Pharmacology Flashcards
List some target sites for drug action
- Biological molecules, most often proteins
- Enzymes
- Carrier molecules
- Ion channels
- Receptors
- Structural proteins
- DNA
Define the term agonist
A molecule/drug that binds and activates the receptor
Has affinity and efficacy
Define the term antagonist
A molecule/drug that binds and has no effect on the receptor (affinity but no efficacy)
Define the term partial agonist
A molecule/drug that binds and has some effect on the receptor (has affinity and reduced efficacy)
Why might a partial agonist be used?
A partial agonist may be used where one drug has a strong effect but also leads to strong side effects, whereas the potency of another may be reduced but there are also fewer side effects
What is a dose-response curve?
A curve that plots the concentration of a drug (usually the log) against its response
What can a dose-response curve be used for?
Can be used to compare drugs acting on the same target to assess affinity, efficacy and margins of safety
Explain the term affinity
The tendency of a drug to bind to the receptor
Explain the term efficacy
The tendency of a drug to activate the receptor once bound i.e. its ability to give a response
Explain the term EC50
Effective concentration
- is the dose required for an individual to experience 50% of the maximal effect
Explain the term ED50
Effective dose
is the dose for 50% of the population to obtain the therapeutic effect
- relates to in vivo experiments where the overall effect is assessed
Explain the term therapeutic index
The safety margin of a drug
= toxic dose/effective dose
What does a larger therapeutic index mean?
Safer, as the toxic dose is much larger than the effective dose used
Explain the term potency
The amount of drug required to produce 50% of its maximal effects
- Used to compare drugs within a chemical class
- Usually expressed as mg/kg
Explain the term specificity
Describes the capacity of a drug to cause a particular action in a population
- Depends on receptor subtype
Describe the actions of a drug of absolute specificity
May increase or decrease a specific function of a given gene, protein or cell type, but must do either not both
Explain the term selectivity
Relates to a drug’s ability to target only a selective population i.e. a cell/tissue/signalling pathway in preference of others
Explain the term competitive antagonist
Competes with the agonist for the receptor binding site. can be overcome
What is the effect of a competitive antagonist on the agonist dose response curve?
The curve will be shifted to the right
Explain the term non-competitive antagonist
Non-competitive antagonists either bind to a different receptor site or block a chain of events post binding, acting downstream of receptor in the signalling cascade
Explain the term irreversible antagonist
An antagonist that dissociates only very slowly or not at all from a receptor, cannot be overcome with additional agonist
What type of bond do irreversible antagonists form with receptors?
Covalent bonds
Explain what is meant by the term inverse agonism
A drug that reduces the activation of a receptor with constitutive activity. can be regarded as drugs with negative efficacy
Explain the term IC50
Concentration of an antagonist to inhibit 50% of the agonist maximal effect. Can be used to measure antagonist drug potency
Define the term tachyphylaxis
“Rapid protection”
Increase in drug tolerance which develops after a short period of repeated dosing leading to a decrease in response to the drug
Define the term self-antagonism
When a drug becomes antagonistic to its own effects over time
List the ways in which loss of target sensitivity may occur
- Change in receptors
- Loss of receptors
- Exhaustion of mediators
- Increased metabolic degradation
- Physiological adaptation
- Drug transporters
Outline how a change in receptors can lead to loss of target sensitivity
Become resistant to drug stimulation/conformational changes
Outline how a loss of receptors may occur to lead to a loss of target sensitivity
Endocytosis of receptorss
How may exhaustion of mediators occur, leading to a loss of target sensitivity?
Degradation/low re-expression level
How may increased metabolic degradation lead to loss of target sensitivity?
Higher concentration of drug is required to exert an effect due to increased elimination of the drug
How may physiological adaptation lead to a loss of target sensitivity?
Cross talk between body systems allowing organs to compensate for discrepancies in others
How may drug transporters lead to a loss of target sensitivity?
Drug is removed from the receptor site before the effect can occur
What are the potential outcomes of drug-drug interaction?
- Action of one or more drugs is enhanced
- Development of totally new effects
- Inhibitory effects on one drug from another
- No change
What are some cases where drug-drug interaction may be likely?
- Pregnancy
- Chronic cases
- Elderly
as there is commonly polypharmacy in these cases
What are the 3 mechanisms of interaction between drugs?
- Pharmaceutical
- Pharmacokinetic
- Pharmacodynamic
What is meant by pharmaceutical interactions between drugs?
Related to the physiochemical properties and formulation
What is meant by pharmacokinetic interactions between drugs?
Related to interactions within ADME
Absorption, distribution, metabolism, excretion
What is meant by pharmacodynamic interactions between drugs?
Related to interactions within receptor signalling
What causes pharmaceutical interactions between drugs?
