Pharmacology

Question 1

What are they drug administration routes?

Answer 1

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

Question 2

Describe oral administration

Answer 2

Easy; no sterile preparations, special skill or apparatus

Convenient and preferred by patients

Question 3

What are some of the problems associated with oral administration?

Answer 3

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

Question 4

What are the benefits of intravenous administration?

Answer 4

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

Question 5

Describe some of the disadvantages of iv administration?

Answer 5

Needs sterile apparatus and skill

Question 6

Give examples of iv drugs

Answer 6

Tubocurarine - muscle relaxant during surgery
Pyridostigmine - reverse effects of tubocurarine
Thiopental - GA

Question 7

Discus the advantages and disadvantages of intramuscular and subcutaneous administration and give examples

Answer 7

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

Question 8

Discuss sublingual/buccal administration

Answer 8

Advantages - absorbed drugs doN’T enter portal vein, enter vena cava (to heart), avoid 1st-pass metabolism
Glyceryl trinitrate rapidly absorbed to relieve angina

Question 9

Discuss rectal administration

Answer 9

Useful when other routes are not suitable 
Nausea - prochlorperazine
Child epilepsy - diazepam
Asthma - aminophyline
Arthritis - indomethacin

Question 10

Describe transdermal administration

Answer 10

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

Question 11

Discuss inhalation administration

Answer 11

Large SA, rapid absorption and onset
Gaseous/volatile anaesthetics - halothane
Bronchodilators - salbutamol

Question 12

What is the importance of first-pass (pre-systemic) metabolism?

Answer 12

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

Question 13

Describe the process of first pass metabolism

Answer 13

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

Question 14

What are the methods of transport across biological membranes? (PHARM)

Answer 14

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

Question 15

What factors affect absorption from the GIT?

Answer 15

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

Question 16

Describe absorption from muscle

Answer 16

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

Question 17

What are the two phases of metabolism?

Answer 17

Phase 1: functionalisation

Phase 2: conjugation

Question 18

Describe phase 1 of metabolism

Answer 18

Introduce groups that undergo phase 2 reactions
Mainly oxidation - also reductions, hydrolyses
Often increase polarity

Question 19

Describe phase 2 metabolism

Answer 19

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

Question 20

What are the two main sites of excretion?

Answer 20

Kidney - urine
Liver - bile, faeces
(Lungs - volatile anaesthetics, ethanol
Milk - lactating mothers)

Question 21

What is the functional unit of the kidneys?

Answer 21

The nephron

Question 22

Describe entry of drugs in the kidney

Answer 22

Drugs filtered at glomerulus

Active secretion of drugs at proximal convoluted tubule - separate carriers for acids and bases

Question 23

Describe the reabsorption of drugs in the kidney

Answer 23

Active re-uptake at glomerulus

Passive reabsorption of lipophilic molecules along proximal convoluted tubule

Question 24

How are weak electrolytes excreted and how is this aided?

