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351 Cards in this Set
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- 3rd side (hint)
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Adenosine
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A1, 2, 3
Cardioprotectant - decreases force of contraction due to B-adrenoceptor activation, inducing coronary vessel dilatation and slowing conduction Increases O2 efficiency Responses limited or absent in the aging heart Produced in increased amounts during stress GPCR - stimulates or inhibits AC |
Cardioprotectant
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A1
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Adenosine Receptor. Blocks AV node conduction
Bronchoconstriction |
Cardioprotectant
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A2
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Adenosine R. Mediates vasodilation of coronary vessels
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A3
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Adenosine R. Mediates mast cell activation
bronchoconstriction |
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Explain inflammation
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Arachanoic acid is liberated from the membrane by phospholipase A2 --> the acid is then metabolised by cyclooxygenases (COX) --> forms prostaglandins and thromboxanes
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Prostoglandins
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Dilate blood vessels and increase blodd flow to an inflammatory site, potentiate the effects of histamine and bradykinin by sensitising afferent C fibres to produce pain.
PG12 - vasodilator/hyperalgesic/stops platelet aggregation PGF2A- vasoconstrictor/contracts myometrium PGE2- vasodilator and hyperalgesic |
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Thromboxanes
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Eicosanoid
A2- thrombotic and vasoconstrictor |
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Method of action of
ASPIRIN/ IBUPROFEN |
Non-steroidal anti-inflammatory drugs
Non-selective COX1/2 inhibitors Inhibit the production of prostaglandins and prevent inflammatory responses. Sensitise afferent C fibres that produce pain Increased risk of ulcers as less control of stomach acid production due to COX1 inhibition. |
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How is L-glutamate produced?
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Formed from glutamine
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What does L-glutamate act on?
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4 receptor groups
NMDA, AMPA, kainate R (ligand-gated cation channels) Metabotropic R (GPCR IP3) |
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What are the mechanisms/therapeutitic functions of NMDA receptors?
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Activate by glutamate and co-activated by glycine
Increases Ca conc. can cause cell death (excitotoxicity) Selective blockers reduce brain damage after stroke/head injury Treatment of epilepsy/ Alzheimers |
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What is the major active ingredient in cannabis?
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Canavanoid
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What is canavanoid?
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An endogenous ligand to morphine.
Works on CV1 (in brain, GPCR) and CV2 (periphery, GPCR) R Inhibition of AC, decreased cAMP, opening of K channels, hyperpolarisation |
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CV1 antagonists
Therapeutic Use Drug Example |
Canavanoid Receptor Antagonists.
Receptors promote lipogenesis, show effect on body weight. Antagonists therefore used in the treatment of obesity, suppression of appetite and lipogenesis, induces nausea and vomiting Eg. Rimonabant |
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CV2 agonists
Therapeutic Use Drug Example |
Treatment of glaucoma
Reduces nausea/vomiting in chemo patients Eg. Nabilone |
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Mechanism of erection?
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Release of NO from NANC (non-adrenergic-non-cholinergic) nerves in the corpus cavernosum increases cGMP, relaxes arteries, allows blood flow into the erectile tissues, decreases blood outflow.
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Clinical approaches to treating erectile dysfunction?
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1. Prevention (treat diabetes, hypertension)
2. Non-invasive - orally active PDE5 inhibitor, PDE breaks down cGMP, therefore inhibition results in increased cGMP, increased relaxation. PDE5 is mainly in the corpus cavernosum Eg. sildenafil, vardenafil 3. Invasive intracavenous injections, suppositories 4. Invasive implantations of prosthesis (pumped by hand) 5. Possible use of testosterone in hypogonadal males but increases the risk of prostatic cancer |
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Digoxin
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binds to ATPase carrier protein and reduces its activity, increases intracellular [Ca] and increases contractility, controls HR
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Drugs act on what 4 types of proteins?
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Membrane carriers
Enzymes Ion channels Receptors |
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Define: Receptor
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A protein molecule in a cell or on the surface of a cell to which a substance can bind, causing a change in the activity of the cell
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What are the 4 theories of D-R interactions?
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Occupancy theory
Rate theory Induced fit/macromolecular perturbation theory Two state/allosteric/activation-aggregation theory |
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What is Occupancy theory?
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That the number of R occupied determines the response
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What is Rate Theory?
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Effect is proportional to the rate of agonist-R interaction
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What is Induced Fit Theory?
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Agonist induces specific conformational change in the R leading to a response
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What is Two state/ activation/aggregation theory?
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Two populations of R in dynamic eqbm, (R - relaxed), (T - tense), binding shifts eqbm between the two states.
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Drug Target Classifications
- Enzymes |
Important in chemotherapy
Usually inhibitory effects Can be competitive/non-competitve/reversible covalent/irreversible Eg. COX inhibitors - asprin/ibuprofen |
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Drug Target Classifications
- Transporters |
Imp for CNS Pharmacology
Eg SSRI |
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Drug Target Classifications
- Structural proteins |
Eg Tubulin by Taxol
(chemotherapy drug) |
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What is a false substrate?
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- Competitive inhibitor of enzyme in biosynthetic pathway
- Structurally similar to normal cellular chemical Metabolised like endogenous agonist, but metabolite is usually a product that inhibits the pathway. Eg. AZT used in the treatment of AIDS |
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Do all targets fit into these target categories?
Example? |
No, some drug targets do not fit into any of these categories.
Eg. Target of cyclosporin A |
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Basic physiol/anatomy of the ANS?
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1) Almost all CNS output are dependant on the CNS
2) Contraction/relaxation of smooth muscle/exocrine and endocrine functions/heart beat regulation/metabolism 3) 2 neurons are arranged in series separated by a ganglion (preganglionic/ postganglionic) 4) P- rest/digest S- fight/flight 5) Transmitters - Ach @ nAchR (all ganglia) - NA @ adrenoceptors (postganglionic nerves) - Ach @ mAchR (post) - Ach @ mAchR (some S nerves) - Adrenoceptors - A1, A2, B1, B2 as defined by role and conc of antagonists 6) Termination is required for rapid response to next stiumulus Ach- inactivated by Achesterase NA - taken back into nerve endings, repackaged. |
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Ach Muscarinic Receptor mechanisms? Why are they named as such?
Name an antagonist? |
- Responses mimicked by muscarine
- Prevented at low doses by atropine - GPCRs - 2nd msngr IP2 or cAMP |
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What are the three M receptors and their functions?
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M1 - neural, usually excitatory
M2 - heart, increases cAMP, increases Ca M3 - Glandular/smooth muscle - excitatory |
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What are the nicotinic receptors? What are their mechanism of actions?
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Ligand-gated ion channels, Na or K
5 subunits - diff subunit composition = diff function |
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How are adrenaline receptors divided?
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R divided based on potency of agonists
- Alpha - NA > A > isoprenaline - Beta - isoprenaline > A > NA |
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What is the mechanism of action for adrenaline R?
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GPCRs in general, differ on 2nd messenger used.
- Alpha - IP3 or diacylglycerol - cAMP (A- inhibitory, B- excitatory) |
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What are 5HT receptors?
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Serotonin receptors
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What is the general mechanism of action for 5HT-R?
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Vasoconstriction due to non-selective GPCR
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What are some of the subytpes/ uses of 5HT-1?
(Type 5HT1A, 5HT1D) |
- GPCR linked to inhibition of AC
- 5HT1A - important in mood and behaviour - 5HT1D - important in migraine |
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What are some of the subytpes/ mechanisms/ uses of 5HT-2?
