of sodium ions at collecting ducts of kidneys (also in colon, lung and sweat glands)
blocked by high affinity diuretic amiloride and thaizide
Proton pump
H+/K+ ATPase= proton pump of stomach
heterodimeric protein (2 genes)
responsible for acidification of stomach
proton-pump inhibitors= most potent blockers
omeprazole is 1st in class, irreversible inhibition with a drug half life of one hour- but works for 2-3 days
irreversible enzyme inhibitors
omeprazole- PPI
aspirin- COX inhibitor
xenobiotic metabolism
xenobiotics are compounds foreign to an organisms normal biochemistry
rate of metabolism determines duration and intensity of a drugs pharmacologic action
cytochrome P450
membrane associated proteins- either in inner membrane of mitochondria or in endoplasmic reticulum
major enzymes involved in drug metabolism (75%)
drugs undergo deactivation by them either directly or by facilitated excretion from the body
adherence
the extent to which the patients actions match agreed recommendations
6 ways to improve adherence
improve communication between patient and doctor
increase patient involvement in the care of their condition
understand the patient’s perspective by asking questions
provide information when prescribing new drugs
regularly assess their adherence
review their medicines at agreed intervals
allergic reactions to drugs
interaction of drug with patient (initial exposure may not be medical, e.g. penicillin in dairy)
subsequent re-exposure
target organs of allergy= skin, resp tract, GI tract, blood and blood vessels
hypersensitivity reactions
type 1= IgE mediated
type 2= IgG mediated cytotoxicity
type 3= immune complex deposition
type 4= T cell mediated
type 1 hypersensitivity
prior exposure so IgE antibodies formed
IgE becomes attached to mast cells or leukocytes, expressed as cell surface receptors
re-exposure causes mast cell degranulation and release of pharmacologically active substances
anaphylaxis
occurs within minutes and lasts for a couple hours
vasodilation
increased vascular permeability
bronchoconstriction
urticaria
angio-oedema
type 2 reaction
drug or metabolite combines with protein
body treats it as foreign and forms IgG andIgM antibodies
antibodies combine with antigen and complement activation damages cells
type 3 reaction
antigen and antibody form large complexes and activate complement
small blood vessels are damaged attracting leukocytes to the site- releasing pharmacologically active substances
leads to inflammatory response
type 4 reaction
antigen specific receptors develop on T lymphocytes
subsequent administration leads to local or tissue allergic reaction
non-immune anaphylaxis
due to direct mast cell degranulation
some drugs recognised to cause this
no prior exposure
main features of anaphylaxis
exposure to drug, immediate rapid onset
rash, swelling of lips and face, wheeze, hypotension (anaphylactic shock) and cardiac arrest
management of anaphylaxis
stop drug infusion
basic life support
adrenaline IM
high oxygen
IV fluid, antihistamine and hydrocortison
adrenaline
causes vasoconstriction to increase peripheral resistance, increasing BP and coronary perfusion (alpha 1 adrenoceptors)
stimulation of beta 1 adrenoceptors causes positive ionotropic and chronotropic affects on the heart
reduces oedema and bronchodilates ( beta 2 adrenoceptors)
risk factors for hypersensitivity
medicine factors= protein or polysaccharide based macro molecules
host factors= females>males and immunosuppression
adverse drug reactions (ADRs)
unwanted or harmful reaction following administration of a drug under normal conditions of use and is suspected to be related to the drug
can be mild (nausea or itching rash) or severe (respiratory depression or anaphylaxis)
side effects
unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment
rawlins thompson ADR classification
type A- augmented, predictable, dose dependent, common
type B- bizarre, idiosyncratic, not predictable or dose dependent
type c- chronic
type d- delayed, e.g. malignancies after immunosuppression
type e- end of treatment, occur after abrupt drug withdrawal
type f- failure of therapy
DoTS classification of ADRs
