Pharmacology Flashcards
What is pharmacology? What is pharmokinetics? What is pharmocodynamics? What does physiochemical mean? What is a drug?
The study of the effects of drugs
How the body affects the drug; absorption, distribution, metabolism and excretion (ADME)
How the drug affects the body
The way in which drugs interact with each other
Any compound that is administered with an intended therapeutic effect
The 3 pharmacokinetic phases of drug uptake? Most pharmacodynamic theory in terms of what? For a dissolved drug in the plasma, what is meant by a first order process? Rate of diffusion is directly proportional to what too?
Uptake into the plasma, distribution from the plasma, elimination from the plasma
Conc times curves
Rate of diffusion= directly proportional to the conc gradient
Temperature- most drugs won’t work outside normal physiological temperature
What does second, third and zero order also mean? Diffusion is a what function?
Rate is directly proportional to the square of the conc of the drug
Proportional to the cube of drug conc
Zero order= rate is unrelated to conc of drug
Exponential function- rate of reaction is governed by one of the components involved in the reaction whose quantity/ magnitude is changing
What is the plasma? Proteins are found here as result of what? pH of what is reflected in the plasma? pH of plasma compared to interstitium?
The fluid fraction/ aqueous solution that remains when cells are removed from the blood
Polar amino acid side chains
The interstitium
Higher due to diffusion gradient
3 main compartments divided by tissue lipid rich barriers in pharmacokinetic theory? What is the ‘‘cellular tissue’’ divided into? 5 ways drug can move from its site of administration to its target?
Plasma (5 litres,) interstitial (15 litres) and intracellular (45 litres)
Vessel rich viscera- muscle tissue
Vessel poor- fat stores/ subcutaneous tissue
Simple diffusion, facilitated diffusion, active transport, through extracellular spaces, non ionic diffusion
What process is active transport at initially but then when saturated? What cannot enter through pores in extracellular spaces? How does non-ionic diffusion work? When pH is increased, weak acid/ base more/ less ionised?
First order, then zero order when becomes saturated
Protein
Ionic molecule= less ionic, can cross lipid membrane to enter the cell e.g. aspirin
Weak acid= more ionised, weak base= less ionised
What has large effect on uptake into plasma? What is bioavailability? Routes of administration?
Route of administration
Amount of drug taken up as proportion of amount administered
Oral, intramuscular, intravenous, transcutaneous, intrathecal(into CSF,) sublingual, inhalation, topical, rectal
What route has greatest variability and why? Most tablets are either what? Water soluble tablets will not pass across cell membranes unless there is what?
Oral- due to different factors involved; surface area of gut, diarrhoea, pH of gut (alkaline at duodenum)
Weak acids or weak bases
Carrier mediated transport
Bioavailability of intramuscular, IV and transcutaneous? Aspirin in the stomach? In plasma? Antacids do what? Ingesting what increases pH? What reduces aspirin uptake from stomach?
Close to 1, should be 1, lower than IV
Is acidic, so dissolves, becomes less ionised, moves rapidly across gut due to un-ionised
More ionised due to higher pH
Act to increase pH e.g. omeprazole and ranitidine act to reduce acid secretion in stomach and increase pH
Alkali foods
Raised pH–> reduced bioavailability
Drug is distributed in plasma according to what? What are found in the aqueous phase? What are only active in the plasma compartment? What are active in plasma and interstitial compartment? What are only active in the intracellular fluid?
Its chemical properties and molecular size
Dissolved gases and small ionic molecules
Proteins/ large molecules
Water soluble molecules
Lipid soluble molecules
What is a steady state? How is volume of distribution calculated? What is it?
Where drug intake is in equilibrium with its elimination
Total amount of drug in body/ conc of drug in plasma
The volume that drug would occupy if it was distributed through all compartments as if they were all plasma
Why may volume of distribution be larger than it actually is? Vd of highly lipid soluble drugs and enter what?