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GPCRs linked to activation of phosphoinositide pathway (increase IP3, diacylglycerol)
- 5HT2A receptors induce vascoconstriction of blood vessels, antagonists used in schizophrenia treatments - 5HT2A receptors also present on platelets - induce local vasodilation if endothelium intact/or/vasoconstriction if endothelium damaged (due to direct action on smooth muscle). |
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What is the mechanism/therapeutic use of 5HT3 receptors?
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Ligand-gated ion channels
Receptors present in postrema (part of brain that controls vomiting reflex) Antagonists such ondansetran used to control emesis |
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What is the mechanism of 5HT4 receptors?
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GPCR found in GI tract, linked to actiation of AC which activates Ach release, increasing the movement of the GUT
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Sumatriptan
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5HT1D agonist
Used to constrict large arteries and inhibit trigeminal nerve transmission during aura or attack (in migraine) to suppress symptoms – orally or intravenously. Also used to constrict coronary arteries in coronary artery disease patients with angina. |
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Ondansetron
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5HT3 antagonist, area postrema in brain – vomiting reflex (control emesis)
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Clozapine, a potent 5HT2 receptor antagonist is useful how, clinically?
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Atypical antipsychotic that inhibits dopamine release in prefrontal cortex, thereby improving cognitive function and negative symptoms of schizophrenia.
Also an antagonist of alpha adrenergic, muscarinic, and D2 receptors therefore there a risk of agranulocytosis. Other side effects include seizures, sedation, salivation, weight gain. |
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Non-steroidal anti-inflammatory drugs (NSAID)
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Aspirin and ibuprofen
competitively inhibit the cycloxoygenase (COX) enzymes which are required to convert the eicosinoids, prostaglandins and thromboxanes from arachidonate. Prostaglandins cause redness, and potentiate vascular permeability and increased sensitivity of afferent C fibres. Ibuprofen inhibits COX3, which is an alternative splice product of COX1. |
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Sildenafil
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Orally active PDE5 inhibitor used to treat erectile dysfunction (stops breakdown of cGMP which is a second messenger involved in mediating vasodilation of blood vessels in the corpus cavernosa to allow erection).
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What are the possible mechanisms behind migraine?
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-Vascular (vasoconstriction followed by vasodilation)--UNLIKELY
- Cortical spreading depression, increased K, decreased blood flow - Activation of trigeminal nerve, release of neuroinflammatory compounds |
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What is the probable mechanism behind schizophrenia?
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Excessive dopamine acting on D2 receptors in the cerebral cortex. Neg and pos symptoms involve abnormal control of 5HT of dopamine actions in prefrontal cortex.
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Memantine, an NMDA-R antagonist is used to treat what?
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Alzheimer's Disease
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Define: Absorption
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How a drug gets into the body
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Define:Distribution
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How a drug moves around in the body
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Define: Metabolism
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How a drug is changed in the body
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Define: Excretion
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How a drug is removed from the body
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What is the oral route of administration?
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Oral administration is administration through the mouth and the GIT.
It is the most common and most convenient. |
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What is the topical rout of administration?
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Local application either through the:
skin - ointments/patches eyes - drops lungs - aerosols |
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What is the parental route of administration?
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Either subcutaneous or intramuscular injections
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What is the intraveous route administration?
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Directly into a vein, rapid onset - straight to the heart for distribution, disadvantage is that this form requires a skilled person. Can be dangerous if incorrectly dosed.
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What are some sites of absorption?
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GIT
Lung Skin |
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How are drugs absorbed across membranes?
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Passive diffusion
Fascilitated transport |
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What factors is the rate of diffusion relient upon?
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1. Surface area of membrane (A)
2. Concentration gradient(ΔC) 3. Partition coefficient (R) 4. Diffusion coefficient (D) 5. Thickness of membrane (Δx) usually 7.5-10 nm Rate of diffusion = D.R.A.ΔC / Δx |
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What are the two characteristics of drug molecules that affect diffusion?
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1. NON-IONISABLE – no charge on molecule (eg ethanol). Usually diffuse readily across membranes.
2. IONISABLE – drug charged to some extent (most drugs). |
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Ionisable drugs are either:
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1. acids (give up a H ion)
2. bases (accept a H ion) |
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The extent of ionisation is determined by:
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1. pH of the environment
2. pKa of the drug |
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How does the pKa of an acid relate to its absorption in the intestine?
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As the pKa of an acid increases, absorption increases.
NOTE: above pKa of 5, no change in absorption of acids. |
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How does the pKa of a base relate to its absorption in the intestine?
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As the pKa of a base increases, absorption decreases.
NOTE: Below pKa of 5 no change in absorption of bases. |
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What is pinocytosis?
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A type of endocytosis whereby soluble molecules are taken up from outside the cell through the formation of vesicles.
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When is pinocytosis used?
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1. Large drugs (eg proteins)
2. Drugs in aggregated forms 3. Drugs bound to proteins |
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What is the pH of the duodenum?
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5-6
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What is the pH of the ileum?
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8
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What is absorption?
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The passage of drugs from its site of administration to the plasma.
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What is the mechanims of drug absorption from the intestine?
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Passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecule.
Absorption occurs for drugs with pKas from 3-10 (neither strong bases or acids). |
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What is the mechanism of drug absorption from the skin?
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Suitable only for lipid soluble drugs. Produce steady rate of drug delivery. Relatively expensive.
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What is the mechanism of drug absorption from the lungs?
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Rapid absorption due to large SA and blood flow. Rapid changes to plasma levels.
Aerosols. Usually only local effects but minor systemic side-effects eg tremor from asthma drugs. Used for volatile and gaseous anaesthetics. |
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How are drug distributed in the body?
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Through the blood stream
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What are the main principles governing distribution?
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Physio-chemical properties of the drugs.
Drug must be un-bound to cross barriers into peripheral tissues. |
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What is the equation used to determine distribution?
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At equilibrium:
k1 x Cp = k2 x Ct k1 - from plasma to tissue Cp - concentation in plasma k2 - from tissue to plama Ct - concentration to tissue |
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What is the driving force behind diffusion?
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Plasma concentrations
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What is the major determinant of rate and extent of distribution?
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Plasma protein binding is the major determinant of the rate and extent of drug distribution to peripheral tissues.
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What are the principle points that need to be understood about plasma protein binding?
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1. Only unbound drug is available to diffuse into peripheral tissues.
2. Albumin is the most abundant and important protein for drug binding. 3. Albumin mainly binds acidic drugs. 4. Glycoprotein and globulin bind basic drugs. 5. Plasma protein binding can be saturable for many drugs 6. Drugs can compete for plasma protein binding. |
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Why is plasma binding important?
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~ Acts as a reservoir – displaced by other drugs
~ Change in plasma proteins (elderly) -> changes in pharmacology ~ Change in blood volume (severe bleeding) -> changes in pharmacology |
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Why is adipose tissue so important?
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It is a non-polar environment in which lipophilic drugs can accumulate. Can act as a reservoir for slow release
into body. |
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How is the CNS protected from unwanted drug entry?
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The blood-brain barrier.
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How do drugs enter the CNS through the BBB?
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Drugs must be very lipophilic, or must be a substrate for specific transporters.
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How are drugs removed from the brain?
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Drugs are removed by ‘Multi-drug resistance proteins’ (MPR’s), non-selective drug transporters (also found in GI tract and liver).
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What is the purpose of metabolism of xenobiotics?
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1. Increase rate of excretion
2. Decrease likely toxicity (metabolites tend to be less toxic with less pharmacological activity) |
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What are the two major types of enzymatic reactions?
