Pharmacology Flashcards
Pharmacokinetics
What the body does to the drug. Study of the relationship between the dose of a drug and the resulting concentrations in the body over time.
Half-life
Time take for the plasma concentration (or total amount) of a drug to reduce by half
Volume of Distribution
Apparent volume into which a drug disperses in order to produce the observed plasma concentration (L)
VD = dose/ plasma concentration
- Not physical volumes as can be»_space;TBW
Bioavailability
Fraction of the administered drug dose that reaches the systemic circulation as intact drug, compared with the same dose given intravenously
Extraction ratio
Fraction of the drug removed from blood by the liver
Distribution
Passage of a drug from the plasma into the peripheral tissues
pKa
pH at which a weak acid or weak base will be 50% ionised
Clearance
Volume of blood from which a drug is removed per unit time (L/hr or mL/min)
Prodrug
A drug that has no inherent activity before metabolism but is converted by the body to an active moiety. E.g enalapril, diamorphine, parecoxib.
Context Sensitive Half Time
Time required for the plasma concentration of a drug to decrease by 50% after cessation of a pseudo steady state infusion that maintained a constant concentration, with the context being the duration of infusion.
Determinants
- Distribution and redistribution
- Clearance
- Duration of infusion
Ligand
An endogenous or exogenous compound that is able to bind to a receptor
Receptor
A protein, often integral to a membrane, containing a region to which a natural ligand binds specifically to bring about a response
Usually proteins or glycoproteins.
Location
- Cell membrane
- Intracellular - organelles, cytosol, nucleus
Graded Response Curve
Studied in one person
- Hyperbolic curbe
- Can measure efficacy (Emax) and potency (EC50)
Quantal Response Curve
Studied in population (y-axis always % of response). All or nothing response
- Can measure ED50
Median effective dose (ED50)
Dose of a drug that us required to produce a specific effect in 50% of the population
Median effective concentration (EC50)
Concentration of a drug that produces 50% of the maximal response
Therapeutic index
Ratio of median toxic dose (or lethal toxic dose) to the median effective dose TI = TD50 (or LD50)/ ED50
Median lethal dose (LD50) - dose of drug that is lethal to 50% of test subjects
Potency
Amount of drug that is required to produce a maximal effect. EC50 and ED50 are markers of potency
EC50 (median effective concentration) - concentration of a drug required to induce 50% of a maximal response.
ED50 (median effective dose) - dose of a drug required to produce a response in 50% of the population to whom it is administered
Intrinsic Activity
Measure of the ability of a drug to produce an effect once it is bound to its receptor.
Full agonist IA = +1
Antagonist IA = 0
Partial agonist 0<IA<+1
Inverse agonist -1≤IA<0
Efficacy
Measure of the maximal response achievable by a drug once it is bound to its receptor. Often described by Emax (drug conc at which max effect achieved)
Affinity
Is the tendency of a drug to bind to the receptor
Law of Mass Action
States that the rate of reaction is proportional to the product of the concentrations of the reactants
Dissociation Constant
Concentration of a drug at which 50% of its receptors are occupied at equilibrium (KD) - measure of affinity (higher the KD, the lower the affinity of the drug)
Adverse event
A noxious or unintended effect associated with administration of a drug at the normal dose
Tachyphylaxis
Development of reduced response to a drug after repeated or continuous short-term administration. Reduced response many not easily be overcome by increasing the dose. Reduced response recovers quickly after cessation of exposure
Tolerance
Development of reduced response to a drug after repeated long term administration. Higher doses are required to achieve the same effect
Mechanism
- Decr receptor density
- Structural changes in receptor morphology
- Altered response to drug receptor activation
- Enzyme induction -> decr quantity of the drug reaches the site of action
- Development of physiological compensatory mechanisms
E.g opioids - cross tolerance
Saturated vapour pressure
Pressure in a closed container at which the liquid and vapour phases are in equilibrium.
