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