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Phase I and Phase II reactions
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What can occur in Phase I?
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Oxidations (CP450)
Reductions (reductases) Hydrolysis (esterases) |
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What can occur in Phase II?
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The addition of water soluble moities to drugs
- glucoronide - glutatione - sulfate group - acetate (make more soluble, increase excretion) |
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Do Phase II reactions have to go through Phase I first?
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NO.
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What are cytochrome P450s?
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Family of metabolising enzymes (heme proteins that use Fe at active site). Found mainly in the liver, have a wide range of substrates, reaction requires O2, NADPH (e- donation) and cytochrome P450 reductase.
Are genetically polymorphic. |
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What are the major families of cytochrome P450s in humans?
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Cyp1
Cyp2 Cyp3 |
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Why does activity of cytochrom P450s vary in individuals?
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Induction
Inhibition Genetic variation |
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What Cyp metabolises over 50% of all drugs?
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Cyp3A4
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How are C P450s induced?
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- By different drugs and other xenobiotics
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What does induction result in?
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Rapid metabolism of substrates/rapid decrease in effect
Lower plasma levels |
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What is an example of another xenobiotic that can change the rate of induction?
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Smoking can reduce the half-life of certain drugs in the liver and lungs
Dietary constituents |
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What is an example of induction of c P450?
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Induction by the Ach receptor fascilitates the removal of foreign chemicals from the body. Drug binds to AchR - chaperones dissociate - moves to nucleus - binds upstream of target genes - increase Cyp transcription levels.
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How does inhibition of Cyp450 occur? What are the consequences?
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When 2 drugs are metabolised by the same P450 enzyme. Consequence can be toxicity of drug with less metabolism. This is an eg. of drug-drug interaction.
Effects are check via AUC (will have a bigger effect for a longer duration). |
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How do dietary constituents effect metabolism?
Give an example. |
Dietary constituents can inhibit metabolism. Eg. St John's wart can inhibit the metabolism of warfarin.
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In general, phase II metabolites are:
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- more highly ionised
- more water soluble - more likely to be excreted by the liver and kidneys - less pharmacologically active - less toxic |
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Details about metabolism of codeine? Relationship with morphine? Mechanism of action?
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Codeine is a low affinity opiate but with greater absorbance than morphine. It must be metabolised by CYP2D6 to morphine to have an effect, therefore it is a prodrug. Morphine in turn acts on opioid receptors (analgesic effects: pain relief and sedation, side effects: constipation and respiratory depression) or may undergo phase II metabolism by glucuronyltransferase to form morphine-6-glucuronide which is equally active or alternatively may undergo a deactivation pathway to form N-demethylated morphine.Cyp2D6 is genetically polymorphic. As such, approx 10% of the population find no therapeutic effect from the administration of codeine as it is never converted into morphine in the liver.
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Details about metabolism of asprin?
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Just remember that there are multiple pathways. Increased administration = increased removal.
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What is bioavailability?
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The fraction of the dose that reaches systemic circulation.
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Should oral drugs have a high or low bioavailability?
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High.
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Give basic renal physiology:
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Drugs enter into the kidney through the renal arteries and are then filtered into the urine in the glomerulus. Active secretion of drugs occurs in the proximal tubule, and water is reabsorbed in the loop of henle to concentrate the drug. The drug is then passively reabsorbed in the distal tubule and then the urine passes to the bladder.
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What are the 4 factors affecting renal excretion?
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- only free drug is filtered at the glomerulus
- competition (for active secretory pathways in proximal tubule) - passive reabsorption (of drugs in distal tubule) - renal failure (may prolong drug half-life) |
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What effect does probenecid have on oseltamivir excretion? Why?
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The addition of probenecid increases the half-life of oseltamivir in the body. This is because both oseltamivir and probenecid are excreted using the organic anion transporter (OAT) in the kidneys. They compete for the same transporters.
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What is proteinurea?
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Protein in the urine. When protein bound drug gets secreted. A disease state, def an exception to the rule.
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What does the ending of 'avir' indicate on a drug name?
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That the drug is an anti-viral agent.
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What influence does urinary pH have on drug excretion?
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- Affects passive diffusion on unionised drug in same way as for drug absorption
- pH of distal tubule can be kept at acid 4-5 with NH4Cl or made alkaline 8 with NaHCO3 NOTE: urinary pH is dependant on our diet and as such can change rapidly. |
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How does transport-dependant excretion occur in the liver? Which direction does transport occur?
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The drug gets taken into the hepatocyte and is then converted to its metabolite by glucoronide. It is then transported into the bile duct via a transporter (MDR1/ MRP2.
Transport is ALWAYS from the inside out and is ALWAYS ATP dependant. |
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Once the drug is in the bile duct where does it go to from here? What is this circuit called?
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The drug is then excreted into the small intestine where it is deconjugated by bacterial glucoronidase. The parent drug is then reabsorbed and returns to the blood stream.
CALLED THE ENTEROHEPATIC CIRCUIT |
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Why should antibiotics not be coupled with the contraceptive pill?
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Antibiotics kill of the bacteria in the gut, recirculation is lost, oestrogen levels decrease and risk of pregnancy increases.
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What is methadone?
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A synthetic opiod agonist, used to treat heroin addiction (some people were injecting it to get a higher dose because it has a low oral bioavailability but adding naltrexone (an opioid receptor antagonist) which also has a low oral bioavailability stopped this practice as then methadone could only have an effect if taken orally and naltroxene was largely eliminated by first pass metabolism).
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What is the difference between SNS and PNS?
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SNS - craniosacral origin
PNS - thoracolumbar origin |
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What does the ANS rely on for function?
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The synapse.
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How does the ANS synapse function?
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AP depol of membrane -- Na increases -- Ca is recruited -- vesicles are stimulated to fuse with the membrane -- NT released from vesicles into cleft -- targets receptors on the post-synaptict side -- NT either degraded (Ach) or taken back up
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What are SNARES?
What do they do? What types are important in the ANS? |
soluble N-ethylmalemide-sensitive factor attachment protein receptors.
They are part of a recognition system between vesicles an specific parts of the plasma membrane. Syntaxin a t-SNARE on the membrane, SNAP-25 a t-SNARE sits next to syntaxin while VAMP a v-SNARE is on the vesicle and docks with the other two on the membrane. |
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How does botox function?
How does botox enter the cell? |
Blocks NT release. Botulinum Toxin is a neurotoxin that cleaves SNAP-25 at a nine amino-acid sequence in the C terminus. The toxin makes key proteins dysfunctional preventing all neurotransmission. Botox enters the cell by hijacking a transporter to take it straight up into the neurone.
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Why is the Ach synapse important clinically?
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- muscle relaxation during anaesthesia
- glaucoma - myasthenia gravis - organophosphate poisoning |
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What are the 5 key characteristics of a NT?
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1. Synthesis
2. Packing into vesicles 3. Release 4. Post-synaptic actions 5. Degradation/reuptake |
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Where does NT synthesis take place?
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It occurs in the cytosolic environment. NT have to be exocytosed to have an effect.
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How is Ach packaged into vesicles?
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- Sequential two step process
- 1 - H+ actively pumped into vesicle using ATP - 2 - H+ pumped out while Ach pumped in |
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What is the essential difference between nAchR and mAchR?
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The essential difference is POSTSYNAPTIC.
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How do nAchR elicit their effects?
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Ligand-gated ion channels
Pentametric structure Ach binding to the alpha subunit opens channel, increasing Na, depolarising cell |
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Where are nAchR found?
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CNS, autonomic ganglia, neuromuscular junction
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Explain the structure of nAchR?