Dose relatedness (toxic, collateral)
Timing
patient Susceptibility
risk factors of ADRs
patient risk: Elderly, neonates, polypharmacy, gender, genetic predisposition, allergies, hepatic or renal impairment
drug risk: steep dose-response curve, low therapeutic index
prescriber risk: limit time and lack of supervision
causes of ADRs
pharmaceutical variation receptor abnormality abnormalities in metabolism immunological drug-drug interactions
ADR type A
extension of primary effect
(bradycardia and propranolol)
or secondary effect (bronchospasm with propranolol)
ADR type B
can’t be readily reversed
less common
life threatening
idiosyncrasy or allergy
idiosyncrasy
inherent abnormal response to drug
may be due to abnormal receptor activity or enzyme deficiency (x-linked)
ADR type C
steroids and osteoporosis
analgesis nephropathy
steroids and iatrogenic cushing’s disease
ADR type D
teratogenesis- drugs taken in first trimester (thalidomide)
carcinogenesis (cyclophosphamide and bladder cancer)
ADR type E
withdrawal seizures when stopping anticonvulsants
withdrawal syndrome when stopping opioids
suspecting an ADR
symptoms after drug is started
symptoms after dosage increase
symptoms disappear when drug is stopped
symptoms reappear when drug is restarted
common drugs to cause ADRs
antibiotics anti-neoplastics CVS drugs hypoglycaemics NSAIDS CNS drugs
most common system affected by ADRs
GI renal haemorrhagic metabolic endocrine dermatologic
common ADRs
confusion nausea diarrhoea constipation hypotension
avoiding ADRs
drug interactions
inappropriate medication
unnecessary medication
all can be avoided ^
yellow card scheme
collects spontaneous reports
collects suspected adverse reactions
voluntary
strengths of the yellow card
early warning system for identification of unrecognised reactions
provides info on factors which predispose patients to ADRs
safety monitoring of a product throughout its lifespan
weaknesses of the yellow card
cannot provide estimates of risk as true number of cases is underestimated
relies on ADRs being recognised and reported
what is the black triangle
indicated medicine is undergoing additional monitoring
what is a serious reaction
fatal
life threatening
disabling or incapacitating
results in or prolongs hospitalisation
information to include on a yellow card
suspected drugs
suspected reactions
patient details
reporter details
any useful information
drug targets
approved small molecule drug target is <400 proteins
G protein receptors
nuclear hormone receptors
ion channels
kinases
medical plants
poppy- morphine
deadly nightshade- atropine
periwinkle- vincristine
organic chemistry
produces most prescribed drugs
chloroform, phenol, isoflurane
inorganic elements/compounds
many drugs use inorganic elements e.g. platinum based anti-cancer agents
magic bullets
selective poisoning of microbe through metabolic pathway absent in humans
sulphonamide nucleus
unreactive and rigid
e.g. acetazolamide for glaucoma
bacteria moulds and fungi
use compounds derived from these
e.g. penicillin
receptor approach
noradrenaline -> propanolol
histamine -> histamine H2 receptor antagonist
stereoisomers
have same molecular formula but differ in 3D orientations of their atoms
monoclonal antibodies
single specificity mouse CD3 antibody which induces cytokine release
tumour necrosis factor alpha
cytotoxic factor released by activated macrophages
it stimulates acute phase proteins and mediates endotoxin poisoning, septic shock and chronic inflammation
three approaches to neutralisation of TNFalpha
Chimeric antibody- infliximab
Fusion protein- etanercept
human antibody- adalimumab
infliximab
initially for crohn’s disease
rheumatoid arthritis
inhibits lymphocyte proliferation
fusion protein (etanercept)
dimeric fusion of TNF II receptor
rheumatoid arthritis and plaque psoriasis
human antibody (suffix -umab)
fully humanised TNF alpha antibody
inhibits lymphocyte proliferation, down-regulates inflammatory reactions associated with autoimmune disease
animal sources of drugs
endocrine hormones- insulin, thyroxine, steroids
insulin
originally extracted from cow/pig pancreas
