Pharmacology Flashcards
Pharmacology
Uses and effects of drugs
Clinical Pharmacology
How this applies to a clinical context
E.G. effects of a drug across a population
Therapeutics
Treatment and care of a patient to prevent, suppress or cure disease / alleviate pain and injury
Drug
Chemical which produces a biological effect when introduced to the body
Can be natural or manufactured
Medicine
Chemical preparation containing one or more drugs plus other substances
Given to produce a therapeutic effect
Pharmacodynamics
Effect of a drug on the body
Pharmacokinetics
What the body does to a drug
What are the 4 phases of pharmacokinetics?
1) Absorption
- from site of administration into the blood
2) Distribution
- drug leaves the bloodstream and goes in
3) Metabolism
- body inactivates the drug through enzymatic modification
4) Excretion
- drug is eliminated from the body in urine, bile or faeces
What is the interaction of a drug with a target dependent on?
Shape - ‘lock and key’ mechanism
Charge distribution - the type of bonds that hold the drug to the target
What are the 4 main targets of drug action?
Receptors
- agonists activate the receptor
- antagonists block the action of agonists
Ion channels
- block or modulate the opening/closing
Enzymes
- inhibit or act as a false substrate
Carriers
- transported in the place of the endogenous substrate or inhibit transport
What are the 4 major receptor subtypes?
1) Ligand gated ion channel
2) G-protein
3) Enzyme linked receptor
4) Intracellular receptor
What is an agonist, describe how an agonist and receptor work together and describe the relationship between potency and affinity
A ligand that combines with the receptor to elicit a cellular response
Agonist + receptor <–> agonist-receptor complex –> action –> effect
High potency tends to mean high affinity
What is an antagonist and describe its efficacy and affinity
A drug which inhibits the action of an agonist but has no effect in the absence of an agonist
They have no efficacy
They do have affinity
What is a competitive antagonist and how do they affect an agonist curve?
Competes with the agonist for the binding site
Agonist curves have the same form, are displaced to the right and have the same maximal response
How do irreversible antagonists affect agonist curves?
Agonist curves don’t have the same form and have a reduced maximal response
Efficacy
Maximal drug effect a drug can elicit from that system
What is potency and what is it dependent on?
Concentration of drug needed to produce an effect
Dependent on affinity, efficacy, the number of receptors and the efficiency of stimulus-response mechanisms used
What is a dose-response curve / concentration-effect curve used to determine?
Used to determine efficacy and potency
Affinity
Strength with which a ligand binds to the receptor
Measured with Kd - the concentration of ligand at which 50% of the available receptors are occupied (measure from agonist-binding curve)
Inverse relationship between Kd and affinity
EC50
Concentration of ligand where 50% of its maximal effect is observed
A measure of potency
Inverse relationship between EC50 and potency
Full and Partial Agonist
AR* = activated receptor
AR = unactivated receptor
Full agonist means AR* is very likely
Partial agonist means AR* is less likely
Drug Selectivity and Specificity
Selectivity - many drugs act preferentially on receptors or subtypes
Specificity - no drug is specific to only one receptor subtype
Because no drug is specific, as the dose increases the desired response in a patient rises to a maximum which induces toxic effects
Therapeutic Window
Measure of drugs safety
Difference between effective and toxic dose
Therapeutic Index
Comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity
A measure of drug safety
TD50 - dose that causes a toxic response in 50% of the population
ED50 - dose that is therapeutically effective in 50% of the population
Therapeutic Index = TD50 / ED50
Larger value suggests a wide margin between effective and toxic doses
Tolerance
Reduction in response to a drug after repeated administration
Routes of Administration
Oral
Parenteral (injection)
- Intravenous
- Intramuscular
- Subcutaneous
Inhalation
Topical
- Creams
- Ointments
- Transdermal
- Patches
Sublingual
Rectal
Advantages of Oral Administration
Easy and convenient
Non-invasive
Less risk of infection
Painless
Cheapest
Self-administered
Disadvantages of Oral Administration
Slower absorption
Some patients can’t swallow
Patient compliance is necessary
Some drugs (e.g. proteins) destroyed by gut acid/flora
Some drugs can be irritant if taken orally
Factors affecting gastrointestinal absorption
Gut motility
- decreased motility can increase drug absorption
Gut pH
- poor absorption of strong acids and bases
Physiochemical interactions
- interactions with food and other drugs
Competition for carriers/transporters
Absorption across physiological barriers
Main site of absorption of oral drugs is the small intestine
Drugs must cross cell membranes:
- Passive diffusion through lipid bilayer
- Diffusion through aqueous channel
- Carrier mediated transport
Passive Diffusion
Lipid solubility is an important determinant of rate of absorption
Non-polar/unionised substances dissolve in lipid
Ionised species have low lipid solubility
Many drugs exist in ionised and unionised forms as many are weak acids and bases
pH and pKa
Ratio of ionised : unionised determined by pH
Proportion of a drug that is ionised depends on the pH of the solution and the pKa of the drug
When pH = pKa, 50% of the drug is ionised
