Pharmacology - Foundation Flashcards
Pharmacokinetics
It is how the drug gets to its site of action. Considerations: What form should the drug be in? Where do you put it? How much is needed? How often does it need to be taken?
What are the four factors that need to be considered when making a drug?
Administration, absorption, distribution and elimination
What is administration?
How the drug is given to the patient?
It can be given orally, subcutaneous, intravenous, rectal, etc…
What are the factors that may influence the choice of route of administration?
Patient convenience: If it is more convenient for the patient then they are more willing to take it regularly or for the course of their treatment (patient compliance).
Cost: Drugs that are cheaper are more readily accessible to more patients. Need to take into consideration the cost of preparation for how the drug is administered (e.g. need for sterility for injectable drug).
Bioavailability: When the drug is administered, it can be metabolised by a number of different pathways that will affect much of the drug makes it to the site of action. Intravenous drugs may require less of the drug as it is not metabolised through first-pass metabolism in the liver compared to oral drugs.
Local vs systemic: Some drugs will act on various site around the body compared to others. Route of administration may reduce the side effect of the drug to other sites of the body that are not needed. Can reduce concentration of drug if administration is local compared to systemic
Types of route of administration
Oral: tablets/capsule/suspension (liquid form)
Skin: nicotine patches/ external creams/ ointment
Lungs: gaseous general anaesthetic
Nose: cocaine
Rectum antibiotics
Injectable: Subcutaneous (under the skin, e.g. insulin - protein would be broken down by enzymes if given orally), intramuscular (into muscle, e.g. penicillin G - stomach acid would break it down), Intravenous (diazepam - for status epilepticus, doesn’t require absorption)
Rapid IV administration
Fastest route, avoids absorption, drug distributes rapidly and reaches equilibrium state the fastest, drug behaves as if in a single compartment, most drugs eliminated at a rate that is proportional to the concentration of the drug in the plasma (fastest elimination rate - first order kinetics)
Drug distribution
Driven by circulation (therefore would not work if person is dead). It is rarely uniform but occurs rapidly.
Steps
1. Drug is diluted by the blood.
2. Drug moves into the extracellular fluid (only drugs that are able to escape the vasculature - small/organic/not protein bound)
3. Binds to cells/taken up into cells (requires specific binding, usually lipid soluble)
Factors that influence drug distribution
Molecular size of the drug: smaller makes it easier for drug to move out of vasculature
Ability to bind to plasma protein: will freely move into extracellular fluid if not bound
Lipid solubility: easier to cross cell membranes (too much —> taken up into lipids and be sequestrated into lipids)
What is the volume of distribution?
“Volume of body water in which a drug appears to be dissolved in after it has distributed throughout the body” —> this give the apparent volume, not real volume
V(d) = X/C, where X is the amount in body and C is the concentration in plasma
What are the factors determining the volume of distribution?
Amount of drug that binds to plasma protein: greater concentration appears in plasma, the smaller the volume of distribution is
Drug elimination
Term used to describe the rate at which the drug disappears from the blood.
Elimination can occur by: excretion (primarily by kidneys - physical expulsion of the drug from the bloodstream) and metabolism (primarily by the liver - chemical change)
Usually drug is eliminated by a combination of both
Process of excretion by the kidneys
Three steps involve:
1. Glomerular filtration: drug move into the Bowman’s capsule due to leaky vessels (removed from blood stream) - passive filtration that is limited by glomerular filtration rate. Only occurs for drugs not bound by plasma proteins
- Tubular secretion: active process where drug is taken out of blood by active carrier (can remove protein bound drugs but this process can be competitively inhibited - probenecid)
- Tubular reabsorption: passive movement of drugs re-entering the bloodstream by diffusing across the cell membrane of the tubule and peritubular capillary (process is pH dependent - can be manipulated, e.g. aspirin overdose)
How do drugs cross cell membranes?
Most drugs move across the membrane via simple diffusion, driven by a concentration gradient. However this only applies to drugs that are soluble in lipids (lipid solubility of a drug).
Lipid solubility can be manipulated by pH. Most drugs are usually a weak acid/base so that when they are placed in a solution, drug become ionised. When uncharged, drug is more lipid soluble - able to move across membranes more easily. When charged, lipid solubility is reduced.