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Pentameric structure, always has 2 alpha subunits, to which Ach binds (so 2 Ach always required). Receptors in different regions have different subunit compositions.
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Name an agonist and an antagonist of the nAchR?
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Agonist - nicotine
Antagonist - d-tubocurarine (competitive) |
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Explain how mAchR elicit a response?
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Ach binds, GTP interacts with the alpha subunits, beta and gamma open K channels, cells hyperpolarise, decreasing excitability
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What are the M receptors?
What are they coupled to and what effects do they mediate? |
M1 - cortex, phospholipase C, increase Ca
M2 - heart, inhibits AC, relaxation M3 - GI tract, Phosphlipase C, increase Ca M4 - neostriatum M5 - substantia nigra |
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Name an agonist and an antagonist of mAchR?
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Agonist: muscarine
Antagonist: atropine (competitive) |
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How is Ach removed from the synapse?
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Acetylcholinesterase chops up the Ach and takes it back into the synpase via a carrier.
Achesterase is recycled, shuffles between free or hydrolysed state. |
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What are some acetylcholineesterase inhibitors and what are their durations of action?
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Edrophonium - acts in NMJ, Short acting
Neostigmine - acts in NMJ, medium acting Dyflos - acts in postganglionic parasympathetic junction, long acting Ecothiopate - acts in postganglionic parasympathetic junction, long acting |
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Hemicholinium, a choline reuptake blocker functions how?
Clinical use? |
By blocking the reuptake of choline through choline carrier on presynaptic membrane for recycling.
Inhibits Ach synthesis. No known clinical applications. |
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Explain anasthetics? Give an example drug.
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Tubocurarine analgues (competitive antagonists to the nAchR) are used as a adjuncts to anaesthesia. Ache inhibitors will act to increase Ach at the NMJ, countering the action of the receptor antagonists. Cause muscular relaxation.
Eg. Neostigmine |
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Explain the pathology of myasthenia gravis?
Symptoms Diagnosis Eg drug |
MG patients have too few nAchR at the NMJ due to autoimmunity.
Symptoms include muscle weakness, drooping eyelids Diagnosed with short-acting Achesterase inhibitor Eg. Edrophonium |
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Explain the pathology of glaucoma?
Treatment Eg Drug |
Increased intraoccular pressure leading to damage of the optic nerve. Opening of the canals of Schlemm using Ach agonists, releases pressure by allowing aqueous humour to drain.
Eg. Pilocarpine, Ach agonist Ecothiopate, irreversible AChe blocker |
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Explain the pathology of organophosphate poisoning?
Treatment? |
Drugs such as Dyflos found in pesticides and nerve gas cause irreversible blockage of Ache via phosphorylation. If caught early,reversible with Pralidoxime
If not, can be fatal. |
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The catecholamine synpase is important for what clinical reasons?
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regulation of heart rate, blood pressure, lung function and many other CNS actions
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What are the steps involved in synthesis of adrenaline?
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tyrosine - DOPA - Dopamine - Noradrenaline - adrenaline
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What is Parkinson's disease? How is it treated?
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Loss of dopaminergic neurons, not enough dopamine produced, early stages are treated with L-Dopa which is converted to dopamin in the brain, used in conjunction with Carbi-Dopa to dampen PNS response and stop systemic effects
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How is adrenaline synthesised/packaged within vesicles?
Name a drug that inhibits this process? |
A pump pumps H into the vesicle which is then substituted with dopamine, bringing dopamine into the cell. Dopamine beta hydroxylase then converts dopamine into noadrenaline and PNMT converts noadrenaline to adrenaline (in adrenal glands)
Eg. Reserpine |
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How does adrenaline mediate its post-synaptic effects?
What are the receptor types? |
Coupling to GPCR.
α1 - Gq - increase IP3, Ca β1 - Gs - increase AC, cAMP found on heart, increase rate and force α2 - Gi, decrease cAMP β2 - Gs, increase AC, cAMP, inhibit MLCK, bronchodilation |
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How is noradrenaline removed from the cleft?
Explain them. |
Uptake 1 and 2 mechanisms
1 - low capacity, high affinity, synaptic 2 - high capacity, low affinity, extra-synaptic (safety mechanism) |
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What is an uptake 1 inhibitor of adrenaline?
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Cocaine
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What is a MAO-inhibitor?
What do they treat? |
Phenelzine
CNS disorders eg. depression |
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Explain the method of action of ecstacy?
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Uptake 1 takes the chemical up into the cell, transported up into the vesicle where it displaces the vesicle contents and pushes them out into the cytosol, with the increased concentration in the cytosol, transporters then work in reverse, pumping the neurotransmitters into the synapse giving the drug-user a high.
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What effects do α-1 adrenergic receptors have?
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Contraction
Secretion |
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What is the mechanism of effect of the α1 adrenoceptor?
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α1 R on smooth muscle activate PLC - cleaves PIP2 - DAG and IP3 activate IP3 receptor - Ca released from ER - Ca activates myosin light chain kinase (MLCK) - phosphorylates myosin - interacts with actin - contraction
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What are some α1 adrenoceptor agonists?
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noradrenaline
adrenaline methoxamine |
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What is a α1 adrenoceptor antagonist?
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Prazosin
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What is the mechanism of action of α2 adrenoceptors?
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NA activates Gi - inhibits AC - decrease cAMP - Close Ca entry - inhibition of NA release - hyperpolarisation
(negative feedback of NA on R) |
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What are some α2 adrenoceptor agonists?
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adrenaline
noradrenaline clonidine |
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What is a α2 adrenoceptor antagonist?
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yohimbine
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Where is the β1 adrenoceptor mainy found?
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In the heart coupled to Gs.
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What are the functions of β1 adrenoceptors in the heart?
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1 - increase heart rate by increasing the rate of AP through the SA and AV node, by increasing Ca through channels
2 - increase force of contraction by increasing Ca by activating the Ryr on the SR |
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What is a β1 adrenoceptor agonist?
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adrenaline
noradrenaline dobutamine |
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What is a β1 adrenoceptor antagonist?
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atenolol
alprenolol (partial) |
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Why are partial antagonists preferable for treating heart failure?
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They increase the force of contraction without going to the whole contraction which limits damage to the already weakened heart. They also act as antagonists against NA, limiting the maximal activity of the heart.
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What is the mechanism of action of β2 adrenoceptors? Where are they mainly found?
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Coupled to Gs - increase cAMP - increase force in the heart - relaxation of bronchi in the lungs
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Explain the mechanism of relaxation of smooth muscle in the lungs by β2 adrenoceptors?
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cAMP is produced, interferes with MLCK (through phosphorylation),blocks MLCK action, decreasing contraction
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What are some β2 adrenoceptor agonists?
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Adrenaline
Noradrenaline Salbutamol |
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What is salbutamol?
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A β2-adrenceptor agonist used to treat asthma. Induces bronchodilation in the lungs through an aerosol.
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Explain the mechanism of action of viagra? (sildenafil)
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Interferes with phosphodiesterase (which normally breaks down cGMP) - increase in cGMP - relaxation of smooth muscle - increased blood flow
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What is a β2 adrenoceptor antagonist?
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Propanolol (non-selective for α and β)
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What are the 2 types of asthma?
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chronic fulminating bronchitis
chronic eosinophilic desquamating bronchitis |
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What are common symptoms of asthma?
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- difficulty in breathing
- tightness in chest - cough, irritation in airways - sputum production - airway inflammation - airway hyperreactivity |
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What are the possible mechanisms of airway hyperreactivity?
