TOPIC 10 - pharmacology Flashcards
what are the two branches of pharmacology?
- pharmacodynamics
- pharmacokinetics
what is pharmacodynamics?
specific to drug or drug class/way drugs act in body at specific points:
- interation with cellular component
- concentration effect relationship
- modification of disease progression
what is pharmacokinetics?
non specific general processes/ quantitive study of drugs movement in the body:
- absorption from site of administration
- time to onset of effect
- elimination from the body
what is a generic name?
approved or official name
what is the chemical name?
based on its chemical structure
what is the use name?
categorised according to use.
eg. anti-inflamatories, pain killer, contraceptives
what is the effect name?
some drugs categorised due to biological response in the body. eg. pain killer
what are + to oral route of transmission?
- convenient
- safe
- economical
what are - to oral route of transmission?
- cannot be used for drugs inactivated by 1st pass metabolism or that irritate the gut
what is first pass metabolism?
metabolism occurs prior to and during absorption
when the drug travels to the liver and gets broken down so 100% of the drug is not absorbed
what are + to intramuscular route of transmission?
(muscles are water based, so drugs have to be water based)
- suitable for suspensions and oily vehicle
- rapid absorption fro solutions
- slow and sustained absorption from suspensions
what are - to intramuscular route of transmission
- may be painful
- may cause bleeding at site of injection
what are + to subcutaneous route of transmission
(fat layer so drugs tend to be more fat loving)
- sutiable for suspensions and pellets
what are - to subcutaneous route of transmission
- cannot be used to deliver large volumes of fluid as layer quite small
- cannot be used for drugs that irritate cutaneous tissue
what are + to intravenous route of transmission
(straight into vein and circulation, bypass 1st pass metabolism)
- bypasses absorption yielding immediate effect
- 100% immediate bioavailibiltiy
what are - to intravenous route of transmission
poses more risk for toxicity: cant remove it once given if person has reaction
what are + to buccal route of transmission
(placement of tablet under cheek)
- rapidly absorbed
- avoids 1st pass metabolism
what are - to buccal route of transmission
- effective only for low doses as space under cheek small
- drugs must be water and lipid soluble
what are + to transdermal route of transmission
(on skin, eg. nicotine patches)
- avoids 1st pass metabolism
what are - to transdermal route (eg.nicotine patches) of transmission
effective only for low doses of drug that are highly lipids soluble as has to cross the skin layer
what are + to inhalation route of transmission
-produce localised effect
what are - to inhalation route of transmission
- drug particles must be correct size
- dependent on patient technique
what are + to intrathecal route of transmission
(administration into spinal chord into brain)
- local and rapid effects
what are - to intrathecal route of transmission
- requires expert administration
- may introduce infection/ toxicity
what are + to epidural route of transmission
(administered into epidural sac close to spinal chord)
provides a targeted effect
what are - to epidural route of transmission
- risk of fialure
- risk of infection
what are + to topical route of transmission
( application to skin)
- non-invasive and easy to administer
what are - to topical route of transmission
- poorly lipid soluble not absorbed via skin or mucous membranes- drug must be very lipophilic
- very slow absorption
what is modified dose forms
less frequent administration of a drug as drugs released over a long period of time
benefits of using modified dose forms
- improved patient adherence
- reduction in incidence and severity of GIT effects
- improved control over therapeutic plasma conc.
dis advantages of using modified dose forms
cost more per unit than conventional forms
- possibilty of unsafe dosage if used incorrectly or in failure of MR tablet
- rate of transmit through GIT. limits the max period for which a therapeutic response can be maintained
- variability in physiological factors, eg. GIT,pH,enzymes, food ect. influence drug bioavailbity
how can we get incorrect route of transmission
- oral medications given intravenously
- intramuscular preparations administered intravenously
- epidural and intravenous lines mix- up
- using intravenous medications orally
- intrathecal administration instead of intravenous admistration
incidents can result it adverse outcomes, inc death
what is ADME
- administration
- distribution
- metabolsim
- elimination/excreation
what happens when the drug is administered orally
- its absorbed and goes through the first pass metabolism
- metabolised by liver
- distribution to systemic circulation, tissue spaces and cells via the hepatic portal vien from liver
- pharmacological action in target tissue
- metabolised by the liver
- excretion via kidneys, lungs, faces
same process when drug administered via injection but no first pass metabolism in liver - straight to systemic circulation
what is absorption
Transfer of the drug from the site of administration into the general or systemic circulation
in first pass metabolism is all of the drug absorbed from the gut?
