General Pharmacology 1 to 10
What do you understand by volume of distribution?
- Volume of distribution is the measure of the apparent space in the body available to contain the drug
- It relates the amount of drug in the body to the concentration of the drug in blood or plasma
- Vd = Amt drug in body/C
- Drugs with a high volume of distribution are very tightly bound by tissues compared with blood, so have a much higher concentration in extravascular tissue than in the vascular compartment. If the drug is tightly bound to plasma proteins and not tissues it has a small volume of distribution
What factors affect Volume of Distribution?
- Drug properties
- lipid solubility, pKa, pH, protein binding, blood flow
- Patient properties – age, gender, disease, body composition
What is the importance of Vd in the overdose situation?
Drugs with large Vd (TCAs) cannot be dialyzed whereas drugs with a small Vd (ASA, lithium) can
Give example of drugs with high and low Vd.
High Vd: diazepam; beta blockers; tricyclics; digoxin; morphine; clonidine; fluoxetine; chloroquine; cyclosporin
Low Vd: warfarin; lithium; phenytoin; aspirin; frusemide; valproic acid; tolbutamide; cephalexin
Pass: two from each group
What do you understand by the term ‘second messenger’?
- A second messenger is an intracellular substance which has its concentration altered by a process initiated by an extracellular ligand. The second messenger then acts to initiate or facilitate an intracellular process.
- 3 basic steps:
- Extracellular process [EC]
- Transmembrane signalling system [TM]
- Intracellular process[IC]
Describe the common steps in the activation of second messengers.
- Extracellular ligand
- Cell surface receptor activated via ligand detection
- G protein activation
- Concentration change of an effector element [enzyme or ion channel
- Change in second messenger concentration
- Second messenger action on a substrate or enzyme
Can you give examples of second messengers?
- Cyclic AMP
- Calcium and phosphoinositides
- Cyclic GMP
In the elderly, what factors change with age and alter pharmacokinetics?
Absorption: No major change unless additional underlying associated condition with age
Distribution: Dec lean body mass, Dec body water %, Inc fat body %, Dec serum albumin, Dec apparent Vd and sometimes increased Vd
Metabolism: Liver metabolism does not decline for all drugs, Dec liver blood flow. Dec phase 1> phase 2 reactions, Liver slower to recover from injury
Elimination: Dec renal function & Cr clearance, Half life inc of drugs variable, Dec excretion of volatile substances by the lung
Associated age related illness affecting any of the above
Pass: Cover 2 of 4 with description
Give some examples of drugs commonly used in the emergency department that must have their prescribing altered in the elderly?
- Benzodiazepines — liver metabolism, renal function; PD
- Opiods —PD sensitivity respiratory effects
- Antipsychotics —PD sensitivity; lean body mass
- NSAID — GI, renal
- Colchicine —renal, narrow therapeutic index
- Other drugs narrow therapeutic index
- Drugs primarily excreted renally —gentamicin, acyclovir
- Digoxin loading dose with dec Vd
- Amiodarone loading — Vd and PD sensitivity
- Many drugs as polypharmacy and must check for interactions
- i.e. Warfarin.
- So could argue extra precautions with all —polypharmacy,
- increase risk of error, compliance and administration issues
- Interactions with age related disease — IHD, COPD (B
- agonists or B Blockers)
- Sulphurs/Baetrim —adverse reactions
- Anticoagulants — falls
- Drugs which switch to zero order kinetics -phenytoin
Pass: Must get 4 relevant and plausible examples with correct associated mechanism & must include benzos and opiods.
- What about commonly used intravenous agents in the ED?
- What about analgesic agents used in the ED?
- What about sedative agents used in the ED?
- Are there any drugs to be reduced with impaired renal function?
What is the half-life of a drug?
- Time required to change the amount of drug in the body by one-half during elimination
How may it be expressed in relation to other pharmacokinetic parameters?
