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Flashcards in Topic C Deck (27):
1

What is pharmacokinetics?

- how the body interacts with the drug e.g. absorption, distribution, metabolism and excretion

2

What is pharmacodynamics?

- how drugs alter the body function e.g. binding to a target tissue receptor (affinity and efficacy)

3

What are the 4 targets of drugs?

- (Most) drugs exert their effects by binding to protein molecules such as:
1. Enzymes
2. Ion Channels
3. Transporters
4. Receptors (a tiny proportion of proteins but a massive target for drugs)

4

What are the 4 properties of a receptor?

1. Found on cell membranes (hydrophilic signals) or are located intracellularly (lipophilic signals)
2. Bind specifically to the ligand via very specific recognition sites
3. Transmit a biological signal in response to ligand binding
4. Respond with selectivity and selectivity

5

How do drugs bind to receptors?

- The binding of a ligand (such as a drug) is reversibly to the receptor is via ionic, hydrogen and van der Waal’s interactions (not covalent)
- This binding can have an agonistic effect or be antagonistic

6

What is an agonist?

- A drug that is aable to bind a receptor and activate it (affinity and efficacy)
- The binding of an agonist causes a response by inducing a conformational change in the receptor which moves it from an inactive to an active state

7

What is affinity?

How tightly the agonist can bind to a receptor; measured by Ka

8

What is efficacy?

How well the agonist once bound can produce a confirmation change in the receptor producing a response
- measured by E

9

What is an antagonist?

- Drugs that are able to bind to a receptor but do not cause a conformational change to cause a response
- High affinity
- Zero efficacy
- Prevents the binding of an agonist, endogenous substance etc.

10

What is a constituitively active receptor?

- Not all receptors require a ligand to be in an active state- these are called constitutively active receptors
- This means that even without the binding of a ligand (drug) there is always some receptors still in an unbound (but active and signaling) state leading to a level of basal activity independent of ligand binding

11

What is an inverse agonist?

- Decrease the proportion of receptors present in the active state by binding to them and inducing a conformational change into an inactive confirmation

12

How are constiuitively active receptors influenced by?
1. Addition of agonist
2. Addition of antagonist
3. Addition of inverse agonist

1. Adding Agonist to constitutively active receptors: increases the level of activity as it pushes more receptors into the active state and thus increases signaling
2. Adding Antagonist to constitutively active receptors: has no effect- as the basal level of constitutively active receptors is independent of ligand binding so blocking ligand binding will not have an effect
3. Adding an Inverse agonist to constitutively active receptors: decreases the level of an activity. Binds to the receptor- but causes a conformational change into an inactive confirmation. It has affinity but causes the receptor to become inactive rather than active in state.

13

What are the 4 principles of neurotransmission?

1. A neuron synthesises and stores the neurotransmitter
- Neurotransmitter is synthesised in the nerve itself so it has the synthetic enzymes
- Once the neurotransmitter is synthesised it will be stored in storage vesicles

2. Stimulation of neuron causes the release of neurotransmitter (from synaptic varicosities)
- Stimulation of the nerve causes the movement of the vesicle to the membrane and the release (via exocytosis) of the neurotransmitter into the extracellular space (synapse)

3. Transmitter binds to receptors on the post-synaptic cell and produces a response
- Smooth muscle, gland, skeletal muscle etc.

4. A system exists for terminating the action of the transmitter at the receptor
- Removal of transmitter: by a transporter (reuptake of nerve for recycling)
- Catabolic enzymes: to destroy the transmitter in the extracellular space

14

How is noradrenaline synthesised?

1. The amino acid tyrosine is taken up by precursor transporters into the nerve
2. The tyrosine is converted into DOPA by tyrosine hydroxylase
3. DOPA is converted into dopamine by DOPA decarboxylase
4. Dopamine is taken up into the synaptic vesicle by a VMAT transporter
5. Within the synaptic vesicle the dopamine is converted into noradrenaline by dopamine hydroxylase (enzyme only found in the synaptic vesicles)
6. Noradrenaline is stored in these vesicles

15

Which of the receptors has a higher specificity for noradrenaline

- alpha adrenoreceptor

16

What is the result of the activation of B-adrenoreceptors in:
1. Liver
2, Heart
3, Smooth muscle

1. Glycogenolysis favoured
2. Increase in heart rate and force of contraction
3. Relaxation

17

How do B-adrenoreceptors cause intracellular events in the cell?

- This is possible as they are G protein coupled receptors that can initiate cascades that phosphorylate different proteins e.g. phosphorylation and activation of glycogen phosphorylase in liver cells

18

What is the result of B1 adrenoreceptor activation in:

1. Liver:
2. Heart:
3. Skeletal muscle:

1. Liver: increasing glycogenolysis via activation of glycogen phosphorylase and inhibition of glycogen synthase

2. Heart: increased force of contraction, increased heart rate =increased cardiac output

3. Skeletal muscle: increased glycogenolysis, increased glucose uptake

19

What is the result of B2 adrenoreceptor activation in:

1. Lungs (bronchiolar smooth muscle)

2. Blood vessel beds in skeletal muscle

3. Skeletal muscle fibres:

1. Lungs (bronchiolar smooth muscle): respond to adrenaline only (not innervated by the nervous system = no noradrenaline affect), B2 activation by agonists causes relaxation of the smooth muscle (dilation of bronchioles)

2. Blood vessel beds supplying skeletal muscle: dilation (relaxation) of arterioles (increased blood supply to working muscles)

3. Skeletal muscle fibres: beta aognist causes muscle tremor; beta antagonist removes tremor

20

What is the result of B3 adrenoreceptor activation in:

1. WAT:
2: BAT:

1. WAT: Increase lipolysis (not innervated by sympathetic nerves= A only)

2. BAT: increase lipolysis and increase thermogenesis (innervated by sympathetic nerves = A and NA)

21

Why do certain individuals in the population respond differently to some drugs targeting adrenoreceptors e.g. betablockers

- This is due to polymophisms in drug receptors that exist in the population that means that certain members of the population have functional versions of a protein (receptor) but it is slightly different in structure and therefore responds differently to drugs

22

What are the 4 Stages of the pharmokinetic phase?

- Absorption
- Distribution
- Metabolism
- Excretion

23

What properties of drugs are required for them to be able to diffuse across membranes?

- High degree of lipid solubility- low level of ionisation
- Molecular shape and size

24

What is the process of distribution?

- Drugs/xenobiotics leave systemic circulation and are distributed across body compartments depending mainly upon the binding of the drug within body compartments

25

What are the 2 phases of metabolism?

1. Liver microsomal enzymes e.g. cytochrome P450 enzymes
- oxidation/reduction/hydrolysis of the drug which makes it into a more water solule metabolite

2. Liver cytosolic enzymes e.g. UDP glucuronosyl transferase
- metabolite is combined with endogenous molecules producing an even more water soluble molecule

26

How are drugs excreted?

- Kidneys: are the major site of excretion of water soluble drugs and water soluble metabolites of lipid soluble drugs
- Lungs
- Gut
- Sweat, saliva, mucous, tears and milk

27

What are the consequences of 2 different forms of polymorphisms in CYP2D6 enzymes

- Defective CYP2D6 enzyme gene: No CYP2D6 enzyme: drug metabolism is too slow, drug levels too high at ordinary dose, high risk for adverse effects and no response from specific prodrugs

- Duplicate CYP2D6 gene: drug metabolism is too fast, no drug response at normal dosages