Pharmacology Flashcards
What are they drug administration routes?
Oral (per os; p.o.)
Intravenous (i.v.) - immediately into circulation
Intramuscular (i.m.) - slow release
Subcutaneous (s.c.) - under skin surface into fat tissue
Buccal - cheek
Rectal
Transdermal - through skin i.e. nicotine patch
Inhalation
Intracerebroventricular (i.c.v.) - into ventricles open brain
Describe oral administration
Easy; no sterile preparations, special skill or apparatus
Convenient and preferred by patients
What are some of the problems associated with oral administration?
Stomach acidity - acid labile (cleaved) drugs broken down in stomach e.g. benzyl penicillin
Proteolytic enzymes - protein drugs digested by enzymes e.g. insulin
Poor absorption - erratic e.g. pyridostigmine
No absorption - quaternary amine (permanently charged) e.g. tubocurarine
Pre-systemic metabolism - absorbed but metabolised in 1st-pass e.g. glyceryl trinitrate
What are the benefits of intravenous administration?
Immediately enters systemic circulation
Know exactly how much is absorbed, all does enters circulation
Instantaneous peak plasma conc.
Slow injection/infection, can be stopped at anytime if adverse reactions
Describe some of the disadvantages of iv administration?
Needs sterile apparatus and skill
Give examples of iv drugs
Tubocurarine - muscle relaxant during surgery
Pyridostigmine - reverse effects of tubocurarine
Thiopental - GA
Discus the advantages and disadvantages of intramuscular and subcutaneous administration and give examples
Advantages - avoid some oral problems, absorbed from injection, less skill than iv
Disadvantages - slow to reach peak conc., sterile prep. and equipment
SC - insulin, sustained release
IM - diazepam, absorption is slow and erratic
Discuss sublingual/buccal administration
Advantages - absorbed drugs doN’T enter portal vein, enter vena cava (to heart), avoid 1st-pass metabolism
Glyceryl trinitrate rapidly absorbed to relieve angina
Discuss rectal administration
Useful when other routes are not suitable Nausea - prochlorperazine Child epilepsy - diazepam Asthma - aminophyline Arthritis - indomethacin
Describe transdermal administration
Through skin thus limited to potent, lipophilic drugs
Depot (slow over numerous weeks) release
Usually in plaster
Trinitrin (glyceryl trinitrate)
Hyoscine - motion sickness
Nicotine - smoking cessation
Discuss inhalation administration
Large SA, rapid absorption and onset
Gaseous/volatile anaesthetics - halothane
Bronchodilators - salbutamol
What is the importance of first-pass (pre-systemic) metabolism?
Metabolise any drug taken up through portal vein
Parent drug is broken down to metabolites: useful in case of aspirin as active compound is v acidic so prodrug aspirin given, metabolites are active
Describe the process of first pass metabolism
Drug absorbed from GIT enter mesenteric capillary network
Drug carried to liver via portal vein
Extensive hepatic metabolism by hepatic enzymes
Metabolites enter systemic circulation
What are the methods of transport across biological membranes? (PHARM)
Filtration - through gaps
Passive - through cell wall
Facilitated (saturable) - Na/glucose, absorption of vit. B12
Active (saturable) - levodopa (L-DOPA)
Pinocytosis - absorption of botulinum toxin
What factors affect absorption from the GIT?
Changing pH of tract - alters ionisation state of drugs (pH>pKa will ionise)
Gastric emptying - stomach-intestines, faster less absorption
Varying transporter expression - patterns, amounts at different areas
GIT motility - digestion, faster less absorption
Interaction with food - won’t be taken up
Describe absorption from muscle
Perfusion limited thus slow absorption as larger blood flow, faster absorption
Capillary wall fenestrations - drugs move past endothelial cells, ionisation isn’t an issue
Little effect on molecular size
What are the two phases of metabolism?
Phase 1: functionalisation
Phase 2: conjugation
Describe phase 1 of metabolism
Introduce groups that undergo phase 2 reactions
Mainly oxidation - also reductions, hydrolyses
Often increase polarity
Describe phase 2 metabolism
Addition of large, heavy groups: glucuronic acid, sulphate, AAs, make large so not absorbed well, can’t bind receptor
Marked increase in polarity
Increase rate of excretion as tag for removal
What are the two main sites of excretion?
Kidney - urine
Liver - bile, faeces
(Lungs - volatile anaesthetics, ethanol
Milk - lactating mothers)
What is the functional unit of the kidneys?
The nephron
Describe entry of drugs in the kidney
Drugs filtered at glomerulus
Active secretion of drugs at proximal convoluted tubule - separate carriers for acids and bases
Describe the reabsorption of drugs in the kidney
Active re-uptake at glomerulus
Passive reabsorption of lipophilic molecules along proximal convoluted tubule
How are weak electrolytes excreted and how is this aided?
pH-partition - non-ionised passively reabsorbed thus more ionised, more remains in tubular fluid, more excreted
Aided by altering pH (of urine) to cause greater ionisation of drug
Give examples of excretion of weak electrolytes
Salicylic acid (aspirin metabolite) - pKa 3.0 Increase excretion by making urine more alkaline using sodium bicarbonate, sodium lactate
Amphetamine - pKa 9.8
Make urine acidic using ammonium chloride
Describe the excretion of penicillin and how it can be manipulated
Actively secreted into tubular fluid, short t1/2 ~30mins
pKa = 2.7
Lower pH - lower degree of ionisation
Non-ionised form passively reabsorbed from urine
Effective increase t1/2
Describe excretion of drugs in bile
Passive diffusion
3 active mechanisms dependent on: MW, polar, acidic, glucuronide metabolites usually good substrates
High MW drugs excreted unchanged e.g. oubain
Describe the process of enterohepatic recirculation
Drug absorbed, carried to liver
Converted to glucuronide conjugate
Conjugate secreted in bile
Bile containing conjugate secreted in response to food
Conjugate hydrolysed by B-glucuronidase in GI flora
Drug reabsorbed
Define drug
Substance that affects the body, elicits a change in physiology
Explain receptor theory
Drug will not have activity unless binds to specific receptor thus inducing response
Define agonist, antagonist, partial agonist and inverse agonist
Agonist: elicit +ve response - mimic bodies response, have affinity and efficacy
Antagonist: inhibitors - prevent activity of endogenous hormones/inhibit enzymes, have affinity no efficacy
Partial: +ve response but not to complete extent possible - functionally inhibit enzyme, affinity reduced efficacy
Inverse: opposite response to endogenous ligand e.g. naloxone treats morphine overdose
Explain the law of mass action
Rate of chemical reaction is directly proportional to product of activities/conc. of reactants
What is KD?
Dissociation constant: conc. of drug at equilibrium occupies 50% available receptors
Measures likelihood DR complex will dissociate at equilibrium
High KD likely to disassociate
Describe the relationship between KD and affinity
1/KD = KA (affinity)
Higher KD lower affinity
KA measures tendency of drug to bind receptor thus high KA = greater affinity
What is the KD equation?
KD = [D][R]/[DR]
Define efficacy and poteny
Efficacy: max. effect achievable by drug (Emax)
Potency: dose drug necessary to have effect - lower dose = greater potency
High potency will trigger response at low dosage avoiding side effects
What is EC50?
Measure of potency
Dose/conc. at half Emax
Why is Emax used?
As receptors become saturated so impossible to know exactly how much is needed or if same effect could be produced at lower dose
Describe the relationship between potency and EC50
Inverse: more potent lower EC50 as need smaller amount of agonist to induce response
Explain the theory of spare receptors
Emax can be reached without maximal receptor occupancy allowing receptor to be stimulated again or by a different drug
Some receptors of more than 1 receptor and have different affinities - detected using Scatchard plot
What is the therapeutic window of a drug?
The gap between the therapeutic and toxic results i.e. gap between EC50 and LD50
What is the therapeutic index?
Ratio of [D]toxic/[D]therapeutic
What is the complication with narrow therapeutic windows?
Makes it very difficult to stay within the window, can easily slip into toxic/lethal doses and effects
What are the 5 types of antagonism?
Chemical - drug destroys ligand
Receptor
Non-competitive - alters response curve
Pharmacokinetic - blocks drug getting to target
Physiological - counteract response trying to block
What are the 3 main types of receptor antagonism?
Reversible, competitive
Irreversible, competitive
Allosteric
Describe and explain reversible antagonism
Drug competes for AS with substrate, blocks receptor preventing activity
High affinity, no efficacy
Emax not depressed due to spare receptors, more agonist required
EC50 parallel shift to right
e.g. tolazoline on a-adrenoreceptors block AD
Describe and explain irreversible antagonism
Drug binds covalently to AS, changing conformation of binding pocket - removes receptors
Emax reduced
EC50 unchanged UNLESS spare receptors present
Only overcome by producing more receptors
e.g. phenoxybenzamine on a-adrenoreceptors
Describe and explain allosteric antagonism
Antagonist binds to allosteric site, alters conformation to limit agonist binding or prevent response
Emax reduced (fewer receptors), EC50 unchanged
Reversible: memantine on NMDA receptors
Irreversible: aspirin on cyclo-oxygenase 1
Explain how antagonists can be compared
Repeated dose response curves +/- doses of antagonist recording changes in EC50
Dose ratio = EC50 + antagonist/EC50 (agonist)
Explain pA2
Measure of antagonist affinity for receptor
-log of [antagonist] which will reduce double dose agonist response to that of a single dose
Explain non-receptor antagonism
Pharmacokinetic: enhance drug metabolism or bind agonist prevent reaching receptor e.g. phenobarbital enhances warfarin breakdown
Physiological: 2 drugs bind different receptor on same tissue counteracting each other e.g. salbutamol induces bronchodilation, histamine induces constriction - response depends on balance
Why do drugs require receptors?
Most can’t pass membrane thus to initiate response must bind a receptor protein
Name the 4 main classes of receptor
Ionotropic (LGIC): milliseconds
Metabotropic (GPCRs): seconds-mins
Tyrosine kinase linked receptor: mins-hours
Intracellular (nuclear): hours-days
Describe the process of signal amplification
Signal molecule binds receptor inducing activation of 2nd signalling molecules, rapidly diffuse from source broadcasting signal to other parts of cell
Either activate next signalling protein or generate small intracellular mediators
Name the main 2nd signalling molecules and their associated enzymes
cAMP - adenylate cyclase cGMP - guanylate cyclise Ca2+ Diacylglycerol (DAG) - PLC Inositol triphosphate (IP3) - PLC Prostaglandins - PLA2
Describe intracellular signalling
Nuclear, cytoplasm or ER
Small, lipophilic molecule cross membrane and bind to intracellular receptor
Lead to transcription of specific genes
What determines if a protein is active or not?
If it is phosphorylated or not
Describe ionotropic receptors
Ligand gated ion channels
Allow very rapid signalling i.e. neurons, muscles
Usually specific for 1 ion
Give an example of ionotropic receptor
Nicotinic receptors - ACh receptor
Present in NMJ, ganglia, CNS
Pentamer of self-assembling units
2ACh must bind opening Na+ channel, influx of Na+ in
Can also be inhibitory GABAA Cl- channel
GABA major inhibitor in CNS, upon binding hyperpolarises neuron diminishing chance of successful AP (threshold increased)
What are G proteins?
7-membrane domain protein made of three subunits; a, B, y with a GDP molecule
Serve as relay molecules by coupling receptor to intracellular enzyme or couple receptor to ion channel
What are the three types of G protein?
Gs - Stimulates adenylate cyclase/open Ca2+ channels
Gi - Inhibits adenylate cyclase/open K+ channels
Gq - stimulate PLC
Describe activation of G protein
- Inactive state (GDP bound)
- Signal molecule binds to GPCR, causes GDP to disassociate allowing GTP to bind
- G-protein splits into a-GTP and By complex
- a-GTP activates target protein
- GTP hydrolyses into GDP
- a-GDP reassembles with By
Describe the cAMP pathway
Ligand binds to GPCR, activates Gs-protein which enhances adenylate cyclase
Adenylate cyclase converts ATP to cAMP which activates PKA then phosphorylates a protein
cAMP converted to AMP by PDE
If GiPCR activated, it will inhibit the process thus less cAMP made, less activated PKA, less phosphorylated proteins
Describe the phosphatidylinositol pathway
Ligand binds to GqPCR, activates PLC which breakdowns PIP2 to IP3 and DAG
DAG activates PKC which phosphorylates proteins inducing tissue response
IP3 opens intracellular Ca2+ stores (ER)
PLC opens Ca2+ channels in membrane
Describe the cGMP pathway
Ligand binds, activates guanylate cyclase which converts GTP to cGMP inducing physiological response
cGMP converted to GMP by PDE
Ca2+ and calmodulin enhance NO synthase converting arginine to NO + citrulline
NO enhances soluble guanylate cyclase producing more cGMP
Describe tyrosine kinase receptors
Receptors with intrinsic enzyme activity in intracellular portion
Ligand binding induces dimerisation of receptor tyrosine kinases and cross-phosphorylation
Phosphorylated receptors act as docking stations for other signalling molecules triggering wide range of pathways
Describe nuclear receptors
Ligand activated transcription factors
Ligand binds, chaperon proteins fall off, receptor translocates to nucleus
Receptor binds to hormone response elements in DNA allowing recruitment of transcription factors
What are the promoter sequence, co-activator, hormone response element?
Promoter: upstream AA sequence not translated but regulates transcription
Co-activator: enhances activity of transcription factors
HRE - 6/7 nucleic acids
Receptor binds HRE, recruiting co-activator and transcription factors
Describe the role of Ca2+ as a 2nd messenger in the IP3 pathway
IP3 release stimulates Ca2+ release from ER into cytosol
Ca2+ activates many PKs like PKC
Describe the role of Ca2+ as a 2nd messenger in the Ryanodine Receptor pathway
AP triggers opening of DHPR (Ca2+VGC) channels and influx of Ca2+
Ca2+ triggers opening of ryanodine receptor channels and release of Ca2+ from SR
How is the peripheral nervous system divided?
