Class Test 1 Flashcards
How do you calculate Kd?
[H] x [R] / [HR]
In what ways can drugs be classified by the components involved?
Receptors
Ion channels
Carrier molecule
Enzymes
What are cells, tissues and organs controlled by?
Nervous system
Humoral agents
Local factors
In what ways can a drug be classified?
By nature
By action
Which cell components are involved
Which of the body systems does the drug affect
How does the drug help in the disease state
What is strength of signal replayed by the receptor dependent on?
Concentration of hormone-receptor complex
Where can other drugs block signal transduction?
Inside the membrane
Intracellular signal reception points
Common features of receptors?
Saturable
Activated by binding of an endogenous ligand
What does the fraction of total membrane receptors occupied by Ligands determine?
Size of transmembrane signal transduction
What is affinity of a drug?
Ability of a drug to bind to a receptor
What do drugs participate in?
Intracellular communication via chemical signals
What happens upon recognition of an appropriate chemical signalling molecule (ligand)?
Receptor proteins transmit the signal into a biochemical change in the target cell
What are the important steps of hormone initiated signal transduction?
Biosynthesis of hormone
Storage and secretion of hormone
Transport of hormone to target cell
Recognition by the hormone receptor protein
Relay and amplification of the signal that leads to defined biochemical reactions within the target cell
Removal of hormone
What properties do receptors have
Recognition
Transduction
What does the signalling cascade allow?
Signal to be amplified to produce multiple responses
Examples of responses produced by signal transduction?
Modulation of gene translation Hormone secretion Energy production Cell division Cell motion
Examples of intracellular second messenger signalling molecules
Cyclic nucleotides (cAMP, cGMP)
Calcium ions
IP3 and DAG
What do second messengers regulate?
Function of specific cellular effectors
Other examples of ligand-gated ion channels
GABA A receptor
Iontropic glutamate receptor
5-HT3 receptor
What type of receptors are on ligand gated ion channels
Multimeric transmembrane receptors
What does gaba a receptors do and used for?
Opens Cl- channel
Used as tranquillisers and anticonvulsant
What’s the composition of GPCRs?
2 highly conserved cysteine residues in extracellular loops that form an intramolecular disulphide bond to stabilise the receptor structure
What are the physiological roles of GPCRs
Sensation Immune system and inflammation Metabolism Behaviour Autonomic nervous system
What do nuclear receptors affect
Gene transcription
Directly bind to DNA
What kind of responses are consequence of this increase in membrane permeability?
Postsynaptic excitatory or inhibitory responses
What is a second messenger?
Intracellular substance that mediates cell activity by relaying a signal from an extracellular molecule
Types of responses GPCRs allow?
Amplification
Diversity
What is efficacy?
Effect of a drug
More effect more efficacious the drug
What is potency?
Refers to the concentration of the drug
Less concentration required more potent the drug
What are nuclear receptors
Ligand activated transcription factors
What do GPCRs do?
Activate signal transduction inside the cell
E.g. cAMP
What does tyrosine receptor kinases do?
Act as an enzyme
Activated by hormones and growth factors
What is the structure and function of RTKs?
For cell growth differentiation
Contain tyrosine (intracellular)
Carry out messages through signal transduction
What is a kinase?
Something that has the ability to transfer phosphorus molecules, usually from a high energy substance like ATP
What are the types of heterotrimeric G-proteins
Gi- activated Cyclase to increase cAMP
Gs- inhibits adenylate cyclase to decrease cAMP
Gq- activates phospholipase C to produce IP3 and DAG
What do beta- adrenoceptors do?
Activate adenylate Cyclades
What are the effects of increased cAMP?
Heart (beta 1)- increased heart rate
Lungs- relaxes bronchial smooth muscle
Effects of agonists in the lung?
Dilates bronchial smooth muscle
Eases respiration
Effects of antagonists in the heart
Slows heart rate and reduces force of beat
What activates alpha alpha1-adrenoceptor?
