Theme II: Pharmacology in dental practice Flashcards
What neurotransmitters are involved in parasympathetic & sympathetic autonomic system (post and pre ganglions), and the somatic system
What are 2 exceptions
1-Parasympathetic: ACh released from long pre & short postganglion.
2-Sympathetic: ACh in preganglion, and NA in postganglion
3-Somatic: ACh from neuron onto NMJ.
- Sweat glands are controlled by sympathetic system but both ganglions release ACh.
- For adrenal glands, neuron releases ACh and synapses onto adrenal medulla (not postganglion) which secretes adrenaline into blood (acts as a hormone)
Describe the mechanisms of acetylcholine neurotransmission (synthesis, storage, release, termination)
1-Synthesis: Choline is the precursor. It enters the preganglion and is converted to ACh by CAT enzyme
2-Stored in vesicles. Depolarisation and influx of Ca causes vesicle fusion with membrane and ACh spills out into synaptic cleft
3-Released by exocytosis.
-ACh binds to muscarinic or nicotinic receptors on post ganglion or target
4-ACh is metabolised in the synaptic cleft by ACh esterase enzyme into choline and can be reused.
Where are muscarinic receptors located, what type of receptor are they, what do they bind and what systems do they control
- On target organs, at postganglionic parasympathetic synapses, controlling parasympathetic system.
- Mainly in brain, also in heart, lungs, bladder, intestine
- Bind acetylcholine
- G protein coupled receptors so slow response. Metabotropic
- M 1, 2 and 3 receptors
What do muscarinic agonists do. Give examples of their functions.
-Activate parasympathetic system = Parasympathomimetics
- Treating glaucoma by contracting ciliary muscle and decreasing focal length to drain aqueous humour.
- Treating xerostomia by increasing salivation
What do muscarinic antagonists do. Give specific examples
-Block muscarinic receptors so block parasympathetic activity= Parasympatholytic
- For dilating pupils for eye surgery
- Decreasing saliva for oral surgery, or for anaesthesia to prevent respiratory secretions getting into lungs due to lost cough reflex
- Treating bradycardia by increasing cardiac output
- Treating asthma by causing bronchodilation
- Treating motion sickness by decreasing gastric motility.
-What responses do neuronal type nicotinic agonists and antagonists cause.
- these receptors are located on both sympathetic and parasympathetic postganglia so both systems are activated,
- Both cause autonomic confusion. Therefore they are not used
What do muscle type nicotinic agonists and antagonists do.
(Located on NMJ) Agonists and antagonist cause paralysis for surgery:
- Agonists: increase effect of ACh neurotransmission so depolarisation which causes muscle contraction. As this synthetic agonist cannot be metabolised, it builds up and the fiber persistently depolarises and there is a loss of further excitability. Results in a depolarisation block.
- Antagonists: Hyperpolarization so no excitability. It is a non-depolarising block.
Other than receptor interaction, how else can drugs affect acetylcholine
- ACh release from ganglion can be inhibited, causing autonomic and motor paralysis. Used in botox and to treat local muscle spasm.
- Metabolism can be inhibited. Anticholinesterases inhibits AChE enzyme which metabolises ACh, therefore transmission increases.
How is noradrenaline (NA) made and how neurotransmission occurs
- Tyrosine taken up into postganglion and is converted to DOPA, DA then NA.
- Stored in vesicles to protect against interneuronal enzymes breaking it down.
- Fuses with membrane and released into synapse by exocytosis in response to AP.
- Acts on alpha and beta adrenoreceptors on tissues of sympathetic system
- Termination: Uptake back into neuron and metabolised into amines by monoamine oxidase or is recycled.
What is different about a2 adrenoreceptors to the other types.
-a2 is a presynaptic receptor located on post ganglion. It turns off further release of NA, whereas the other receptors are located on tissues, control the sympathetic system
What are the functions of the different types of alpha and beta adrenoreceptors. Agonists.
- a1: Smooth muscle contraction & vasoconstriction. (Eg. treats anaphylactic shock by increasing BP and used with LA)
- a2: on presynapse so inhibits further NA release so decreases sympathetic activity. (Eg. Vasodilation treats hypertension)
- B1: Heart. Increases cardiac output to treat anaphylaxis or heart failure
- B2: Lungs. Bronchodilation to treat anaphylaxis or asthma (salbutamol).