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- reduced epithelial barrier
- sensitisation of airways by inflammatory mediators - structural remodeling - airway resistance (resistance proportional to the 4th power of the airway radius = very small changes in diameter lead to large changes in resistance) |
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How is contraction mediated in the bronchial smooth muscle?
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Efferent parasympathetic innervation by Ach
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How is relaxation mediated in bronchial smooth muscle?
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NO (NANC)
Sympathetic innervation only |
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Who gets asthma in Australia?
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Children
More common in women Less common in adults |
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What role do eosinophils play in asthma?
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They release non-specific free radicals, ECP protein that damages all cells of the lining of the brochioles inducing vascular leakage of fluid, swelling
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What are some known trigger factors for asthma?
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Pollens, dust, mites, fur, exercise, cold air, smoke, fumes, drugs, foods, stress, infections
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How are patients diagnosed with asthma?
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By measuing lung capacity (FEV1)
Bronchila provocation tests Peak expiratory flow meters (PEF) |
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What are the 2 phases of an asthma attack?
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1. Early phase - rapid reflex bronchoconstriction
2. Late phase - eosinophils enter and cause inflammation |
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What drugs are used to treat asthma and how do they work?
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Bronchodiators 'relievers'
- selective β2-agonists - relax airway smooth muscle - symptomatic treatment Anti-inflammatory corticosteroids 'preventors' - work slowly - reduce sensitivity of airways |
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What are some of the side effects of using salbutamol type drugs?
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- shakiness, increased heart rate
- these side effects are greater when drug used orally however |
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Long term use of β2 adrenoceptors (to treat asthma) have been associated with what?
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Toxicity/death and loss of control of asthma
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Explain Xanthines?
Side effects? Give an example? |
Bronchodilators
Eg. Theophylline Not as effective or safe as β2 agonists, low therapeutic index, have CNS effects - side effects include nausea, vomiting, CNS stimulation, headache, tremor |
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What is the action of inhaled steroids?
Drug examples? |
Always inhaled
Little normally absorbed into the body Reduce hyperreactivity Slow acting Use when β2 agonists ineffective Start in high doses and then decrease - side effects include thrush of the mouth Associated with stunting and glaucoma |
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Give treatment example for use of oral steroids in treating asthma?
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Injectable for severe attacks
Takes a day to work Short-course treatment only Side-effects: weight gain, fluid retension, osteoporosis, psychological effects |
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Are anti-leukotriene drugs useful in asthma?
Mechanism? |
Not in acute asthma attacks.
Useful with exercise-induced asthma Reduces eosinophils in sputum |
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What is the equation used to determine voltage?
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V = IR
(Voltage = Current x Resistance) |
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What is tetrototoxin?
Where was it originally found? |
A neurotoxin that causes external Na ion channel blockage.
Produced by puffer fish. |
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What is saxitoxin?
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An external Na ion channel blocker located from dinoflagellates.
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What is tetraethyl ammonium (TEA)/4-aminopyridine (4-AP)?
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External potassium ion channel blockers
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Why is TTX so interesting?
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It has been used to determine function and density of Na channels in membranes.
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How does batrachotoxin function?
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Binds to the INSIDE of Na ion channels of nerve axons and muscle cells, inhibiting closure, inducing paralysis.
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Explain the composition of a K channel?
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Four transmembrane α subunits with 4 β−subunits that lie just inside the membrane. 4 ball and chain mechanisms present, only one needed for inactivation.
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What pharmacological tools were originally used to isolate and purify K channels?
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Selective blocking of Na and K channels using pharmacological agents.
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What is the major excitatory NT of the CNS?
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Glutamate
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What roles does glutamate play in the CNS?
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- Learning and memory
- Pathology of the brain (epilepsy and Alzheimer's) |
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How is glutamate synthesised?
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Initially from the cytric acid cycle. It then goes on to be a precursor for all of the other CNS NTs.
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Is the BBB permeable to Glu? Is this the same throughout life?
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Initially, yes. The BBB then becomes impermeable at seven days after birth.
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How does glutamate have an effect on the CNS if the BBB stops its uptake into the brain?
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Glutamate cannot cross but glutamine can. Astrocytes have chemicals that are able to convert to glutamate, as do glutaminergic neurones. Once glutamine crosses the BBB, astrocytes either take up glutamine and send it to glutaminergic neurons or it changes it to glutamate itself.
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How is glutamate cleared from the synapse by:
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100% by high-affinity presynaptic and glial transporters - REUPTAKE.
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What are the glutamate receptors? How are they distinguished?
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NMDA R - ionotropic
Kainate - ionotropic AMPA - ionotropic mGluR - metabotropic |
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Explain the structure of NMDA receptors?
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Contain a pore in the middle of a multi-uni barrel structure. Allows both Na and Ca movement. Must go bind with glycine. Effects modulated by polyamines. Mg block NMDA R in voltage-dependant fashion.
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What are the steps of long term potentiation?
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- Rapid stimulation of neurons depolarises them
- NMDA R open, Ca flows in and binds to calmodulin - activates ca-calmodulin-dependant-kinase (CCDK) - CCDK phosphorylates AMPA R making them more permeable to the flow of Na - # of AMPA R at the synapse increase - increased gene expression and additional synapses form |
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What is the mechanism of long term potentiation?
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A high frequency signal (or convergence of several
signals) arrives at the glutamatergic synapse leading to a massive glutamate release. 2. Glutamate binds to both NMDA and AMPA receptors, however only the later is activated initially since positively charged Mg2+ blocks the NMDA receptor channel. 3. Continued activation of AMPA receptors leads to a significant influx of Na+ ions into the cell which, in turn, leads to a decrease in membrane potential (partial depolarization). 4. This depolarization removes blockade by Mg2+ since the relative charge of the neuronal membrane is now much less negative ( due to the influx g of positively charged Na+ ions). At this stage, Ca2+ ions can freely enter the cell via the NMDA receptor channel and initiate a number of enzymatic processes that are involved in the fixation of increased synaptic strength (neuronal memory formation). This post synaptic change is manifested as an enhancement of AMPA receptor sensitivity and number. |
AMPA/NMDA interaction
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If you block NMDA R do you stop LTP?
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Yes
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What is PCP?
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A non-competitive NMDA R blocker.
Once used as an anaesthetic, but found to be responsible for psychotic reactions and behaviour. Illegal use has continued as 'angel dust' - hallucinogen - caused many serious long-term psychological problems in recurrent users. |
Angel Dust
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What is riluzole?
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A NMDA presynaptic glutamate release blocker. Mech unknown
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Memantine, a non-competitve NMDA R blocker has what clinical uses?
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Used in neurological disorders.
Mechanism of action in AD called signal to Noise Hypothesis - more effective than Mg in blocking channel. Thought that memantine suppresses synaptic noise but allows relevant physiological signals to be sent, thought to preserve neurons as well as synaptic plasticity in the AD patient. Also Parkinson's, Huntington's, other diseases caused by excessive NMDA-R activation including glaucoma, MS, epilepsy and neuropathic pain. |
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What is Alzheimer's Disease?
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Progressive dementia. Caused by gradual death of neurons and their synapses in the cerebral cortex leadin to death of life-sustaining neurons in the lower brain regions.
Patients lose the ability to create new memories and gradually lose old ones also. Takes about 10 year to debillitate a patient and death is usually due to an illness or infection not AD. Amyloid plaques are deposited in the brain and interfere with the reuptake mechanism of glutamate in the glial and neuronal cells. Leads to excitotoxicity. |
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What is the major inhibitory NT in the CNS?