When calculating, concentration and volume is taken from plasma- when drug infected, can be taken up by organ systems, so blood conc will decrease
High volume of distribution and enter the CNS
3 things found in plasma? In interstitial fluid? 6 in intracellular? Vd of amiodarone?
Plasma expanders, immunoglobulin, warfarin
Aspirin/ other NSAIDs, antibiotics, muscle relaxants
Steroids, local anaesthetics, opioids, CNS drugs, paracetamol, amiodarone- 450L, very easily taken up by tissue
What does compartment modelling assume? Shows plasma conc against what during when? Line of best fit to what? For every compartment, what is added?
That plasma is in equilibrium
Against time during distribution of drug phase
To 1,2 or 3 compartment models of distribution
Another C0e-kt
Most lipid soluble drugs have how many compartment models? Elimination of drug is from what compartment? What 2 routes are for vast majority of drugs? What process type?
3- suggests movement is plasma–> viscera–> adipose tissue
Plasma
Renal and/ or hepatic elimination
First order process
2 definitions of clearance? Both are measures of what? Can influence rate of elimination how? Units?
Removal of drug from plasma by liver/ kidney
Volume of plasma that can be completely cleared of drug per unit time
Rate at which plasma drug is eliminated per unit plasma conc
Efficiency
Depending on plasma conc of drug
Mls minute-1 (ml/ min)
All factors affecting what affect clearance? How are water soluble molecules eliminated? Larger can be eliminated how?
Renal blood flow- notably blood pressure
Which pass through glomerular endothelia= eliminated by glomerular filtration
By active tubular secretion
Calculation of rate of elimination assumes what? What is assumed to be constant? Clearance=? What is used as a marker substance in the kidney?
Rate of elimination= rate of appearance in urine
Plasma conc during clearance= constant
Rate of appearance in urine/ plasma conc
Creatinine
Renal blood flow= what % of cardiac output and value? Renal plasma flow= what % of blood flow? Glomerular filtration= what % of renal blood flow?
18%= 1 L/min 60%= 600mls/ min 12%= 130ml/ min
Many drugs are eliminated by the kidney by either what? Highly lipid soluble are metabolised how? What drugs have little exposure to renal clearance?
Glomerular filtration e.g. digoxin and gentamicin/ active secretion e.g. penicillin, furosemide, thiazides
Metabolised to water soluble glucuronic acid conjugates–> actively secreted e.g. morphine 3 and 6 glucuronides
Highly protein bound drugs
Acute and chronic renal impairment due to what? Drugs for patients with renal impairment? Hypoalbuminaemia results in what?
Acute= secondary to reduced pre-renal perfusion
Chronic= diabetes and hypertension
Ones eliminated by liver instead
Lipid soluble drugs= highly freely diffusible fractions and greater effects
Elevated plasma creatinine and urea compete for what? Management of renal impairment?
For lipid binding sites on protein and displace more lipid soluble free drug
Avoid nephrotoxic drugs, make corrections based on plasma creatinine- estimate % reduction in clearance and then alter dose, measure plasma cones if toxicity risk
Hepatic blood flow= % of cardiac output? All hepatic clearance involves what? Active secretion from where to where if what?
24%- 3/4 from portal vein, 1/4 from hepatic artery
Active transport
Liver–> bile duct if water soluble
What is the hepatic excretion ratio (HER)? High HER so clearance only limited by what? Low HER so clearance only limited by what? What can alter HER?
Proportion of drug removed by 1 passage through the liver
Hepatic blood flow
Diffusion
Liver enzymes
Liver does what if exposed to low HER drug? Effect of high HER drugs? Described as having a high what?
Produces more enzymes to enable it to increase clearance
Have little effect on number of new enzymes
First pass metabolism- first go to liver before can reach its target, but by then most of it will have been eliminated, limited uptake from oral administration
What is a pro-drug? 95% phase 1 reactions are where? Involves? Known as what? Mainly catalysed by what?