2 peptide chains joined by disulphide bridges both derived from a single sequence
recombinant human insulin= human gene inserted into bacteria DNA
shorter acting insulin
switch lysin and proline residues
faster onset, shorter duration of action
inject before a meal
long acting insulin
slow release, lower risk of nocturnal hypoglycaemia
recombinant proteins in clinical use
insulin
erthypoietin
growth hormone
interleukin 2
steroids
work through nuclear hormone receptors
clinical uses of glucocorticoids
skin- eczema, psoriasis lung- asthma, COPD GI- inflammatory bowel disease MSK- inflammatory arthritis CNS- multiple sclerosis
adverse effects of glucocorticoids
hypertension fluid retention osteoporosis muscle wasting peptic ulcer Cushing's syndrome
development of methotrexate
- folic acid worsens leukaemia
- structural analogues of folic acid developed
- methotrexate inhibits enzyme dihydrofolate reductase, has a high affinity for folate
high-throughout screening
used in drug discovery
uses robotics, data processing and sensitive detectors
rapidly identifies active compounds, antibodies or genes that modulate particular bimolecular pathways
provides starting points for drug design
rational drug design
finds new medications based on knowledge of biological target
most commonly a small organic molecule that activates or inhibits the function of a biomolecule
druggability
the ability of a protein target to bind to small molecules with high affinity
aka ligandability
use of cholinergic and adrenergic pharmacology
control BP control HR anaesthetic agents regulate airway tone control GI function
parasympathetic nervous system
cranial nerves carry signals to the body
sacral outflow innervates the pelvis
short postsynaptic nerve fibres reach the targets and release ACh which acts on muscarinic receptors
sympathetic nervous system
regulates fight and flight
nerve fibres originate in spinal cord and then send out long nerve fibres to blood vessels and muscles
they release noradrenaline which activates adrenergic receptors
2 main neurotransmitters
acetylcholine
noradrenaline
NANC system
non-adrenergic, non-cholinergic autonomic nervous system
releases and uses other neurotransmitters
cholinergic pharmacology
nicotine stimulates all autonomic ganglia in both symp and parasymp
separate nicotinic receptors where ACh is a neurotransmitter
muscarine activates muscarinic receptors of para system
muscarinic receptors
M1- in brain
M2- in heart (activation slows heart)
M3- glandular and smooth muscle
M4/5- in CNS
muscarinic agonists and antagonists
agonist= pilocarpine
stimulates salivation, contracts iris smooth muscle, slows heart
antagonists= atropine
hyoscine
muscarinic antagonists/anticholinergic uses
dry secretions
bradycardia
treatment of bronchoconstriction
anti-cholinergic side effects
in the brain it worsens memory and causes confusion
peripherally it causes constipation, dries mouth, blurs vision, worsens glaucoma
cholinergic side effects
cause muscle paralysis and twitching
salivation
confusion
catecholamines
noradrenaline- sympathetic fibre ends, manage shock in ICU
adrenaline- released from adrenal glads, manage anaphylaxis
dopamine- precursor for both above
outcomes of signalling depends on:
receptor
the cell it’s on
which G protein
alpha agonists
alpha 1 activation causes vasoconstriction in skin and splanchnic beds
treat septic shock
adrenaline raises BP and cardiac work
alpha 1 and 2 are not the same
alpha 1 raise BP
alpha 2 lowers BP
alpha blockers
opposite effect to agonists
beta agonists
beta 1 increases HR and chronotropic effects
beta 2 helps with muscle relaxation - asthma
beta 3 can reduce over active bladder symptoms
beta blockers
propranolol blocks 1 and 2, slowing HR, reduce tremor but can cause wheeze
lowers BP by reducing cardiac work
uses= angina, high BP, anxiety, arrhythmias
side effects= tiredness, bronchoconstriction, cardiac depression
naturally occurring opioids
from the opium poppy
morphine
codeine
simple chemical modifications to opioids
diamorphine- heroin
oxycodone
dihydrocodeine
synthetic opioids
pethidine
fentanyl
alfentanil
remifentanil
opioid synthetic partial agonist