How is it synthesised? |
GABA
From glutamate by glutamic acid decarboxylase |
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How is GABA removed from the synapse?
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Reuptake by presynaptic and glial transporters or reuse or degredation by GABA transaminase.
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What is the structure of the GABA receptor?
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Heterodimer composed of two
seven transmembrane‐spanning units Linked by carboxyl‐termini. Ligand binding domains are on the extracellular surface of R1 and R2. Activation modulates adenyl cyclase activity via G‐proteins Increase outward K+ and reduce inward Ca2+ conductance Effects reduce postsynaptic excitability. |
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Explain the sedative/anxioltyic effects of benzodiazepine agonists?
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Bind to the γ subunit at a modulatory site, cause conformational change, giving it a greater affinity for GABA. Increases inward Cl-.
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Explain the mechanism of picrotoxin?
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Blocks the Cl- channel of GABA R - giving convulsant effects.
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Explain the mechanism and use of GABA B receptor agonists?
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GABA B receptors are GPCR, that can reduce spasticity. Baclofen, an anti-spasmodic can not cross the BBB however, so it is pumped directly into the SC where it binds to presynaptic receptors on
excitatory terminals within the spinal cord. |
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What is the synthesis, packaging, clearance details for glycine?
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Synthesised from glutamate via glutamate transaminase.
Packaged into vesicles. Cleared by GlyTransporter 1 or 2. Can either be repackaged or hydrolysed. |
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What is strychnine?
Effects? |
A competitive glycine antagonist.
Horrific seizures, no loss of consciousness, body bent in double. |
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Explain the mechanism of action of tetanus toxin?
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competitive glycine antagonist, a convulsant
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Define: anaesthesia?
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a state characterised by loss of sensation, the result of pharmacological depression of nerve function or of neurological disease
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Define: local anaesthesia
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regional, produced by direct application of drug into the operative site. blocks nerves which may transmit pain, while maintaining consciousness
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Define: general anaesthesia
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the loss of ability to perceive pain associated with a loss of consciousness produced either by intravenous or inhalation of anaesthetic agents
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Where does cocaine originally come from?
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Cocoa leaves
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Explain local administration mechanism of cocaine?
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Used recreationally and sometimes in lacrimal duct or nasal surgery as it has both vasoconstriction and anaesthetic properties
Blocks sodium channels by both the hydrophobic (uncharged species) and hydrophilic (charged species) pathways to cause blocking of action potential generation. Reversible with time (becomes displaced and is then metabolised). |
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Explain effects of cocaine in the bloodstream?
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At the brain to cause reduced monoamine reuptake and in turn increased levels of DA in the NA, part of the mesolimbic reward pathway.
Causes euphoria, increased motor activity and talkativeness without negative consequences associated with amphetamines (such as hallucination, delusion and paranoia). Can cause serious cardiovascular damage (cerebral/myocardial infarction/haemmorage, aortic dissection, cardiac dysrhythmia) as well as increased blood pressure, convulsions and tremor. Taken during pregnancy causes foetal defects. |
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Why is the charged status important for anaesthetics?
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Because only uncharged bases may be hydrophobic enough to enter the neuronal membrane without assistance.
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What will occur with a local with low pKa values?
What is this pathway called? |
Will cross the axonal membrane in greater conc over a shorter period of time.
The hydrophobic pathway. |
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What is the hydrophilic pathway?
What is this process called? |
Charged form of the drug can enter sodium ion channels when they are open, binding and blocking. If the neuron is actively firing, Na channels will open frequently, allowing greater access. This is called use-dependance.
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Use-dependance
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Sodium channels exist in three states. Name them.
Which state does LA have a greater affinity for? |
Open, closed, inactivated.
Inactivated. |
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What is the mechanism of action of LA?
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Binding to inactivated Na channels - blocks reopening.
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Which pain fibres are affected by LAs?
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Small diameter afferent neurons of peripheral nerves.
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What are systemic side effects of LAs?
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tremor, agitation, convulsins, CNS depression, respiratory depression, decreased contraction of the heart, vasodilation of periphery, drop in BP, dangerous!
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Define: hypertension
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a systolic above 140 mmHg, diastolic over 90 mmHg
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Why treat hypertension?
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Leads to stroke, heart failure, heart attack and renal failure
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What are the most important modifiable risk factors for cardiovascular disease?
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hypertension, smoking, increased blood lipids
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What is the aim of therapy of hypertension?
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To prevent catastrophic events
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What are the key issues in treating hypertension?
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Compliance and adverse effects
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Mechanism of action of codeine, morphine, heroin.
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Full agonists of opioid mu receptor
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Buprenorphine, a partial agonist of the opioid mu receptor would have what clinical use?
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Treating heroin addiction, pain relief in cancer patients.
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Phenytoin, a dose-dependant sodium blocker, has what clinical uses?
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Reduces Na+ channel opening, used to limit CNS excitability in epilepsy, also possible use in cardiac disrythmias but not currently being used clinically.
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Give further details of the local amide anaesthetics lidocaine and lignocaine
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Local amide anaesthetic with low pKa (therefore fast absorption), metabolised by hepatic amidases and extremely rare hypersensitivity reactions
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How to α-adrenoceptor agonists treat hypertension?
What side effects are associated with their use? Why? How are these side effects reduced? |
α-adrenoceptor antagonists prevent NA from acting as a vasoconstrictor
postural hypotension tachycardia nasal congestion impotence Due to non-selectivity of α-adrenoceptor antagonist. The use of α1-adrenoceptor specific antagonists. |
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What is one common classification system for the treatment of hypertension?
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A
- α-adrenoceptor agonist and antagonists - ACE inhibitors 'pril' - angiotensin receptor antagonists B - β-adrenoceptor antagnoists (β-blockers) 'ol' C - Ca entry antagonists/blockers D - diuretics E - endothelin antagonists - endopeptidase inhibitors |
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How do selective α1-adrenoceptor antagonists benefit in treating hypertension?
Side effects? |
Blocks the vasoconstrictor responses to the endogenous NA
Possible salt and water retention |
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How to ACE inhibitors work?
Side effects? |
inhibit enzyme which converts inactive angiotensin I to the active angiotensin II.
Angiotensin II initiates vasoconstriction, hypertrophy, hyperplasia, increased oxidative stress and fibrosis. ACE inhibitors decrease BP, reverse/prevent hyperplasia, hypertrophy and fibrosis. Dry unproductive cough, hyperkalaemia, loss of sense of taste, proteinuria |
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Explain the mechanism of action of angiotensin receptor antagonists.
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"sartans"
Selective antagonists of the angiotensin type I. More effective than ACE inhibitors as independant of mechanism of formation, therefore no effect on bradykinin. Decrease BP, oxidative stress. |
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Explain the mechanism of action of β-blockers.
Side effects |
β-adrenoceptor antagonists. "lol"
Mechanism is unclear. Possibly due to downregulation of endogenous vasoconstrictors such as Ang II or up-regulation of endogenous vasodilators such as NO and prostacyclin. Decrease damage to the heart. Decrease renin secretion, inhibition of NA release. Bradycardia, arrhythmias, insomnia, depression, impotence, decrease HDL. NOTE: NOT VASODILATORS |
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Metoprolol
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β-adrenoceptor antagonist
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Perindopril, an ACE inhibitor would function how in treating hypertension?
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Inhibit ACE enzyme which catalyses Ang I into Ang II
Vasodilator, decrease oxidative stress |
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Candesartan, an Ang R antagonist has what clinical use? Any side effects?