no only proportion of drug absorbed
what factors affect oral absorption
- Particle size and formulation
- GIT enzymes/AIDS
- GIT motility
- Physicochemical factors
- Food
why is particle size and formulation important in oral absorption?
– time taken for drug to disintegrate to small enough size for distribution
– compound must be small enough and lipid soluble to cross gut wall
why is GIT enzymes/acid important in oral absorption?
GI tract acidic but less acidic than stomach so breakdown from stomach can continue to smaller particles in GIT
why is GIT motility important in oral absorption?
- GIT constantly moving
– rate which gastroempties occurs determines rates drug delivery to gut and absorbed to blood stream to go to right area to be absorbed
-Hyper-motility- gut moving too fast= diarrhoea = lack of absorption = not staying in small intestines long enough to be absorbed
Hypo-motility= constipation – gut not able to move and open our bowels
why is physiochemical factors important in oral absorption?
- drug size
- point at which drug disintegrates
why is food important in oral absorption?
eg. Take with food, on empty stomach – compounds in food may contain electrolytes which effect how drug absorbed
are drugs acids or bases?
both
properties of whether acidic or basic determine how drug will work and where it will be absorbed
NB- For drugs to pass membrane have to be uncharged
are acidic drugs ionised or unionised in stomach?
Acids are compounds that can dissociate to donate one or more protons= become ionised in stomach
are basic drugs ionised or unionised in stomach?
Bases are proton acceptors= Start off being charged and then become unionised
what is the degree of ionisation dependent on?
pH of their environment- whether they are in stomach or small intestine
what is distribution
- movement of drug in body
-The process by which the drug is transferred reversibly
•from the general circulation into the tissues as concentrations in blood increase
•from the tissues into blood as blood concentrations decrease - needs to have free movement in different areas
what is the distribution of a drug dependent on?
lipid solubility, ionisation and physiological ph of envriroment
how does distribution normally happen
Mainly occurs by passive diffusion of un-ionised form across the cell membrane
what is the volume of distribution
Volume of plasma that accounts for total amount of drug
what is volume of distribution used for
•Used to determine the loading dose necessary for a desired blood concentration of a drug, half life and how long take to be cleared
•Also used for estimating a blood concentration in the treatment of overdose
- proteins have large role in this
what factors effect drug distribution
- plasma protein binding
- specific drug receptor sites in tissues
- regional blood flow
- lipid solubility
- disease
why is plasma protein binding important in distribution of drugs
- helping transfer drugs to site of action
- protein binding can enhance or detract from drugs performance
- Agents that are minimally protein bound penetrate tissues better than those highly protein bound as less difficult to leave protein and carry out job
- Drug only effective when unbound
- eg. low albumin can effect how well protein binds to protein and how much free drug we have
what barrier do dopamine agonists cross
blood brain barrier
results are CNS based and effect CNS
why is regional blood flow important in distribution of drugs
more blood flow= better distribution
why is lipid solubilty important in distribution of drugs
like drugs more lipophilic – can cross into different tissues as all made of lipids
why is the drug protein complex important
- allows for distribution of drug
- if highly protein bound= difficult to break
what proteins do drugs become bound to in a drug protein complex
- Binding of drugs with albumin and glycoproteins
* Reversible structure
what happens if you administer a highly protein binding drug to a patient who is already taking a drug that is highly protein bound
•Results in displacement of drug already bound to protein
•Produces increased unbound concentration of drug and biological activity
-If drug is widely distributed in tissues, the increase in unbound drug is rapidly redistributed to body tissues and unbound plasma concentration rapidly returns to negligible amount
are changes in plasma protein binding significant?
