Pharmacology Flashcards
What PK parameter determines dose rate?
Clearance (volume/time)
What PK parameter determines the loading dose
Volume of distribution
What PK parameter determines dose adjustment between routes of administration?
Bioavailability
What PK parameter determines frequency of dosing?
Half life (interplay of Vd + CL)
What is PK?
What the body does to the drug
What is PD?
What the drug does to the body
What are the components of PK?
- Liberation
-
Absorption
- 1st pass metabolism
- Bioavailability
-
Distribution
- Volume of distribution
- Protein binding
- Compartment models
-
Metabolism
- Hepatic extraction
- Phase 1 (HOR) hydrolyses, oxidation, reduction
- Phase 2 (MMAGGS) methylation, mercapturic acid formation, acetylation, glucuronide + glycine conjugation, sulfate conjugation
-
Elimination
- Clearance
- Elimination
- Zero order
- 1st order
- Saturable
- t1/2
- Steady state
Definition of absorption
Extent to which intact drug is absorbed from the gut into the portal circulation
Definition of bioavailability
- Fraction of a drug dose administered by an extravascular route (oral / IM / SC) that is absorbed into the systemic circulation
- High bioavailability = 1
- Low bioavailability = 0
- Affected by;
- Absorption
- 1st pass metabolism
Bioavailability equation
AUC oral
AUC IV
Absolute bioavailability equation
AUC oral x dose IV
AUC IV x dose oral
Equation for bioavailability if absorption = 100%
1 - hepatic extraction ratio
Definition of 1st pass metabolism
- Extend to which drug is removed on initial passage through an organ before reaching the systemic circulation
What is the definition of Vd?
- The hypothetical volume that would be required to dissolve the total amount of the drug at the same concentration found in the blood
- If the drug has a plasma concentration of 10mg/L when there is 1000mg of drug in the body, Vd is 100L
What are the factors that affect volume of distribution?
- Strength of binding of the drug to tissue compartments compared with plasma proteins
- Molecular size
Characteristics of LOW Vd drugs
- Suggests drug is confined to the intravascular space (high blood [] )
- Occurs if poorly lipophilic and highly plasma bound
- E.g. heparin, warfarin, aspirin, gentamicin
Characteristics of HIGH Vd drugs
- Suggests the drug is distributed to tissue/fat widely
- Occurs if bound to tissue and not blood, most of drug in tissues and little in plasma
- Usually highly lipophillic
- E.g. nortriptyline, chlorpromazine
What determines steady state concentration?
Clearance
If a drug is highly protein bound…..
- Vd will be large
- Elimination half life will be long
What is hepatic extraction ratio?
Amount of drug cleared by liver metabolism on first passage through
Extration ration = 1 - (concentration out / concentration in)
What are the determinants of the hepatic extraction ratio?
- Liver blood flow
- Unbound fraction – ability of liver to remove drug depends on protein binding as it is only the free (unbound) drug that is available for diffusion from blood into liver where metabolism occurs
-
Intrinsic clearance – ability of liver to remove (metabolise) drug (it is what hepatic clearance would be without restrictions of blood flow and protein binding)
- Cannot exceed hepatic blood flow
- Intrinsic clearance determined by
- Maximum velocity of reaction
- Michaelis Menten constant – how tightly enzyme binds to drug substrate – tighter binding (lower Km) the higher the greater the intrinsic clearance
Effects of low hepatic extraction ratio (<0.3)
When very low enzyme activity – SYSTEMIC CIRCULATION affecting clearance
- I.e. LOW hepatic ability to remove drug = low hepatic ER
- DEPEDENT on unbound fraction or intrinsic clearance
- Not much influence on blood flow and extraction low anyways
- Example – diazepam, warfarin, theophylline, phenytoin, carbamazepine
Effects of high hepatic extraction ratio (>0.7)
When very high enzyme activity
- I.e. HIGH hepatic ability to remove drug = HIGH hepatic ER
- DEPENDENT on blood flow
- Not much influence on unbound fraction or intrinsic clearance as already high
- Example – GTN, propranolol, verapamil, lignocaine, morphine
What are phase I metabolism reactions?
-
Hydrolysis (esterases)
- Addition of a water molecule
-
Oxidation (CYP450)
- LOss of electrons
-
Reduction (flavin enzymes)
- Gain of electron
OIL RIG: Oxidation Is Loss, Reduction Is Gain
Aim: more H2O soluble + less toxic. Introduce/reveal a functional group within the substrate that serves as a site for phase II reaction.
What are the reactions in phase II metabolism?
- Mercapturic acid formation
- Methylation
- Acetylation
- Glycine conjugation
- Glucuronide conjugation
- Sulphate conjugation
Aim: add on a group to a drug molecule to assist with elimination
Increase polarity to make it more water soluble
What is the aim of phase III of metabolism?
Transport of conjugated drug into bile- transporters are part of ATP binding cassette superfamily
Why are neonates more sensitive to morphine?
Have an increased number of mu receptors
What is the definition of clearance?
- Is the volume of plasma completely cleared of a drug per unit time measured in ml.min-
Does not include redistribution
Is calculated from the area under the concentration time curve:
- Cl= Dose
AUC
- Irreversible elimination of drug from the systemic circulation – either by excretion of the unchanged drug (into urine, gut, expiration) or the metabolic conversion of the drug into a different chemical compound
What is the definition of elimination?