Sensory and motor
Motor divided into somatic (voluntary) and autonomic (involuntary)
Autonomic to sympathetic and parasympathetic
What are the 3 types of peripheral NS neurons?
Sensory (afferent - Arrive in cell): exteroceptors receive external info, proprioceptors receive internal positional/motor info, interoreceptors receive internal organ info
Motor (Efferent - Exit cell): carry info to effector organs
Interneurons: cells connect CNS to other neurons
Compare the somatic and autonomic NSs
Control: somatic voluntary; autonomic involuntary
Effectors: skeletal muscle; smooth + cardiac muscle, glands
Neurons: single efferent neuron; multiple efferent neurons
Axon terminals: release ACh; ACh + NAdr
Excitatory; excitatory and inhibitory
Control: cerebrum (cognitive); homeostatic centres (pons, hypothalamus, medulla oblongata)
Describe the somatic motor reflex
Receive stimulus, sensory afferent travels along synapse, enters interneuron, motor efferent travels along myelinated synapse to effector region
Very fast
Describe autonomic motor reflex
Receive stimulus, sensory afferent travels along synapse to interneuron, motor neuron travels along lightly myelinated preganglionic fibre synapses at terminal causing release of ACh, continues along postganglionic fibre (non-myelinated)
Compare the sympathetic and parasympathetic NSs
Sympathetic: fight or flight; increase HR, dilate pupils, decrease gut motility; SHORT PRE-ganglionic fibres, long post-ganglionic
Para: rest and digest; slow HR, constrict pupils, increase gut motility; LONG PRE-ganglionic fibres, short post-ganglionic fibres
What cranial nerves are CNS-ANS connections?
Oculomotor - 3
Facial - 7
Glossopharyngeal - 9
Vagus - 10
What nerves are associated with peripheral nervous system?
Cranial: 3,7,9,10 Cervical: 1-7 Thoracic: 1-12 Lumbar: 1-5 Sacral: 1-5
What nerves are associated with para outflow?
Post-ganglionic fibre close to tissue innervated
Oculomotor (CN3): iris radial and ciliary muscle
Facial (7): lacrymal gland, nasal mucosa, submandibular and sublingual glands
Glossopharyngeal (9): parotid salivary gland
Post-ganglionic fibres in tissue innervated (intramural)
Vagus (10): heart, lungs, upper abdominal organs
Sacral (1-3): lower abdominal organs, urinary, genitalia
What nerves are associated with symp outflow?
Thoracic 1-12
Lumbar 1-3
What is a ganglia?
Points where neurons synapse with each other
Describe innervation in SymNS
Ganglia close to spinal cord (sympathetic trunk)
Synapse in paravertebral chain of ganglia; lie on both sides of vertebral column OR
Celiac, superior/inferior mesenteric ganglia (prevertebral); lie anterior to vertebral column, occur only in abdomen and pelvis
Highly branched: influence many organs
Release ACh at ganglion and NAdr at target tissue
What does the Short pre-ganglionic fibres in SymNS allow for?
Allows firing of neurons in coordinated manner at same time
Describe innervation in the ParaNS
Ganglia located close to target organ (long pre-ganglionic fibres)
Few branches so have localised effect
Release ACh at ganglion and target tissue
Describe the types of dual innervation
Some organs receive innervation from both Symp and Para NS
Antagonistic: counteract each other - HR
Complementary: similar effects - salivary gland
Cooperative: work together for same effect - sexual function
Describe antagonistic control of HR
Increase Symp causes HR increase: NAdr acts on B1 receptors, increases rate of contraction
Increase Para causes HR decrease: ACh acts on M2 receptors, causes release of K+, hyperpolarising cell making AP less likely to continue
B blockers act as antagonists to Symp NS, Para dominates thus HR and BP decreased
Describe the control of blood vessels, smooth muscle and sweat glands
Only innervated by SympNS thus rely solely on frequency of the signal
Increase signal rate, NAdr released from Symp neurons, bind to a1 receptors on blood vessels, vasoconstricted
What is the enteric NS?
Described as the 2nd brain - more neurones than spinal cord
Capable of initiating involuntary responses independent of rest of ANS
Consists of 2 plexuses in mucosal wall:
within the muscularis externa (myenteric)
submucosal plexus in the submucosa
What is the function of the ENS?
Receives considerable input from ANS
Sensory neurons transmit info on mechanical and chemical conditions of GIT
Motor neurons act to control peristalsis and release of digestive enzymes
What 6 things does a molecule require to be classified a neurotransmitter?
- Precursor and neurotransmitter present in nerve terminal
- Systems for synthesis and storage
- Transmitter release by nerve stimulation Ca dependent
- Mechanism for termination of transmitter present
- Enzymes must be present for biodegradation of transmitter
- Action of transmitter modulated by drugs at specific receptors
Describe the role of ACh
Neurotransmitter for both pre and post ganglionic fibres in ParaNS
Neurotransmitter for pre-ganglionic neurone in SympNS
Describe how ACh in made
Acetyl-CoA and choline reacted with choline acetyltransferase forming ACh and CoA
What are muscarinic effects?
Those that can be replicated by muscarine, abolished by low doses of antagonist atropine
Muscarinic actions correspond to those of Para stimulation
After atropine blockade, large doses of ACh can have nicotinic responses as no muscarinic receptors left
What are the 5 muscarinic receptors and where are they?
M1: salivary glands, stomach, CNS
M2: heart
M3: salivary glands, bronchi, sweat glands, eye
M4+5: CNS
What pathway do M1 and M3 use?
Gq IP3 DAG
What pathway does M2 use?
Gi cAMP
Describe the pathway for M1+3
ACh binds to M1/3 GqPCR, activates PLC which cleaves PIP2 to IP3 and DAG
IP3 induces release of Ca2+ activating Ca2+-dependent protein kinase
Causes smooth muscle contraction and glandular secretion
Describe the pathway of M2 receptor
ACh activates GiPCR, activates K+ channels allowing K+ to leave cell, hyperpolarises cell reducing likelihood of AP reaching threshold and continuing thus muscle can’t contract, HR reduced
Describe the muscarinic/Para effects on cardiovasculature, smooth muscle, exocrine glands, eye
Cardiovascular: sinoatrial node - bradycardia; atria - reduced force of contraction; atrioventricular node - reduced conduction
Smooth muscle: increased gut motility, urination, defecation, broncho-constriction
Exocrine glands: increased salivation, sweating, lacrimation, gastric secretion and bronchosecretion
Eye: controls contraction of ciliary muscle for near vision, pupil diameter
What are the effect of muscarinic antagonists? (Symp innervation)
Heart: trachycardia Eye: mydriasis, cycloplegia GIT: reduced tone, motility, secretion Bladder: urinary retention Salivary: dry mouth Sweat: reduced, dry, warm skin
What are nicotinic receptors?
LGIC - require 2ACh molecules to activate
5 subunits: a, B, y, delta, epsilon
Subunit combination determines ligand binding properties of receptor, particularly antagonist
What are the 2 types of nicotinic receptor?
N1 - Ganglion (+ CNS)
N2 - Muscle
Differ in combination of subunits
Explain N1 (ganglion) receptor pathway
2ACh molecules bind, opens Na+ channel causing depolarisation and subsequent AP at all ganglia and the adrenal medulla
Explain N2 (muscle) receptor pathway
2ACh molecules bind, opens Na+ channel causing depolarisation and subsequent action at NMJ
Describe the affinity’s of N1 and N2 for both decamethonium and hexamethonium
N1: greater affinity for hexamethonium
N2: greater affinity for decamethonium
Describe the effect of nicotinic antagonists
Arterioles: vasodilation
Veins: dilation
Name muscarinic agonists and antagonists
Agonist: ACh, bethanechol, pilocarpine
Antagonist: atropine, tropicamide
Name nicotinic agonists and antagonists
Agonist: ACh, nicotine
Antagonist: hexamethonium, tubocurarine
What is AChE?
Enzyme that catalyses breakdown of ACh to acetic acid and choline
Choline is uptaken again by pre-synaptic neuron, reproduces ACh
Compare AChE and pseudocholinesterase
AChE present in ganglia, neuroeffector junctions, NMJ, RBC
BuChE free in plasma, made by liver, rapidly replaced
What is a volume of distribution?
Theoretical volume containing total amount of drug at observed plasma conc.
Small VoD suggests bound in plasma, will stay there
High VoD confers drug moved out of plasma
What is the general rate equation?
Rate = k.C^n
What happens when order of reaction is 1 or 0?
1: rate proportional to conc., higher plasma conc greater amount eliminated
0: rate independent of conc i.e. is constant
What is half-life?
Time required to reduce plasma conc to half initial value
For 1st order always constant - decay rate declines
For 0 order variable - decay rate constant
What does proportion eliminated show?
% drug eliminated after number of half lives
Explain constant rate infusions
After infusion drugs immediately started being eliminated
Equilibrium between elimination and constant rate infusion = steady state conc
How can infusion rate be calculated?
k0 = (V.Css)/k
Describe rate of attainment of Css
How many half lives to reach Css - usually 5
Allows planning of how long need to wait so has therapeutic effect
What problems are faced when trying to rapidly reach therapeutic window/Css?
Can’t just give larger dose - will go into toxic effects
How can loading doses and multiple dosing be used to rapidly obtain Css?
Give bolus dose at start - to instantly reach Css need C=Css
Loading dose = VCss = k0/k
A long half life drug has small fluctuations between doses and can relatively easily be maintained within therapeutic window, applied with bolus dose avoid lag
A short half life has large fluctuations, rapid attainment of Css but difficult to maintain e.g. morphine
What dose the passive diffusion of drugs depend on?
Lipophilicity - how soluble in lipid
Size - smaller molecules diffuse rapidly
How does the pH-partition hypothesis effect diffusion?
Ionised molecule can’t diffuse through membrane
Ionised state depends on pH of environment and pKa
pKa = -log[Ka]
What is the Henderson-Hasselbalch equation?
pH = pKa + log[A-]/[HA]
Compare nicotinic and muscarinic receptors
Both ACh receptors
Nicotinic - LGNa+C
Muscarinic - GPCR
Nicotinic: post-ganglionic neurons in both Para and Symp NS (N1)
NMJ (N2)
Found at ganglia
Muscarinic: GqCR (M1,3) - many tissues
GiCR (M2) - heart
Found at effector
QIQIQ
M1 - Gq - many tissues - Ca2+ M2 - Gi - heart - cAMP M3 - Gq - many tissues - Ca2+ M4 - Gi - CNS - cAMP M5 - Gq - CNS - Ca2+
How does ACh affect ciliary smooth muscle?
Constricts ciliary muscle decreasing diameter of lens for near vision
How does ACh effect iris circular muscle?
Causes constriction, causing pupil constriction opening space to canal of Schlemm so aqueous humour can drain, reducing intra-ocular pressure
How do M2 receptors function in the heart?
AChR in nodes and atria, M2 receptors function by Gi mechanism
- AChR stimulated
- Gi inhibitory mechanism decreases cAMP
- Dec Ca2+ entry into heart
- Extracellular Ca2+ entry required for contraction
- HR/cardiac contraction decreased
By
- Activates K+ channels, K+ leaves
- Cell becomes hyperpolarised increasing AP threshold
- AP less likely to meet threshold and continue
- HR decreased
Describe muscarinic effects on the vasculature
Blood vessels doN’T have Para innervation
Circulating ACh acts on M3 AChR on vascular endothelium to release NO
NO induces vasodilation despite blood vessels being Symp innervated
Decreases BP
How does non-vasculature SM respond to muscarinic stimulation?
Contracts
Lungs: bronchoconstriction
Gut: increased peristalsis
Bladder: increased bladder emptying
Describe muscarinic effects on exocrine glands
Increased glandular secretion
Salvation
Bronchial secretion
GI secretion, gastric HCl production
In SympNS - increased sweating
Describe pilocarpine and bethanechol
Pilocarpine: selective muscarinic agonist, not broken down by AChE, treat glaucoma and dry mouth
Bethanechol: M3 selective agonist, inc bladder emptying and gastric motility
Describe some of the effects of AChEIs
Low dose: enhanced muscarinic activity as more ACh present
Moderate: enchantment of muscarinic, inc transmission of ALL autonomic ganglia
High: depolarising block at autonomic ganglia - ACh builds up, receptors constantly stimulated become desensitised causing spastic paralysis, respiratory depression and death
Describe reversible AChEI drugs
Compete with ACh for AS on AChE
Donate carbamyl group to enzyme blocking AS prevents ACh binding
Carbamyl removed by slow hydrolysis, increases duration of ACh activity
Give examples of reversible AChEI drugs
Pyridostigmine, Neostigmine: can’t cross BBB, treat myasthenia gravis
Physostigmine: cross BBB, glaucoma
Describe irreversible AChEIs
Rapidly react with AChE AS leaving large blocking group which is stable, resists hydrolysis requiring production of new enzymes
Give examples of irreversible AChEI drugs
Dyflos, sarin: nerve gas
Ecothiopate: glaucoma
What is the effect of AChEIs on the CNS?
Only non-polar organophosphates (physostigmine) cross BBB
Low dose: excitation, possible convulsions
High: unconsciousness, respiratory depression, death
What are the effects of organophosphate poisoning?
Salvation Lacrimation Urination Diaphoresis Gastro-intestinal motility Emsis Bronchorrhea Bronchoconstriction Bradycardia
What systems of the body receive only Symp innervation?
