Pharmacodynamics & Pharmacokinetics Flashcards
What is the definition of a drug?
Agonist?
Antagonist?
Partial agonist?
How do drugs produce an effect?
On what 4 proteins can drugs have an effect?
Chemical agent affecting a biological process
Drug that binds to receptor to produce a biological response
Binds to receptor but does not produce a biological response (basal level)
Binds to receptor & produces small biological response but less than agonist
Interacting with endogenous proteins
- Receptors
- Transporters
- Enzymes
- Ion channels
What are the 4 classes of receptors in a cell?
What are the 2 types of ligands that bind to which receptors?
- Ligand-gated ion channel (ionotropic)
- G-protein coupled receptors (metabotropic)
- Kinase-linked receptors (dimerise on activation)
- Nuclear receptors
Hydrophilic - 1, 2, 3
Hydrophobic - 4 (diffuse across plasma membranes)
What are the 2 types of ion selectivity of ionotropic receptors?
What is the structure of the nAChR?
How many times does it span the membrane?
What happens once ACh binds?
What happens to the state of the cell?
So what type of NT is it?
- Cationic (Ca2+, Na+, K+)
- Cl-
made up of 2 alpha subunits, gamma subunit, beta subunit & delta subunit to form a-helices central pore/gate
4 times
2 ACh bind at alpha subunits to change conformation to allow Na+ flow into cell
Depolarises (becomes more positive)
Excitatory
What is the structure of the GABA-A ionotropic receptor?
Where are the 3 binding sites?
What happens on its activation?
What happens to the cell?
Hence what kind of response?
What structure do both nAChR & GABA receptors have in common?
2 alpha, 2 beta & 1 gamma subunit
2x GABA binding site at a-ß interface
1x benzodiazepine site at a-gamma interface
Changes shape of channel such that chloride ions allowed flow into the neurone
Hyperpolarised
Inhibitory (brain)
Alpha helices spanning the membrane with exterior N-terminal tail with ligand binding domain & C-terminal tail on exterior too
What is the structure of the glutamate superfamily of ionotropic receptors? 4 things
What is a type of glutamate receptor?
What is the Q/R-site?
What are the characteristics of the glutamate receptors? 3 things
What kind of response is produced?
Polypeptides that span the membrane 3 times, has 2 glutamate binding sites exteriorly, flip/flop region exteriorly and interior Q/R-site (between TM1-2)
AMPA
Selectivity filter to close ions from passing through membrane to regulate the polarisation state of the membrane
- Very rapid as ligands are the effectors at post-synaptic membrane
- Not useful for signalling downstream as very localised at membrane
- 1ms speed
Excitatory & inhibitory
How are GPCR characteristics different to ionotropic? 2
Why are GPCRs so important in the pharmaceutical industry?
What is the structure of a GPCR?
How are G-proteins activated?
How is the G-protein reassembled?
What are the 4 classes of G protein & what do they do?
How does PKA regulate gene expression?
- Slower of 100ms - minutes
- Extrasynaptic - can regulate gene expression, create new synapses
Associated most with disease - pain, asthma, obesity, cancer etc so most drugs target these
7-transmembrane domain spanning the membrane - with glycosylation at N-terminal extracellular domain & G-protein coupling domain internally
Ligand binding promotes exchange GDP to GTP on alpha subunit so alpha & beta-gamma dissociate
Alpha subunit has GTPase activity (like a GAP) so hydrolyses GTP into GDP & re-associates with beta-gamma
Gs = AC stimulation
Gi = AC inhibition
Go = Ca2+ & K+ ion channel regulation
Gq = PLC-ß stimulation
G12/13 = activates small GTPases to regulate actin cytoskeleton
Regulates transcription factor CREB which binds to CRE promoter to regulate expression of genes included in long-term memory
What ligands bind to tyrosine kinase receptors?
What pathway do they regulate?
What does the pathway do? 2 things
What is the cascade of the pathway from tyrosine kinase ligand binding? 7
Growth factors
MAP pathway
Change protein activity (phosphorylation) & gene expression (pro-survival & cell proliferation)
- Receptor dimerises & kinase domains phosphorylate tyrosine residues on intracellular domain
- SH2 domains of GRB2-Sos binds to pY
- Sos of GRB2-Sos acts on Ras-GDP & becomes Ras-GTP
- Ras-GTP phosphorylates Raf (MAPKKK) for its activation
- Raf kinase phosphorylates MEK kinase
- MEK phosphorylates MAPK x 2 to form active homodimer
- MAPK phosphorylates Rsk
What G protein activates PLC-ß?
What is the signalling cascade of PLC-ß in 3 steps?
What is the significance of lithium in this cycle?
What is lithium used to treat?
Gq
- Converts PIP2 into IP3 & DAG
- IP3 activates Ca2+ channels in ER causing release from ER into cytoplasm - Ca2+ involved in membrane hyperpolarisation (-ve), muscle contraction, enzyme activation
- DAG activates PKC which phosphorylates GSK-3
Inositol-1-phosphatase is inhibited by Li (breakdown from IP -> inositol) therefore increasing intracellular IP3/DAG signalling
Bipolar disorder - treats mania
What enters through nuclear receptors?
What are the effects?
How long does it take to have an effect?
What happens when the drug is stopped being taken?
Drugs to alter gene expression
New proteins are synthesised/not synthesised
Steroids take ~3 weeks
Takes time to reverse to basal state & to degrade protein
What is the definition of a ligand?
Agonist?
Antagonist?
Affinity?
Potency?
Efficacy?
Inverse agonist?
