intro to pharmacology

Question 1

What are some drug targets + some examples of drugs acting on these targets?

Answer 1

1. receptors (nicotine binds/activated nicotinic acetylcholine receptor)
2. enzyme (aspirin binds COX enzyme to block production of prostaglandins
3. ion channels (local anaesthetics block sodium ion channel preventing nerve conduction)
4. transport proteins (prozac blocks serotonin carrier proteins preventing serotonin reuptake from synapse)

Question 2

What can drugs do when they act on target?

Answer 2

Can either enhance activation of target (stimulate effect) or prevent activation of target (block effect being produced)

Question 3

What is selectivity?

Answer 3

Ability of drug to bind to particular drug target. Drugs often structurally similar so can act on other targets as well.

Question 4

What is specificity?

Answer 4

Ability of drug to produce one effect (often have same target in other part of body - produces effects there)

Question 5

How does dose affect selectivity?

Answer 5

At low dose, effect is more specific but as dose increases effect becomes less specific (can interact with other targets), increasing side effects too

Question 6

How do drugs interact with receptors?

Answer 6

-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)

Question 7

What is affinity? What is it strongly linked to?

Answer 7

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)

Question 8

What is efficacy?

Answer 8

Ability of drug to produce effect once bound to receptor. Can be complete response, no response or partial response

Question 9

What is difference between agonists, partial agonists, antagonists?

Answer 9

• Agonists have both affinity & efficacy (maximal effect) (produce effect)
• partial agonists have affinity but have sub-maximal efficacy.
• Antagonists have affinity but no efficacy.

Question 10

What is potency? How is it measured? What does a highly potent drug do?

Answer 10

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)

Question 11

How does dose affect potency and efficacy?

Answer 11

Potency related to dose (increase dose makes it more potent). Dose not related to efficacy

Question 12

Which is more clinically relevant: efficacy or potency?

Answer 12

Efficacy because want to know if drug can induce maximal response. Potency just determines dose needed to produce response

Question 13

What is bioavailability of a drug?

Answer 13

Fraction of initial dose that gains access to systemic circulation (eg IV drug 100% bioavailability)

Question 14

How does site of administration affect absorption & bioavailability?

Answer 14

Eg IV drug will have 100% bioavailability whereas other methods of administration will have less than 100% because don’t go straight into circulation

Question 15

How do drugs move around in the body?

Answer 15

1. bulk flow transfer (in blood stream)

2. diffusional transfer (molecule by molecule across short distances)

Question 16

What are the methods that drugs can diffuse across plasma membrane?

Answer 16

1. pinocytosis (membrane envelopes molecule, forms vesicle around it and releases it to other side - uncommon)
2. diffusion across aqueous pores (uncommon because too small for most drugs)
3. diffusion across lipid membrane (need to be suitably lipid)
4. carrier mediated transport (transmembrane protein binds it and transfers it)

Question 17

What is lipid solubility?

Answer 17

Most drugs are water soluble because given orally and need to dissolve in GI tract.
Lipid solubility helps molecules cross plasma membrane

Question 18

What will a weak acid do in ionised state? What will a weak base do in ionised state?

Answer 18

Weak acid in ionised state proton donor. Weak base in ionised state accepts protons.

Question 19

What does an unionised form of drug have? What affects whether drug is ionised or unionised?

Answer 19

Unionised form of drug retains more lipid solubility. Depends on

1. dissociation constant pKa of drug
2. pH of particular part of body

Question 20

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?

Answer 20

Weak acid pka 3-5.
pH=pka equally dissociated.
As pH decreases unionised form dominates.
As pH increases ionised form dominates

Question 21

What is usual pH of weak base? What happens to it when at body part where pH = drugs pKa, or pH lower or higher?

Answer 21

Weak base pka 8-10.
ph=pKa equally dissociated.
As pH increases unionised form dominates.
As pH decreases ionised form dominates

Question 22

Will weak base be absorbed well in stomach? Will weak acid be absorbed well in stomach?

Answer 22

No because better absorbed at higher pHs.

Weak acids yes

Question 23

Once absorbed what are important carrier systems?

Answer 23

Renal tubule, biliary tract, BBB, GI tract (responsible for absorption & excretion of drug from body)

Question 24

After drug absorption what affects tissue distribution (distribution of drug to different tissues)?

Answer 24

1. regional blood flow
2. plasma protein binding
3. capillary permeability
4. tissue localisation

Question 25

How does regional blood flow affect tissue distribution?

Answer 25

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

Question 26

How does plasma protein binding affect tissue distribution?

Answer 26

``` 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. ```

Question 27

What drugs bind well to albumin etc? what happens to drugs bound to plasma proteins?

Answer 27

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

Question 28

How does capillary permeability affect tissue distribution? How is this different in different organs?

Answer 28

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

Question 29

How does tissue localisation affect tissue distribution?

Answer 29

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

Question 30

What do we ideally want for a drug to be excreted?

Answer 30

Ideal that they are water soluble (easier to excrete)

Question 31

What are the 2 phases of drug metabolism in order to be excreted?

Answer 31

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

Question 32

What is first pass hepatic metabolism? What can this cause and what is the solution?

Answer 32

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)

Question 33

How can drug be excreted?

Answer 33

Lungs, breast milk, most commonly kidney (urine) and liver (bile)

Question 34

What are the 3 routes of kidney excretion?

Answer 34

1. glomerular filtration (depends on size - smaller dugs) 2. active tubular secretion (best method, more blood delivered to proximal tubule - where we have 2 active transporter carrier systems for acidic and basic drugs) 3. passive diffusion across tubular epithelium (lipid soluble drug). -reabsorbed back into blood - depends on phase 2 making more water soluble less reabsorbed & urine pH

Question 35

How are drugs excreted through? what is enterohepatic cycling?

Answer 35

- 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

Question 36

What is difference between pharmacology & therapeutics?

Answer 36

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

Question 37

What is apparent volume of distribution?

Answer 37

Hypothetical fluid volume through which drug is dispersed

Question 38

What is drug half life?

Answer 38

Time it takes for amount of drugs active substance in body to reduce by half

Question 39

What are the 4 major pharamokinetic factors?

Answer 39

Absorption, distribution, metabolism, excretion