only for drugs which are greater than 90% bound to plasma proteins
what drugs are bound to albumin
- furosemide
- ibuprofen
- phenytoin
- thiazides
- warfarin
what drugs are bound to glycoproteins
- chorpromazine
- propranolol
- tricyclic antidepressents
- lidocaine
what must a drug be to be able to cross membranes
- not bound to protein
- Drugs needs to be lopophilic to move around
how are drugs transported across the membrane
- Passive diffusion
- Transporters
- Membrane pores
- Vesicle mediated transport (Pinocytosis)- molecules engulfed by cell membrane and vesicle formed which then releases molecule in cell
why do we metabolise drugs?
to alter drugs to facilitate their removal from the body
what are the 4 roles of drug metabolism
- Activation of inactive drug:
Drug should only have affect on certain part of body
Liver breaks down drugs to active form
-Production of active drug with increased activity from active drug
When drug broken down again produces more active compound so can manage symptoms even more - Inactivation of active drugs
Once drug has had effect- eliminate from system - Change in the nature of the activity: Sometimes drug metabolism changes structure of drug so much no longer has effect
what are the 4 major metabolic barriers a drug must overcome in first pass metabolism
- intestinal lumen: digestive enzyme secreted by mucosal cells and pancreas- certain enzymes break down proteins and stop them being absorbed
- intestinal wall: rich in enzymes- further metabolism
- liver- major site of drug metabolism
- lung: cells of lung= high affinity for many drugs and are site of metabolism for lots of hormones
this means slow breakdown of drug throughout our system
what are the phases of metabolism
phase 1: reaction (oxidation,reduction and hydrolysis)- lipophilic drug made into more reactive drug
-phase 2: reaction/cojugation: drug made more hydrophilic and so water soluble to be excreted from kidneys
what factors effect drug metabolism
- first pass effect
- hepatic blood flow: good blood supply= better breakdown
- liver disease: could mean some enzymes are not present
- genetic factors
- other drugs
- age
what is CYTOCHROME P450 (CYP450) system
• A large family of enzymes and individual one is called an isoenzyme.
how do isoenzymes break down drugs?
•Substrate: drug metabolised by isoenzyme
- Then introduce a drug which is enzyme inducer/inhibitor for same isoenzyme
- result depends on whether inducer or inhibitor
what do enzyme inducers do
•Enhance production of liver enzymes which breakdown drugs
•Faster rate of drug breakdown
End up with smaller levels of substrate = less drug in system
what do enzyme inhibitors do
•Inhibit production of enzymes which breakdown drugs
•Reduced rate of drug breakdown
So more drug in system as its not being broken down efficiently enough
How is paracetamol metabolised normally
undergos conjugation turning into inactive metabolites paracetamol glucuronide and paracetamol sulphate
what kind of additional metabolism takes place if we have an overdose of paracetamol
conjugation pathway oversaturated so oxidation pathway used
1- oxidation
2- produces N-acetly-p-benzoquinoneimine (NAPQI)= toxic metabolite- effets liver
3- cysteine derivatives
We use acetylcysteine to push it back down conjugation pathway – to get inactive not toxic metabolites
what is bioavailibility
Proportion of a dose that reaches systemic circulation
what effects bioavailibitly
taking drug orally - not 100% drug in systemic ciruclation
- Intravenous route- 100% in systemic circulation
what is bioequivalence
Two or more chemically or pharmaceutically equivalent products – similar dosage forms but from diff companies
why is bioequivalnce useful
may be appropriate to replace one product with another without causing clinical problems
where does get eliminated
liver or kidney
what does elimination via the liver depend on?