- B3: increases lipolysis so used for fat loss and muscle gain
Examples of noradrenic antagonists. Mention possible side effects too. Why a2 antagonist not used
-A1: vasodilation to treat hypertension
-A1: relaxes smooth muscle in bladder neck so increases urination
BUT can cause postural hypotension where low BP & dizzy when stand up
-A2: it stops the inhibition of NA release so can increase unwanted anxiety. So not used
- B1: decreases cardiac output to treat hypertension ( BUT can cause rebound hypertension on withdrawal)
- B2: ciliary muscle contraction and decreased intraocular pressure to treat glaucoma
- B1 and B2 (non-selective): decreases cardiac output for hypertension but also causes bronchoconstriciton so shouldn’t be used for asthmatics.
Other than receptor interactions, how else can noradrenaline neurotransmission be increased or decreased.
1- Use a false substrate to inhibit enzyme activity for producing NA. Decreases transmission so can treat hypertension.
2-Inhibiting NA storage in vesicles decreases NA available for release. Less neurotransmission so can treat hypertension.
3-Inhibiting release also decreases neurotransmission.
4-Reptake into presynaptic ganglion can be blocked which prolongs the action of NA in the synapse. Antidepressant effect.
5-Inhibiting the metabolism enzyme (monoamine oxidase) increases NA available for release.
Difference between analgesics and anaesthetics. Difference between local and general anaesthetics
- Anaesthesia: drugs used to prevent pain for a limited time for surgical procedures
- Analgesics: drugs used to control pain. No total loss of feeling (eg. morphine)
- Local: prevents pain in a localised area (eg. lidocaine)
- General: loss of feeling and also loss of consciousness (eg. propofol)
What factors affect the efficiency of inhalation anaesthetics. How they are eliminated
1-Blood/ gas partition coefficient = blood solubility. Low solubility means rapid induction & recovery as less drug is needed to be inhaled to produce equilibrium. It means less retention of the drug following distribution.
2-Oil: gas partition coefficient= lipid solubility. High solubility means high potency
3-Vascularisation - Good blood flow in brain means high levels of drug. Poor blood flow in body fat means drug doesn’t accumulate.
4-Ventilation rate: high rate means high rate of removal.
Most drug is eliminated in the lungs, little is metabolised via hepatic metabolism as it is toxic (halothane is metabolised a lot by liver so toxic)
Side effects of inhaled anaesthetics
- Malignant hyperthermia: hypermetabolism, increased sympathetic activity
- Hypotension, vasodilation, decreased cardiac output
- Respiratory depression
- Hepatic toxicity
- Decreased glomerular filtration and urine output (although not usually a problem due to the decreased cardiac output)
How do local anaesthetics work.
-Block the electrical signalling in neurons by blocking voltage gated Na channels so no AP can be propagated. So no pain felt:
- The weak base is in unionised form when it crosses the membrane as outside a cell the pH is 7.4. So it is lipid soluble.
- Inside of the cell is slightly acidic so it becomes ionised which allows it to bind to the alpha subunit of the voltage gated sodium channel.
What nerve fibres are more sensitive to local anaesthetics
- Small myelinated fibres (nociceptive fibres) are blocked more effectively.
- Then non-myelinated axons
- Large myelinated fibres (motor axons) are less sensitive
Unwanted side effects of local anaesthetics
- Occur if drug escapes into systemic circulation
- In the CNS it can cause confusion and agitation
- In the cardiovascular system it causes hypotension, decreased cardiac output, inhibition of sodium conduction in cardiac tissue.
Why are anaesthetics not very effective in infected or inflamed tissues
-The local tissue pH decreases in an infected area so when injected, the weak basic drug exists in an ionised form meaning it is less lipid soluble and difficult to penetrate the membrane.
Difference between pain and nociception
- nociception is the neural encoding of a stimuli. It is the process whereby noxious stimuli are sensed by nociceptors in the peripheral tissues and transmitted to the CNS. Nociception leads to pain.
- Pain is a subjective experience where it is how someone processes the stimulus which will be influenced by emotions, opinions, sensation and the circumstance.
- Nociception is always consistent but pain will differ between people depending on the circumstance
Nociception pathway
1-Primary afferent neurons travel from peripheral tissue to CNS
- The nociceptor fibres are C, A beta and A delta which detect different types of pain and synapse in different lamina layers in the dorsal horn of the spinal cord.
2- Secondary afferents go to the brain stem
3-Neurones then go the thalamus and to different systems in the brain so that efferents can be activated
4- Efferents go from CNS to PNS, to allow the body to respond in a specific way.
Acute and chronic pain difference
- Acute pain: Excessive mechanical/ thermal stimulation increases transmission and hypersensitizes the nerve fibres. Signals prompt action to relive the pain to prevent harm and to protect. Short-term.
- Chronic pain is often a consequence of stimulation of chemical mediators. Stimuli not always there and nociception pathway not being signalled to but is still responding. Disordered pathway that continues when it shouldn’t.