buprenorhine
opioid antagonist
naloxone
routes of opioid administration
- trans dermal patches
- epidural
- patient controlled analgesia IV
- parenteral (IM, IV, sub-cutaneous)
- oral
opioid pharmacodynamics
- opioid drugs use existing pain modulation system
- natural endorphins and G protein coupled receptors
- inhibit the release of pain transmitters at spinal cord and midbrain
- modulate pain perception in higher centres: euphoria
- not designed for sustained use as it leads to tolerance and addiction
opioid receptors
Mu (micro symbol )opioid receptors
delta and kappa opioid receptors
nociceptin opioid like receptors
MOP,KOP,DOP,NOP
currently all drugs used are mu (micro symbol) agonists
opioid tolerance and dependence
tolerance- down regulation of receptors with prolonged use so higher doses required
dependence- craving, euphoria
withdrawal- starts within 24 hours, lasts 72 hours
opioid side effects
respiratory depression sedation nausea constipation itching endocrine effects
opioid induced respiratory depression
naloxone IV (400 micrograms/ml) titrate to effect- dilute 1ml to 10ml of saline
opioid use in chronic pain
for non-cancer patients it starts to lose effectiveness relatively quickly
addiction is likely and leads to manipulative behaviour
opioid pharmacogenetics
- codeine needs to metabolised by CYP2D6 to work
- this activity is decreased in 10-15% of caucasian people and is absent in a further 10% of people
- therefore codeine effect is reduced or absent in these people
- it is overactive in 5% of caucasians so the risk of respiratory depression is higher
opioid metabolism
morphine is metabolised into morphine-6-glucuronide which is more potent than morphine and is renally excreted
in renal failure it builds up and causes respiratory depression
tramadol
- weak opioid agonist slightly stronger than codeine
- metabolised by CYP2D6 to o-desmethyl tramadol and is now activated
- secondary affect in analgesia as a serotonin re-uptake inhibitor
pharmacokinetics
action of drugs in the body
absorption
distribution
metabolism
excretion
absorption
process of transfer from the site of administration into general systemic circulation
routes of administration
oral IV Intra-arterial IM SC inhalation topical sublingual rectal
passage across membranes
passive diffusion through lipid layer
diffusion through pores or ion channels
carrier mediated processes
pinocytosis
passive diffusion
need to be lipid soluble to cross the bilayer- steroids
rate of diffusion is proportional to conc. gradient, the area and permeability of the membrane
ion channels and pore diffusion
occurs down conc. gradient
restricted to small water soluble molecules e.g. lithium
active diffusion- carrier mediated
uses ATP
against conc. gradient
ATP-binding cassette family (ABC)
facilitated diffusion
carrier aids passive movement down conc. gradient
can use electrochemical gradient of solute to transport another molecule to move against conc. gradient
300+ members of solute carrier super family
pinocytosis
carrier mediated entry
involves uptake of endogenous macromolecules
e.g. amphotericin can be taken into liposome
drug ionisation
basic property of drugs that are weak acids (aspirin) or weak bases (propanolol)
ionisable groups are needed for mechanism of action for ligand-receptor interaction
PKa of drug= dissociation/ionisation constant, and is pH at which half of substance is ionised
pH affects ionisation- weak acids are best absorbed in stomach and weak bases are best absorbed in intestine
oral absorption
this route is easiest and most convenient for many drugs
large surface area and high blood flow of small intestine can give rapids and complete absorption
factors that affect oral absorption
drug structure
drug formation
gastric emptying
first pass metabolism
drug structure
- needs to be lipid soluble to be absorbed in gut
- polarised tend to only be partially absorbed- passing into faeces
- some drugs unstable at low pH or in presence of digestive enzymes
drug formulation
capsule or tablet must dissolve to be absorbed
must do so rapidly
some dissolve slowly or have an acids resistant coating