- blood flow to the liver
* activity of the enzymes in the liver
what do liver enzymes do
chemically alter the drug to form ‘metabolites’ which are:
•inactive
- water soluble so kidneys can get rid of it
•equally or more active than the parent drug
how elimination via the kidney get rid of drug
Any ionised lipid soluble drugs eliminated by urine
what is clearence
Volume of blood/plasma cleared of drug per unit time
- This includes metabolic as well as renal and biliary clearance
- Clearance does not indicate the amount being removed
whats half life
time taken for the conc to reduce by 50%
When drug undergoes 5 half lives = drug cleared from system
what is creatinine
- Creatinine is a substance produced in skeletal muscle when skeletal muscles broken down which is excreted through the kidneys
- It is neither passively reabsorbed nor actively secreted
- Estimation of creatinine clearance, gives idea of how well kidney function is estimates clearance of drugs filtered at glomerulus
why might patients have a raised creatinine level
renal failure OR
have more muscle mass
test doesn’t take that into consideration
why might patients have a decreased creatinine level
renal failure OR
old age, not as much muscle mass
what is the COCKCROFT GAULT EQUATION
Gives real idea of renal function
= {(140-Age) x Weight x Constant} /Serum Creatinine
Age in years
Weight in kilograms
Serum creatinine in micromol/litre
Constant 1.23 for men 1.04 for women
does age affect absorption?
- in elderly generally unchanged
- in children unrelaible in neonates
does age affect distribution?
in children and elderly fat components of body mass tends to be proportionally greater- act as resevior
does age affect metabolism?
in infants = reduced capacity = immature liver = drug effects prolonged
in elderly = reduction = impaired liver function = effects more pronounced, last longer
does age effect excretion
in children reduce capacity die to immature kidneys
in elderly reduction due to impaired glomerular filtration rate
what are the three properties of drugs?
affinity, efficacy and potency
what is drug affinity?
the chemical forces that cause the drug to bind to the receptor site
(drugs with low affinity= need high conc to have effect)
what is drug efficacy?
the extent of functional change in response to a drug binding to a receptor
-relative ability of drug receptor complex to produce a response
(high efficacy drugs = only need few receptors bound to drug for output)
what is drug potency?
dose of drug needed to produce a biological effect (higher efficacy/affinity = lower dosage)
(highly potent= larger response at low conc)
what is an agonist?
drug that binds to receptors and initiates a cellular response - normally mimic naturally occurring hormones
- have high affinity and efficacy= strongly bound to receptor
what is a partial agonist?
act on same receptor but do not produce a maximal response no matter how much receptors activated (eg debutamine mimic noradrenaline)
what is an inverse agonist?
acts on same receptor but produces an opposite affect (eg naloxone reverses opioid toxicity)
what is an antagonist?
drug that binds to receptors but does not initiate a cellular response
- has affinity but no efficacy
what is a competitive antagonist?
reversibly bind to same site as the agonist but does not activate it
what is a non-competitive antagonist?
irreversibly binds to an allosteric site(not the active site) to prevent activation of the receptor
- changes structure of molecule completely = no resposne
what kind of dose response curve is used to compare drugs and what shape does it produce?
- log scale
- sigmoidal
what is drug threshold?
dose that produces a just-noticeable effect/ lowest dose we can give
what is ED50?
dose that produces 50% of maximum response
what is ceiling?
lowest dose that produces maximal effect
- max dose of drug we can give
what is relative potency?
ED50(lower potency drug)/ ED50(higher potency drug)
- potency good way to see which agonist has higher affinity for given receptor
will an agonist + competitive antagonist reach a maximum response?
yes - sigmoidal curve still produced, just shifted right as takes longer to reach maximum
- because of reversible binding, agonist can still bind to sites
will an agonist + non-competitive antagonist reach a maximum response?
no - cannot be reached as antagonist binds irreversibly and changes the structure of the molecule
- some response can still be reached as agonist can occupy receptor site before antagonist (curve shifted right )
what are the 4 general mechanisms of drug action?
- action on receptors
- action on synapses
- enzyme action
- inhibit cell transport
how do histamine H2 receptor antagonists (ranitidine, cimetidine) work?
block H2 receptor - inhibiting action of histamine - reduces cAMP formation - reduced gastric induced acid secretion all happens in the gut
what is gastric acid secretion stimulated by?
histamine, acetylcholine and gastrin
what is the function of acetylcholine (Ach)?
enables muscle action, learning and memory
what does low levels of acetyl choline cause?