Vascular SM
Sweat glands
Arrector pili SM of hair follicles
Describe the nerves that supply SympNS
T1-L2 (thoraco-lumbar)
Visceral organs and superficial body regions
Unpaired ganglia
Abdomen and pelvis, anterior to vertebral column
Celiac, superior/inferior mesenteric, inferior hypogastric ganglia
Describe paravertabral ganglia and how they synapse
Located alongside vertebrae, united into Symp chain by preganglionic collaterals parallel to spinal cord
Synapse: on same level; travel down white ramus connect into paravertebral ganglia OR
Ascend/descend chain through gray ramus synapse on another level
Describe prevertebral ganglia
Nerve passes through chain ganglia, synapses in prevertebral ganglia anterior to vertebral column
In the Symp chain what do divergence and convergence mean?
Divergence: preganglionic fibre branches, synapse with several post ganglionic cells
Convergence: postganglionic cell receives input from numerous preganglia (lots of pathways activate single cell)
What is noradrenaline?
Major postganglionic NT in SympNS
Has a and B receptors (GPCR)
What is the fate of NAdr?
Metabolised in synapse Neuronal reuptake Extraneuronal uptake Postjunctional receptor (a, B) Diffuse into blood Prejunctional receptor (a2)
Describe how NAdr is synthesised
- Tyrosine converted to DOPA by tyrosine hydroxylase
- DOPA to dopamine by dopa decarboxylase
- Dopamine to NAdr by dopamine B-hydroxylase
- NAdr to Adr by phentolamine N-methyltransferase
Describe the catecholamine synthetic enzymes
Tyrosine hydroxylase: rate limiting, low Km, end product inhibition, biopterin cofactor, a-methyl-p-tyrosine inhibitor
DOPA decarboxylase: pyridoxine cofactor low Km, high Vmax, a-methyldopa inhibitor
Dopamine B hydroxylase: ascorbate cofactor, copper chelator inhibitor
What are the adrenergic receptors?
Gq - a1 - IP3 Ca2+ release
Gi - a2 - inhibit cAMP
Gs- B1 - stimulate cAMP
Gs - B2 - stimulate cAMP
What is special about a2 receptor?
Can be post-synaptic receptor and regulatory auto-receptor
NA feeds back on own neuron shut down own system
How is BP controlled?
a1 - vasoconstriction through Ca2+ mobilisation (Gq)
B2 - vasodilation through cAMP production (Gs)
Adr binds both but less potent at a1 however a1 outnumber B2 resulting in constriction
Low levels B2 dominates
What drugs can cause vasoconstriction and vasodilation?
a1: phenylephrine
B2: salbutamol
Describe catecholamine metabolism
Carried out by mitochondrial monoamine oxidase (MAO) or cytoplasmic catechol-o-methyl transferase (COMT)
MAO-A: NAdr, 5-HT, dopamine
MAO-B: dopamine
In nerve terminals
Irreversibly inhibited by phenelzine (treatment for depression)
MAO-B inhibited by selegiline (Parkinsonism)
COMT
Active in liver, kidney, cardiac, SM
Inhibitors: tolcapone, entacapone
What effect do MAO and COMT inhibitors have on Adr?
Allow greater Adr signalling as block its breakdown
Describe reuptake of catecholamines
Reuptaken into presynaptic terminals after release
Na+/Cl-/ATP dependent
ATPase pushes Na+ out, K+ in; change in ionic balance causes conformational change in transporter allowing dopamine, Adr, NAdr, Na+, Cl- in rebalancing ionic balance
Uptake 1: into pre-synaptic cell, highly specific, rapid, quickly saturated
Uptake 2: into surrounding cells, non-neuronal, low rate, high capacity
How are direct acting Symp agonists classified?
By receptor subtype:
a1: selective a2: selective, non-selective
B1: selective B2: selective, non-selective
What are indirect acting Symp agonists?
Releasers and reuptake inhibitors
Describe the modes of action of Symp agonists
Direct: bind to receptor
Indirect: cause release of stored CAs, inhibit reuptake of CAs at nerve terminals (uptake 1), increase transmitter presence/longevity in synapse
Describe how a1 receptors function
GqPCR
Phenylephrine activates Gq which activates PLC which cleaves PIP2 to IP3 and DAG, IP3 causes release is Ca2+ activating Ca2+-DPK causing contraction of SM
Describe how a2 receptors function
GiCPR
Clonidine activates Gi which inhibits adenylate cyclase reducing production of cAMP causing reduction of release and synthesis of NAdr AND decrease Symp outflow
Describe how B1 receptors function
GsPCR
Dobutamine binds, Gs activated causing stimulation of adenylate cyclase producing more cAMP causing increased force of contraction, increased HR, increase AV node conduction velocity
Describe how B2 receptors function
GsPCR
Salbutamol binds, Gs activated enhances adenylate cyclase produces more cAMP causing relaxation of GI, vascular, bronchi, ciliary SM
Describe a1 receptor actions
Eye: iris radial muscle contracted - mydriasis
Arterioles(skin, cerebral, abdominal, salivary): constriction
Stomach, intestine: sphincter constriction
Glandular secretion: increase lacrimal, saliva, sweat; decrease bronchial, pancreatic, mucosal
Describe a2 receptor actions
Eye: ciliary epithelium - decrease aqueous humour
Arterioles: presynaptic decreases synthesis and release of CAs
Stomach, intestine: decreased motility
Pancreas: decreased insulin releas
Brain: increased Para outflow, decrease Symp outflow
Describe B1 receptor actions
Kidney: increased renin secretion
Heart SA: increased HR
AV: inc conduction velocity
Atria, ventricles: inc contractility and conduction velocity
Describe B2 receptor actions
Eye: ciliary muscle dilation, epithelium (mediated humor production)
Arterioles(coronary, skeletal M, pulmonary, abdominal, renal): dilation
Lungs: tracheal, bronchial SM dilation
Stomach, intestine: decreased motility
Bladder: detrusor muscle relaxation
Describe Symp innervation of the vasculature
a1 agonist (phenylphrine): constrict skin, cutaneous, visceral, pulmonary, renal vessels a2 agonist (clonidine): constrict veins Increases BP and peripheral vascular resistance (PVR) - compensatory bradycardia often invoked
B2 agonists(salbutamol): dilate arterioles in skeletal M and coronary arteries reducing BP and PVR
Describe cardiac Symp innervation
B agonist (isoprenaline): increases rate of cardiac pacemakers, force of contractions, AV node conduction velocity B2 minimal compared to B1
Describe GI Symp innervation
a and B receptors located on intestinal SM and on neurons of ENS Antagonise Para input: Increase stomach, intestine motility and tone (a2,B2) Sphincter contraction (a1) Intestinal secretion (a2 - inhibits salt and water secretion)
Describe the metabolic and hormonal effects of Symp innervation
Kidney: renin release (B1) - Na+ and water homeostasis (indirect BP)
Pancreatic B cells: inhibit insulin release (a2), stimulate insulin release (B2), glycogenolysis in liver and skeletal M (B2)
Adipose: lipolysis (B3) increase lactate from lipid metabolism
Name some general Symp agonists
Direct: Adr, ephedrine
Releases: tyramine, amphetamine
Metabolism inhibitors: selegiline, moclobemide
Uptake inhibitors: cocaine, tricyclic antidepressants
Name some selective Symp agonists NAPCIDSS
NAdr a Adr a Phenylephrine a1 Clonidine a2 Isoprenaline Dobutamine Salbutamol Salmeterol
Describe the effect of tyramine when taking MAO-Is
Tyramine can displace stores monoamines from vesicles especially Adr, NAdr
MAO-Is prevent metabolism of CAs leading to tachycardia, vasoconstriction thus hypertension
Name some Symp antagonists PPPDYPABL
Prazosin, doxazosin - a1
Yohimbine - a2 (limits Symp effects to vasodilator B2, dec PVR, low BO)
Propranolol - B
Atenolol - B1
Buxatamine - B2 (used after heart attack as reduce demand on heart, limit HR and cardiac output)
Describe motor division of the NMJ
Controls body movement: appendages, locomotion (whole body)
Single neuron: CNS origin, myelinated
Terminus: branched (coordinated contraction at same time), NMJ
What is NM transmission dependent on?
ACh, AChRs, nicotinic receptors, LGNa+C
Describe the structure of skeletal muscle
Fasiciles (bundles of cells) of muscle fibre made up of myofibrils surrounded by sarcolemma and nucleus
Whole myofibril in communication
What are T-tubules?
Invaginations in the sarcolemma, run perpendicular to length of myofibril
Describe transmission of AP along muscle fibre
AP passes along T-tubule activating VGCa2+C in SR, Ca2+ entry causes actin/myosin contraction, shortening of myofibril
What do T-tubules allow for?
Rapid transmission of the AP across whole myofibril
Explain what miniature end plate potentials are
Small changes in potential caused by spontaneous exocytosis of ACh containing vesicles
Describe how an end plate potential is formed
AP activates VGCa2+C in nerve terminals, Ca2+ influx induces release of ~50 synaptic vesicles producing EPP that initiates AP in muscle fibre
Name drugs that can inhibit NMJ transmission by limiting ACh release
Hemicholinium: competes with choline reuptake transporter
Botulinum: prevents fusion of vesicles to presynaptic membrane
Streptomycin antibiotics: Ca2+ channel blocker
a-latrotoxin: promotes exocytosis resulting in block due to depletion
Describe some of the functions of botulinum
Treat muscle spasticity, excesssive sweating, neuropathic pain, cosmetic treatment
Describe how botulinum functions
Toxin endocytosed by nerve cell, splits into heavy and light chains (toxic enzyme)
Light chain cleaves SNARE proteins (synaptobrevin, syntaxin, SNAP25) thus ACh not released - APs don’t do anything
Causes flaccid paralysis (floppy)
What are neuromuscular blockers and what are the 2 types?
Drugs which relax skeletal M by acting at NMJ
- Non-depolarising: prevent ACh reaching nicotinic NMR, preventing depolarisation of the motor end plate (tubocurarine)
- Depolarising: excessive depolarisation of motor end plate by over stimulating nicotinic NMR (succinylcholine)
Describe non-depolarising blockers
Not preceded by stimulant
Blocking summates with drugs of similar action
Tetanic (contraction) stimulation not maintained
Hypothermia reduces magnitude
Affects all skeletal M, flaccid paralysis
Reversible with AChEI treatment (neostigmine)
What are some of the side effects of non-depolarising blockers?
Tubocurarine: histamine released, ganglion blocker, Symp blocker
Others more specifically active at NMJ, fewer side effect
Main toxicity is inhibitor of ventilator muscle function
Describe depolarising blockers
Long-lasting nicotinic receptor agonists causing persistent depolarisation
Block preceded by muscle fasciculation (spastic paralysis)
Tetanus does not wane
Block enhanced by AChI
Hypothermia potentiates block
Requires plasma AChE to terminate
Describe the mechanism of depolarising blockers
Phase 1: suxamethonium binds to N2 receptor, Na+ enters causing motor end plate depolarisation, muscle contraction
Suxamethonium not metabolised at synapse so depolarisation persists, membrane remains unresponsive to subsequent impulses
Phase 2: exposure leads to receptor desensitisation and membrane repolarisation, new impulses no longer activated
Describe the side effect of depolarising blockers
Muscarinic stimulation: bradycardia, increased salivation, gastric secretions
Excessive K+ release: hyperkalaemia (no longer set RMP)
Increased intra-ocular pressure
Prolonged paralysis
What are some of the clinical uses for NMJ blockers?
Skeletal muscle relaxation during GA: reduces GA conc, paralyses ventilatory muscles and diaphragm for artificial ventilation
Convulsions: control spasms due to bacterial infection and electroconvulsive therapy (depression)
Orthopaedics: relaxation while manipulating fractured or dislocated bones
What is myasthenia gravis?
Autoimmune disease characterised by muscle weakness due to decreased NM signal transduction
How does myasthenia gravis come about?
Antibodies bind to postsynaptic nicotinic receptor at NMJ, trigger immune system to destroy AChRs thus inhibiting ability to bind ACh and undergo conformational changes for ion transport
How can myasthenia gravis be treated?
AChEIs relieve system by blocking AChE metabolism thus potentiate ACh
Physostigmine, pyridostigmine
Act as competitive antagonist to autoantibodies
What is a type 1 antibacterial?
Agents that prevent cell wall synthesis
How do T1 antibacterials work?
Target peptidoglycan in bacterial cell wall
B-lactams & glycopeptides relevant to dentistry
Describe B-lactams
Antibiotics that contain a B-lactam ring e.g. penicillin and cephalosporins
How do B-lactams function?
Bind to penicillin binding protein enzyme
Inhibit X-linking of CW
CW precursor subunits accumulate
Cell lysis
How can resistance to B-lactams arise and how can this be overcome?
B-lactamases which break B-lactam ring
Overcome by B-lactamase inhibitors e.g. clavulanic acid
What are the 5 types of penicillins and give an example of each
- Benzylpenicillin and long-lasting parenteral forms
- Orally absorbed - phenoxymethylpenicillin
- Staphylococcal B-lactamase resistance - flucloxacillin
- Extended spectrum - amoxycillin
- Pseudomonas aeruginosa active - azlocillin
How do glycopeptides function?
Bind terminal acyl-D-alanyl-D-alanine residues
Prevent incorporation of subunits into growing peptidoglycan
What are vancomycin and teicoplanin? Describe their function
Glycopeptides active in gram +ve bacteria, must be injected
Widely used to treat MSRA
What are T2 antibacterials?
Inhibitors of protein synthesis
What are the 5 types of T2 antibacterials?
- Aminoglycosides - streptomycin
- Tetracyclines - oxytetracycline (periodontitis)
- Macrolides - erythromycin
- Lincosamides - clindamycin
- Mupirocin, fusidic acid
What are T3 antibacterials?
Inhibitors of nucleic acid synthesis
How do T3 antibacterials function?
Disrupt DNA-associated enzymic processes
What are the 4 types of T3 antibacterials?
- Inhib of precursor synthesis - trimethoprim
- Inhib DNA replication - quinolones (nalidixic acid)
- Inhib RNA polymerase - rifamycins (rifampicin)
- DNA stand breakage - 5-nitroimidazoles (metronidazole)
Why are 5-nitroimidazoles used by dentists?