Activated in the liver, cleaved into the active drug via metabolism e.g. hydrocortisone–> cortisol
In liver SER- introduce/ expose hydroxyl group and reactive group for conjugation
Functionalisation- small increase in hydrophilicity
By cytochrome P450 enzymes
Cytochrome P450 uses what to oxidise substances? Requires what? E.g. drugs inhibit cytochrome P450?
Fe2+ group
Energy and molecular oxygen
Amiodarone and cimetidine
Phase II conjugation also known as what? Involves? Uses what enzyme? Co-enzyme needed to conjugate glucuronic acid?Forms what bonds?
Glucuronidation Adds glucuronic acid- more hydrophilic Glucuronosyltransferase UDPGA Covalent bonds--> glucuronides
Phase 1 water soluble metabolites and phase 2 glucuronides enter what? Enters what during cholestasis and reduced renal function?
Bile and gut via cystic duct, some I and II= blood and excreted in urine
Increased by kidneys/ biliary secretion
How can enterohepatic circulation prolong action of some drugs? What risk? Minimal effect on drug metabolism until what % of liver if not functioning? Pharmacodynamic alterations= often due to what?
Large bowel flora= metabolise glucuronic acid on phase II–> re-diffuse from gut into blood and have prolonged effect before going back to liver to be re-conjugated and excreted again
Drug accumulation and toxicity
70%
Secondary to disease
Drugs with active metabolites? 5 main types of drug targets?
Prednisone, isosorbide denigrate, codeine, diamorphine, L-dopa, cortisone, morphine
Receptors, enzymes, transporters, ion channels, most= proteins
3 methods of chemical communication? What is a receptor? Can be either what? 4 types of receptors?
Neurotransmitters- Ach, serotonin
Autoacids; cytokines, histamine
Hormones; testosterone, hydrocortisone
Component of cell that interacts with specific ligand and initiates change of biochemical events–> ligands observed effects
Exogenous (drugs) or endogenous (hormones, neurotransmitters)
Ligand-gated ion channels, G protein coupled receptors, kinase- linked receptors, cytosolic/ nuclear receptors
E.g. of ligand-gated? E.g. of G-protein coupled? Kinase-linked? Cytosolic/ nuclear receptors?
Nicotinic Ach receptor
Beta-adrenoreceptors- serpent-like receptors
Receptors for growth factors- show intrinsic kinase activity, tyrosine phosphorylation
Steroid receptors- can modify gene transcription, zinc fingers can recognise discrete regions of DNA
M3R (muscarinic receptor) couples with what to produce what second messengers? Beta-2- adrenoreceptor couples with what to produce what second messengers? Majority of GPCRs interact with what?
Gq and PLC–> IP3 or DAG
Gs and AC–> cAMP
PLC or AC
Imbalance of receptors/ chemicals can lead to what?
Chemicals: allergy- increased histamine, Parkinsons= decreased dopamine
Receptors: myasthenia gravis= loss of nicotinic Ach receptors, mastocytosis= increase in C-kit receptor
What is a receptor ligand? What is potency? What is EC50? Agonist?
Anything that acts at a receptor e.g. propranolol
Measure of how well a drug works
Conc that gives half the maximal response
Compound that binds to a receptor and activates it
2 types of normal response curve? Full and partial agonist meaning? Maximal response known as what? How is intrinsic activity calculated?
Linear and sigmoidal (more often used)
Full= 100% response on curve, partial= cannot get maximal response
Emax
Emax of partial agonist/ Emax of full agonist
Antagonist meaning?Competitive vs non-competitive antagonism? Does what to the curves?
Compound that reduces effect of agonist
Compete with agonist to bind receptors- curve shifts to right
Shifts right and down- even more agonist is needed to illicit same response, as it binds near receptor and prevents activation
2 cholinergic receptor types? 2 agonists? Antagonist of muscarinic and nicotinic?
Muscarinic, nicotinic
Muscarine, nicotine
Atropine, curare
Agonist of histamine receptor? Use? Antagonist?
Histamine- contraction of ileum, acid secretion from parietal cells
Mepyramine- reverse contraction of ileum, no effect on acid secretion
What is affinity? What is efficacy? Shown by agonists and antagonists?
