pharmacology basics 2 Flashcards
Which type of receptors typically show signal amplification?
Receptors coupled to enzymes
What secondary responses can ligand binding initiate?
- (De)phosphorylation of peptides
What is affinity?
The tenacity/probability to which a drug binds to its receptor. Determines the range of drug conc at steep portion of cone-effect curve
What is the formula for fraction of occupied receptors?
F = D / Kd + D
D = Drug
Kd = Dissociation constant
How is Kd and affinity associated?
Inverse relationship. Lower Kd = greater drug affinity
Define potency
The conc/amount of a drug needed to produce a defined effect
How is potency measured?
EC50 - The conc at which a drug produces 50% its maximal response
- Drug with low EC50 = high potency
What type of receptors are inotropic?
Ligand-gated
What does Lidocaine bind to?
Binds to internal surface of phospholipid cell membrane to Na voltage-gated ion channels leading to inactivation
How does NorAdrenaline work?
- Activates Gq-proteins and Gs-proteins
- Increases intracellular Ca & cAMP
-Stimulates alpha-1 adrenoreceptors - Positive inotropic/chronotropic effects on beta-1 adrenoreceptors
How does Propofol work?
- Binds to beta subunit of GABA-A
- Activation results in increase in channel opening allowing inc Cl- entry and cell hyper polarisation
How do opioids affect their receptors?
- G protein coupled receptors linked to inhibitory G proteins
- Agonists hyperpolarise the cell
- Reduces levels of cAMP = inhibition of neurotransmitter release
How do Benzos act on receptors?
- Act on allosteric binding sites on inotropic GABA-A (ligand gated)
- Exert anxiolytic/sedative effects \
- GABA-B receptors are metabotropic = stimulate K+ conductance = hyper polarising neuronal membrane
What does mass action state?
The rate of a reaction is proportional to the conc of the reacting elements
What is the affinity constant?
- The strength of the drug-receptor bond (Ka)
- Ka = K(on) / K(off)
What is the dissociation constant?
- Reflects tendency drug-receptor complex has to dissociate back to its drug & receptor components (Kd)
- OR molar conc of a drug when 50% of its receptors are occupied at equilibrium
- Kd = K(off) / K(on)
What is median effective dose?
- ED50
- Dose of a drug that produces a response in 50% of the population it is administered to
- Drug with low ED50 = high potency
What is intrinsic activity?
- Drugs maximal efficacy as a fraction of the maximal efficacy produced by a full agonist acting on the same receptor under the same conditions
What happens if a system has a partial & full agonist at the same time working on the same receptors?
Partial agonist will act as a competitive antagonist to the full agonist
How does Buprenorphine work?
- Partial agonist at MOP & NOP opioid receptors
- Analgesic effects at low/middle doses
- Anti-analgesic effects at high doses
- Therefore in the presence of Morphine (full agonist) acts as a competitive antagonist
What is constitutive activity?
Most receptors can signal in the absence of an agonist
Magnitude is dependent on: Conformational flexibility & efficiency which receptor produces system change once activated
What is an inverse agonist?
A drug which inhibits constitutive activity
Has intrinsic activity -1 - 0
What do the action of G-Coupled protein receptors depend on?
- Receptor: 7 transmembrane helices
- G protein: Heterotrimeric protein of 3 subunits (a, b,y)
- Effector molecule: Activated by a-subunit , synthesises secondary messengers
What are the 3 parts of an enzyme-linked receptor?
- Extracellular ligand-binding domain
- Transmembrane domain
- Intracellular ‘active enzyme’ domain (mostly kinases that phosphorylate serine/tyrosine/threonine)
Give an example of an enzyme linked receptor
- Insulin
- Binds to receptor
- Activates P13K causing GLUT vesicle to bind with Glucose transporter allowing glucose to enter cell
Give an examples of drugs that acts on voltage-gated ion channels
CCBs
Local anaesthetics
Class III anti-arrhythmics
NA channel blockers
Give an examples of drugs that acts on ligand-gated ion channels
Muscle relaxants
Induction agents
What are the 2 main types of intracellular receptors?
- Type 1: Ligands bind to protein receptors in cytoplasm/nucleus (sex hormone, cortisol, mineralocorticoid)
- Type 2: Ligands bind directly to DNA (Vit A, D, Retinoid, thyroid)
What are the components of intracellular receptors?
- Transcription-activating domain
- DNA-binding domain (zinc containing loops)
- Ligand-binding domain
What are the types of steroid receptors?
- Oestrogen
- Progesterone
- Androgen
- Glucocorticoid
- Mineralocorticoid
How does steroid hormone receptor activation occur?
- When inactive associated with chaperone proteins (HSP) keeping them stable
- On hormone binding undergo conformational change
- HSP dissociates to reveal nuclear localisation sequence allowing passage of complex into nucleus
- Interacts with HRE via DNA-binding domain
- Activates gene transcription or silence gene expression
How does thyroid hormone receptor activation work?
- Hormone binds to receptor = conformational change
- DNA-binding domain binds to thyroid response element (TRE) located in promoter region of T3-responsive gene
- Gene transcription & expression occurs
Which channels are more sensitive to general anaesthetic?
Ligand-gated ionic (mainly GABAa)