Good activity against anaerobic bacteria
What are antifungal agents?
Antibiotics that act in synthesis/function of fungal CM
How do polyenes work?
Bind sterols in fungal CM
Interfere with membrane integrity
Essential metabolites leak
What are polyenes used in?
Topical preparations incl. mouthwashes, lozenges to treat oral candidosis
Give examples of polyenes
Nystatin
Amphotercin B
How do azoles function?
Disrupts synthesis of ergosterol
Disrupts fungal membrane function
Name azoles and what they would be used to treat
Fluconazole, itraconazole, micronazole
Topical candida infections
Why is it difficult to develop antivirals with selective toxicity?
Replicate within host cell so have similar metabolisms
Long incubation periods and latent infections
What is aciclovir and how does it work?
Antiviral
Viral thymidine kinase phosphorylates aciclovir traps virus within infected cell (inhibits viral DNA synthesis)
What are the 2 ways a organism can be resistant to antimicrobial?
Innate resistance - lack susceptible target/impermeable to drug
Develop/acquire resistance e.g. MRSA
What are the 3 mechanisms of resistance?
- Altered target: lowered affinity for drug OR new target produced
- Altered uptake: altered entry OR actively pumped out (efflux system)
- Drug inactivation: enzymes that inactivate drug (B-lactamases)
What are the 2 different killing patterns?
- Conc. dependent: high conc. = greater rate and extent of killing
- Time-dependent: dependent on duration of exposure
Give an example of both the different killing patterns
Conc. dependent: amphotericin
Time: B-lactams
What is hypertension?
Blood pressure consistently over 140/90 mmHg taken in multiple readings
What are the 8 consequences of hypertension?
- Occlusive stroke
- Haemorrhage stroke
- Angina
- Cardiac infarct
- Kidney disease/failure
- Sexual dysfunction
- Hypertensive retinopathy: blindness
- Heart failure
What are the 3 consequences hypertension can have on the heart?
- L ventricle hypertrophy
- Cardiac infarction
- Coronary artery disease and atherosclerosis
What are the 3 major target sites for pharmacological treatment of hypertension?
- Renal system
- Vascular SM
- SNS
What are the 4 aims of hypertensive medication?
- Suppress renin/angiotensin production
- Suppress HR and/or vasoconstriction
- Inc. vasodilation
- Inc. diuresis
What is angiotensin 2?
Direct vasoconstrictor acting through AT1 receptors on vascular SM
How does angiotensin 2 work?
Causes release of ADH (vasopressin) from ant. pituitary which acts on hypothalamus to inc. desire for water and salt
Inc. aldosterone release
What does aldosterone do?
Promotes Na channel and Na/K transporter expression in distal tubule and collecting duct through mineralocorticoid receptor actions
What is the consequence of inc. aldosterone release?
Enhance Na re-uptake, inc. K excretion
Water follows Na, inc. fluid vol. putting more stress on heart
What 2 types of drug are currently used to target vascular SM in hypertension?
- Angiotensin converting enzyme (ACE) inhibitors: captopril, enalapril
- AT1 antagonists: losartan
How do diuretics work in combatting hypertension?
Red. blood vol. and depleting Na
What are the 2 types of diuretics commonly used to treat hypertension?
- Thiazides
2. K-sparing diuretics:
How do thiazide drugs work and give a named example
Inhibit Na, Cl reabsorption in distal tubule
Inc. Na in collecting duct causes inc. Na/K antiporter activity
Hydrochlorothiazide
Give an example of K-sparing diuretics and explain how they work
Spinolactone
Inhibits aldosterone effect on Na reabsorption and K excretion in distal tubule
For hypertensive drugs that target the heart what is the primary approach?
Block beta 1 adrenoreceptors in heart to cause bradycardia
What are some typical hypertensive drugs that target the heart?
ATENOLOL, oxordnolol, pindolol, acebitolol, celliprolol
What is the aim of Ca channel blocking hypertensive drugs?
Inhibit influx of extracellular Ca into cardiac and smooth muscle preventing contraction
Target L-type channels: coronary and peripheral vasodilation
Why is there a limited effect on skeletal muscle by Ca channel blockers?
Large excess of L-type Ca channels in skeletal muscle
What are the 2 types of Ca blockers used in hypertension treatment?
- Dihydropyridines
2. Non-dihyropyridines
Give examples of dihydropyridines and explain how they work
Nifedipine, amlodipine
Favour vasculature over heart
As potent vasodilator cause reflex tachycardia
What are nifedipine and amlodipine not effect at treating and why?
Supraventricular tachyarrhythmias
Has no effect on AV conduction
Name non-dihydropyridines, how they work and possible side effects
Verpamil, diltiazem
Dec. HR by slowing AV node conduction thus may treat supraventricular tachyarrhythmias
Adverse effects: bradycardia, AV block
Where do ventrally acting hypertension drugs that work on the SNS target?
Medullary cardiovascular regulatory centres
Describe how clonidine and alpha-methyldopa drugs work in combatting hypertension
Selective alpha 2 agonists
Alpha 2 receptors in medulla red. SNS outflow
Centrally mediated vasodilation and red. HR
What is moxonidine and how it works?
Imidazoline subtype 1 receptor (I1R) agonist
I1R in depressor area of medulla, causes dec. SNS outflow thus dec. BP
What are the 3 types of hypertensive drugs that are peripheral nerve modulators?
- Ganglionic transmission
- False NTs
- Non-selective alpha adrenoceptors antagonists
What is trimethaphan and how does it work?
Short-acting N1 antagonist
Prevents SNS stimulation in vasculature causing vasodilation
Net tachycardia but dec. BP dictated by dec. vasculature resistance
What is guanethidine and how does it work?
False NT drugs
Displaces NA from vesicles thus reducing effect of SNS stimulation
Why is guanethidine used?
Acute hypertensive crisis, is rarely long term
What are phenoxybenzamine and phentolamine
Non-selective alpha-adrenceptor antagonists used in treatment of hypertensive crisis due to monoamide oxidase inhibitors and pheochromocytoma
Why are phenoxybenzamine and phentolamine not used in regular hypertension treatment?
Can cause postural hypotension and tachycardia
What 2 drugs may be used in hypertensive crisis and what type of drug are they?
- Hydralazine: liberate NO
- Sodium nitroprusside: stim. guanylate cyclase
Direct vasodilators
What is anxiety?
Unpleasant state of emotional turmoil often associated by nervous behaviours
Differentiate between fear and anxiety
Fear: response to real or perceived immediate threat
Anxiety: response to expectation of future threat w/ or w/o justification
What are the 4 subtypes of anxiety?
- Existential: angst, nihilism
- Social: meeting new people
- Mathematical: stage, test, stranger
- Somatic: physical
What is an anxiety disorder?
Group of medical conditions characterised by excessive or prolonged anxiety
Describe the causes and diagnosis of anxiety disorders
Causes: complex, genetic and environmental bases
Diagnosis: symptoms present for 6mns longer than if just anxiety and impaired functioning
What are 7 examples of anxiety disorders? Highlight main 2
- Generalised anxiety disorder - main
- Specific phobias: main
- Social
- Separation
- Agoraphobia
- Panic disorder
- Selective mutism
What are the 5 autonomic physical symptoms of anxiety?
Due to excessive SNS
- Agitation
- Tachycardia
- Inc. sweating, tear production
- GI disorders
- Restlessness
What are the 5 medical conditions that are associated with or can be aggregated by anxiety?
- CV: angina, hypertension, arrhythmias
- GI: IBS, peptic ulcers
- Respiratory: asthma
- Endocrine: anaemia, hypoglycaemia
- Neurological: migraine, tremor, seizures
What is a specific phobia?
Unreasonable or irrational fear of specific object/concept
Person will avoid contact object or even mention of it
What are the 5 categories of phobias?
- Animals: dogs, spiders
- Natural environment: water, heights
- Situational: small spaces
- Blood/injury/injection: needles
- Other: loud noises, costumed characters
What is the treatment for phobias?
Cognitive behavioural therapies
Anxiolytics generally unhelpful
What is generalised anxiety disorder?
Uncontrollable, irrational, excessive worry about daily activities/events
What are 3 causes of generalised anxiety disorder?
- Genetic
- Anti-anxiety drugs, caffeine intake, tobacco smoking
- Dysfunctional amygdala connectivity: encoding for inappropriate threat level to innocuous sensory info
What treatments exist for generalised anxiety disorder?
- Cognitive behavioural therapy
2. Anxiolytics
What is insomnia and its relation to anxiety?
Inability to sleep
Associated with many anxieties, can potentiate each other
What are 4 common causes of insomnia?
- Age: body clock shifts
- Personal tragedy/grief: bereavement
- Disease: alcoholism, dementia, anxiety
- Modern society: jet lag, shift work
What is the treatment for insomnia and the associated risks?
Hypnotics
- Dependency/addiction
- Dementia
- Injuries
Describe cognitive behavioural therapy
Empirically-derived psychological intervention
Helps patient develop coping strategies to change unhelpful thoughts and behaviours
As effective as medication for less severe depression, PTSD, anxiety, eating disorders
Used w/ medication for severe OCD, depression, opioid addiction, bipolar disorder
First line intervention for childhood mental illness and eating disorder
What are the 5 major classes of anxiolytics?
- Barbiturates
- Benzodiazepines
- Tricyclic antidepressants
- Beta adrenoceptor antagonists
- Buspirone
How do barbiturates work and what is the consequence of this?
Potentiate GABA signalling in brain i.e. suppress brain activity meaning v narrow therapeutic window: easy to OD which can cause coma and death due to suppression of medullary respiratory centres
What do barbiturates induce?
Liver cytochrome P450 enzymes: major source of drug interactions
What are the 6 withdrawal symptoms of barbiturates?
- Vomiting
- Seizures
- Agitation
- Nausea
- Tremors
- Anxiety
What are the 4 uses for barbiturates now?
- Hypnotics for intractable insomnia: amobarbital
- Anaesthesia: thiopental
- Small animal euthanasia: pentobarbital
- Human death penalty: thiopental, pentobarbital
What are the 5 general effects of benzodiazepines?
- Anxiolytic
- Amnesiac
- Sedative
- Muscle relaxant
- Anticonvulsant
How do BZDs function?
Bind selectively to GABA-A receptors act as +ve modulators:
inc. Cl- conductance caused by GABA, hyperpolarising cell making AP less likely
How are the 5 BZDs effects each mediated?
- Anxiolytic: promote alpha-2 GABA-A transmission, inhibit limbic system
- Sedative: greater dose, alpha-1 GABA-A
- Amnesiac: alpha-1 GABA-A
- Anticonvulsant: alpha-1 GABA-A
- Muscle relaxant: spinal cord alpha-2 GABA-A, large dose
Describe the BDZs used for anxiety
Diazepam, clonazepam (sustained)
Used for GAD
Not widely used due to addictive properties and withdrawal syndrome
Don’t develop tolerance
What BDZ is used for muscle disorders with spasm?
Diazepam
Effective in spasticity caused by spinal cord degeneration e.g. motor neuron disease
What BDZs are used as sedatives?
Temazepam, diazepam
Dec. sleep latency, inc. sleep depth
Tolerance rapidly develops and withdrawal symptom of insomnia
Describe the use of benzodiazepines as used as amnesiacs
Lorazepam, temazepam
Used prior to unpleasant/invasive treatment: endoscopy, some dental, ECT
Sedative: makes treatment easier for patient and clinician
What 3 benzodiazepines are used as anticonvulsants? Compare and state what they are used to treat
Epilepsy
- Clonazepam: more potent anticonvulsant
- Diazepam: fastest onset
- Lorazepam: greatest duration
Why are benzodiazepines not suitable for long term treatment?
Additive and develop tolerance
What are the 4 general side effects of benzodiazepines?
- Over-sedation, mental confusion, ataxia, poor memory
- Additive effects with other CNS depressants
- Withdrawal syndrome
- Addiction and tolerance
What is flumazenil?
Benzodiazepine antagonist
How does flumazenil work?
Binds to BDZ binding site preventing BDZ binding preventing action
What is the clinical use for flumazenil?
Treat BDZ overdose and dependence
What is the consequence of taking flumazenil?
May precipitate side effects: confusion, toxic psychosis, convulsions
What is buspirone?
Anxiolytic that acts solely on CNS 5-HT pathways
Agonist to 5-HT1-A autoreceptors, red. serotonergic cell firing
Compare buspirone to benzodiazepines
Buspirone as potent anxiolytic as BDZs w/o causing sedation
What is a side effect of buspirone?
May cause psychological dependence
Name a beta adrenoceptor antagonist and how it can function as an anxiolytic
Propranolol
As many symptoms of anxiety caused by excessive SNS tone beta receptor blockers prevent many effects
Explain how antidepressants are able to function as anxiolytics
Many have sedative/hypnotic properties
What is heart failure?
State in which heart can’t provide sufficient CO to satisfy metabolic needs of body
What are the 9 symptoms of congestive heart failure?
- Shortness of breath upon motion
- Coughing
- Fluid retention
- Oedema in lower limbs and abdomen
- Inc. nocturnal urination
- Tiredness
- Muscle weakness
- Dizziness
- Irregular HB
Define myocardial infarction, coronary heart disease, cardiac arrest
MI: death of piece of heart tissue
Coronary heart disease: failure of heart oxygen supply
Cardiac arrest: complete cessation of blood supply
What diseases does HF have similar symptoms to?
Liver or kidney failure
Obesity
Anaemia
What can trigger HF and what will this ultimately lead to?
MI or coronary heart disease
Will lead to cardiac arrest
What are the 6 conditions that affect myocardial efficiency that can cause HF?
- MI
- Valve disease
- Inc. alcohol intake
- Hypertension
- Infection
- Amyloidosis: abnormal deposition of amyloid proteins in tissues
What 4 problems can cause HF?