Answer 24

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

Question 25

Give examples of excretion of weak electrolytes

Answer 25

``` 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

Question 26

Describe the excretion of penicillin and how it can be manipulated

Answer 26

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

Question 27

Describe excretion of drugs in bile

Answer 27

Passive diffusion 3 active mechanisms dependent on: MW, polar, acidic, glucuronide metabolites usually good substrates High MW drugs excreted unchanged e.g. oubain

Question 28

Describe the process of enterohepatic recirculation

Answer 28

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

Question 29

Define drug

Answer 29

Substance that affects the body, elicits a change in physiology

Question 30

Explain receptor theory

Answer 30

Drug will not have activity unless binds to specific receptor thus inducing response

Question 31

Define agonist, antagonist, partial agonist and inverse agonist

Answer 31

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

Question 32

Explain the law of mass action

Answer 32

Rate of chemical reaction is directly proportional to product of activities/conc. of reactants

Question 33

What is KD?

Answer 33

Dissociation constant: conc. of drug at equilibrium occupies 50% available receptors Measures likelihood DR complex will dissociate at equilibrium High KD likely to disassociate

Question 34

Describe the relationship between KD and affinity

Answer 34

1/KD = KA (affinity) Higher KD lower affinity KA measures tendency of drug to bind receptor thus high KA = greater affinity

Question 35

What is the KD equation?

Answer 35

KD = [D][R]/[DR]

Question 36

Define efficacy and poteny

Answer 36

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

Question 37

What is EC50?

Answer 37

Measure of potency | Dose/conc. at half Emax

Question 38

Why is Emax used?

Answer 38

As receptors become saturated so impossible to know exactly how much is needed or if same effect could be produced at lower dose

Question 39

Describe the relationship between potency and EC50

Answer 39

Inverse: more potent lower EC50 as need smaller amount of agonist to induce response

Question 40

Explain the theory of spare receptors

Answer 40

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

Question 41

What is the therapeutic window of a drug?

Answer 41

The gap between the therapeutic and toxic results i.e. gap between EC50 and LD50

Question 42

What is the therapeutic index?

Answer 42

Ratio of [D]toxic/[D]therapeutic

Question 43

What is the complication with narrow therapeutic windows?

Answer 43

Makes it very difficult to stay within the window, can easily slip into toxic/lethal doses and effects

Question 44

What are the 5 types of antagonism?

Answer 44

Chemical - drug destroys ligand Receptor Non-competitive - alters response curve Pharmacokinetic - blocks drug getting to target Physiological - counteract response trying to block

Question 45

What are the 3 main types of receptor antagonism?

Answer 45

Reversible, competitive Irreversible, competitive Allosteric

Question 46

Describe and explain reversible antagonism

Answer 46

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

Question 47

Describe and explain irreversible antagonism

Answer 47

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

Question 48

Describe and explain allosteric antagonism

Answer 48

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

Question 49

Explain how antagonists can be compared

Answer 49

Repeated dose response curves +/- doses of antagonist recording changes in EC50 Dose ratio = EC50 + antagonist/EC50 (agonist)

Question 50

Explain pA2

Answer 50

Measure of antagonist affinity for receptor | -log of [antagonist] which will reduce double dose agonist response to that of a single dose

Question 51

Explain non-receptor antagonism

Answer 51

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

Question 52

Why do drugs require receptors?

Answer 52

Most can't pass membrane thus to initiate response must bind a receptor protein

Question 53

Name the 4 main classes of receptor

Answer 53

Ionotropic (LGIC): milliseconds Metabotropic (GPCRs): seconds-mins Tyrosine kinase linked receptor: mins-hours Intracellular (nuclear): hours-days

Question 54

Describe the process of signal amplification

Answer 54

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

Question 55

Name the main 2nd signalling molecules and their associated enzymes

Answer 55

``` cAMP - adenylate cyclase cGMP - guanylate cyclise Ca2+ Diacylglycerol (DAG) - PLC Inositol triphosphate (IP3) - PLC Prostaglandins - PLA2 ```

Question 56

Describe intracellular signalling

Answer 56

Nuclear, cytoplasm or ER Small, lipophilic molecule cross membrane and bind to intracellular receptor Lead to transcription of specific genes

Question 57

What determines if a protein is active or not?

Answer 57

If it is phosphorylated or not

Question 58

Describe ionotropic receptors

Answer 58

Ligand gated ion channels Allow very rapid signalling i.e. neurons, muscles Usually specific for 1 ion

Question 59

Give an example of ionotropic receptor

Answer 59

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)

Question 60

What are G proteins?

Answer 60

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

Question 61

What are the three types of G protein?

Answer 61

Gs - Stimulates adenylate cyclase/open Ca2+ channels Gi - Inhibits adenylate cyclase/open K+ channels Gq - stimulate PLC

Question 62

Describe activation of G protein

Answer 62

1. Inactive state (GDP bound) 2. Signal molecule binds to GPCR, causes GDP to disassociate allowing GTP to bind 3. G-protein splits into a-GTP and By complex 4. a-GTP activates target protein 5. GTP hydrolyses into GDP 6. a-GDP reassembles with By

Question 63

Describe the cAMP pathway

Answer 63

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

Question 64

Describe the phosphatidylinositol pathway

Answer 64

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

Question 65

Describe the cGMP pathway

Answer 65

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

Question 66

Describe tyrosine kinase receptors

Answer 66

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

Question 67

Describe nuclear receptors

Answer 67

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

Question 68

What are the promoter sequence, co-activator, hormone response element?

Answer 68

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

Question 69

Describe the role of Ca2+ as a 2nd messenger in the IP3 pathway

Answer 69

IP3 release stimulates Ca2+ release from ER into cytosol | Ca2+ activates many PKs like PKC

Question 70

Describe the role of Ca2+ as a 2nd messenger in the Ryanodine Receptor pathway

Answer 70

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

Question 71

How is the peripheral nervous system divided?

Answer 71

Sensory and motor Motor divided into somatic (voluntary) and autonomic (involuntary) Autonomic to sympathetic and parasympathetic

Question 72

What are the 3 types of peripheral NS neurons?