- T1/2 directly proportional to Vd / Cl
Describe the 3 major steps in a second messenger receptor system.
Intracytoplasmic activation of a G-protein
Activation of an effector (eg adenylate cyclase) with production of the 2nd messenger (eg cAMP)
Pass Criteria: 3 to pass
Give 3 examples of ligands that work via a second messenger.
|cAMP System||Phosphoinositol system||Arachidonic acid system||cGMP System||Tyrosine kinase system|
|Ligand:Neurotransmitters(Receptor)||Epinephrine (alpha2, beta1, beta2)Acetylcholine (M2)||Epinephrine (alpha1)Acetylcholine (M1, M3)||Histamine (Histamine receptor)||–||–|
|Ligand:Hormones||ACTH, ANP, CRH, CT, FSH, Glucagon, hCG, LH, MSH, PTH, TSH||AGT, GnRH, GHRH, Oxytocin, TRH||–||ANP, Nitric oxide||INS, IGF, PDGF|
|Transducer||Gs (beta1, beta2), Gi (alpha2, M2)||Gq||Unknown G-protein||–||–|
|Primary effector||Adenylyl cyclase||Phospholipase C||Phospholipase A[disambiguation needed]||guanylate cyclase||receptor tyrosine kinase|
|Secondary messenger||cAMP (cyclic adenosine monophosphate)||IP3 (inositol 1,4,5 trisphosphate) and DAG (Diacylglycerol), both from PIP2||Arachidonic acid||cGMP||protein phosphatase|
|Secondary effector||protein kinase A||Ca++ release (see calcium-binding protein) and PKC (protein kinase C)||5-Lipoxygenase, 12-Lipoxygenase, cycloxygenase||protein kinase G||–|
What are 'spare receptors'?
- Receptors in excess of number required for maximal physiological effect.
Describe the 2 main mechanisms that account for 'spare receptor' phenomenon?
- Temporal – prolonged effect after transient binding
- Numerical- limited substrate with excess receptors
What is the effect on the dose-response curve of an agonist with increasing concentrations of an irreversible antagonist?
Describe Phase 1 and Phase 2 reactions.
What organs are involved?
- Intestinal wall
Pass Criteria: At least 2
Define the term 'volume of distribution'.
- Amount of drug in body /concentration in blood or plasma
How is it possible for a drug to have a VD of 1600L/70kg?
- Higher concentrations in extra vascular tissues than in blood – e.g. lipid soluble
Pass Criteria: discuss pros and cons of at least two
Give examples of drugs with high Vd and Low Vd.
- High VD (>70L/70kg)
- Morphine, chloroquine, digoxin, clonidine, fluoexitine, tricyclics, beta blockers, diazepam
- Low VD (<50 L/70kg, approximating TBW or ECF volume)
- Aspirin, frusemide, antibiotics (gentamicin, amoxicillin, cephalexin), tolbutamide, phenytoin, valproic acid, lithium, warfarin
If a drug is distributed in the TBW, what is it’s VD?
- TBW: 0.6 L/kg or 42 L/70kg
What formula describes Drug Clearance?
What is Flow Dependent Elimination?
Pass Criteria: Must mention drug delivery / blood flow to pass
Can you name any drugs that have Flow dependent elimination?
Pass Criteria: 1 example
What are the sites of drug biotransformation?
Pass Criteria: Must get Liver and two others
What is a Phase 1 biotransformation reaction?
- Conversion of a parent drug to a more polar / water soluble form by the adding or unmasking of a functional group, most commonly by oxidation but also by reduction or hydrolysis.
- The hepatic CYP (P450) enzymes are responsible for the majority of these reactions
Pass Criteria: Must mention more polar or water soluble & oxidation
What is meant by enzyme induction, in liver biotransformation?
- Repeated administration of a substrate brings about either enhanced enzyme synthesis or reduced enzyme degradation causing increased metabolism of the substrate