- Red. stroke vol: failure of systole, diastole or both
- Red. spare capacity
- Inc. HR due to inc. SNS activity
- Hypertrophy: anabolic steroids or EPO
What is the Frank-Starling law of the heart?
Inc. of blood filling heart (end diastolic vol) stretches the walls of heart inc. force of contraction and quantity of blood pumped during systole
CO = HR x stroke vol
What are the 4 physiological responses to HF and red. CO?
- Fall in arterial BP: activates baroreceptors, cause peripheral vasoconstriction restores BP and inc. heart workload
- Inc. pituitary ADH release: inc. fluid retention, inc. BP
- Red. kidney perfusion: stimulates RAAS system, Na and H2O retention, vasoconstriction
- Hormones induce structural remodelling: cardiac hypertrophy
What are the 3 aims of HF treatment?
- Inc. contractility
- Red. preload/afterload
- Red. water load (blood vol)
What drugs inc. cardiac contractility?
Cardiac glycosides: digoxin, digitoxin
How do cardiac glycosides work?
Bind to K+ site of Na/K antiporter preventing Na efflux raising intracellular Na
Prevents efflux of Ca from Na/Ca antiporter inc. intracellular Ca which inc. contractile strength w/o inc. O2 demand
What is the main problem associated w/ cardiac glycosides?
Improve symptoms but don’t prevent mortality
What are the 3 side effects of digoxin?
- Inc. AV conduction time: inc. vagal tone
- Inc. incidence of ectopic pacemaker activity: inc. automaticity
- Inc. diuresis
What are some of the toxic affects of digoxin?
Nausea Vomiting Delirium Vision disturbance Diarrhoea Abdominal pain Headache Dizziness Confusion
Who is most at risk of digoxin toxicity and how are toxic effects managed?
Patients w/ hypokalaemia
Managed w/ anti-digoxin antibodies
What are the 3 types of diuretics?
- Thiazides
- Loop
- K-sparing
Describe thiazides
Hydrochlorothiazide
Acts on early DCT: inc. Na and K excretion, prevents Na reabsorption
Describe loop diuretics
Frusemide
Act on ascending limb of loop of Henle, inc. Na and K excretion
Describe K-sparing diuretics
Spironolacetone
act of DCT to inc. Na excretion
Important when using cardiac glycosides
What are the 2 methods used to red. preload and afterload?
- Direct vasodilators
2. Modulate renin/angiotensin/aldosterone system
Name ACEIs and angiotensin II receptor antagonists and how they function
ACEIs: enalapril, captopril
Angiotensin II R antagonists: losartan, candesartan
Both dec. afterload by antagonising vasopressor effect of angiotensin, dec. cardiac work
What is the additional benefit of blocking angiotensin?
Angiotensin may directly cause cardiac hypertrophy thus blocking activity slow cardiac deterioration
What are the 2 drug types used as direct vasodilators in treatment of HF?
- Organic nitrates: isosorbide dinitrate
2. Arterial vasodilators: hydralazine, minoxidil
How do organic nitrate drugs work?
Intracellular NO activates guanylate cyclase inc. cGMP
Causes inc. Ca2+ sequestration and SM relaxation
Venodilator: red. preload
What problems are associated w/ organic nitrates?
Headaches
Tolerance
Flushing
Tachycardia
How do hydralazine and minoxidil work in treatment of HF?
Are arterial vasodilators, dec. afterload
Hydralazine: unclear
Minoxidil: K channel opener
What treatment is used for HF in African and Caribbean patients?
Isosorbide-hydralazine combination therapy
Patients respond less to ACEIs
What is epilepsy and what is it characterised by?
Wide range of paroxysmal brain disorders caused by many neurological and metabolic conditions
Characterised by failure of inhibitory synapses between neurons and large groups of neurons being activated repetitively and hyper-synchronously
Describe the genetic cause of epilepsy
More common in children and young
~200 genes have been identified but only 1-2% cases is caused by single gene
Appear to effect ion channel function of GABA receptor activity
What are the 4 acquired causes of epilepsy?
More common in older people
- Trauma
- Stroke
- Tumours
- Infection-induced
What are the 2 types of seizures?
- Partial
2. Generalised
What are the 2 types of partial seizures?
Simple: no loss of consciousness
Complex: loss of consciousness to some degree, not necessarily full loss
Describe partial seizures
Discharge is confided to only 1 part of brain
Motor cortex: Jacksonian
Temporal (mood): psychomotor
Often precursor to generalised seizures termed aura, effect dependent on part of brain effected
What are the 5 types of generalised seizures?
- Absence
- Myoclonic
- Clonic
- Tonic-clonic
- Atonic
Describe the 5 generalised seizures
- Absence: loss of consciousness, vacancy, unresponsive
- Myoclonic: extremely brief muscle contraction, jerky movements
- Clonic: repeated myoclonic seizures
- Tonic-clonic: initial muscle contraction followed by rhythmic muscle contraction
- Atonic: loss of muscle tone, cause collapse
What is status epilepticus?
Rapid chain of seizures
Medical emergency
What is grand mal epilepsy?
Another name for tonic-clonic seizure
Classic epileptic fit
What is petit mal epilepsy?
Absence and atonic seizures
What is the rationale behind epilepsy treatment methods?
Limit neuronal over activity by suppressing excessive synaptic activity OR by enhancing inhibitory NT function
What are the 3 types of drug that are used in epilepsy treatment?
- VGNaC inhibitors
- GABA enhancers
- VGCaC modifiers
What 2 drugs are used as Na channel modifiers in treatment of epilepsy?
- Phenytoin
2. Carbamazepine
Describe the action of phenytoin
Prolongs Na channel inactivation, regulating membrane excitability
Use dependent blockade: effectiveness inc. w/ higher rate discharges i.e. effective in epilepsy and not other disorders
Used to treat all forms except petit mal
Describe the pharmacokinetics of phenytoin
- Orally well absorbed
- Eliminated by hepatic metabolism
- Promotes hepatic enzyme expression
What are the 3 adverse effects of phenytoin?
- Megaloblastic anaemia (large RBCs): treated w/ folic acid
- Hirsutism: abnormal hair growth due to androgen
- Gingival hyperplasia
Describe carbamazepine
Prolongs Na channel inactivation
1st choice in treatment of grand male and psychomotor partial seizures but may worsen petit mal seizures
Hepatic enzyme inducer:
Red. effectiveness of phenytoin, oral contraceptives, warfarin
Own metabolism inhibited by antibiotics (erythromycin)
What are the 3 acute and 5 chronic adverse effects of carbamazepine?
Acute
- Respiratory depression
- Coma
- Convulsion
Chronic
- Vertigo
- Vomiting
- Hyperatraemia
- Ataxia
- Hypersensitivity
Describe phenobarbitone
Prolongs GABA-A opening inc. Cl- inward current hyperpolarising post-synaptic membrane
Net effect red. glutamate excitation
Effective against all seizures but absence
Describe the pharmacokinetics of phenobarbitone
- Orally bioavailable
2. Potent hepatic enzyme inducer
What are the 4 adverse effects of phenobarbitone and effect of OD?
- Megaloblastic anaemia
- Sedation
- Osteomalacia: softening of bone, give VitD
- Hyperactivity in children
OD: respiratory and circulatory failure
Describe benzodiazepine use in treatment of epilepsy
Diazepam/lorazepam
Augment inhibitory actions of GABA @ GABA-A receptors
Inc. Cl- channel opening, red. AP likelihood
Used in treatment of status epilepticus: IV rapid but sedative, aid muscle relaxation
Lorazepam used for all seizures
Withdrawal symptoms include seizures
Describe tiagabine
Selective GABA re-uptake inhibitor acting pre-synaptically and on glia
Blocks GAT-1 transporter: important in release of Ca from ER
Re-uptake block prolongs GABA actions post-synaptically
Used only for partial seizures, may induce status epilepticus
Describe the pharmacokinetics of tiagabine
Good oral absorption
Highly protein bound
Few drug interactions
What are the 4 adverse effects of tiagabine?
- Ataxia
- Dizziness
- Tremor
- Depression
What 3 drugs are used as GABA modifiers in treatment of epilepsy?
- Phenobarbitone
- Diazepam/lorazepam
- Tiagabine
What 2 drugs are used to treat grand and petit mal seizures?
- Valpronic acid
2. Ethosuximide
Describe valpronic acid
Multi-action anti-epileptic used to treat grand and petit mal seizures
Inhibits GABA transaminase (breakdown GABA in cell, dec. conc. gradient thus less diffusion) GABA remains in synaptic cleft
May inc. rate GABA synthesis
Use-dependently inhibit VGNaC activity
What are the 2 acute and 4 chronic adverse effects of valpronic acid?
Acute
- Nausea
- Vomiting
Chronic
- Wight gain
- Hair loss
- Tremor
- Thrombocytopenia: platelet deficiency
What is the adverse effect of valpronic acid important for pregnant women?
Significant teratogenicity in 1st trimester
Caused malformation of embryo and possibly induce abortion
Describe ethosuximide
Used in treatment of petit mal
Inhibits neuronal T-type VGCaC, dec. Ca influx
Currents important in bursting behaviour of thalamic neurons: common site for initiation of epileptiform waves
What are the 5 adverse effects of ethosuximide?
- Ataxia
- Aggression
- Drowsiness
- Euphoria
- Anxiety
What is schizophrenia?
Most complex disorder of thought and emotion resulting in difficulty distinguishing between real and false perceptions
Generally describe symptoms of schizophrenia. What are the 3 types of symptoms?
Often heterogenous and liable to change
- Positive: delusions and hallucinations (auditory), bizarre behaviour
- Negative: social withdrawal, avoilition, poverty of speech
- Cognitive: poor conc., disorientation, difficulties in abstract thought and memory
What is the single greatest risk factor of schizophrenia?
Having an affected first degree relative
What are the 4 other risk factors of schizophrenia?
- Male: 40% more likely, symptoms earlier; incidence peaks @ 21,40 whereas females 22, 37, 60
- Living in urban environment when young: 2x risk
- Birth season: late winter/early spring; low VitD, infection
- Poor nutrition during 2nd trimester
Describe the brain abnormalities seen in schizophrenics
Smaller vol.: hippocampus, amygdala, thalamus, nucleus accumbens, intracranial space
Hippocampus changes reversed by antipsychotics
Larger: pallidum and ventricular vols
Pallidum correlates w/ duration of illness
What are the 4 pieces of evidence that corroborate the dopamine theory of schizophrenia?
- All antipsychotics are DA receptor antagonists
- Almost perfect correlation between therapeutic dose of typical antipsychotic and D2 receptor affinity
- Cis-flupenthixol is neuroleptic, has DA antagonist properties: trans-flupenthixol not neuroleptic has no DA antagonist properties
- Amphetamine and cocaine inc. DA release and cause schizophrenic like syndrome
What is the relation between glutamate and schizophrenia?
Schizophrenic brains have significantly red. glutamate receptor expression
Glutamate blockers (phencyclidine, ketamine) mimic schizophrenic symptoms and cognitive problems
Lower glutamate activity linked to poor performance in tests utilising frontal lobe and hippocampus
Glutamate can modulate DA activity
What evidence discredits glutamate link to schizophrenia?
Glutamate agonists have been unsuccessful thus far
Describe the link between inflammation and schizophrenia
Recent studies show microglia active in schizophrenic brains prior to medication
Inc. inflammation, inc. risk
Describe neuroleptics
Treat major psychoses: schizophrenia and bipolar disorder
Effective for short term, less so w/ longer use
More effective on +ve symptoms, less evidence for -ve, cognitive symptoms
1st line treatment, effective within 8-15 days
What are the 2 general classes of neuroleptics?
- First gen/typical antipsychotics: DA antagonists
2. 2nd gen/atypical antipsychotics: DA and serotonin antagonists
What are 2 1st gen antipsychotics?
- Chlorpromazine
2. Haloperidol
Describe chlorpromazine
Highly successful
D2R antagonist, also blocks to D1,3and5: most antipsychotic effects
Weaker antagonist for 5-HT1 and 2, H1, alpha 1and2, M1and2: some antipsychotic effects, most adverse effects
What are the 6 adverse effects of chlorpromazine?
- Extrapyramidal motor effects
- Breast swelling or discharge
- Anti-muscarinic: drowsiness, dizziness, dry mouth, constipation, blurred vision
- Weight gain
- Anxiety
- Impotence
Describe haloperidol
Most commonly used
Prescribed for schizophrenia, bipolar, acute psychoses, Tourette’s
Binds preferentially to D2 and a1 at low doses and 5-HT1 at higher doses
Orally active or can be given has long-lasting depot injection
Greater effect on +ve symptoms
What are the 6 adverse effects of haloperidol?
- Extrapyramidal motor effects
- Anxiety
- Impotence
- Breast swelling or discharge
- Hypotension
- Toxic to developing embryos
What neuroleptic is an atypical antipsychotics?
Clozapine
Describe clozapine
Used when other treatment has been unsuccessful
D2 antagonist, high affinity for D4
Induces glutamate release
Partial antagonist of 5-HT2A, more effective on -ve symptoms
What are the 9 adverse effects of clozapine?
- Extrapyramidal motor effects
- Anxiety
- Impotence
- Breast swelling or discharge
- Agranulocytosis
- Weight gain
- Cardiac inflammation
- Seizures
- Hypersalivation
What are the 5 extrapyramidal motor effects?
- Bradykinesia: slowness of movement
- Tardive dyskinesia: involuntary, repetitive writhing movements of face and limbs
- Dystonia: continuous spasms and muscle contraction
- Akathisia: motor restlessness
- Tremor
Describe tardive dyskinesia
Involuntary, repetitive writhing movements of face and limbs
Thought to be caused by DA hypersensitivity in nigrostriatal pathway and resulting change in basal ganglia function
Slow onset, often take several weeks
What are the 3 risk factors of tardive dyskinesia?