Depends only on temperature, independent of total environmental pressure (I.e altitude)
Decr temp -> Decr SVP
Incr temp -> incr SVP as incr vapour present
Critical temperature
Temperature at and above which vapour of a substance cannot be liquefied, no matter how much pressure is applied
MAC
Minimum alveolar concentration of an inhaled anaesthetic agent at steady state that will prevent movement in 50% of patients in response to a surgical incision at 1 atm and 100% O2
Minimum effective concentration of LA (Cm)
Minimum concentration of a LA that results in a complete block of a nerve fibre in 50% of the subjects under standard conditions.
- Measure of potency
Mechanisms of drug transfer across cell membrane
- Diffusion (simple passive, facilitated)
=> Movement of drug molecule down their concentration gradient without using energy - Active transport (primary active, secondary active)
=> Movement of drug molecules against conc gradient using energy - Endocytosis
=> Vesicle containing drug molecules are moved across cell membrane into the cell by invagination (e.g Via B12 with IF) - Exocytosis
=> Reverse of endocytosis
Mechanisms of drug action
Action on receptors
- Alteration of ionic permeability
- GPCR
- Receptors acting as enzymes
- Regulation of gene transcription
Effects on enzymes
- Inhibition - reversible/ irreversible
- Activation
Action on ion channels
Actions dependent on physicochemical properties
- Osmotic activity
- Acid-base activity
- Chelation
- Oxidation
- Reduction
NAChR
- Located in NMJ (pre- and post- junctional), extra-junctional (fetal + denervation injuries), neuronal (CNS, autonomic ganglia, adrenal medulla)
- Pentameric structure (2a, 1B, 1delta, 1epsilon (adult), 1 gamma (embryonic)
- Non-specific central ion channel (Na/K > Cl)
- 2ACh molecules bind to 2a subunits -> conformation change -> opening of central ion port -> cations (most importantly Na+) moves down conc and electrical gradient -> membrane depolarisation
- Orifice of receptors negatively charged - anions do not pass
GABA
Gamma aminobutyric acid
- Amino acid
- Major inhibitory neurotransmitter in brain
- Glutamate -> GABA + CO2 (catalysed by glutamate decarboxylase)
GABAA receptors
- Pentameric structure (2a, 2B, 1gamma)
- Ligand gated ion channel (Cl)
- Altered by GAs except ketamine and xenon
- GABA + GABAA receptors (binding site a-subunits)-> conformational change -> opening of Cl- channel -> membrane hyper polarisation
- BDZ + GABAA receptor (agonist at alpha/gamma interface -> positive allosteric modulation) -> conformation change -> incr affinity of GABA for receptor -> incr frequency of opening of Cl- channel -> hyper polarisation -> potentiation of inhibitory effect of GABA
=> Flumazenil - antagonist of alpha/gamma interface
- Propofol, etomidate, barbiturates and halogenated volatiles - agonists at B-subunits that produce positive allosteric modulation. Anaesthetic + GABAA receptor -> conformational change -> incr Cl- channel opening time -> hyper polarisation -> potentiation of inhibitory GABA effect
=> Direct activation also possible, e.g propofol - Cl channel opening in the absence of GABA
GABAB receptors
- GPCRs
- Predominately pre-synaptic (e.g baclofen)
GABAC receptors
- Ligand gated chloride channel
- Retina
NMDA receptor
- Located in dorsal horn of spinal cord and brain
- Heterotetramer - two obligatory NR1 and two NR2 subunits
- Ligand gated - glutamate ligand, glycine co-agonist
- Voltage dependent - ion pore blocked by Mg2+, requires partial depolarisation of cell membrane to remove plug via activation of adjacent AMPA
- Ca2+ influx most important
- Secondary effect - NO production, activation and production of second messenger, activation of enzymatic processes
- Role - central sensitisation, wind up, learning and memory, cerebral ischaemic damage
NMDA antagonists - ketamine, N2O, xenon