Answer 72

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

Question 73

Compare the somatic and autonomic NSs

Answer 73

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)

Question 74

Describe the somatic motor reflex

Answer 74

Receive stimulus, sensory afferent travels along synapse, enters interneuron, motor efferent travels along myelinated synapse to effector region Very fast

Question 75

Describe autonomic motor reflex

Answer 75

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)

Question 76

Compare the sympathetic and parasympathetic NSs

Answer 76

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

Question 77

What cranial nerves are CNS-ANS connections?

Answer 77

Oculomotor - 3 Facial - 7 Glossopharyngeal - 9 Vagus - 10

Question 78

What nerves are associated with peripheral nervous system?

Answer 78

``` Cranial: 3,7,9,10 Cervical: 1-7 Thoracic: 1-12 Lumbar: 1-5 Sacral: 1-5 ```

Question 79

What nerves are associated with para outflow?

Answer 79

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

Question 80

What nerves are associated with symp outflow?

Answer 80

Thoracic 1-12 | Lumbar 1-3

Question 81

What is a ganglia?

Answer 81

Points where neurons synapse with each other

Question 82

Describe innervation in SymNS

Answer 82

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

Question 83

What does the Short pre-ganglionic fibres in SymNS allow for?

Answer 83

Allows firing of neurons in coordinated manner at same time

Question 84

Describe innervation in the ParaNS

Answer 84

Ganglia located close to target organ (long pre-ganglionic fibres) Few branches so have localised effect Release ACh at ganglion and target tissue

Question 85

Describe the types of dual innervation

Answer 85

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

Question 86

Describe antagonistic control of HR

Answer 86

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

Question 87

Describe the control of blood vessels, smooth muscle and sweat glands

Answer 87

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

Question 88

What is the enteric NS?

Answer 88

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

Question 89

What is the function of the ENS?

Answer 89

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

Question 90

What 6 things does a molecule require to be classified a neurotransmitter?

Answer 90

1. Precursor and neurotransmitter present in nerve terminal 2. Systems for synthesis and storage 3. Transmitter release by nerve stimulation Ca dependent 4. Mechanism for termination of transmitter present 5. Enzymes must be present for biodegradation of transmitter 6. Action of transmitter modulated by drugs at specific receptors

Question 91

Describe the role of ACh

Answer 91

Neurotransmitter for both pre and post ganglionic fibres in ParaNS Neurotransmitter for pre-ganglionic neurone in SympNS

Question 92

Describe how ACh in made

Answer 92

Acetyl-CoA and choline reacted with choline acetyltransferase forming ACh and CoA

Question 93

What are muscarinic effects?

Answer 93

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

Question 94

What are the 5 muscarinic receptors and where are they?

Answer 94

M1: salivary glands, stomach, CNS M2: heart M3: salivary glands, bronchi, sweat glands, eye M4+5: CNS

Question 95

What pathway do M1 and M3 use?

Answer 95

Gq IP3 DAG

Question 96

What pathway does M2 use?

Answer 96

Gi cAMP

Question 97

Describe the pathway for M1+3

Answer 97

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

Question 98

Describe the pathway of M2 receptor

Answer 98

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

Question 99

Describe the muscarinic/Para effects on cardiovasculature, smooth muscle, exocrine glands, eye

Answer 99

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

Question 100

What are the effect of muscarinic antagonists? (Symp innervation)

Answer 100

``` Heart: trachycardia Eye: mydriasis, cycloplegia GIT: reduced tone, motility, secretion Bladder: urinary retention Salivary: dry mouth Sweat: reduced, dry, warm skin ```

Question 101

What are nicotinic receptors?

Answer 101

LGIC - require 2ACh molecules to activate 5 subunits: a, B, y, delta, epsilon Subunit combination determines ligand binding properties of receptor, particularly antagonist

Question 102

What are the 2 types of nicotinic receptor?

Answer 102

N1 - Ganglion (+ CNS) N2 - Muscle Differ in combination of subunits

Question 103

Explain N1 (ganglion) receptor pathway

Answer 103

2ACh molecules bind, opens Na+ channel causing depolarisation and subsequent AP at all ganglia and the adrenal medulla

Question 104

Explain N2 (muscle) receptor pathway

Answer 104

2ACh molecules bind, opens Na+ channel causing depolarisation and subsequent action at NMJ

Question 105

Describe the affinity's of N1 and N2 for both decamethonium and hexamethonium

Answer 105

N1: greater affinity for hexamethonium N2: greater affinity for decamethonium

Question 106

Describe the effect of nicotinic antagonists

Answer 106

Arterioles: vasodilation Veins: dilation

Question 107

Name muscarinic agonists and antagonists

Answer 107

Agonist: ACh, bethanechol, pilocarpine Antagonist: atropine, tropicamide

Question 108

Name nicotinic agonists and antagonists

Answer 108

Agonist: ACh, nicotine Antagonist: hexamethonium, tubocurarine

Question 109

What is AChE?