- Female
- African/Afro-Caribbean
- -ve schizophrenia symptoms
What is the treatment for tardive dyskinesia?
No specific treatment
benzodiazepines effective but use limited due to developmental tolerance
What are affective disorders?
Mental disorders characterised by changes in mood rather than thought including depression and mania
What are the 6 depressive symptoms?
- Feeling misery, apathy, pessimism
- Low self-esteem: guilt, ugliness, inadequacy
- Lack of motivation, indecisiveness
- Insomnia
- Slow thoughts and actions
- Loss of appetite
What are the 4 symptoms of mania?
- Delusions of grandeur
- Excessive exuberance, over-confidence
- Irritability, anger, impatience
- Excessive physical activity
What are the 2 types of depression?
- Dysthymia: mild
2. Major (MDD): severe
What genetic factors are believed to play a role in depression?
Familial component
Genes regulating 5-HT regulation
What social factors play a role in depression?
- Bereavement
- Financial strain
- Sexual, physical, emotional abuse
- Childhood abuse/trauma
- Social exclusion
What medical factors can play a role in depression?
- Alcohol/illegal drug use
- Chronic/serious ill health
- Medicinal drugs: antihypertensives
What are the 3 key pieces of evidence that support the monoamine theory of depression?
- Treatment w/ NA packaging blocker reserpine for hypertension caused depression
- TB treatment w/ MAOI iproniazid improved symptoms
- Most antidepressants potentiate monoamine (NA, 5-HT, DA, AD) signalling
What are the 3 flaws in the monoamine theory?
- Treatment w/ monoamine interacting drugs have immediate neurochemical effect but behavioural effect takes 3/4wks to appear - why is there delay?
- No evidence of monoamine signalling deficient
- Atypical antidepressants don’t target monoamine systems but still effective
Explain the hypothalamo-pituitary-adrenal axis
Long-term adaptation to stressors
Results in release of glucocorticoids that regulate many physiological parameters
Target limbic system, regulating mood and arousal
Normally -vely self regulate, lost in 70% MDD
Evidence of overactivity of HPA in MDD
Overexposure thought to damage serotonergic pathways in brain resulting in neuronal retraction
What are the 5 classes of antidepressants?
- Tricyclic antidepressants
- Serotonin Selective Re-uptake Inhibitors (SSRIs)
- Serotonin and NA RIs, NA Selective RIs
- Monoamine Oxidase Inhibitors (MAOIs)
- Atypical antidepressants
What 2 other therapies can be used in treatment of depression?
- Cognitive behavioural therapy: mild
2. Electroconvulsive therapy: severe
How do TCAs work? Name three
Inhibit uptake of 5-HT and NA prolonging synaptic lifetime
- Imipramine: NA»5-HT
- Amitriptyline: NA and 5-HT
- Desipramine: NA; active metabolite of imipramine
What are the 5 adverse effects of TCAs (amitriptyline)?
- Epileptogenic
- Antimuscarinic: dry mouth, blurred vision, constipation, urinary retention
- Alpha-adrenoceptor antagonist: postural hypotension
- H1 antagonist: sedation
- Cardiotoxic in OD: induction of atrial and ventricular arrhythmias
What are the drug interactions of TCAs?
Strongly potentiate sedative properties of alcohol
Reverses adrenergic antagonists
What are the 2 isoforms of monoamine oxidase?
MAO-A: serotonin, NA
MAO-B: serotonin, DA, NA
Inhibition of MAO-A associated w/ antidepressant effects
What are the 2 types of MAOIs? Give examples
- Nonreversible: phenelzine
- Reversible: moclobemide
Moclobemide has fewer side effects
What are the 4 adverse effects of MAOIs?
- Hypotension: DA accumulation in periphery; vasodilation
- Central: agitation, tremors, insomnia
- Antimuscarinic: less than TCAs
- Foetal abnormalities during pregnancy
Explain the ‘cheese reaction’
MAOIs can interact w/ tyramine in foods (blue cheese, smoked fish, cured meats)
Tyramine is indirectly acting sympathomimetic, inducing release of NA
MAOIs block breakdown of NA, preventing clearance
Potentially fatal during hypertensive crisis
How do MAOIs interact w/ pseudoephedrine and phenylephrine?
Sympathomimetics in cold cures
Block NA clearance: hypertension
Which MAOIs are hepatotoxic? What is the effect of this?
Irreversible MAOIs
Red. metabolism of drugs such as barbiturates, alcohol leading to prolonged, exaggerated effects
Describe the interaction between MAOIs and pethidine
Pethidine is opioid analgesic, metabolised by MAOs
Block can result in hyperthermia, hypotension, coma and respiratory depression
Name 4 SSRIs
- Fluoxetine
- Paroxetine
- Citalopram
- Fluvoxamine
How do SSRIs function?
Block re-uptake of 5-HT prolonging synaptic lifetime and effects
What forms of depression are SSRIs best suited for?
Less effective for short-term mild depression
Effective in chronic/severe depression
Describe the side effects of SSRIs
Lack sedative and antimuscarinic affects but more prone to epileptogenic effects
What is serotonin syndrome?
Acute toxic reaction caused by use of 2+ types of monoamine modulators
What are the 6 symptoms of serotonin syndrome?
- High body temp: >41
- Agitation
- Diarrhoea
- Dilated pupils
- Sweating
- Seizures
What is the treatment for serotonin syndrome?
Cessation of monoamine modulators
Administration of serotonin antagonists: cyproheptadine
What are 4 new an antidepressants?
- Venlafaxine: Serotonin and NA RI
- Nefazodone: Serotonin and NA RI
- Mirtazapine: NA and Selective Serotonin Antidepressant
- Reboxetine: Selective NA RI
How does venlafaxine work?
Potent block of NA and serotonin re-uptake
SNARI
How does nefazodone work?
Potent 5-HT2 receptor antagonists w/ weak SNARI activity
More sedative than venlafaxine, causes nausea
How does mirtazapine work?
Alpha-2, 5-HT 2 and 3 receptor antagonists (all autoreceptors)
Inc. both NA and serotonin transmission
NASSA
How does reboxetine work?
NARI
Antimuscarinic and pro-sympathetic side effects: dry mouth, constipation, urinary retention, tachycardia, insomnia
What is bipolar affective disorder?
Mental disorder characterised by fluctuating states of depression and mania
Describe structural and functional MRI imaging in bipolar affective disorder
Structural: inc. vol. pallidum and lat. ventricles
Functional: abnormal modulation of amygdala likely underlie emotional and mood regulation: inappropriate emotional labelling of sensations
How is lithium used in antidepressants?
Mood stabiliser
Used in treatment of bipolar manic phases
Can be used in resistant depression
Red. freq. and severity of relapses, red. likelihood suicide
What are the 5 acute and 4 severe toxic affects of lithium?
- Drowsiness
- Ataxia
- Nausea
- Blurred vision
- Coarse tremor
- Delirium
- Convulsion
- Coma
- Death
Explain the 2 mechanisms of lithium action
Glycogen synthase kinase 3-beta: modulates NT release; Li red. fluctuations in GSK3B activity, stabilising monoamine release
Inositol cascade: Li inhibits inositol recycling, limiting actions of GqPCRs, red. CNS glutamate, NA, DA, ACh, 5-HT, glycine signalling
Describe ECT
Induction of epileptic seizure by conduction of electric current through temporal region of brain
Causes short term retrograde amnesia and temporary anterograde
Highly effective for some patients and in drug-resistant bipolar and psychotic depression
What are the 3 brain areas involved coordination of movement?
Motor cortex
Basal ganglia
Cerebellum
Motor cortex branch to cerebellum via pons, cerebellum enhance motor cortex via thalamus
Basal ganglia inhibit motor cortex via thalamus
What are the functions of cerebellum?
Motor coordination
Regulates posture and movement
Influences muscle tone and eye movements
Regulates balance by integrating proprioception info from muscles and joints w/ movement intentions from motor cortex, making appropriate corrective adjustments
Plays role in motor learning
What are the 4 nuclei of the basal ganglia?
Striatum: caudate nucleus, putamen
Globus pallidus: int. (med.), ext. (lat.)
Subthalamic nucleus
Substantia nigra: pars reticulata, pars compacta
What are the 4 functions of the basal ganglia?
- Integrate desire and fine movement: stop and start movement
- Fine smooth motor behaviour
- Suppress unwanted movements
- Exerts inhibitory influence on motor functions, relief allows motor behaviours to occur
How is the basal ganglia modelled?
3 interacting pathways that regulate cortical activity through thalamus
- Direct
- Indirect
- Hyper-direct
How is the basal ganglia organised?
Topographically: specific sub parts of each nucleus regulate specific motor functions
Describe the direct pathway
Relieves inhibitory drive of internal globus pallidus upon thalamocortical pathways
Permits amplification of cortical signals, leading to motor activation
Motor cortex release glutamate activate striatum, release GABA act on globus pallidus internal, release GABA act on thalamus which releases glutamate to act back on motor cortex
Describe the indirect pathway
Inhibits thalamocortical pathways that target areas that would interfere w/ desired motor behaviour
Restricts movement to desired muscles only
Motor cortex release glutamate, act on striatum which releases GABA, acts on globus pallidus internal and external
External release GABA and act on subthalamic nucleus which releases glutamate act on internal globus pallidus
Internal release GABA act on thalamus which releases glutamate act on motor cortex
Describe the hyper-direct pathway
Rapid stimulation of subthalamic nucleus by motor cortex
Proposed to prevent premature movements
Glutamate from motor cortex act directly on subthalamic nucleus. Releases glutamate acts on internal globus pallidus, releases GABA act on thalamus which releases glutamate act on motor cortex
Describe DA regulation of the basal ganglia
Nigrostriatal dopaminergic pathway major regulator of BG function: prevents activity
Substantia nigra release DA which acts on striatum
Inhibits direct pathways through D1 receptors
Stimulates indirect pathways through D2 receptors
How do basal ganglia disorders manifest?
Involuntary movements: dyskinesias
What are hyperkinetic disorders? What are the 4 types?
Excessive involuntary movements
- Chorea: involuntary, rapid, freq., purposeless jerks of extremities, head, trunk w/ facial grimaces
- Athetosis: slow, writhing, worm-like motions of distal extremities
- Ballism: violet, flinging continuous movements of limbs
- Dystonia: twisting, slow, contorting movements
What are kypokinetic disorders? What are the 2 types?
Impairment in initiation of movement
- Akinesia: impairment of initiation, rigidity
- Bradykinesia: red. amplitude and velocity movements
What is Parkinson’s caused by and what are the 7 symptoms?
Degeneration of nigrostriatal DA neurons and consequent dysregulation of BG
- Resting tremor
- Dementia
- Micrographia
- Difficulties speech and swallowing
- Postural instability
- Bradykinesia
- Rigidity
What is the rationale and targets of Parkinson’s treatment?
Replace lost DA
Target: DA synthetic pathways, DA catabolism, DA receptors
What is levodopa?
Immediate precursor of DA
Converted to DA by endogenous L-DOPA decarboxylase
What 2 symptoms does L-DOPA red. in Parkinson’s?
- Bradykinesia
2. Rigidity
What are the 6 adverse effects of L-DOPA? Highlight the 2 main ones
- Involuntary writhing: dyskinesia
- On-off effects: effectiveness fluctuates
- Nausea and vomiting
- Hypotension
- Clouds thoughts
- Schizophrenia like syndrome
What is carbidopa? How does it help adverse effects when taken in combination w/ L-DOPA?
Peripheral DOPA decarboxylase inhibitor
Prevents nausea
What are the 2 methods of DA modulation in Parkinson treatment?
- MAO-B inhibitors: selegiline
2. DA agonists: bromocriptine
Describe the use of MAO-B inhibitors in PD treatment
MAO-B predominate in CNS
Improve motor function in early and advanced
Lack cheese reaction of MAO-A inhibitors
What are bromocriptine and apomorphine?
D 1 and 2 receptor agonists used in treatment of PD
Apomorphine stabilises patients during L-DOPA treatment
What is benzatropine?
Centrally acting M1 receptor antagonist
Anticholinergic
How can anticholinergic drugs be used in PD treatment?
Inhibitory nigrostriatal DA pathway regulated by striatonigral inhibitory pathway driven by cortical activity
Striatal ACh drives inhibitory GABA influence upon DA pathway activity
ACh suppression stimulates NSDA pathway
What is amantadine?
Anti-viral drug that is weak antagonist at glutamate NMDA receptors
Inc. DA release, block DA re-uptake, antimuscarinic effects
Weak PD therapy: red. rigidity, tremor
Used in combination w/ L-DOPA to improve on-off effects, limit dyskinesias
Sudden withdrawal causes dramatic worsening PD
May protect DA neurons from degeneration
What is an analgesic?
Drug that acts in the CNS to relieve pain w/o affecting other sensory perception or consciousness
What are the 3 classes of analgesics? Give examples
- Opioids: morphine, codeine, diamorphine (heroin)
- Non-steroidal anti-inflammatory: aspirin, ibuprofen, diclofenac
- Local anaesthetics: lidocaine, novocaine, benzocaine
Define opium
Dried poppy latex
Mix of analgesic, non-analgesic, inert agents
Define opiate
Drugs derived from opium: morphine, codeine, heroin
Semi-synthetic drugs derived from them and thebaine: naloxone, nalorphine, buprenorphine
Define opioid
All agonists and antagonists w/ morphine-like pharmacology
Name 4 synthetic opioids
- Pethidine
- Fentanyl
- Methadone
- Pentazocine
Name the 4 classes of endogenous opioids
- Enkephalins: leu and met-enkephalin
- Dynorphins: A and B
- Endorphins: beta-endorphin, beta-neoendorphin, alpha-neoendorphin
- Endomorphins: 1 and 2
What are the 5 classes of opioid receptor? Which are involved in analgesic? How do they all function?