Due to chemical or physical incompatibility/interaction
Give examples of drugs that have pharmaceutical interactions
- Sodium bicarbonate and calcium
- Insulin is denatured by glucose
- Diazepam binds to plastics (syringes)
Outline how absorption may be affected by drug interactions
- One drug may alter the acidity or motility of the stomach, affecting absorption of drugs taken orally
- May also have gastric emptying
Outline how chemical alterations may occur and affect drug-drug interactions
- pH may be altered by one drug and thus affect another as many are pH dependent
- Oxidation/reduction
- Loss of drug potency
- Complex formation
Outline how distribution may be affected by, and affect drug-drug interactions
- Some drugs reduce circulation and may therefore reduce clearance and elimination of others
- Competition for binding sites on plasma proteins (albumin most common)
Outline the pharmacodynamic effects of drug-drug interaction
- Agonist/antagonist negate an effect
- Agonist/antagonist induce harmful effect
- Syngergistic effects
What is meant by summation of effect?
When 2 drugs are administered together, effect seen is equal to sum of individual effects of each drug
1+1=2
What is meant by potentiation of effect?
When a drug or food increases the effect of another drug, but has no effect when administered alone
1+0=2
What is meant by synergism of effect?
When 2 drugs are administered together producing effects that are greater than would be produced if either drug was administered individually or would be seen with summative effects
1+1=3
What is meant by Ki?
The dissociation constant for inhibitor binding and is an indicator of enzyme affinity for inhibitor
What is the significance of Ki?
Can be used to establish at what concentration an agonist will overcome the inhibitor
What is meant by enteral routes of drug administration?
- Administration via the gastrointestinal tract
- Includes sublingual, swallowing and rectal
Where does absorption take place with enteral administration?
Along the length of the GI tract
What is meant by parenteral routes of drug administration?
Routes other than oral, go into blood stream
Give examples of parenteral routes of drug administration
- Topical
- Intradermal
- Subcut
- Intramuscular
- Intravenous
- Inhalation
Outline the effects of topical administration at different sites
- Skin: local, slow and sustained effects (hours to weeks e.g. patches)
- Eye drops: local effect, renew frequently
- Nasal instillation: local systemic effect
Compare the rates of absorption between intradermal, subcutaneous and intramuscular absorption
- ID: slow
- Subcut: faster (but fat layer may trap lipid soluble compounds)
- IM: very fast absorption
How does formulation of an injectable drug affect drug absorption?
- Liquid > suspension > emulsion
- Thinner formula = faster absorption
- Can extend half life by altering formulation
Outline the pros/cons of intravascular administration
- Accurately control body concentration of drugs e.g. narrow therapeutic window
- BUT cannot be recalled and slow admin needed to avoid side effects
Discuss the absorption of drugs administered via inhalation
- Rapid systemic effect
- Dependent on tidal volume and size of aerosol particle
- Smaller more likely to reach alveolar ducts and sacs
What are the chemical properties of drugs that are rapidly absorbed?
- Low degree of ionisation
- High lipid/water partition in the non-ionised form
- Low MW (<1000)
- Biological affinity with transporters/facilitated diffusion
What are the chemical properties of drugs that are not rapidly absorbed?
- High degree of ionisation
- Higher affinity to water vs lipid in the non-ionised form (flows with perisaltic mvt and eliminated or need transporters)
- Large MW
- Degraded by specific enzymes
Explain the importance of the charge of a drug
- In a protonated environment, acids neutral and bases charged so higher membrane permeability for acids
- In non-protonated environment, acids charged and bases neutral, higher membrane permeability for bases
Compare the absorption of enteral and parenteral drug administration
- Enteral absorbed along entire GIT, goes through first pass metabolism
- Parenteral bypasses first pass metabolism
Explain the importance of the first pass metabolism in drug absorption
- Occurs in the liver
- Only affects orally administrated drugs
- Many compounds inactivated and excreted via biliary system
What is meant by first pass metabolism?
When a drug is metabolised before it reaches the systemic circulation
Describe the movement of drugs through the first pass metabolism
- From the portal vein from the GI tract, to the hepatocytes where they can be metabolised, then hepatic vein and into circulatory system
- Can be recycled several times via the biliary system before entering the systemic circulation
What processes occur in phase I of hepatic metabolism of drugs?
- Oxidation
- Reduction
- Hydrolysis
- I.e. catabolic processes
What process occurs in phase II of hepatic metabolism of drugs?
- Synthetic conjugation
- I.e. anabolic processes
What is the most significant enzyme regarding drug metabolism?
CYP450
What is the function of the CYP450 enzyme?
- Acts in phase I of metabolism
- Adds hydroxy molecules to make drug more polar
Where are mammalian CYPs found?
- Majority in liver but can be present in wall of intestine
- Membrane bound to endoplasmic reticulum
What enzymes are important in phase II of drug metabolism?
- Transferases
- Esp glucoronyl transferase
What is the function of the transferase enzymes?
Attach water soluble, endogenous molecules to make the drug more soluble
E.g. glucoronyl transferase adds glucoronic acid to make molecules very water soluble
What are some potential results of drug metabolism?