How well a ligand binds to the receptor- shown by agonists and antagonists
How well a ligand activates the receptor- only agonists
Less number of receptors at a tissue will result in what? Drug that inactivates a receptor? What equation calculates how many receptors are available?
More drug being required to illicit same effect
BAAM= irreversible B-adrenoceptor antagonist
Furchgott equation
What is a receptor reserve? What is signal amplification? What does it determine?
Hold for a full agonist in a given tissue- can be large/ small, none for partial agonist
Ligand–> receptor–> signalling cascade
How powerful the response will be- this is determined by type of tissue receptor is based in
2 main factors governing drug action? What is allosteric modulation? 2 types? Positive/ negative modulation known as what?
Receptor-related= affinity, efficacy
Tissue-related= receptor number, signal amplification
Binding of an allosteric ligand–> receptor can affect agonists effect on receptor
Affinity- change EC50 value, efficacy- change in Emax
Positive= allosteric, negative= orthosteric
E.g. of allosteric ligand? What is inverse agonism? Tolerance in relation to this? What happens when receptors become desensitised?
Benzodiazepine
Ligand binds to same agonist binding site and has antagonising effect to agonist effect
Reduction in drug effect over time, seen with continuous, repeated high conc of drug over time
Uncoupled- receptor can’t interact with G-protein, receptor= internalised in vesicle of cell, receptor becomes degraded
What does selectivity describe? E.g.s?
The agonist activity
Isoprenaline= non selective B adrenoceptor agonist as it works at both B1 and B2
Salbutamol= selective for B2 although works at B1 too- works better at B2 at lower concs
What is an enzyme inhibitor? 2 types?
Molecule binds to enzyme and decreases normally its activity, prevents substrate–> active site
Irreversible= changes enzymes chemically e.g. via covalent bond formation
Reversible- bind non-covalently, different types depending on whether these bind to enzyme, enzyme-substrate complex, or both
Drugs that target enzymes as drug target? 3 actions of these? Inhibit what enzyme?
NSAIDs e.g. aspirin and ibuprofen, about 50
Analgesic, anti-pyretic (reduces fever,) anti-inflammatory
COX- breaks down arachidonic acid–> prostaglandin H2
Prostaglandin H2 is acted on by specific syntheses to generate what 4 prostanoids? Synthases that produce these are found where? How do NSAIDs prevent PGH2 from forming? How does aspirin differ?
PGD2, PGE2, PGI2, TXA2
PGD2= mast cells, PGE2= macrophages, TXA2= platelets, PGI2= vascular endothelial cells
Prevent arachidonic acid from reaching active site of COX enzyme= competitive inhibition
It binds irreversibly to COX enzyme
COX-1 and COX-2 found where? Aspirin and celecoxib act on what?
COX-1= widely around body, COX-2= inflammation only Aspirin= on both, celecoxib= COX-2 selective
2x e.g. of ACE inhibitors? How do they reduce hypertension? Enalapril and captopril mimic what?
Captopril and enalapril
Prevent ACE (bind to active site) and conversion of angiotensin I to angiotensin II, less vasoconstriction and aldosterone= reduced further
Enalapril (pro-drug)= tripeptides
Captopril= dipeptide
Transporters transport what and most have what activity? E.g. drugs that affect these? PGE2 from chromatin cells bind to what receptors on parietal cells? This reduces what?
Ions and small organic molecules Active- some degree of ATPase activity PPIs- omeprazole, lansoprazole EP3 receptors Activity of H+/ K+ ATPase pump- H+ conc
Histamine from histaminocytes bind to what receptor on parietal cells? This increases what?
H2 receptors
Activity of H+/ K+ ATPase pump- H+ conc increases in gastric lumen
2x e.g. of diuretics? Inhibit what? Furosemide inhibits what resulting in what?