Opioid agonist + NMDA antagonists - methadone, tramadol
GPCR
- 7 transmembrane spanning receptors
- Heterotrimers - 3 diff subunits (a, B, gamma)
- G-proteins - proteins binding guanine nucleotides (GDP + GTP)
=> Three main classes based on a-subunit
=> Gs - stimulate adenylate cyclase, e.g all B, D1 + D5 receptors
=> Gi - inhibit adenylate cyclase, e.g a2, D2-4, M2, M4 + opioid receptors
=> Gq - activate phospholipase C, e.g a1, AT-II, M1, M3, M5 - Events - ligands + GPCR -> conformational change -> a-subunit exchanges GDP for GTP -> a-subunit dissociates from a/B/gamma complex -> a-GTP activates or inhibits intermediate mechanisms
Effector proteins
=> Adenylate cyclase => incr or decr cAMP
=> Phospolipase C -> incr DAG -> activation of PKC; incr IP3 -> Ca2+ release from endoplasmic and sarcoplasmic reticulum
Ion channels
Inverse agonist
A drug that binds to a receptor to produce an effect in the opposite direction to that of the endogenous agonist for the same receptor
- Can be either partial or full
- BDZ site on the GABAA receptors is an example of agonist-inverse agonist system
Decrement time
Time predicted for the plasma drug concentration to fall by a certain percentage after the cessation of an infusion designed to maintain a constant plasma concentration.
- CSHT is a decrement time for 50% decrease
Blood/ gas partition (solubility) coefficient
Applies to inhalation agents.
Ratio of the concentration of the anaesthetic in blood to the concentration of anaesthetic in gas when the two phases are of equal volume and in equilibrium at STP.
- Temp dependent
High blood/gas coefficient
- High uptake of gas in blood -> slower rate of rise in partial pressure -> slower induction of anaesthesia
Decreases with haemodilution
Increases after ingestion of fatty meals
Concentration effect
Rise in the PA of N2O (and xenon) is disproportionately rapid when it is administered in high concentrations.
N2O 34x more soluble in blood than N2 -> N2O diffuses out»_space;N2 diffuses in -> decr volume of alveoli + incr tracheal inflow
Second gas effect
The speed of onset of inhalational anaesthetics is increased when they are administered with N2O as a carrier gas
Incr uptake of N2O (1st gas) -> incr rate of rise of PA of concurrently administered gas (2nd gas)
MAC-95
MAC preventing 95% of subjects moving when exposed to a noxious stimulus
MAC-awake
MAC at which consciousness is regained or at which 50% of patients will response to a simple command.
For modern inhalational anaesthetics, MAC-awake is approx 1/3 of MAC
MAC-BAR
MAC-BAR (block autonomic response)
MAC at which the autonomic reflex is attenuated in 50% of patients (unmeasured using plasma norad concentration, incr HR and BP) to nociceptive stimuli
MAC-BAR can be reduced significantly by opioids - ceiling effect
MAC-BAR (Block Adrenergic Response)
MAC at which the adrenergic response (autonomic reflex) is attenuated in 50% of patients (using plasma norad concentration, incr HR and BP) to nociceptive stimuli
MAC-BAR can be reduced significantly by opioids - ceiling effect
Diffusion hypoxia
- When a low potency gas like N2O is discontinued, it rapidly diffuses rapidly into alveoli
- N2O 34x more soluble than N2, hence N2O rapidly diffuses out of blood and dilute alveoli as N2 can only diffuse in much more slowly
- Dilution of alveoli which increases the gradient for removal of more potent agents, this can also dilute O2 -> hypoxic mixture
- Large volume of N2O can also dilute alveolar CO2 -> hypocapnia -> ↓resp drive
- Hypoxic effect minimised by incr FiO2
- Beneficial effect is reducing alveolar partial pressure of volatile agents (reversal of second gas effect) incr rate of washout
Oil/gas partition coefficient
Ratio of the concentration of anaesthetic in oil to the concentration of anaesthetic in gas when the two phases are of equal volume and in equilibrium at STP.