Drug Distribution
Reversible transfer of a drug from one location to another within the body
For most drugs this occurs through passive diffusion of the unionised form across the cell membrane until equilibrium is reached
Factors Affecting Rate of Distribution
Membrane permeability
- Drugs perfuse faster through a more permeable membrane
Blood perfusion
- Drugs reach highly vascularised tissues more rapidly
Factors Affecting Extent of Distribution
Lipid Solubility
- Ionised lipid is insoluble so drugs can’t easily enter cells
Plasma protein binding
Tissue binding
Plasma Protein Binding
Drugs can bind reversibly to plasma proteins in the blood
Some drugs are ~1% ppb, while some are ~99%
Albumin is the most important plasma protein as it binds many acidic and some basic proteins
Acid-glycoprotein and beta-globulin plasma proteins bind basic drugs
PPB drugs are not pharmacologically active
Extensive ppb slows drug action and elimination (slower acting but with prolonged therapeutic effects)
Tissue Binding
Drugs diffuse from the plasma into tissues
Tissues can bind drugs:
- their composition –> lipid soluble drugs will accumulate in fat
- binding to cellular components –> proteins, pigments, minerals
Volume of Distribution
Distribution of a drug between plasma and the rest of the body
If drugs are confined to the plasma, Vd is low
If drugs accumulate outside the plasma, Vd is high
Bioavailability
Proportion of a drug that passes into the systemic circulation after administration
Dependent on absorption and metabolism
- metabolism in the gut/liver = first pass metabolism
High first pass metabolism leads to low bioavailability
First Pass Metabolism
Liver and gut wall have drug metabolising enzymes
For certain drugs extensive metabolism occurs before the drug reaches the systemic circulation
Only a small proportion of the dose reaches the systemic circulation
Can be countered with a larger oral dose or a different route of administration (IV, inhalation, sublingual)
Drug Metabolism: Reducing Lipid Solubility
Most drugs are lipophilic
- allows absorption of drugs across membranes to reach site of action
Lipophilic compounds not efficiently eliminated by kidney so they need to be made hydrophilic so they can be excreted via urine
Metabolism introduced hydrophilic components onto drug to aid excretion
Hydrophilic drugs tend to be excreted unchanged
Drug Metabolism: Altering Biological Activity
End result of metabolism is usually the abolition of biological activity
Various steps in between may cause:
- Conversion of a pharmacologically active to an inactive substance (most drugs)
- Conversion of one pharmacologically active substance to another (prolongs drug action)
- Conversion of a pharmacologically inactive substance to an active substance
Phase 1 Metabolism
Reactions involve oxidation, reduction and hydrolysis
- form more chemically reactive products
- involves cytochrome P450 enzymes in liver
Reactions create functional groups that allow the drugs to be acted upon by phase 2 conjugative mechanisms
Main function is to prepare chemicals for phase 2 metabolism and then excretion
Phase 2 Metabolism
Conjugation reaction (e.g. glucuronidation)
Conjugations lead to inactive and polar products that are readily excreted
First pass metabolism reduces bioavailability of many drugs when orally administered
How are drugs removed from the body?
By the processes of metabolism and excretion –> elimination
Major systems concerned with excretion:
- kidneys (urine)
- hepato-biliary system (faeces)
- lungs (for volatile compounds such as anaesthetics)
- liver (bile)
Enterohepatic Circulation
Glucuronide conjugates (more water soluble) excreted in bile may undergo enterohepatic circulation
1) Drug is metabolised to conjugate in liver
2) Conjugate is excreted in the bile from gallbladder into the gut
3) Conjugate undergoes bacterial hydrolysis in gut back into drug and free glucuronide
4) Drug is reabsorbed into hepatic portal vein and transported to liver
5) Drug is reabsorbed into the blood causing a prolonged duration of action
What does EHC create?
A reservoir of recirculating drug and increases the half life
Renal Excretion
Drugs differ greatly in the rate at which they are excreted by the kidney
Metabolites are nearly always cleared quicker than the parent drug
3 processes for renal drug excretion:
1) Glomerular filtration
- not affected by lipid solubility and pH
- pbp almost completely held back
2) Active tubular secretion
3) Passive diffusion across tubular epithelium
Prodrug
Biologically inactive compound which can be metabolised in the body to produce a drug
Internal Factors affecting Variability in Response to Drugs
Disease
Age
Genetics
External Factors affecting Variability in Response to Drugs
Drug formulation
Drug interactions
Smoking/alcohol
Diet
Environment
What can tablets be manufactured for so the rate of disintegration and dissolution varies?
Rapid effect
Sustained release
Controlled release
Delayed release
Drugs can be manufactured so the drug disintegrates in?
Duodenum
Jejunum
Colon
CYP1A
Important for paracetamol metabolism
CYP2C
CYP2C9 = important isoform
It metabolises ibuprofen and warfarin
CYP2D
Major isoform
CYP2D6 metabolises codeine, propranolol, many SSRIs (antidepressants)
CYP2E
Metabolises alcohol and paracetamol
CYP3A
Main isoform in liver and intestine
It metabolises ~ 50% of current drugs
Substrate
The drug being metabolised
Inhibitors
Drugs which inhibit the activity of the P450 enzyme
Inducers
Drugs which increase the activity of the P450 enzyme