- Definition = irreversible removal of the drug from the body
- Divided into two components
- Excretion = removal of the intact drug
- Kidneys = renal (correlates to renal function)
- Liver = biliary excretion (parent compounds or metabolites)
- Lungs = pulmonary (MINOR)
- Biotransformation = chemically converted into a metabolite
- Enzymatic process
- Mostly occurs in the liver, but does NOT correlate with LFT
- Other site = intestine, lung, kidney
- Excretion = removal of the intact drug
What is potency defined by?
EC 50
What order kinetics is this?
-
First order kinetics
- Most common
- Definition = elimination rate proportional to the concentration of drug in body
- If more drug is present, elimination is more rapid a constant proportion of the drug is eliminated per unit time
- The elimination rate can be represented by a constant k
- Drugs will have a consistent half life
- Time to steady state (or >95% drug elimination) = five half lives
- Most drugs are first order kinetics - do not saturate the elimination pathway
What order kinetics is this?
-
Zero order kinetics
- AKA saturation kinetics
- Definition = elimination occurs at the same irrespective of the concentration
- Amount of drug in the body determined by volume - a constant amount of drug is eliminated per unit time
- Examples = alcohol, phenytoin (1st order at low doses but then zero order within therapeutic range), aspirin (high dose), theophylline
- Essentially NO steady state / half life: if drug input exceeds output, plasma levels will continue to rise
- Consequences
- Large increases in drug concentration with small increases in drug doses
- High risk of drug toxicity
What is the calculation for therapeutic index?
TD50 (50% toxic effect)
ED50 (50% effective)
Drugs that have a broad + narrow therapeutic index
BROAD: penicillins, beta 2 agonists, thiazide diuretics
NARROW: digoxin, theophylline, lithium + phenytoin
What is a competitive antagonist?
Displace other ligands from a binding site. Competitive antagonists can be:
- Reversible
- The effect can be overridden by increasing the dose of agonist.
- Irreversible
- Drug cannot be overridden by increasing dose of agonist. Dose-response curve appears similar to that of the non-competitive antagonist.
What is a non-competitive antagonist?
Create a conformational change in the receptor. They cannot be overridden by increasing the dose of agonist.
What is potency?
The amount of drug required to have an effect.
Given by the (typically the ED50)
This relates to Bowman’s principle, which states that the least potent anaesthetic agents have the quickest onset
This is because they are administered in higher doses (as they are less potent, more is required to get an effect), which results in a high concentration gradient and a rapid distribution into tissues.
What is efficacy?
The maximal effect that a drug can generate.
First order kinetic = double dose double drug concentration
Zero order kinetics = double dose MORE than a double in concentration
A, B and C all have the same efficacy
D has a lower efficacy + lower potency than A and B
D has the same potency as C
A1 = full agonist with high potency (i.e. effective at lower doses)
A2 = full agonist with less potency (but can reach maximal effect at higher dose)
A3 = less efficacy than full agonist = partial agonist, but higher potency than A2 (as it has a lower EC50)
A2 + RA = full agonist given together with a competitive antagonist – meaning the antagonist and agonist are acting on the same receptors (when the curves are parallel but shifted to the right)
A2 + IA = full agonist + non-competitive antagonist
-
Delayed distribution / anticlockwise hysteresis – concentration goes up but effect at highest
-
Intermediate step between drug and effect
- Warfarin = give drug now but no effect for 3 days
-
Delay in reaching the effective compartment
- Antibiotic = drug has to cross a barrier eg. BBB
-
Intermediate step between drug and effect
-
Acute tolerance (Tachyphylaxis) / clockwise hysteresis
- Example = amphetamine, cocaine
- Drug concentrations soon after a single dose cause a greater effect than the same concentrations cause at a later time
- Mechanisms – tolerance, induced metabolite breakdown, minimizing of response, translocation of receptors
- Example = amphetamine, cocaine
Type I Concentration-dependent killing: antibiotics
Description
Antibiotics
Goal of Therapy
PK/PD Parameter
- As concentration of an antibiotic increases, rate of killing increases (best when peak 10x MIC)
- Eliminate bacteria more rapidly when concentrations significantly above MIC
- Significant post-antibiotic effect with duration dependent on peak
- Peak concentration limited by toxicity
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Maximise concentrations
24h-AUC/MIC
Peak/MIC
Type II Time-dependent killing
Type II
Time-dependent killing
- Mainly dependent on time at binding site to kill organisms
- Increasing concentration will not increase effectiveness (maximum killing rate at 2-4x MIC)
- Amount of time above MIC in any one dosing interval is best predictor of clinical response (dosing interval important)
- Minimal to NO post-antibiotic effect
Penicillins
Cephalosporins
Carbapenems
Erythromycin
Linezolid
Maximise duration of exposure (ie. dosing interval)
T above the MIC
Type III Time and concentration dependent
Type III
Time and concentration dependent
- Combination of the two
- Rate of bacterial killing related to both time above MIC and total exposure of antibiotic to organism
Azithromycin
Vancomycin
Clindamycin
Oxazolidinones
Tetracyclines
Maximise amount of drug
24h-AUC/MIC
Full agonist vs partial agonist
Full agonist = affinity + efficacy
Partial agnosist= affinity + less efficacy
