Topic C Flashcards
1
Q
What is pharmacokinetics?
A
- how the body interacts with the drug e.g. absorption, distribution, metabolism and excretion
2
Q
What is pharmacodynamics?
A
- how drugs alter the body function e.g. binding to a target tissue receptor (affinity and efficacy)
3
Q
What are the 4 targets of drugs?
A
- (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
Q
What are the 4 properties of a receptor?
A
- Found on cell membranes (hydrophilic signals) or are located intracellularly (lipophilic signals)
- Bind specifically to the ligand via very specific recognition sites
- Transmit a biological signal in response to ligand binding
- Respond with selectivity and selectivity
5
Q
How do drugs bind to receptors?
A
- 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
Q
What is an agonist?
A
- 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
Q
What is affinity?
A
How tightly the agonist can bind to a receptor; measured by Ka
8
Q
What is efficacy?
A
How well the agonist once bound can produce a confirmation change in the receptor producing a response
- measured by E
9
Q
What is an antagonist?
A
- 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
Q
What is a constituitively active receptor?
A
- 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
Q
What is an inverse agonist?
A
- Decrease the proportion of receptors present in the active state by binding to them and inducing a conformational change into an inactive confirmation
12
Q
How are constiuitively active receptors influenced by?
- Addition of agonist
- Addition of antagonist
- Addition of inverse agonist
A
- Adding Agonist to constitutively active receptors: increases the level of activity as it pushes more receptors into the active state and thus increases signaling
- 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
- 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
Q
What are the 4 principles of neurotransmission?
A
- 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 - 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) - Transmitter binds to receptors on the post-synaptic cell and produces a response
- Smooth muscle, gland, skeletal muscle etc. - 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
Q
How is noradrenaline synthesised?
A
- The amino acid tyrosine is taken up by precursor transporters into the nerve
- The tyrosine is converted into DOPA by tyrosine hydroxylase
- DOPA is converted into dopamine by DOPA decarboxylase
- Dopamine is taken up into the synaptic vesicle by a VMAT transporter
- Within the synaptic vesicle the dopamine is converted into noradrenaline by dopamine hydroxylase (enzyme only found in the synaptic vesicles)
- Noradrenaline is stored in these vesicles
15
Q
Which of the receptors has a higher specificity for noradrenaline
A
- alpha adrenoreceptor
16
Q
What is the result of the activation of B-adrenoreceptors in:
1. Liver
2, Heart
3, Smooth muscle
A
- Glycogenolysis favoured
- Increase in heart rate and force of contraction
- Relaxation
17
Q
How do B-adrenoreceptors cause intracellular events in the cell?
A
- 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
Q
What is the result of B1 adrenoreceptor activation in:
- Liver:
- Heart:
- Skeletal muscle:
A
- Liver: increasing glycogenolysis via activation of glycogen phosphorylase and inhibition of glycogen synthase
- Heart: increased force of contraction, increased heart rate =increased cardiac output
- Skeletal muscle: increased glycogenolysis, increased glucose uptake
19
Q
What is the result of B2 adrenoreceptor activation in:
- Lungs (bronchiolar smooth muscle)
- Blood vessel beds in skeletal muscle
- Skeletal muscle fibres:
A
- 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)
- Blood vessel beds supplying skeletal muscle: dilation (relaxation) of arterioles (increased blood supply to working muscles)
- Skeletal muscle fibres: beta aognist causes muscle tremor; beta antagonist removes tremor
20
Q
What is the result of B3 adrenoreceptor activation in:
- WAT:
2: BAT:
A
- WAT: Increase lipolysis (not innervated by sympathetic nerves= A only)
- BAT: increase lipolysis and increase thermogenesis (innervated by sympathetic nerves = A and NA)
21
Q
Why do certain individuals in the population respond differently to some drugs targeting adrenoreceptors e.g. betablockers
A
- 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
Q
What are the 4 Stages of the pharmokinetic phase?
A
- Absorption
- Distribution
- Metabolism
- Excretion
23
Q
What properties of drugs are required for them to be able to diffuse across membranes?
A
- High degree of lipid solubility- low level of ionisation
- Molecular shape and size
24
Q
What is the process of distribution?
A
- Drugs/xenobiotics leave systemic circulation and are distributed across body compartments depending mainly upon the binding of the drug within body compartments
25
Q
What are the 2 phases of metabolism?
A
- Liver microsomal enzymes e.g. cytochrome P450 enzymes
- oxidation/reduction/hydrolysis of the drug which makes it into a more water solule metabolite - Liver cytosolic enzymes e.g. UDP glucuronosyl transferase
- metabolite is combined with endogenous molecules producing an even more water soluble molecule
26
Q
How are drugs excreted?
A
- 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
Q
What are the consequences of 2 different forms of polymorphisms in CYP2D6 enzymes
A
- 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