Difference between C, A delta and A beta fibres
- A beta: Thick and myelinated. Mechanoreceptor - touch and pressure
- A delta: Myelinated and rapid conduction. Sharp localised pain. Nociceptor, mechanoreceptors.
- C fibers: Thinnest, non-myelinated so low conduction velocity. Dull and achy pain. Nociceptor, mechanoreceptor, thermoreceptor. Heat
What mediators stimulate nociceptive endings. What analgesics can inhibit these and therefore inhibit the nociceptive pathway
- 5-HT, Kinins, metabolites of intermediary metabolism (eg. lactic acid), capsaicin, prostaglandin.
- Opioids and NSAIDs decrease prostaglandin so reduces inflammation and reduces sensitivity of nociceptors to the mediators.
How do NSAIDs work.
- analgesics, reduce inflammation, anti platelet, antipyretic.
- They irreversibly inhibit COX 2 which inhibits prostaglandin production, which are made at damaged sites to induce inflammation to deal with injury. Decreased prostaglandin means nociceptors are less sensitive to the effects of chemical mediators (5-HT, kinins)
-Drugs need to be selective for COX2 to prevent GI effects if COX1 was to be inhibited (this would decrease stomach mucous causing ulcers)
What are the NSAIDs aspirin, ibuprofen and paracetamol used for
-Aspirin: Analgesic and anti-inflammatory due inhibition of COX and prostaglandin which makes nociceptors less sensitive to mediators and inflammation.
Antipyretic as decreases prostaglandin that raises body temperature.
Antiplatelet as it acetylates platelet COX so less thromboxane A2, and epithelium makes more prostacyclin.
For mild analgesia.
-Ibuprofen: same 4 effects as aspirin, but maybe not anti platelet.
First choice in inflammatory joint disease. Less gastric irritation, more effective and better tolerated than other NSAIDs.
-Paracetamol: Analgesic and antipyretic effects, but not anti-inflammatory or platelet.
Effective in mild analgesia, less so in inflammatory conditions.
Overdose causes heptatoxicity
How do opioid analgesics work. Receptors. How are they administered and why
- Agonists on mainly u opioid receptors which are G-protein couples receptors on neurons that regulate pain perception.
- Binding inhibits adenylate cyclase, increasing potassium influx so decreases Ca and causes hyperpolarization which turns off neuronal excitability.
- There are u, delta and k opioid receptors but u is the main target for opioid drugs
- Causes euphoria and analgesia
- Oral or rectal but usually IV or intramuscular due to unreliable gut absorption and extensive first pass metabolism
Side effects of opioid drugs
- Drowsiness and sedation
- Respiratory depression, cough suppressive, nausea
- Tolerance: patient no longer responds to it in the same way so needs a higher concentration to get the same analgesic effect.
- Dependance: sudden withdrawal after chronic treatment causes sweating or tremors for example
- Constipation (inhibition of smooth muscle in gut)
- Allergic reactions, urinary retention, pinhole pupils
Give examples of strong and weak opioids and when they are used. Which one is a naturally occurring opioid
1-Strong: used for moderate to severe pain.
- Morphine-for severe pain relief, terminal care
- Pethidine- more lipid soluble, rapid onset, short duration, less constipation.
2-Weak: used for mild to moderate pain.
- Dextroproxyphene
- Dihydrocodeine- cause nausea and constipation
Morphine is naturally occurring.
What does chemotherapy and effective chemotherapeutic agents mean. What is selective toxicity
-Chemotherapy is the elimination of invading cells or microbes
- Effective Chemotherapeutic agents are selectively toxic, meaning the drug is toxic to the invading cells but non-toxic to the host cells
- Exploitable differences between invading species and host such as differences in metabolism and cell structure. Drug targets uniques properties to invading species
What are the 4 major mechanisms of antibacterial action and the drugs used
1-B lactam ring of penicillins target peptidoglycan. Inhibits transpeptidase which is used in cross-linking
2-Ribsomes are targeted to inhibit protein synthesis. Tetracycline binds to 30S subunit which stops initiation of synthesis. Macrolides bind to 50S to block translocation
3-DNA gyrase used for preventing supercoiling is inhibited by fluoroquinolone, so DNA replication is inhibited
4-Sulphonamides and trimethoprim inhibit folate metabolism so inhibit DNA synthesis.
How does acyclovir treat viral infection
- Treats recurrent human herpes simplex type 1 and 2
- phosphorylated in infected cells by thymidine kinase to the active triphosphate form
- This is a nucleoside analogue so terminates the chain, inhibits DNA polymerase and viral DNA synthesis