Estimates solubility of inhalational anaesthetics in CNS and thus potency
IV Anaesthetic MoA
GABAA receptors
- Targets for benzos, barbs, etomidate and prop
NMDA receptors
- Activated by glutamate and co-agonist glycine (Mg2+ displaced from ion pore)
- Ketamine acts by pore-blocking mechanism - only binds in open conformation
=> Non-competitive antagonist
Glycine receptors
- Inhibitory role in lower brainstem and spinal cord
- Contributors to anaesthetic immobility - esp for volatiles
(Propofol effect on immobility primarily via GAVA, volatile via glycine)
- Prop, etomidate, and thio have some positive modulation of glycine receptors, ketamine does not
ke0
Rate of equilibration between plasma and effect site concentrations and follows first order kinetics
Incr Ke0 = faster equilibration = faster onset of action
T1/2ke0
T1/2ke0 = ln2/ke0 = 0.693/ke0
Time taken for the effect site concentration to reach 50% of the plasma concentration when plasma levels are maintained at steady state.
CYP2D6 genetic polymorphism
Poor metaboliser
- Little or no CYP2D6 function
- Limited opioid analgesia
Intermediate metaboliser
- Metabolise drugs at a rate somewhere between the poor and extensive metabolisers
Extensive metaboliser
- Normal CYP2D6 function
Ultrarapid metaboliser
- Multiple copies of the CYP2D6 gene expressed, so greater than normal CYP2D6 function
- Ultrafast metabolisers convert codeine to morphine very rapidly and experience unpleasant side effects of morphine rather than an effective analgesic effect
E.g codeine, tramadol, metoprolol
Hepatic Drug Clearance
Dependent on:
- HBF
- Fraction of unbound drug
- Intrinsic clearance ability of hepatic enzyme
Ratio of hepatic clearance of a drug to HBF is the hepatic extraction ratio (HER)
- High HER (>0.7) = blood flow dependent, less sensitive to changes in protein binding or intrinsic clearance e.g morphine, lignocaine, ketamine
- Low HER (<0.3) = independent of blood flow; determined by intrinsic metabolising capacity of liver and free drug fraction -> restrictive or capacity limited, low degree of first pass metabolism when given PO e.g warfarin, diaz, phenytoin
Hepatic failure effect
Metabolic
- Decreased clearance of drugs -> longer T1/2
Synthetic function
- Liver synthesises plasma proteins - PPB influences VD
- Low protein -> raised free drug
- Synergistic with decr HBF + HER
- Liver synthesises plasma esterases + peptidases (prolong e.g sux)
Secretory function
- Drugs relying on biliary excretion may be retained
- Drugs with enterohepatic recirculation may have decr T1/2 due to failure to recirculate
- High bili -> displacement of drugs from albumin
- Decr bile secretion -> malabsorption
Portal HTN
- Shunting of portal venous blood into systemic circulation -> decr first pass metabolism
Liver failure
- Incr sensitivity to sedates due to lots of BBB integrity + baseline encephalopathy
- Incr sensitivity to drugs which target hepatic storage or synthesis
- Decr sensitivity to drugs which rely on proteins synthesised by liver
- Decr sensitivity to fuse (decr albumin binding on which its delivery to the tubule is dependent)
- Decr sensitivity to B-blockers (down regulation of receptors due to chronic sympathetic activation in cirrhosis)
Biotransformation
Phase I - activate or deactivate a compound. Expose or introduce a functional group. Result in a small increase in hydrophilicity
- Hydrolysis
- Reduction
- Oxidation
Phase II - conjugation of parent drug with endogenous substance to incr water solubility (more hydrophilic)
- Glucuronidation
- Sulfation
- Acetylation
- Methylation
- Conjugation with glutathione
- Conjugation with amino acids
CSHT
Time it takes for the plasma concentration of a drug to fall by half once an infusion designed to maintain a constant concentration has been ceased. The context is the duration of the infusion.