Epinephrine
Expressed in smooth muscle
How does alpha-adrenoceptor increase intracellular Ca2+ concentration?
Release from SR (IP3)
Through membrane channels (DAG)
Ca2+ stimulates smooth muscle contraction
What is hypertension
High blood pressure
What is hypotension
Low blood pressure
What other cell responses are regulated by Gq inositol-phospholipid signalling
Liver- vasopressin- glycogen breakdown
Pancreas- acetylcholine- amylase secretion
Smooth muscle- acetylcholine- contraction
Blood platelets- thrombin- aggregation
What is dimerisation?
Coupling by an agonist binding to 2 receptors
Examples of drugs that inhibit RTK signalling
Imatinib (Gleevec)- for leukaemia
Lapatinib (Tykerb)- EGF receptor inhibitor for breast cancer
Trastuzumab- antibody against EGF for breast cancer
What is thioureylene?
Converts T4 to T3
What do thyroid hormones promote the synthesis of?
Adrenoceptors
What is hypothyroidism for Hashimoto’s thyroidtis?
Lack of hormone
Treated by giving T4
What does TSH act on?
Receptors on the membrane of the thyroid follicle cells through the mechanism that involves cAMP
What do thyroid hormones do?
Increase basal metabolic rate
Increase heat production
Increase glucose uptake
How can hyperthyroidism be treated
With beta adrenoceptors antagonists
Zones of adrenal cortex
Glomerulosa- aldosterone
Fasiculata and reticularis- adrenal androgens and cortisol
Adrenal medulla secretes
Catecholamines
E.g. Epinephrine and norepinephrine
Adrenaline in response to sympathetic nervous system
What are adrenocortical hormones?
Steroid hormones
What does failure of adrenal medulla cause?
What does tumour of adrenal medulla cause?
Failure- hypotension
Tumour- hypertension
E.g. Phrenocheomocytoma, neuroblastoma
What are glucocorticoids
Cortisol Actions Metabolic Negative feedback on AP and H Anti inflammatory and immunosuppressive effects
What are mineralcorticoids
Aldosterone
What are sex hormones
Testosterone
What are HREs?
Short segments of DNA able to bind a specific hormone receptor complex affecting transcription
What are oestrogen receptor antagonists for?
Prevention and treatment of breast cancer (tamoxifen)
What is the composition of a typical ligand
Lipophillic hormones with steroid hormones and dedicates of vitamin A and D
When is a mineralcorticoid receptor antagonist used?
Liver cirrhosis and heart failure
What are oestrogen receptor agonists used for?
Hormone replacement therapy in postmenopausal women
Adverse effects of glucocorticoids
Osteoporosis Cushing's syndrome Metabolic effects Suppression of infection Suppression endogenous glucocorticoid synthesis
What is glucocorticoid receptor agonist for?
Inflammation
What are the actions of adrenalin in tissues
Increase cyclic AMP
What do anti-inflammatory and immunosuppressive activity reduce?
Blood vessel dilation and leakage
Glucocorticoids inhibit phospholipase A2- blocks production of arachidonic acid, pstoglanduns and leukotrienes from cell membrane phospholipid
What are androgen receptor antagonists used for?
Prostate cancer treatment
How do ADR and Na maintain blood pressure
Iontropic effects on heart and vasoconstrictor
I.e. Increases heart rate and contracts blood vessels
Dose vs concentration?
Dose- amount of drug (micro grams, nanomoles)
Concentration- amount of drug per unit volume (micromolar, nanomolar)
What are drug receptor controls?
Selectivity of drug effect
Magnitude of response
Mechanisms to prevent/mimic physiological function
What is magnitude of response?
Hyperbolic
[AR] = [A]
[RT] Kd + [A]
What is EC50?
Concentration required to get half the maximum response
How do allosteric Ligands produce effects
By increasing/decreasing potency
Causing an increase/decrease in efficacy
What is implied by receptors ability to spontaneously adopt an active site
Level of constitutive activity
What is an inverse agonist?
Ligand that binds to the receptor and limits constitutive activity
