intro to pharmacology Flashcards
What are some drug targets + some examples of drugs acting on these targets?
- receptors (nicotine binds/activated nicotinic acetylcholine receptor)
- enzyme (aspirin binds COX enzyme to block production of prostaglandins
- ion channels (local anaesthetics block sodium ion channel preventing nerve conduction)
- transport proteins (prozac blocks serotonin carrier proteins preventing serotonin reuptake from synapse)
What can drugs do when they act on target?
Can either enhance activation of target (stimulate effect) or prevent activation of target (block effect being produced)
What is selectivity?
Ability of drug to bind to particular drug target. Drugs often structurally similar so can act on other targets as well.
What is specificity?
Ability of drug to produce one effect (often have same target in other part of body - produces effects there)
How does dose affect selectivity?
At low dose, effect is more specific but as dose increases effect becomes less specific (can interact with other targets), increasing side effects too
How do drugs interact with receptors?
-Electrostatic interactions (commonly H bonds & Van der waal forces), hydrophobic interactions (important for lipid soluble drugs), covalent bonds (not ass common), stereospecific interactions (drugs can exist as stereoisomers interacting stereospecifically with receptors)
What is affinity? What is it strongly linked to?
Affinity is strength of binding of drug to receptor.
Linked to receptor occupacy (giving 2 drugs where one has higher affinity means higher chance that drug will be bound to receptor at given moment)
What is efficacy?
Ability of drug to produce effect once bound to receptor. Can be complete response, no response or partial response
What is difference between agonists, partial agonists, antagonists?
- Agonists have both affinity & efficacy (maximal effect) (produce effect)
- partial agonists have affinity but have sub-maximal efficacy.
- Antagonists have affinity but no efficacy.
What is potency? How is it measured? What does a highly potent drug do?
Concentration of drug needed to produce defined effect.
- Dose of drug needed to produce 50% of tissue response (EC50 - half maximal effective concentration) - 50% of effect.
- ED50 half maximal effective dose (desired effect in 50% of people)
How does dose affect potency and efficacy?
Potency related to dose (increase dose makes it more potent). Dose not related to efficacy
Which is more clinically relevant: efficacy or potency?
Efficacy because want to know if drug can induce maximal response. Potency just determines dose needed to produce response
What is bioavailability of a drug?
Fraction of initial dose that gains access to systemic circulation (eg IV drug 100% bioavailability)
How does site of administration affect absorption & bioavailability?
Eg IV drug will have 100% bioavailability whereas other methods of administration will have less than 100% because don’t go straight into circulation
How do drugs move around in the body?
- bulk flow transfer (in blood stream)
2. diffusional transfer (molecule by molecule across short distances)
What are the methods that drugs can diffuse across plasma membrane?
- pinocytosis (membrane envelopes molecule, forms vesicle around it and releases it to other side - uncommon)
- diffusion across aqueous pores (uncommon because too small for most drugs)
- diffusion across lipid membrane (need to be suitably lipid)
- carrier mediated transport (transmembrane protein binds it and transfers it)
What is lipid solubility?
Most drugs are water soluble because given orally and need to dissolve in GI tract.
Lipid solubility helps molecules cross plasma membrane
What will a weak acid do in ionised state? What will a weak base do in ionised state?
Weak acid in ionised state proton donor. Weak base in ionised state accepts protons.
What does an unionised form of drug have? What affects whether drug is ionised or unionised?
Unionised form of drug retains more lipid solubility. Depends on
- dissociation constant pKa of drug
- pH of particular part of body
What is usual pH of a weak acid? What will happen to it when at body part where pH = drugs pKa, or pH lower or higher?
Weak acid pka 3-5.
pH=pka equally dissociated.
As pH decreases unionised form dominates.
As pH increases ionised form dominates
What is usual pH of weak base? What happens to it when at body part where pH = drugs pKa, or pH lower or higher?
Weak base pka 8-10.
ph=pKa equally dissociated.
As pH increases unionised form dominates.
As pH decreases ionised form dominates
Will weak base be absorbed well in stomach? Will weak acid be absorbed well in stomach?
No because better absorbed at higher pHs.
Weak acids yes
Once absorbed what are important carrier systems?