- Mu: analgesic
- Kappa: analgesic
- Delta: analgesic
- NOP (nociceptin)
- Zeta
All 7TM GPCRs acting through Gi/o
What are the 4 classes of opioids?
- Agonists
- Antagonists
- Agonists/antagonists
- Partial agonists
What are the 3 groups of opioid agonists? Give examples
- Opiate: morphine, codeine, heroin
- Synthetic opioid: pethidine, fentanyl, methadone
- Endogenous: endorphins
Name a opioid antagonist
Naloxone
Name 2 opioid agonists/antagonists
Nalorphine and pentazocine
Different effects on different receptors
Competitive mu antagonists and kappa agonists
Dose dependent effects, agonists at high conc.
Name a partial opioid agonist
Buprenorphine: partial mu agonist
10x more potent than morphine but lower maximal effects
Most cases block morphine actions
Describe the effectiveness of opioid analgesics and where they act
More effective for dull pain (C fibres) than fast intermittent pain (A delta)
Effective for visceral and stomach pain
Act in both brainstem and spinal cord
Explain descending pain control and how opioid analgesics interact w/ this
Periaqueductal gray sends inhibitor GABAergic projections to midline raphe nucleus and locus coeruleus
Midline raphe nucleus and locus coeruleus send inhibitor 5-HT and NA projections to substantia gelatinosa limiting nociceptive pain transmission
Opioids act on mu receptors in PAG to inhibit GABA outflow this relieves 5-HT and NA inhibition ultimately suppressing pain signalling
Explain the spinal actions of opioid analgesics
Directly stimulate inhibitory interneurons in spinal cord
Mu receptor on C fibres stimulated by endogenous endorphins or exogenous opioids
Suppress excitatory NT release directly onto 2nd order neuron and suppress inhibitory signally onto inhibitory interneuron
Morphine inhibits adenylate cyclase, dec. cAMP; open K channels block Ca channels, hyperpolarise and dec. Ca conc.; dec. NT release
Suppress transmission of nociceptive info. into brain
Why is euphoria important in analgesia? Explain the mechanism
Permits tolerance of higher levels of pain
Stimulation of ventral tegmental area causes release of DA in nucleus accumbens and frontal cortex
Meso-limbic meso-cortical DA pathways encode reward and +ve emotional salience
Exerts -ve effect on pathways encoding fear and aversion
How do opioids suppress respiration? Why is this a major problem?
Direct effect on brainstem respiratory centres
Red. responsiveness of centres to plasma partial pressure CO2
Red. activity of pontine and medullary centres involved in breathing rhythm and depth
Hypoxic stim. of chemoreceptors may still be effective
Dangerous as can be lethal due to respiratory depression leading to hypoxia and CV collapse
How do opioids cause miosis?
Morphine and mu/kappa agonists cause contraction by excitatory action at oculomotor nucleus
Activate parasympathetic innervation of pupil
What is the clinical relevance of miosis in opioids?
Diagnostic feature of opioid OD
Distinguish between opioid induced coma/respiratory depression from other causes (usually cause dilation)
Explain the anti-tussive effect of opioids
Suppress cough reflex by inhibiting cough control system in medulla
No relationship between analgesic, respiratory depression and anti-tussive
Codeine and pholcodine potent anti-tussives
Why is anti-tussive dangerous?
Coughing reflex is protective mechanism: allows clearing of airways
Describe the effects of opioids on the GIT
Stomach: dec. gastric motility and delayed emptying
Small intestine: red. biliary, pancreatic, intestinal secretions; SM resting tone inc., red. amplitude of propulsive contractions (suppressed peristalsis)
Large: significant faecal desiccation; anal sphincter tone inc.
What are the 3 general effects of opioids on GIT?
- Constipation
- Delayed digestion of food in small intestine
- Retarded absorption of other drugs
Explain how nausea/emesis is triggered in opioid use. Describe changes in recumbent and ambulatory patients
Direct stimulation of chemoreceptor trigger zone in area postrema in medulla
Relatively uncommon in recumbent patients
Nausea 40% and emesis 10% ambulatory patients
Relatively transient, disappear w/ repeated use
How are opioids usually administered?
IV injection
Oral dosage produces less effect due to variable but significant first-pass metabolism
Oral preferred for chronic pain whereas more direct routes for acute cases
Describe the metabolism of morphine
Conjugated w/ glucuronic acid in liver to form inactive morphine-3-glucuronide and extra-hepatically to form highly active morphine-6-glucuronide
Excretion via kidneys usually in 3-glucuronide form
Describe the onset of tolerance to opioids
Occurs rapidly
Affects most effects: analgesic, euphoria, respiratory depression
Mechanism not understood: suggested that gene expression changes are responsible
What are the 2 types of tolerance to opioids? Describe them
- Physical: withdrawal syndrome; pupillary dilation, sweating, fever, piloecrection, nausea, diarrhoea, insomnia
- Psychological: craving irrespective whether to ward off withdrawal or for euphoric actions
What are the 5 major LAs?
- Lidocaine
- Articaine
- Procaine
- Prilocaine
- Mepivacaine
What are the 6 uses of LAs?
- Infiltration
- Nerve block
- Spinal
- Epidural
- Ventricular dysrhythmias
- Surface
Describe a infiltration LA
Injection into tissues to reach nerve branches and terminals for minor surgery
Describe the use of nerve block LA
Close to nerve trunk
Causes loss of peripheral sensation, used in surgery and dentistry (lidocaine, prilocaine)
Describe the use of spray LA
Applied as spray (lidocaine) or powder to mucus membrane of mouth, nose, cornea
Describe use of spinal LA
Injected into subarachnoid space to act on spinal roots and cord (lidocaine)
Describe epidural LA use
Injected into epidural space to block spinal roots (lidocaine, bupivacaine)
What LA is used for ventricular dysrhythmias?
Lidocaine
Compare procaine, lidocaine, prilocaine
Procaine: ester, rapidly hydrolysed by plasma cholinesterase, short duration; high incidence of unwanted effects, replaced
Lidocaine: amide, slower onset, medium duration; widely used
Prilocaine: amide, rapid onset, low toxicity, can cause methaemoglobin
Briefly describe the action of VGNa+Cs and their 3 stages
Driver of AP propagation
Voltage opening responsible for rapid depolarisation phase of AP
Following opening, channels blocked by slow-acting inactivation gate
- Resting
- Open
- Inactivated
What is the relationship between VGNa+Cs and LA?
LA block channels, prevent neuronal depolarisation
LA binds on intracellular side
What 3 factors determines LAs effectiveness?
- MUST enter neuron
- Lipophilicty: inc. lipophilicity, inc. potency
- Ionisation: inc. protonated, inc. potency
What conformation of VGNa+C do LAs bind most strongly? What is the effect of this?
Inactivated form, hold in conformation
Inc. proportion of inactivated channels impairing AP propagation; neuronal membrane can’t depolarise
What is the relationship between nerve stimulation and LA onset?
More nerve stim., more rapid anaesthetic onset
Use dependent block
Describe the relationship between ionisation and diffusion across PM. What is ionisation dependent on?
Only non-ionised drugs cross lipid PM
Ionisation depends on relationship between drugs pKa and environmental pH
Describe the relationship between pH, pKa and ionisation
pH < pKa: drug accepts H+; non-ionised/protonated
pH > pKa: drugs disassociates; ionised/non-protonated
What are most LAs? What is the relevance of this to their action?
Weak bases pKa ~8.9 thus mostly ionised (not completely) @ physiological pH (7.4)
Less cross PM
What are the 2 pathways by which LA can block VGNaCs?
- Use dependent (hydrophobic)
2. Use independent (hydrophilic)
How do LAs prevent pain?
Preventing conduction along nerve fibres
What is the relationship between fibre diameter and ease of blocking?
Smaller, myelinated fibres (A delta) blocked more easily than larger, unmyelinated fibres
Myelinated blocked before unmyelinated
What is the rate of LA blockade dependent on?
How quickly sufficient Na channels can be inhibited to prevent neuronal depolarisation
Explain why autonomic fibres and blocked before pain fibres by LA
Autonomic fibres and myelinated: NaCs clustered @ nodes of Ranvier making it easier for LA to block fibre
C fibres are unmyelinated so NaCs are along length thus require a greater degree of blockade to prevent AP
What is the relevance of vasodilation to LA?
LA block sympathetic vasoconstrictive alpha-1 stimulation causing vasodilation
Inc. blood flow causes more rapid clearance of drug
What is administered w/ LA to combat vasodilation?
AD to induce vasoconstriction red. loss of LA
Why must care be taken when using AD w/ LA?
Must not inject intravenously as risk systemic effects
Why LAs come w/ AD preparations?
Lidocaine
Articaine
Mepivacaine
What affects the potency of LA?
pKa and lipophilicity
What are the 2 classes of LAs? How do they differ?
- Esters
- Amides
Toxic potential, metabolism, duration
Describe ester LA
Rapidly hydrolysed by plasma pseudocholinesterase
Short t1/2
Almost no potential for accumulation
Can be toxic by direct IV injection (cocaine) OR by repeated exposure (benzocaine, cocaine)
Describe amide LAs
More stable to hydrolysis
Primarily hepatic metabolism
Can accumulate on repeated dosage
Dose-related toxicity, can be delayed by mins-hrs
What are the 7 amide LAs?
- Lidocaine
- Bupivacaine
- Levobupivacaine
- Etidocaine
- Ropivacaine
- Mepivacaine
- Prilocaine
What are the 5 ester LA?
- Procaine
- Cocaine
- Chloroprocaine
- Tetracaine
- Benzocaine
What are the 2 principal target systems of toxicity to LAs?
- CNS
2. CVS
What are the 3 early signs of CNS LA toxicity?
- Tinnitus
- Dizziness
- Light-headedness
What are the progressively worsening toxic affects of LA on CNS?
Anxiety -> disorientation -> unconsciousness -> seizures -> respiratory arrest
What are the effects on the CVS of LA?
Hypotension
-ve inotropism: red. contractile force
Vasodilation: direct action on VSM and blockade of sympathetic nerve activity
Bradycardia leading to asystole due to cardiac NaC block
What order do toxic effects of LA follow? Why is this useful? How can they be treated?
Usually CNS before CVS; show warning signs: tinnitus, motor twitching, grand mal seizures, coma
Maintain O2 and normal CO2
What 4 factors inc. risk of seizure and CVS collapse of LAs?
- Cold temp (slow metabolism)
- Metabolic/respiratory acidosis
- Hypoxia
- Pregnancy
Describe platelets
Small (2-3 micro m) cells w/o nucleus
Originate from megakaryocytes from bone marrow. Each can produce thousands of platelets
10 day lifespan
150-400x10^9/L
Describe the structure of platelets
Have surface-connected canalicular system continuous w/ endoplasmic reticulum (outside cell internalised)
External coat rich in receptors (glycoproteins)
Circumferential band of microtubules made of tubulin provide inner skeleton
Actin and myosin present internally
Explain the feedback control of platelet production
Platelets and megakaryocytes control production
Platelets have thrombopoietin (TPO) receptor which binds and removes plasma TPO
Hypoplastic marrow generating few megakaryocytes = thrombocytopenia (platelet shortage)
little TPO removal stim. megakaryocyte production correcting shortage
Hyperplastic marrow producing many megakaryocytes = thrombocytosis (excess platelets)
greater TPO removal inhibits megakaryocyte production
What are the 2 special organelles present in platelets?
- alpha granules: store von Willebrand factor, platelet fibrinogen (originate from liver), clotting factor V
- Dense-cross granules: store ADP, ATP, serotonin, Ca2+
What is the main role of platelets?
Essential for haemostasis (stopping blood flow) by formation of clot
Describe clots and thrombi
Clot: semisolid mass composed of platelets and fibrin; RBCs, WBCs, serum entrapped
Thrombus: intravascular clot; different compositions between arteriole (higher platelet) and venous (higher fibrin) circulation
Describe the formation of a clot
Many substances released by platelet (ADP, thrombin, thromboxane A2)
Recruit more platelets to site
Thrombin convert fibrinogen to fibrin stabilising platelet plug
Platelet factor 4 and beta-thromboglobulin promote clotting by neutralising heparin
Why must clotting be regulated?
Inadequate clotting would lead to leakage of blood from vascular
Overactive would cause thrombosis and cessation of blood flow
Discuss antithrombotic
Endothelium cells lining vascular system
thrombomodulin: control thrombin
Heparin sulphate: naturally occurring, inhibit thrombin
Enzymes: degrade platelet-derived molecules (ADP - promote aggregation)
Prostacyclin, NO: inhibit aggregation, discourage platelets sticking to wall
Discuss prothrombotics
Vascular damage: failure of endothelium to produce proper antithrombotic factors
Physical removal/injury to endothelium: blood contacts thrombogenic factors beneath surface, platelets adhere to collage surface, release factors promoting clotting and vasoconstriction to red. blood loss (TXA2)
Activation by ligands binding to platelet receptors
Shear forces: flowing past mechanical heart valves
What are the 2 stages of the coagulation cascade?
- Coagulation: formation of clot, arrest bleeding
2. Fibrinolysis: dissolve clot after served purpose
In what state are clotting factors present in the blood? Why is this important?
Present as zymogens (inactive)
Prevent unwanted clotting but allow for rapid clotting when required
What are the 3 pathways of the coagulation cascade?
- Intrinsic: triggered by contact w/ -ve phospholipid surfaces, mimic w/ glass
- Extrinsic: contact w/ material from damaged cell membranes, cell debris
- Common: both converge, leads to thrombin clot and stable fibrin
Compare where the intrinsic and extrinsic coagulation pathways occur
Intrinsic: at membrane of activated platelets
Extrinsic: at membrane bound tissue factor
What is thrombin? What are its 3 main actions?
