Would you be likely to prescribe a higher dose of a drug if you learned that it had a high TI?
Yes, in general, relative to another drug with the same effect that had a low TI.
TI means therapeutic index. The lower the TI, the finer the line between the dose required to achieve the desired effect and a dose that would bring on unwanted effects.
If a TI is high, it means the margin between "good" dosage and "bad" dosage is large, so you can prescribe a higher dose of the drug without worrying too much about causing unwanted effects.
Describe the different ways in which drugs can reduce or reverse an unwanted effect.
1. COMPETITIVE IRREVERSIBLE ANTAGONISM
2. COMPETITIVE REVERSIBLE ANTAGONISM
3. NON-COMPETITIVE ANTAGONISM
4. PHYSIOLOGICAL ANTAGONISM
Give an example of a competitive non-reversible antagonist and how it reverses or reduces an unwanted effect.
These drugs bind IRREVERSIBLY to target molecules, forming strong covalent bonds that disassociate very slowly.
Aspirin (acetyl salicylic acid) - a non-steroidal anti-inflammatory drug that binds irreversibly to an active site on the cyclo-oxygenase enzyme (COX) that is normally occupied by agonist arachidonic acid.
By inhibiting the action of COX, aspirin blocks the first step in the formation of thromboxane (TXA2), a chemical mediator that encourages platelets to aggregate (clotting). This antagonistic effect lasts the life-span of platelets in circulation.
(COX is responsible for catalysing the synthesis of PGH2 from arachidonic acid. That PGH2 is then converted via thromboxane synthase, found in platelets, into TXA2)
Give an example of a competitive reversible antagonist and how it reverses or reduces an unwanted effect.
Competitive reversible antagonists are the most common type of antagonists. They compete with agonists to bind reversibly to an agonist's receptor while the agonist has disassociated with receptor. They can reduce the unwanted effects of the agonist.
Prazosin is an alpha-1 adrenergic receptor antagonist. These receptors are found on vascular smooth muscle, where they are responsible for the vasoconstrictive action of norepinephrine. They are also found throughout the central nervous system.
The heart rate and contractility go back down over time and blood pressure decreases.
Give an example of a non-competitive antagonist and how it reverses or reduces an unwanted effect.
These don't compete for the same target molecules (eg., receptors) as agonists, but instead they prevent the events set in motion by the agonist binding to the receptor.
Class IV anti-dysrhythmic or antiarrhythmic drugs block the heart muscles' "slow Ca2+ channels", which are responsible for increasing contractility in the heart. By blocking these channels, the effects of norepinephrine binding to the ß1 adrenergic receptors in the heart muscle are reduced.
Eg., Verapamil & Diltiazem
Also note that drugs that block calcium channels in the arterioles of other vascular smooth muscle end up reducing the effects of alpha-1 & alpha-2 adrenergic receptors there, causing vasodilation of arterioles.
What is physiological antagonism?
This is a loose term to describe how two different drugs or agonists working on different receptors cause effects that cancel each other out.
For example, the endogenous agonist norepinephrine binding to a ß2 adrenergic receptor will cause the vascular smooth muscle to vasodilate, even if angiotensin II binding to AT1 receptors caused the vascular smooth muscles to contract.
Drugs-wise, isoprenaline and dopamine are ß-adrenoceptor agonists; Isoprenaline will cause bronchodilation (ß2 effect) even if, for example, endothelin-1 is causing vasoconstriction.
How do inverse agonists work and what is an example?
These are drugs of negative efficacy - ligands that bind to constitutively active (always-on) receptors to REDUCE the level of constitutive action. These ligands have a higher affinity for the resting state of receptors than the active state, so basically "switches off" consitutively active receptors.
An inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level activity in the absence of any ligand. An agonist increases the activity of a receptor above its basal level while an inverse agonist decreases the activity below the basal level.
A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either.
The efficacy of a full agonist is by definition 100%, a neutral antagonist has 0%, while an inverse agonist has < 0% (i.e., negative) efficacy.
If a drug is water soluble, what happens to it at the site of administration?
It will be absorbed into aqueous solution of the ECF, blood plasma etc. But it won't enter cells because it's not lipid soluble. Only lipid-soluble drugs enter the plasma membrane of cells.
Which can cross plasma membrane into cells?
A. Neutral drugs (100% un-ionised)
B. Very weakly acidic drugs
C. Very weakly basic drugs
D. Polar drugs
A, B & C
Neutral drugs that are 100% un-ionised, very weakly acidic drugs & very weakly basic drugs can cross cell membranes.
Polar drugs -- those that are very acidic or very basic -- cannot.
In plasma, will a weakly acidic drug be able to cross a cell's plasma membrane?
No. Plasma pH is 7.4 (slightly basic), so a weakly acidic drug would more easily dissociate into ions and not be able to cross the membrane.
A weakly basic drug would not dissociate so it would be able to cross.
In the stomach, would a weakly basic drug cross the cell membrane?
No. Stomach is very acidic (pH about 2.3), so a weakly basic drug would likely pick up protons easily and end up becoming ionised, so it wouldn't cross over the cell membrane.
A weakly acidic drug, however, wouldn't dissociate to become ionised, so it could cross the membrane.
Why can't drugs of high molecular weight, higher than 1000 amu, enter cells via passive diffusion or facilitated transport such as pinocytosis, carrier-mediated transport & via aquaporins?
High MW drugs will remain at the site of administration because they can't make it through the gaps between the cells of the vascular epithelium. The size of these gaps do vary - easy to pass through the liver endothelium because there are lots of discontinuous gaps, while the CNS has tight junctions and impermeable pericytes that make drug entry nearly impossible (blood-brain barrier).