Renal tubule, biliary tract, BBB, GI tract (responsible for absorption & excretion of drug from body)
After drug absorption what affects tissue distribution (distribution of drug to different tissues)?
- regional blood flow
- plasma protein binding
- capillary permeability
- tissue localisation
How does regional blood flow affect tissue distribution?
Different tissues receive different amounts (%) of cardiac output. More blood will be distributed to those with higher blood flow. Can increase/decrease depending on circumstances like exercise
How does plasma protein binding affect tissue distribution?
In circulation usually drug bind to plasma proteins usually albumin (better at binding acidic drugs). Amount bound dependents on 1. free drug concentration 2. affinity for protein binding sites 3. plasma protein concentration.
What drugs bind well to albumin etc? what happens to drugs bound to plasma proteins?
Affinity for protein binding site.
Acidic drugs bind well to albumin so more heavily plasma bound.
Only free drugs available to diffuse out of blood into tissues, so the bound drugs need to dissociate first
How does capillary permeability affect tissue distribution? How is this different in different organs?
Capillaries can have different structures eg. Continuous (h20 filled gap junction), BBB (tight junctions) or fenestrated or discontinuous.
- Most continuous with small gap junctions (if very lipid soluble drug can diffuse across). If cant get through gap junctions (polar) transported by carrier proteins.
- BBB tight junctions so hard to get through.
- Liver discontinuous - big gaps between endothelial cells so drugs can diffuse into tissue (metabolic purposes).
- Glomerulus of kidney fenestrated because involved in excretion allowing small drugs to pass from blood to tubules
How does tissue localisation affect tissue distribution?
Position of equilibrium.
Lipid drug equilibrium more heavily weighted towards retention in areas of high fat content (eg brain) and water soluble drugs more in water.
Larger proportion of lipid drug localised in brain compared to water soluble drug
What do we ideally want for a drug to be excreted?
Ideal that they are water soluble (easier to excrete)
What are the 2 phases of drug metabolism in order to be excreted?
In liver mostly.
- phase 1: introduce reactive polar group to drug (via oxidation, reduction or hydrolysis) using P40 enzymes to produce metabolites with functional groups serving as point of attack for conjugating systems of phase 2 (often pharmacologically active drug)
- phase 2: add conjugate to reactive group to make it inactive and far less lipid soluble. Facilitates excretion in urine or bile. Mainly transferase enzymes involved and groups are glutathione, glucouronidation, acetylation, sulfation
What is first pass hepatic metabolism? What can this cause and what is the solution?
Drugs absorbed in GI tract enter hepatic portal blood supply passing liver before reaching systemic circulation.
- Can be heavily metabolises as a result so less reaches systemic circulation, but is needed for pro-drug metabolism.
- Solution: give larger dose . Problem: extent of first pass varies amongst people so amount reaching circulation varies (side effects + drug effects unpredictable)
How can drug be excreted?
Lungs, breast milk, most commonly kidney (urine) and liver (bile)
What are the 3 routes of kidney excretion?
- glomerular filtration (depends on size - smaller dugs)
- active tubular secretion (best method, more blood delivered to proximal tubule - where we have 2 active transporter carrier systems for acidic and basic drugs)
- passive diffusion across tubular epithelium (lipid soluble drug). -reabsorbed back into blood - depends on phase 2 making more water soluble less reabsorbed & urine pH
How are drugs excreted through? what is enterohepatic cycling?
- Liver cells transport drugs from plasma to bile by transporters. Good at removing phase 2 glucuronide metabolites.
- From bile go to intestines and eliminated in faeces.
- Enterohepatic cycling prolongs drug effect as glucuronide metabolite excreted into small intestine where hydrolysed by gut bacteria releases glucoranide conjugate, increasing lipid solubility, allowing greater reabsorption back into blood and can have effects on body still
What is difference between pharmacology & therapeutics?
Pharmacology is study of drug action to understand how it interacts with us and influences physiology. More focused on drug.
Therapeutics concerned with drug prescribing & treatment of disease, more focused on patient
What is apparent volume of distribution?
Hypothetical fluid volume through which drug is dispersed
What is drug half life?
Time it takes for amount of drugs active substance in body to reduce by half
What are the 4 major pharamokinetic factors?
Absorption, distribution, metabolism, excretion