Central protease of coagulation cascade
- Activation of downstream components
- catalyse proteolysis of fibrinogen to fibrin - +ve feedback on upstream components
- catalyse formation of thrombin from prothrombin, platelet factors Va, VIIIa - Paracrine actions that influence haemostasis
- endothelial cells release NO, PGI2, ADP, vWF
What are the 2 paracrine anticoagulant factors?
- Prostacyclin: vasodilation, inhibit platelet activation and clotting
- cGMP: NO inhibits platelet adhesion and aggregation
What are the 5 anticoagulant factors?
- Tissue factor pathway inhibitor: blocks VIIa protease activity
- Antithrombin III: inhibits Xa, thrombin
- Thrombomodulin: forms complex w/ thrombin, removing from circulation
- Protein C: protease; inhibits Va, VIIIa
- Protein S: protein C cofactor
Describe fibrinolysis
Breakdown of thrombus/clot
Begins w/ conversion of zymogen plasminogen to active fibrinolytic (serine) protease plasmin
- catalysed by: tissue-type and urokinase-type plasminogen activator
- t-PA serine protease; u-PA must bind receptor of cell membrane
Plasminogen: made in liver
Plasmin: serine protease, breakdown fibrin and fibrinogen; proteolytically cleaves stable fibrin to fibrin breakdown products
What is thrombocytopenia?
Low platelet count: <30x10^9/L
Results in bleeding from nose, mucous membranes, GIT, puncture sites, skin
Caused by radiation or chemotherapy, toxic chemicals, malignancy
Can be distribution or destruction (non-immune and immune)
Describe Von Willebrand disease
Autosomal
Mucocutaneous bleeding, joint bleeding if severe
Normal platelets but abnormal bleeding time as vWF required for platelet adherence
Inc. partial thromboplastin time: red. VIII (vWF carrier for VIII)
What liver factors are dependent on VitK?
Prothrombin
F VII IX X
Define general anaesthetic
Compounds that induce reversible loss of consciousness in humans or loss of righting reflex in animals
Define sedative, hypnotic, analgesic
Sedative: red. irritability/excitation
Hypnotic: induce sleep
Analgesic: red. pain sensation w/o loss of consciousness
What are the typical GAs?
Desflorane, isofluorane, sevoflurane, halothane Nitrous oxide Fentanyl Thiopentone Propofol Ketamine
What 4 actions should a GA induce?
- Hypnosis/sedative
- Immobility
- Analgesia
- Amnesia
What are the 7 characteristics of an ideal GA?
- Cause loss of sensation, especially pain
- Cause loss of noxious reflex
- Induce muscular relaxation
- Induce amnesia
- Have smooth onset and recovery
- Have no systemic toxicity
- Cause no hazard to others
What are the 4 stages of anaesthesia?
- Analgesia: induction to loss of consciousness
- Excitement: loss of consciousness to automatic breathing
- Surgical Anaesthesia: automatic respiration to respiratory paralysis
- Medullary Depression: stoppage of respiration to death
Describe the 3 planes of stage 1 anaesthesia
- No analgesia or amnesia
- Amnesia, partial analgesia
- Complete analgesia and amnesia, disorientation, vertigo/ataxia; inc. respiration, BP, HR
Describe the excitement stage of anaesthesia
Coughing, vomiting, struggling, irregular respiration w/ breath holding
Describe the 4 planes of surgical anaesthesia
- Cessation of eyeball movement, loss of swallowing reflex
- Laryngeal reflex lost, inc. lacrimation, regular deep breathing, response to skin stim. lost
- Progressive intercostal paralysis, diaphragmatic respiration persists, pupils dilation, loss of light reflex
- Paralysis of intercostal and diaphragmatic (apnea)
Describe stage 4 anaesthesia
Medullary paralysis: respiratory depression, vasomotor collapse, death
How are the changes between the stages of anaesthesia prevented?
Use of neuromuscular blockers
Explain the lipid theory of anaesthetic mechanism
Relationship between lipid solubility and anaesthetic potency
Anaesthesia occurs if solubilisation of GA in lipid bilayer causes redistribution of membrane lateral pressure
Ion channels highly sensitive to membrane lateral pressure
Inc. pressure prevents channel opening, limiting neuronal excitation
Explain the protein theory of anaesthetic mechanism
Specific targeting of CNS receptors
GABA, glycine, ionotropic glutamate receptors
VGIC
What are the 2 classes of GAs? Give examples
- Intravenous: propofol, thiopentone
- Inhalation:
- gaseous: nitrous oxide
- volatile liquids: desfluorane, sevofluorane, isofluorane, halothane
Describe minimum alveolar conc.
Steady state partial pressure (%) of inhalational agent required for immobility of 50% subjects exposed to noxious stimuli (surgical incision)
Means to compare potency of inhalational agents
Guide to determine dose
Values are additive, dec. w/ age
What is the relationship between MAC value and anaesthetic potency?
Indirect
Lower MAC value, more potent anaesthetic
Describe sevofluorane and its mechanism of action
Rapid-acting, volatile liquid agent
Non-irritant, rapid recovery
+ve allosteric modulator of GABAA receptors
NMDA R antagonist
Potentiates glycine R activity
Inhibits nicotinic ACh, 5-HT3 receptors
What are the adverse effects of sevofluorane?
Trigger malignant hyperthermia
Inc. intracranial pressure
Describe isofluorane and its effects
Rapid acting
Analgesic and muscle relaxer
Maintain anaesthetic induced by other agents
Vascular effects
- inc. incidence coronary ischaemia
- inc. HR (younger)
- dec. systemic vascular resistance, red. arterial pressure, CO
Stim. bronchial secretions, coughing, laryngospasm
May cause malignant hyperthermia
May be associated w/ post-operative cognitive dysfunction (elderly)
Describe nitrous oxide
Insufficient alone for GA use due to low potency
MAC: 104% would cause asphyxia
Used in combination w/ other GA, red. dose
Inhaled and excreted via lungs
Rapid onset, good analgesic actions
No significant effect on respiratory drive, liver, kidney, GIT
Causes euphoria
What is malignant hyperthermia and how is it treated?
Life threatening syndrome characterised by:
- hyoermetabolism in skeletal musculature
- muscle rigidity
- muscle injury
- inc. sympathetic NS activity
- hyperkalaemia
First sign: elevated CO2 production
Treatment: IV dantrolene (suppress excitation-contraction coupling in muscles) and supportive therapies (cooling, O2)
Why are IV GAs preferable?
Faster, more stable and more reliable
Describe propofol
Rapid onset and metabolism (hepatic)
Used for induction and maintenance of anaesthesia, supplemented by NO or opioids
Potentiates inhibitory GABAA R activity: slowing channel closing time, blocking VGNaC
Causes pain on injection, given alongside lidocaine
What are the 4 adverse effects of propofol?
- Respiratory depression
- Hypotension: peripheral vasodilation
- Induction cardiac dysrhythmias
- Induce priapism: persistent, painful erection
Describe thiopentone
Barbiturate w/ high lipid solubility
No analgesic properties
Smooth and rapid induction of anaesthesia
Terminated by redistribution into adipose tissue; rapid recovery from anaesthesia but produces prolonged sedation
Induces respiratory depression and hypotension
Lack of analgesic effects causes inc. sympathetic activity on recovery: tachycardia, tachypnea, sweating, inc. BP, pupil dilation
Narrow margin between anaesthesia and CV depression
Blocks GABAA, nicotinic, 5-HT3, glycine receptors
What are the 6 effects of pre-medications?
- Anxiety relief w/o excessive sedation and stress red.
- Amnesia during preoperative period, retain cooperation
- Relief preoperative pain
- Red. requirement for inhalational agents
- Red. side effects: salivation, bradycardia, postoperative vomiting
- Red. acidity and vol gastric contents
What are the 3 types of premedication?
- Anti-emetics
- Opioid analgesic
- Benzodiazepines
Describe anti-emetics
Droperidol, domperidone
Act in chemoreceptor trigger zone in brainstem
Highly effective
Describe opioid analgesic use as premedication
Alfentanil, fentanyl, remifentanil
Pain relief, sedation, red. GA dose
Adverse: respiratory and CV depression, emesis
Describe benzodiazepine use as premedication
Diazepam, lorazepam
Anxiolytic/sedative
Little respiratory and cardiac depression
Amnesia
What are diuretics?
Drugs w/ primary function of inc. excretion Na and Cl
H2O loss secondary to excretion of ions
- alterations in osmolality by movement of ions in and/or out nephron lumen alters gradient between nephron and interstitial fluid
- H2O moves down osmotic gradient through aquaporins
What are the 2 main mechanisms by which diuretics work?
- Direct actions on epithelial cells of nephron
2. Indirectly modifying filtrate content
What are the 5 classes of diuretics?
- Osmotic
- Carbonic anhydrase inhibitors
- Loop: Na/K/2Cl transporter
- Thiazide: Na, Cl transporters
- K-sparing: Na channel blockers, mineralocorticoid receptor antagonists
Describe loop diuretics
FUROSEMIDE, bumetanide, torasemide
Most effect diuretics: excrete 15-20% filtered Na
Enter tubular lumen via proximal tubular secretion: treated as toxin
Inhibit Na/K/2Cl transporter, red. NaCl reabsorption in thick ascending limb of loop of Henle
Accumulation intracellular K+; synergy w/ Na/K ATPase
Results in back diffusion of K into tubular lumen, red. lumen +ve potential and inc. Mg, Ca excretion
What are the 5 uses for loop diuretics (furosemide)?
- Pulmonary oedema: due to L ventricle failure
- Congestive heart failure
- Diuretic-resistant oedema
- Control resistant hypertension
- Hypercalcaemia
What are the 6 adverse effects of loop diuretics (furosemide)?
- Hypokalaemia
- Hyperuricaemia
- Metabolic alkalosis
- Hyponatremia
- Ototoxicity
- Mg depletion
What are the 6 contra-indications of loop diuretics?
- Severe hypokalaemia
- Severe hyponatremia
- Anuria
- Liver cirrhosis
- Drug-induced renal failure
- Pregnancy
Describe thiazide diuretics
Chlortalidone, indapamide
Inhibit Na reabsorption at DCT
Red. intracellular Na activates Na/Ca antiporter, directly inc. Ca reabsorption
K loss by similar mechanism to loop diuretics, lesser extent
What are the 3 uses of thiazide diuretics?
- Hypertension (diuretic treatment): effective at low dose
- Renal stones: inc. DT Ca reabsorption slows stone growth
- Heart failure: not first line
What are the 4 adverse effects of thiazide diuretics?
- Hypokalaemia: aggravates cardiac arrhythmias
- Metabolic alkalosis
- Hyperuricaemia: aggravate gout
- Hyperglycaemia: impaired pancreatic insulin release (K dependent)
What are the 4 contra-indications of thiazide diuretics?
- Hypokalaemia
- Hyponatraemia
- Symptomatic hyperuricaemia
- Hypercalcaemia
Describe osmotic diuretics
Mannitol, isosorbide
Pharmacologically inert molecules
Pass through glomerulus and inc. filtrate osmotic pressure
Red. tubular and loop of Henle H2O reabsorption
2ndary effects on Na reabsorption
- vol. filtrate greater than usual
- greater Na gradient, greater Na excretion
What are the 3 uses of osmotic diuretics?
- Acute renal failure
- Cerebral oedema
- Glaucoma
What are the 3 adverse effects of osmotic diuretics?
- Headache
- Nausea
- Vomiting
What are the 2 types of K-sparing diuretics?
Mineralocorticoid receptor antagonists
Epithelial Na channel blockers
Describe spironolactone
K sparing diuretic Mineralocorticoid receptor antagonist Weak diuretic Limits aldosterone Na retention Down-regulates ENaC expression
Describe amiloride and triamterene
K sparing diuretics
ENaC blockers
Limit Na re-uptake
How do K sparing diuretics work?
Limit intraepithelial Na accumulation thus prevent resulting excess K excretion
What are the uses of K sparing diuretics?
Weak along, given alongside loop or thiazide diuretics
Prevent hypokalaemia more effectively than K supplements
Not given alongside K supplements, ACE inhibitors, angiotensin II antagonists: severe hyperkalaemia and cardiotoxicity
What are the side effects of K sparing diuretics?
Hyperkalaemia
GIT disturbances, nausea, vomiting
Triamterene, spironolactone: sexual dysfunction
Spironolactone: precipitate gynecomastia
Describe carbonic anhydrase inhibitors
Acetazolamide
Blocks HCO3- production leads to less bicarbonate reabsorption consequently less Na reabsorption
Greater HCO3- loss causes metabolic acidosis
Weak diuretics
What are the 3 uses of CAIs?
- Glaucoma treatment
Acetazolamide: oral administration; weak diuresis, metabolic acidosis
Dorzolamide, brinzolamide: topical administration; red. intraocular pressure, no diuretic or systemic metabolic effect - Acute mountain sickness: due to respiratory alkalosis
- breathing rate inc. to maintain O2 delivery
- ppCO2 falls, alkalising plasma - Metabolic alkalosis
Explain the relationship between filtrate pH and drug clearance
Entry of non-carrier transported molecules into filtrate depends on them crossing epithelial membrane
Highly dependent on drug pKa and local pH
Describe the uses of drugs that modify urinary pH
Useful: detoxification
- NaHCO3 raises urinary pH, inc. excretion aspirin (pKa 3.5)
- in urine, aspirin rapidly becomes charged and trapped
Less useful: preventing elimination
- amphetamine pKa 9.8
- NaHCO3 dec. proportion uncharged amphetamine in urine, slowing clearance
Explain the cause of gout
Uric acid is a by-product of purine base metabolism by xanthine oxidase
Poorly soluble in plasma so precipitates in joints causing gout (painful inflammation of joints)
Outline the treatment of gout
- Allopurinol: xanthine oxidase inhibitor
- Probenecid: block uric acid reabsorption by inhibiting specific uric acid transporter in tubule epithelium
Agents that inc. filtrate pH (NaHCO3), inc. uric acid clearance