Alzheimer’s disease
what is the function of noradrenaline?
helps control alertness and mood, increases heart rate
what does low noradrenaline cause?
depression
what does high noradrenaline cause?
insominia
what is the function of dopamine?
influences movement, attention and emotion
what does low levels of dopamine cause?
parkinson’s disease
what does high levels of dopamine cause?
schizophrenia
what is the function of Gamma Amino Butyric Acid (GABA)?
major inhibitory neurotransmitter
what does low levels of GABA cause?
anxiety
what is the function of serotonin (5-HT)?
affects sleep, mood, hunger and arousal
what does low levels of serotonin cause?
depression
what do SSRI’s do?
selective serotonin reuptake inhibitors - block reuptake of serotonin so more in synaptic cleft, so more stimulation of receptors
what do TCA’s do?
tricyclic antidepressants - block reuptake of serotonin and noradrenaline but can cause cognitive impairment (so don’t use in old people)
what is released following tissue injury that triggers COX?
arachidonic acid
what does COX 1 do?
cytoprotective prostaglandins
- protect gastric mucosa
- protect renal perfusion
thromboxanes
- aid platelet aggregation
what does COX 2 do?
inflammatory prostaglandins
- recruit inflammatory cells (inflammation, vasodilation)
- sensitise skin pain receptors
what do NSAIDs do?
non-steroidal anti-inflammatory drugs
- eg iburpfen and aspirin
- inhibit cycloxeganses
what do ACE inhibitors do?
inhibit angiotensin converting enzymes
- prevent angiotensin 1 –> 2
- reduce blood pressure
what do ARB’s do
angiotensin II receptor antagonist
- block action of angiotensin II receptors
= no vasoconstriction or aldosterone release
what do calcium channel blockers do?
bind to calcium channels on smooth muscle, block influx of calcium —> smooth muscle relaxation and decreased heart rate
what are the three classes of calcium channel blockers?
- dihydropyridines - most smooth muscle selective (most commonly used- work mostly on vascular points)
- phenylakylamine - selective to myocardium, less effective vasodilator (work mostly on calcium channels near the heart)
- benzothiazepine - cardiac depressant and vasodilator
Last 2 more work more on calcium channels near heart – more cardioselctive = make sure don’t work too well
what do local anaesthetics (LAs) do?
- produce a transient and reversible loss of sensation in restricted area of the body without loss of consciousness
- cause depression of excitation in nerve endings or inhibition of conduction process
- Used for analgesia too – for pain management not just during procedure but also post operatively
what is the general structure of LAs?
- lipid-soluble hydrophobic aromatic group
- charged hydrophilic amine group
- can be joined by and an amide or ester bond (bond determines class of drug)
- are weak bases-proton acceptors = become unionised
what are the properties of ester LAs?
- rapidly hydrolysed
- breakdown product = PABA
- PABA associated with allergic and hypersensitive reactions
- eg cocaine and amethocaine
what are the properties of amide LAs
- relatively stable and safer than esters
- hypersensitivity reactions rare
- eg lignocaine, bupivacaine and prilocaine
which LA is more commonly used and why?
amides - more stable and so can be stored for longer as ester linkage is more commonly broken down
what is the LA mode of action?
intracellular blockage of Na+ channels
- therefore nerve signal not transmitted as no action potential = if pain is being experienced nit registered by the brain
- blocking sodium channels we work on nerves= decrease ability for conduction= vasodilation by causing smooth muscles relax – working on CNS and heart rate also
what are potential adverse affects of LAs?
- can cause myocardial depression and vasodilation as block Na+ channels in conduction system of heart
- restlessness or convulsions- effects on CNS
- adrenaline causes constriction of vessels, less distribution , prolonging action and producing nearly bloodless field
how are ester LAs metabolised?
(except cocaine)
broken down by plasma esterases to inactive compounds and have a short half life
how are amide LAs metabolised?
hepatically by amidases, half life is longer and can accumulate if given by repeated doses or infusion
where are LAs administered
usually to site
why would you never use ACE inhibitors and ARBs together?
no additional benefit as work at different points of cycle
what are the side effects of NSAIDs such as ibuprofen?
- GI irritation- no longer COX1 to protect gastric mucosa
- fluid retention- no longer protect renal perfusion and so kidneys