Furosemide, thiazides
Symporters
NKCC2 pump on thick ascending part of loop of Henle- reduced Na+, Cl- and K+ entering medullary interstitium, reduced hyperosmolarity, more water loss in urine
Thiazides inhibit what? 4x e.g. of neuronal uptake inhibitors? Fluoxetine prevents reuptake of what?
Na+, Cl- co-transporter on distal tubule of nephron–> increased water loss
Fluoxetine, imipramine, coacine, tiagabin
Serotonin (SSRI)
Imipramine mostly inhibits reuptake of what? Cocaine? Tiagabin?
Tri-cyclic anti-depressant, noradrenaline (majority) and serotonin
Dopamine
GABA- for panic disorders
3x e.g. of calcium channel blockers used in hypertension? Where does amlodipine block voltage dependent calcium channels?
Amlodipine, verapamil, diltiazem
In cardiac muscle and vascular smooth muscle- prevents influx of Ca2+
What does local anaesthetics like lidocaine and procaine interrupt? They block what? Why pain relief? They can diffuse through what?
Axonal neurotransmission in sensory nerves
Voltage dependent sodium channels- prevents neurones from depolarising
Mucus membrane easily- sometimes can act on muscles too
What does adherence acknowledge? E.g. of lack of adherence?
The importance of patients beliefs, a more patient-centred approach is needed
Not taking medication, taking bigger/ smaller doses than prescribed, more/ less often, stopping without finishing course, modifying treatment to accommodate other activities, continuing behaviours against medical advice
Unintentional reasons for non-adherence?
Practical barriers, difficulty understanding instructions, problems using treatment, inability to pay, forgetting- capacity and resource
Intentional reasons for non-adherence?
Motivational barriers, patients’ beliefs about their health/ condition, beliefs about treatments, personal preferences- perceptual barriers
Ways to tackle non-compliance? Key beliefs in influencing patient evaluations of prescribed medicines can grouped under what 2 categories?
Better patient selection, more education and simplified medical regimens designed to reduce non-compliance
Necessity beliefs- perceptions of personal need for treatment
Concerns- about range of potential adverse consequences
What does patient-centred care encourage?
Focus in consultation on patient as whole person who has individual preferences situated in social context
Shared control of consultation, decisions about interventions or management of health problems with patient
4 pros of good doctor- patient communication?
Better health outcomes, higher adherence to therapeutic regimens in patients, higher patient and clinician satisfaction, decrease in malpractice risk
10 steps in sharing decision making?
Define problem- take in yours and patient’s views, convey that professionals may not have set opinion about best treatment, outline options- consequences of no treatment, provide info in preferred format, check patient’s understanding of options, explore patient’s concerns and expectations, check patient accepts decision sharing process, involve patient in decision-making process to extent patient wishes, review the needs and preferences after patient has had time for further consideration, review decisions over time
Barriers to concordance from health professional and patient point of view?
Patient- may want doctor to tell them what to do, where decisions complex or based on complicated statistical risks
Health professionals- relevant communication skills, time/ resources/ organisational constraints, challenging- patient choice V evident
Key principles in improving concordance?
Improve communication, increase patient involvement, understand patient’s perspective, provide information, assess adherence, review medicines
Ethical considerations with medicines adherence?
Mental capacity e.g. dementia, severe learning disability, brain injury, mental health condition, decision may be detrimental to patient’s wellbeing, potential threat to health of others
What are opiates good for? Bioavailability of morphine if given orally? Lasts how long? Side effects? % population cannot metabolise morphine?
Acute post op/ palliative care- can lead to addiction/ dependency
50% due to liver metabolism
3/4 hours
Resp depression, sedation, nausea, constipation, itching, endocrine effects, immune suppression
10%
Antagonist to morphine? Naturally occurring opioids from opium= what? Simple chemical modifications x3? Synthetic opioids x4?
Naloxone- 400mg/ ml, short half-life so give some IV and some SC so depot will maintain levels
Morphine and codeine poppy
Diamorphine (heroin,) oxycodone, dihydrocodeine (more predictable than codeine)
Pethidine, fentanyl, alfentanil, remifentanil