- Detoxification
- Production of metabolites with similar activity to drug
- Metabolite with different activity to drug
- Production of toxic metabolites
List variables that may affect drug absorption via enteral routes
- Individual variation
- Age
- Temperature
Outline how individual variables may affect drug absorption via enteral routes
- Amount of food eaten
- Peristaltic movement
- Metabolic rates/organ function (age and size related)
Outline how age may affect drug absorption via enteral routes
- More chronic illness = more chance for adverse reaction
- Elderly have less proteins and water in body
- Infants more water (human)
- pH of GIT may change with age
Outline how temperature may affect drug absorption via enteral routes
Cold blooded animals have variable metabolism that may change depending on season and with environment
What are the main routes of drug excretion?
- Kidneys (mechanical)
- Hepatobiliary system
- Lungs (volatile compounds e.g. gas)
What are some secondary routes of drug excretion?
- Milk
- Sweat
What is the function of phase I in liver metabolism of drugs?
Make drug more polar
What is the function of phase II in liver metabolism of drugs?
Make molecule inactive and water soluble and thus excretable by the body
What are the 3 processes of renal excretion of drugs?
- Passive filtration
- Secretion
- Reabsorption
What influences renal passive filtration of drugs?
- GFR
- Plasma protein binding (bound will not be filtered)
What influences renal secretion of drugs?
- Affinity for transporters (OATs, OCTs)
- Lipophilicity, polarity
What influences renal reabsorption of drugs?
- Lipophilicity
- Polarity
- Urine pH
Explain the role of transporters in renal secretion of drugs
- Some membrane transporter recognise weak acids, others weak bases
- Can put drug into proximal tubule to then be excreted
- OAT: organic anion transporters
- OCT: organic cation transporters
Outline the process of renal reabsorption of drugs
- Distal tubule
- Only neutral molecules
- Reabsorbed into blood
What is the net renal excretion?
Filtration + secretion - reabsorption
How is filtration excretion calculated?
GFR xfu
- where fu = drug plasma free fraction = 1-fraction of drug bound to plasma
What is the significance of a renal excretion > GFRxfu?
Active secretion is taking place
What is the significance of renal excretion
Net reabsorption is taking place
- may still have secretion but there is more reabsorption
What are the consequences of metabolic acidosis on drug excretion?
- pH of urine > pH of blood
- Urine non-protonated in comparison
- Acids in form of H+ i.e. charged, trapped in urine and excretion increased
- Bases in neutral form, reabsorbed, excretion reduced
What are the consequences of metabolic alkalosis on drug excretion?
- pH urine < pH blood i.e. acidic urine
- urine protonated
- Acids in neutral form, reabsorbed and excretion reduced
- Bases in charged form so cannot be reabsorbed, trapped, excretion increased
How may drug interactions occur?
- Pharmaceutical interactions i.e. interaction prior to administration
- Pharmacokinetic i.e. tissue/plasma levels of a drug altered by another
- Pharmacodynamic: action of one drug altered by a second
What are the potential outcomes of drug interactions?
- Action of one or more drugs is enhanced
- Development of new effects
- Inhibitory effects of one drug on another
- No change
Give examples of some pharmaceutical drug interactions
- Chemical or physical incompatibility/interaction
- E.g. sodium bicarbonate and calcium
- Insulin denatured by glucose
- Diazepam binds to plastics so cannot be used in plastic syringes
- Insolubility e.g. amphotericin B precipitatesin electrolyte solutions
- Chemical incompatibilities e.g. pH, oxidation/reduction, complex formation between 2 drugs
How may pharmacokinetic interactions between drugs occur?
- Absorption
- Excretion
- Reduced circulation
- Metabolism
Outline how drugs may interact to affect absorption
- Change in gastric pH
- Alteration in bacterial flora
- Competition for binding sites on plasma proteins
- Decreased gastric emptying (more absorption)
Outline how drugs may interact to affect excretion
- Sodium bicarb makes urine more alkaline and thus increases excretion of weak acids
Outline how drugs may interact to affect circulation
- e.g. alpha-2 agonists reduce circulation
- May reduce clearance and elimination
Outline how drugs may interact to affect metabolism
- Enzyme inhibition/induction
- Inhibiting the enzyme will slow rate of metabolism, extend half life
- e.g. grapefruit juice inhibits subtypes of CYP450
- Some drugs induce CYP450 and increase metabolism of other substances, can lead to adverse reactions e.g. hepatitis
Outline some pharmacodynamic mechanisms of drug interaction regarding receptor sites
- Agonist/antagonist can negate and effect e.g. vit K is an antidote to coumarin anticoagulant
- Agonist/antagonist can induce a harmful effect e.g. alpha-2 agonist and alpha-2 antagonist
- Synergistic effects: combination of drugs may produce therapeutic/toxic effect greater than sum of each drug’s action