Example: acidic drugs get taken into cells in low pH (more acidic solutions) while basic drugs get into cells more at higher pH (more basic solutions)
Drug metabolism
Drug metabolism is the biotransformation of a drug. This involves a chemical change to a drug which normally includes enzyme-catalysed reactions. Process usually occurs in most tissues but mainly in the liver. Process try to increase water solubility of the drug to facilitate in its excretion
Phase I metabolism
Involves adding a chemical functional group onto the drug (e.g. hydroxyl, carboxyl)
Cytochrome p450 is responsible for many phase I drug metabolism reaction. It belongs to a superfamily of enzymes. It’s action can be inhibited or enhanced by drugs - leads to drug-drug interaction
Phase II metabolism
Conjugation of water soluble molecule to function group on the drug. Water soluble group (sugar) is added to the drug, replacing the functional group to make the drug more water soluble
First order kinetics
Usually fall in exponential manner
Features: rapid rise, drug has half life (time taken for concentration to fall by half), peak concentrations determined from V(d) which allows us to determine dose
Short term infusion
This normally occurs in a hospital environment via a computer infusion system. This allows the drug to enter the bloodstream at a constant rate. With increase drug concentration, rate of elimination increases. Drug concentration eventually plateaus out if long enough infusion. Rate of accumulation decrease as drug concentration increase
Peak not as height for IV bolus - this is because drug gets eliminated continuously as drug enters
This process is useful for drugs that show toxicity at concentration not much greater than concentration that that produces therapeutic effect
Oral administration
Most common route of administration as it is the most convenient for the patient. Drug most be absorbed from GI tract (predominantly by small intestine).
Absorption takes place primarily via lipid diffusion. Requires times for it to take place. Drug moves across cell membrane into the hepatic portal vein —> travels to liver where major site of drug metabolism takes place before it enters systemic circulation
Most of the drug undergoes first pass hepatic metabolism - most of the drug gets rendered inactive by metabolism
Features of oral administration
Peak of concentration is not as high as IV due to elimination by first pass hepatic metabolism and not all the drug would have be absorbed
Bioavailability
Proportion of active drug which enters blood circulation. This would be 100% for IV administered drugs and less for other routes. It is affected by how much of the drug is absorbed and how much it is metabolised during first pass. Dose must babe consider due to bioavailability. If bioavailability is low/variable, may need to administer drug by other routes
Pharmacology
The study of the effects of drugs on living things
Effect on: whole body (homeostasis), systems (cardio/respir/renal), tissues (blood vessels), cell (single/culture), membranes, molecule (specific target), genes
Pharmacokinetics: What factors do you need to determine the best dose?
Need to understand the processes influencing dose-concentration relationship.
* look at bioavailability (proportion reaching circulation), first pass metabolism (GIT/liver) and plasma protein binding (disease/drug interaction)
Pharmacokinetics: What factors do you need to determine the dosing interval?
The dosing interval is depends on the rate of absorption vs elimination. These depend on the volume of distribution (which give indication of extent of distribution but not location - initial dose), clearance (irreversible removal of drug - metabolism/excretion - stead state dose) and the half life (composite of Vd and Cl - time to steady state and dose interval)
How to quantify drug action?
All drugs have more than one action - dependent on dosage
How do drugs interact with molecular targets?
They can interact with receptors, ion channels, enzymes and transporters.
Type of drug action
Agonist: bind and activate receptor
Antagonist: bind and do not activate receptor
Affinity
It is a quantifiable measure of the molecular attraction to the receptor
- Law of mass action
- Dissociation constant (Kd) - concentration at which 50% receptors are bound
Drugs can have affinity for different receptors
- constant for a given drug-receptor pair
- Relative affinity gives an indication of the selectivity of a drug
Drug selectivity
Dose (concentration) determines effect???
Receptors
- Initiate cellular signalling by hormones and neurotransmitters
- Contribute to specific responses based on drug selectivity
- Make drugs powerful & potent - amplification through 2nd messengers
- Targeted by 30-40% of therapeutic drugs
- Principles applicable to other targets (enzymes, carriers, ion channels)
The concentration-response curve
…