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Ang receptor antagonist
1000x more selective for AT1 receptors over AT2 Block all physiological actions of Ang II without effect on bradykinin No known adverse effects ?!?! |
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Explain the mechanism of Ca entry blockers in treating hyptertension.
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Decreased entry produces vasodilation, decreased force of contraction and slowing of AV conduction.
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Verapamil/Nifedipine, non selective Ca entry blockers have their effect where? They are useful how clinically?
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Non selective Ca entry blockers in the heart. Useful in treating arrhythmias. Hyptertension drug.
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Explain the mechanism of diuretics in treating hypertension?
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Increase urine volume by action in the tubules. Inhibits Na reabsorption into the blood.
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Frusemide
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Diuretic that acts at ascending loop of henle to inhibit Na reasorption.
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Explain mechanism of action of endothelin antagonists?
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GPCR that increases BP, vasoconstriction, hypertrophy, fibrosis, hyperplasia. Competitive antagonists therefore decrease these effects.
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Explain mechanism of endopeptidase inhibitors in treating hypertension?
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Inhibits endopeptidase, which normal breaks down ANP, which induces relaxation. Extends duration of relaxation with increased levels of ANP.
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Define heart failure:
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The inability of the heart to pump enough nutrients to the metabolising tissues of the body.
During heart failure, preload, afterload and heart rate increase while contractility decreases. |
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What 4 factors regulate cardiac output?
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Preload
Afterload Intrinsic contractility Heart Rate |
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How does the body try to overcome heart failure?
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Homeostatic mechanisms - that give short term improvements but long term problems.
Tachycardia, hypertrophy, cardiac dilatation, oedema, exercise intolerance. |
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Treatment aims to do what in heart failure?
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Improve the ability of the heart muscle to contract, decrease the workload.
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Digoxin, a positive ionotropic agent, functions by what mechanism and has what adverse effects?
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Positive ionotropic agent.
Inhibitor of the Na pump which leads to increased Ca concentrations, increased force of contractions Adverse effects - nausea, vomitting, AV block, increased risk of ventricular arrhythmias |
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Dopamine
Dobutamine Class, route of administration and mechanism |
β-adrenoceptor agonists
(β-blockers) GPCR Must be given in continuous intravenous infusion due to rapid metabolism in the gut and blood by MAO. Increase HR, cause arrhythmias |
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How would you vasodilate the heart in a patient with heart failure?
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Use of ACE inhibitors, Ang II antagonists, endothelin antagonists.
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Spironolactone, a diuretic has what role in treating heart failure?
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Potassium sparing diuretic.
Mech unclear. Decreases arrhythmias, decreases fibrosis, improved control, weak diuretic effect. |
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Role of β-adrenoceptor antagonists in heart failure.
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Once contraindicated in heart failure. Now standard treatment. Mech unclear, most likely a reduction in the production of pro-inflammatory cytokines. Reduces damage to cardiovascular system.
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What kinds of chemicals activate brain reward mechanisms directly?
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Caffeine, alcohol, nicotine
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What produces addiction?
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The ability of drugs to strongly activate brain reward mechanisms and their ability to chemically alter the normal functioning of these systems.
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What are the physical reward pathwys in the brain?
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Ventral tegmental area (VTA)
Nucleus accumbens Prefrontal cortex |
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Where does cocaine have its effect in the brain?
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Mesolimbic reward pathway
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How do cocaine, amphetamines and nicotine exert their actions?
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They elevate the synaptic levels of dopamine at the nucleus accumbens. The enhanced activity produces mood elevation and euphoria.
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What is the method of action of heroin/morphine at the mu opiate receptor?
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Mu receptor inhibits dopamine release, heroin/morphine prevents inhibition of dopamine release, dopamine is released, increased in reward centre.
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What is a speed-ball?
Why is it so dangerous? |
The combination of heroine/cocaine. They work on different parts of the dopamine neurons, can be combined to illicit a stronger dopamine response.
Heroin increases dopamine release, while the cocaine keeps the released dopamine in the synaptic cleft longer. Associated with a high fatality rate. |
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How does nicotine in smoking become addictive? What effects are noted by high and low concentrations?
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Binds to nAchR in the reward centres. Causes increased numbers of R and desensitisation. Small doses = stimulatory, high doses = relaxation.
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Brupropion, a weak monoamine transporter (MOA-T) blocker has what clinical use?
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Replacement drug for treating nicotine addiction, thought to weakly block monoamine transporter in NA (similar but weaker effect to cocaine) thereby activating reward pathway. However can reduce seizure threshold (especially in patients already taking medications with this effect).
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Clonidine, an α-adrenergic agonist, is used how in a clinical setting?
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Reduces withdrawal effects of nicotine, opiods and cocaine. Side effects: hypotension, dry mouth, drowsiness. Does NOT lower seizure threshold (better option overall, especially in patients with multiple addictions). Also used for ADD and hypertension.
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What are the (MANY!) targets of alcohol?
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Does not seem to have a specific receptor but seems to interact with GABA receptor to increase GABA release.
Effects (overall reduces neuronal activity) - Enhanced 5HT action at 5HT3 receptors - Enhanced ACh action at nAChRs - Inhibits voltage-dependent Ca2+ channels - Inhibits action of glutamate at kainate receptors - Inhibits action of glutamate at NMDA receptors - Enhances GABA action at GABAA-Rs - Moderate increase of dopamine in reward circuit - Increased release of endorphins from pituitary |
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Define: pharmacogenetics
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Inherited variation in the handling and effect of therapeutic agents.
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What is the Hardy-Weinberg Law?
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1 = A2 + 2.A.a + a2
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Define: Autosomal dominant
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One allele dominates so the phenotype is the same in AA and Aa.
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Define: Autosomal recessive
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The phenotype is only present if both alleles are present.
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Define: X-linked recessive
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Phenotype only occurs on the x-chromosome.
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Define: Autosomal co-dominant
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Phenotype is the average of each allele.
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How does genetic variation occur?
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1. Errors in DNA copying
2. DNA exchange between individuals 3. Founder effects 4. Random drift 5. Selection |
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Give an example of an autosomal recessive trait of pharmacological importance?
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Alcohol-induced flushing in orientals. Co-dominant effect, reduced activity of aldehyde dehydrogenase (which breaks down ethanol).
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What is drug disposition affected by?
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1. Metabolic capacity
2. Transporters |
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Do all R need to be occupied to produce Emax?
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No. There are limited numbers of 2nd messengers. Spare receptors exist therefore activation of small % can cause Emax.
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What are spare R used for?
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Effect of agonists, which have to bind 100% to have an effect
- desensitisation - down-regulation |
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What is desensitisation?
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Decrease in affinity without a decrease in Emax. Usually caused by partial uncoupling of R from 2nd messenger system.
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What is down-regulation?
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Decrease in Emax without change in affinity (EC50). Usually caused by R internalisation/destruction.
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What is the physiological significance of cooperativity?
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Neg - slope is reduced, requires more drug for Emax.
Pos - slope is greater, requires less drug for Emax. |
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What happens when more than 1 drug can bind to a single receptor?
What is the equation? |
Cooperativity
1. Independant 2. Once inhibits binding of another (neg) 3. One enhances binding of other (pos) See lecture notes. |
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What is efficacy?
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Ability of D to stimulate R (change in Emax).
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How does efficacy differentiate agonists from anagonists?
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Agonist - α = 1
Partial agonist - 0<α<1 Antagonist - α = 0 |
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What is Emax?
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Occurs when maximum R are bound (maximum effect)
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What is EC50?
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Concentration of drug that gives 1/2 maximal effect
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What is potency?
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Specificity for R (shifts in EC50 without shifts in Emax).