What is bioavailability?
Bioavailability = fraction of administered dose that reaches the systemic circulation in an active form
Drugs given IV have 100% bioavailability; orally adminstered drugs have lower bioavailability due to first-pass metabolism in wall of GIT, portal blood or liver
= % total amt of drug that has been administered
How do drugs normally get across cell membranes?
Passive diffusion. Their molecular weight needs to be <1000 amu.
How do drugs usually get from the blood stream into target tissue?
They pass through GAPS in the vascular endothelium via passive diffusion (usuallly).
The gaps are packed with a loose matrix of proteins that acts to retain molecules of high MWt (e.g. plasma proteins)
What does first-pass metabolism mean?
The drug is extensively metabolised in the GIT or the liver before it reaches the systemic circulation.
Define volume of distribution(Vd) in terms of drugs.
VOLUME OF DISTRIBUTION Vd -
A high Vd means the drug has left the circulation and has thus been distributed into the target site(s).
A drug that has a LOW PLASMA CONCENTRATION measured after it has been administered indicates it has a HIGH Vd.
HIGH LIPID SOLUBILITY - Drugs with high lipid solubility can end up accumulating in fat because fat isn't vascularised and therefore drugs take longer to leave.
How does ion-trapping help prolong the effect of a drug at the target site or inside a cell?
Drugs can stay longer in a cell if they become ionised, such as if a weakly basic drug, which leaves the plasma really easily, ends up in a very acidic environment such as the GIT.
Then it can become ionised, and would then stay there longer, which can have positive therapeutic effect since it can prolong the drug impact.
What feature of a drug would enable it to accumulate in fat?
Highly lipid-soluble drug.
Fat isn't vascularised and therefore drugs take longer to leave.
Explain how drugs are eliminated from the body via metabolism.
Drugs can be metabolised into more water-soluble units by conjugating them to acetates, sulphates, etc. Metabolism can take place in liver, lungs, GIT & kidneys.
What is enterohepatic recycling? What is the effect on plasma drug concentration?
Metabolism often INACTIVATES drugs, but some metabolites can become biologically active when their conjugates are removed in the liver and the free drug is sent back into the bile via ENTEROHEPATIC RECYCLING. The free drug is sent on to the intestines/GIT, where it is reabsorbed.
This causes an increased drug effect, like another dose.
How are drugs excreted from as urine?
Filtered by the renal glomeruli:
Water-soluble drugs, lipid-soluble drugs
Small molecules smaller than 70000 kD
"Free" drugs that are not bound to plasma proteins
Reabsorbed in the proximal convoluted tubule:
Non-ionised drugs, or the non-ionised fraction of drugs
(water-soluble drugs are not reabsorbed, just excreted)
Actively secreted in the collecting ducts using transporter proteins:
Excretion in urine
Explain why the half life of some drugs varies with the dose administered, in particular first-order kinetics and zero-order kinetics.
Drugs can be removed and reach T-1/2 by FIRST-ORDER KINETICS or ZERO-ORDER KINETICS.
Rate at which drug concentration decreases is proportional to the amount of drug present.
The elimination pathways are not saturated, so there is a lot of slack to remove more of the drug should there be a higher dose. Therefore, the greater the dose, the more that's removed.
aka saturation pharmacokinetics
Fixed amount of drug is removed from system per unit time, thus it can take longer for drug to be eliminated.
The elimination pathways such as renal tubules or hepatic enzymes become saturated. Problem with this is that drug concentration in system will rise as dose is increased.
What happens to small, water-soluble drug molecules when they are filtered in the renal glomeruli?
They are excreted in urine. They are not reabsorbed in the PCT once they've been filtered into the filtrate.
What is the solubility of drugs that are metabolised by the liver?
They are lipid-soluble, not water soluble, because the drug has to cross the liver cell membrane to reach the microsomal enzymes where metabolism takes place.
NB: The intracellular cytochrome P-450 (CYP) enzyme family plays a key role in drug metabolism
What is the definition of a drug's half-life?
The time taken for the drug concentration in the plasma to fall by 50%.
What is the impact of a drug's chirality on its rate of distribution, absorption and elimination?
Chirality occurs in drugs that are mixtures of two enantiomers, which are mirror images structurally but may be handled differently in the body e.g. R + S salbutamol, a bronchodilator
They are structurally mirror images of each other but there's evidence that sometimes there's different rate of removal, conversion of one to another, differing per species, therefore unpredictable. One might be inert, the other might have active properties.
What is enzyme induction?
ENZYME INDUCTION - when metabolic enzymes are (over) activated; this can be caused by repeated administration of some drugs.
- The plasma concentration of the drug & other drugs metabolised in the liver that are being given concurrently may be decreased.
- The therapeutic efficacy of the drug & other drugs metabolised in the liver that are being given concurrently may be lost.
- The time between doses (dosing interval) may need to be decreased as enzymes are working quickly
What is enzyme inhibition?
ENZYME INHIBITION - when metabolic enzymes are not working optimally; this can be caused by some drugs.
- Plasma concentration of the drug & other drugs concurrently metabolised in the liver can be higher
- Toxic effects may develop
- The time between doses may need to be increased to allow enzymes to work
How does urine pH of different species affect the acidity or alkalinity of drugs excreted?
Animals producing acidic urine (carnivores, concentrate-fed herbivores) will eliminate *weakly basic* drugs most effectively because these will pick up protons, thus becoming ionised, and ionised drugs are not readily reabsorbed by renal tubules but just excreted.
Animals producing alkaline urine (herbivores on forage) will eliminate weakly acidic drugs most efficiently.