What is the difference between a full agonist and partial agonist?
Reversible competitive antagonist?
Irreversible antagonist?
Specific molecule that binds to a receptor
Drug that binds to receptor & produces pharmacological effect
Drug that binds to receptor & produces no direct cellular effect (no pharmacological response - blocks agonist action)
How tightly a drug binds to a receptor
Concentration of a drug that gives 50% response - ED50
Concentration of a drug that gives 100% maximal response
Reduces basal level response - full R vs R*
Full agonist = equilibrium shift to R* (active) completely - no R binding
Partial agonist = binds to both R and R* but more R* (active)
Drug binds reversibly to R & effects can be overcome by increasing agonist concentration
Antagonist dissociates slowly/not at all - no change in antagonist occupancy of receptors when [agonist] increased
What are the 6 processes of drugs in the body?
What can administration route affect? 3 things
How does route of administration affect drug absorption? 4 things
- Administration (in)
- Absorption
- Distribution
- Biotransformation
- Inactivation/elimination
- Excretion (out)
kk
- How much drug enters body
- How much drug enters site of action
- Magnitude of drug effect
kk
- Absorbing surface
- Number of membranes to cross
- Amount of drug destroyed e.g by metabolism
- Amount of depot binding
What are the pros of oral administration? 5
What are the cons of oral administration? 3
What are the pros of intravenous administration? 3
What are the cons of intravenous administration? 3
What is the pro of intramuscular administration?
What are the cons of intramuscular administration? 2
What are the pros of subcutaneous inhalation? 4
What are the cons of subcutaneous inhalation? 2
Safe, done at home, no needles, economical, don’t need sterile environment
Slow & variable absorption from gastrointestinal tract, subject to first-pass metabolism (stomach pH), less predictable blood levels
Rapid absorption, accurate blood concentration, easy to control dose
Overdose danger, can’t be reversed readily, requires sterile & medical techniques
Slow & even absorption
Irritation at site injection, needs sterile technique
Slow prolonged absorption, large absorption surface (lungs), rapid onset, no injection equipment
Irritation nasal passage, dangerous/small particles can be inhaled & harm lungs
What is topical administration?
What are the pros of topical administration? 2
What are the cons of topical administration? 1
What is transdermal administration?
What are the pros of transdermal administration? 1
What are the cons of transdermal administration? 2
What is epidural administration?
What are the pros of epidural administration? 2
What are the cons of transdermal administration? 3
What is intranasal administration?
What are the pros of intranasal administration? 5
What are the cons of intranasal administration? 2
Applying drug to a surface e.g skin (cream)
Localised action & effect, easy self-administration
Can be absorbed into general circulation
Place patch onto upper epidermis/skin
Controlled & prolonged absorption
Local irritation, only lipid soluble drugs (phospholipids)
Injection into epidural space around spinal cord
Bypasses blood-brain barrier, rapid CNS effect
Irreversible, needs anaesthetist, possible nerve damage
Administered by way of nasal structures
Easy to use, local & systemic effects, rapid, no first-pass metabolism, bypasses blood-brain barrier
Not all drugs can be atomised, irritation nasal mucosa
How does diffusion & transportation across membranes affect absorption?
How does lipid solubility affect absorption?
How is lipid solubility measured? When it is higher what does this mean?
How does ionisation affect absorption?
What is the pH in the gastrointestinal tract?
What does the lower pKa value mean?
Concentration from high to low - potentially no diffusion gradient
Membrane made up of phospholipids - drugs of high lipid solubility can passively diffuse through membrane so absorption increased
Partition coefficient - higher permeability
Drugs that ionise in water (e.g NaCl into Na+ Cl-) depending on pH and pKa - such that if they are highly charged will not pass through the membrane & hence poorly absorbed from gastrointestinal tract
5-6 - where ionisation happens
Higher the Ka so stronger brønsted acid & hence greater ability to donate protons - so ionised at lower pH . pKa = pH where 50% drug is ionised
What happens when the pH is kept the same in the environment?
When it is changed?
Therefore what is absorption going to be like when the pH is similar to pKa?
If aspirin has a pKa of 3.5, where is it most likely going to be absorbed and why?
What would happen to aspirin at a higher pH?
Less ionisation, greater lipid solubility so greater absorption
More ionisation, less lipid solubility, less absorption
Less ionisation, more lipid solubility & more absorption
More readily absorbed in the stomach as pH ~ 2 - high [H+] means protonated aspirin (non ionised as COOH group) so can cross hydrophobic lipid membranes into bloodstream
Readily donates protons, so COOH -> COO- and is ionised
eDescribe first-order kinetics of drug metabolism
Describe zero-order kinetics of drug metabolism
How does grapefruit juice affect first-pass metabolism?
What 5 factors affect drug elimination?
Rate of metabolism is proportional to plasma concentration of the drug (exponential) - e.g 50% removed each time frame
Rate metabolism constant regardless of the amount of drug taken - e,g alcohol/ethanol & some anti-depressants
Inhibits CYP450 3A4 & hence biotransformation & causes drug accumulation
- Renal function - acidic drug in alkaline urine makes drug ionised & so more easily soluble in water for excretion - hence acidic urine & acidic drug can facilitate re-absorption into blood (poisoning)
- Hepatic function - liver disease (hepatitis) & cytochrome P450 functioning
- Metabolites can interfere with renal excretion (change pH)
- Drug effects of same drug - e.g diuretics helps remove water from blood & release sodium into urine
- Polypharmacy - effects of additional drugs - neutralising stomach acids with antacids & increase pH urine