gastric emptying
determines how soon a drug taken orally is delivered to small intestine
can be slowed by food or drugs
and faster by gastric surgery
first pass metabolism
drugs have to pass 4 major metabolic barriers to reach circulation:
- intestinal lumen
- intestinal wall
- liver
- lungs
absorption routes: order of time until effect
- IV (30-60s)
- intraosseous
- endotracheal (2-3 min)
- inhalation
- sublingual (2-5 min)
- IM (10-20min )
- SC (15-30 min)
- rectal (5-30 min)
- ingestion (30-90min)
- transdermal
transcutaneous
slow and continuous absorption is useful with transdermal patches
effective barrier to water soluble compounds so needs to be lipid soluble
intradermal
avoids barrier or stratum corneum
mainly limited by blood flow
use for local affect or to deliberately limit absorption
intramuscular
good blood supply and water solubility means enhanced removal of drug from injection site
intranasal
good surface area
used for local (decongestants) or system (desmopressin) effect
inhalational
large surface area and blood flow but limited by risks to damage to alveoli
volatile drugs only
asthma drugs are non volatile so given as aerosol
distribution
process by which a drugs is transferred reversible from general circulation to the tissues
once equilibrium is reached across a cell membrane, any process that reduces the conc. on one side causes movement to restore equilibrium
protein binding
drugs bind to plasma or tissue proteins
can be reversible or irreversible
most common reversible= albumin
drugs that bind irreversibly cannot re-enter circulation so it is equivalent to elimination
drug distribution in the brain
lipid soluble pass from blood to brain
water soluble enter slowly due to blood-brain barrier
efflux transporters return some drugs to circulation
the brain does little metabolising so drugs are removed by diffusion into plasma, active transport in choroids plexus or elimination in CSF
drug distribution on foetus
crosses placenta (lipid soluble more readily)
large molecules such as heparin do not cross placenta
foetal liver has low level of metabolising enzymes so relies on maternal elimination
elimination
removal of drugs from the body
may involve metabolism and/or excretion
metabolism
necessary for elimination of lipid soluble drugs
converted into water soluble products that are removed in urine
it produces one or more new compounds which show differences to parents drug
phase 1 metabolism reactions
involve transformation of drug to more polar metabolite
done by unmasking or adding a functional group e.g.-OH or -SH
oxidations are most common reactions catalysed by important enzymes called CYP450
other phase 1 reactions
not all require CYP450
some are metabolised in plasma, lung or gut
ethanol is metabolised by alcohol dehydrogenase
monoamine oxidase inactives noradrenaline
phase 2 metabolism reactions
conjugation
involves formation of covalent blond between the drug or its phase 1 metabolite and endogenous substrate
resulting products are less active and readily excreted by the kidneys
urine excretion
total excretion= glomerular filtration+tubular secretion-reabsorption
faecal excretion
high molecular weight molecules taken up into hepatocytes and eliminated into bile
bile passes into gut and some may be reabsorbed and enter hepatic portal vein
reaction kinetics
drug via IV is rapidly distributed
taking repeat plasma samples, the fall in plasma conc. can be measured
first order kinetics
decline in plasma conc. is exponential as a constant fraction is eliminated per unit time
dC/dT= -kC where k= rate reaction constant
zero order kinetics
change in conc. per time is a fixed amount, independent of concentration
dC/dT= -k
half life calculations
time taken for a conc. to reduce by half
units of rate constant are hard to use practically so usually use half life
half life = 0.693/k
bioavailability calcultions
fraction of administered drug that reaches the systemic circulation unaltered (F)
IV drugs F=1
oral drugs have F<1 if they are incompletely absorbed or undergo first pass metabolism
if oral bioavailability is 0.1 it’s does needs to be 10x IV dose