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What are some of the macro and micro effects of D-R binding?
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Macro
- decreased BP - treat infection - prevent seizures - decrease blood glucose - dilate lungs Micro - increase intracellular Ca - block Na channels - induce apoptosis - increase gene transcription - block GPCR |
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What is Ka?
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Association constant
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What is Kd?
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Affinity constant
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Is it better to have a high or low Kd?
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The smaller the Kd the higher the affinity
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What is the free energy equation?
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change in free energy = -RT ln(Kd)
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What is the relationship between change in free energy and Kd?
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increase free energy, decrease Kd, increase binding
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What is Bmax?
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Maximum binding (total number of R)
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How do Bmax and Kd relate?
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50% Bmax
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How do drugs bind to their R?
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Using chemical forces
- Van der waals - hydrophobic - hydrogen bonds - ionic bonds |
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What is affinity?
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The higher the affinity, the more sites bound.
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What is Chatelier's principle?
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D + R --> <-- DR
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What is K1?
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Rate of D-R association
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What is K-1?
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Rate of D-R disassociation
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What is Km?
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Equilibrium constant
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How do most drugs elicit their biological response?
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Drugs bind to R and produce some change in the protein
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What is an agonist?
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Drug that activates the R
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What is an antagonist?
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Drug that inhibits the R
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What are most kinds of drugs?
Why? |
Most are antagonists. They are easier to manufacture, require less specificity.
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What is the potency of alcohol?
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Low potency, require high concentrations.
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What is a partial agonist?
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Only produce a partial max response no matter how high the drug concentration
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What is physiological antagonism?
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Opposing downstream effects, bind to different receptors.
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What is the pD2?
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The -log of EC50
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What are radio-ligand binding assays?
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Use standards (hot) w high specificity, use non-specific binding to non-R sites using cold excess ligand. Affinity is calculated. Unknowns are assayed to determine relative affinity to the standard.
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How does AZT function?
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Targets the enzyme reverse transcriptase which dries out HIV, which then loses structure and can no longer replicate its genome.
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What are the phases of clinical trials?
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Phase I: limited/acute testing with escalating doses to check for toxicity
Phase II: Limited testing in disease sufferers looking for efficacy (long term) Phase II: Large, multicentre, double-blind studies using 100,000s of patients $100 000 000..... ~20 years... |
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What important processes are NATs involved in?
What is it about the nature of NATs that is important for cancer risk? |
The detoxification of carcinogens.
They are polymorphic, high NAT2 activity is correlated with an increased likelihood of cancer. |
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What affects occur due to polymorphism in drug transporters?
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-altered absorption
-altered uptake across BBB -altered excretion in bile -altered excretion in the kidney |
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What would be the factors included in the genetic fingerprint of a patient?
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Genetic variation in absorption, metabolism, distribution, excretion and interaction of drugs.
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What did Paracelsus say?
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That all substances are poisons in the right dosage, the right dosage can mean either a remedy or a poison.
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What is the therapeutic window/range?
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The range of conc where therapeutic effect is obtained without unacceptable toxicity?
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What is the therapeutic index?
How do you interpret therapeutic indexes? |
The ratio of the dose required to produce a toxic effect over the dose required to produce the therapeutic effect.
The higher the index the safer the drug (the bigger the gap between the two ranges). |
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What are the possible clinical problems with a drug?
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Type A - augmented response, dose related toxicity (aggrevated/atypical/highly variable pharmacokinetics)
Type B - Bizarre - idiosyncratic effects, drug hypersensitivity Type C - Chemical - predictable from the chemcical nature of the drug or its metabolites D - Delayed - carcinogenicity/teratogenicity E - end of treatment - withdrawal reactions |
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Does metabolism always = detoxification?
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No. Some metabolites can be more toxic then the parent chemical.
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Are drugs known to be carcinogens still used in clinical practice?
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Sometimes. If the disease being treated is worse than cancer. Usually a long latency period, sometimes expands lifetime overal, ie in older patients.
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What are the phases of metaboism?
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Phase I - functionalisation - makes drug more water soluble
Phase II - conjugation - makes more water soluble (attach hydrophilic group) Phase III - active pumping (enhances active excretion out of cells and out of tissues as a whole) |
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What are the general charaacteristics of cytochrome P450 enzymes?
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- many related forms, one superfamily
- use multiple forms of closely related enzymes or transporters in gene families - all forms slightly different but catalyse the same type of reaction - Individual forms have wide substrate and overlapping substrate specificities - often poor catalysts - not able to become specialised to any one substrate (inefficient) |
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How are causal relationships identified?
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Dose-response relationships
Identification mechanisms Exposure assessment over time |
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ID of causal relationships require?
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A: Dose-respose relationship
B: Elucidation of mechanisms |
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The incidence ofa toxic effect depends on:
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Exposure (pharmacokinetics)
- intensity - frequency - duration |
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Toxic mercury effects include:
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Hg-vapour
- acute: bronchitis, emphysema, cyanosis - chronic: polyneuropathy (CNS) Hg salts - acute: corrotion of mouth, throat and eosophagus, eodema, GIT-inflammation (collapse), kidney damage |
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How do you treat mercury poisoning?
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- acute: activated coal
- chronic: increased elimination with chelate forming agents - kidney failure: haemodialysis |
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Define: genetic toxicology
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Toxic effects to the hereditary material or genetic processes of living cells by chemical or physical agents
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What would occur if a mutation occurred in a somatic cell?
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Cancer due to mutation in oncogene or tumour suppressor gene.
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What would occur if a mutation occurred in a germ cell?
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Inherited genetic disease. Mainly basepair substitutions.
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What happens at the initiation stage of chemical carcinogenesis?
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The DNA damage can no longer be repaired. Mutation is irreversible
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What is needed at the promotion stage of chemical carcinogenesis?
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External stimuli is needed.
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What are the many ways DNA damage can occur?
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Single strand breaks
Small adducts Intra-strand crosslinks Bulky adducts Double strand breaks (joined back together incorrectly) Pyrimidine dimers DNA-protein crosslinks Intercalation |
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What forms of DNA repair can occur?
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Base excision repair
MGMT Nucleotide excision repair system Mismatch repair system Strand specific repair Double strand break repair (most vulnerable) |
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What is the multiple step model for carcinogenesis?
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Exposure - DNA-damage - initiated cell - preneoplastic clone - cancer
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What is an electrophile?
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Wants electrons
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What is a nucleophile?
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Has spare electrons
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What types of chemicals are electrophiles?
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- chemicals with e- deficiency
- charge separations - "good leaving groups" - strained ring system |
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What are the consequences of protein adducts?
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1. Loss of protein function
2. Neoantigen formation |
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What is the Hapten hypothesis?
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chemical -> reactive metabolite -> neoantigen -> appears foreign to immune system -> immune response
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What is an examples of the hapten hypothesis causing a drug reaction?
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Penicillin reactions
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What are the 4 reasons why the liver is a target for toxicity?
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1. High conc of P450s
2. Extensive role in intermediary metabolism 3. Liver is exposed immediately to xenobiotics in diet/air due to direct portal circulation 4. Xenobiotics and their products can be concentrated in bile and can persist in the portal system due to enterohepatic circulation |
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What is necrosis?
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Chromatin becomes diffuse, nuclear fragmentation is random, mitochondria and cell as a whole swell, and ER dilates
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What is apoptosis?
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Cells shrink, chromatin condenses and organelles become grouped. Nuclear DNA is fragmented into regular units of specific length.
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What are the 2 types of cell death?
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Necrosis and apoptosis
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