Answer 109

Enzyme that catalyses breakdown of ACh to acetic acid and choline Choline is uptaken again by pre-synaptic neuron, reproduces ACh

Question 110

Compare AChE and pseudocholinesterase

Answer 110

AChE present in ganglia, neuroeffector junctions, NMJ, RBC | BuChE free in plasma, made by liver, rapidly replaced

Question 111

What is a volume of distribution?

Answer 111

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

Question 112

What is the general rate equation?

Answer 112

Rate = k.C^n

Question 113

What happens when order of reaction is 1 or 0?

Answer 113

1: rate proportional to conc., higher plasma conc greater amount eliminated 0: rate independent of conc i.e. is constant

Question 114

What is half-life?

Answer 114

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

Question 115

What does proportion eliminated show?

Answer 115

% drug eliminated after number of half lives

Question 116

Explain constant rate infusions

Answer 116

After infusion drugs immediately started being eliminated | Equilibrium between elimination and constant rate infusion = steady state conc

Question 117

How can infusion rate be calculated?

Answer 117

k0 = (V.Css)/k

Question 118

Describe rate of attainment of Css

Answer 118

How many half lives to reach Css - usually 5 | Allows planning of how long need to wait so has therapeutic effect

Question 119

What problems are faced when trying to rapidly reach therapeutic window/Css?

Answer 119

Can't just give larger dose - will go into toxic effects

Question 120

How can loading doses and multiple dosing be used to rapidly obtain Css?

Answer 120

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

Question 121

What dose the passive diffusion of drugs depend on?

Answer 121

Lipophilicity - how soluble in lipid | Size - smaller molecules diffuse rapidly

Question 122

How does the pH-partition hypothesis effect diffusion?

Answer 122

Ionised molecule can't diffuse through membrane Ionised state depends on pH of environment and pKa pKa = -log[Ka]

Question 123

What is the Henderson-Hasselbalch equation?

Answer 123

pH = pKa + log[A-]/[HA]

Question 124

Compare nicotinic and muscarinic receptors

Answer 124

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

Question 125

QIQIQ

Answer 125

``` M1 - Gq - many tissues - Ca2+ M2 - Gi - heart - cAMP M3 - Gq - many tissues - Ca2+ M4 - Gi - CNS - cAMP M5 - Gq - CNS - Ca2+ ```

Question 126

How does ACh affect ciliary smooth muscle?

Answer 126

Constricts ciliary muscle decreasing diameter of lens for near vision

Question 127

How does ACh effect iris circular muscle?

Answer 127

Causes constriction, causing pupil constriction opening space to canal of Schlemm so aqueous humour can drain, reducing intra-ocular pressure

Question 128

How do M2 receptors function in the heart?

Answer 128

AChR in nodes and atria, M2 receptors function by Gi mechanism 1. AChR stimulated 2. Gi inhibitory mechanism decreases cAMP 3. Dec Ca2+ entry into heart 4. Extracellular Ca2+ entry required for contraction 5. HR/cardiac contraction decreased By 1. Activates K+ channels, K+ leaves 2. Cell becomes hyperpolarised increasing AP threshold 3. AP less likely to meet threshold and continue 4. HR decreased

Question 129

Describe muscarinic effects on the vasculature

Answer 129

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

Question 130

How does non-vasculature SM respond to muscarinic stimulation?

Answer 130

Contracts Lungs: bronchoconstriction Gut: increased peristalsis Bladder: increased bladder emptying

Question 131

Describe muscarinic effects on exocrine glands

Answer 131

Increased glandular secretion Salvation Bronchial secretion GI secretion, gastric HCl production In SympNS - increased sweating

Question 132

Describe pilocarpine and bethanechol

Answer 132

Pilocarpine: selective muscarinic agonist, not broken down by AChE, treat glaucoma and dry mouth Bethanechol: M3 selective agonist, inc bladder emptying and gastric motility

Question 133

Describe some of the effects of AChEIs

Answer 133

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

Question 134

Describe reversible AChEI drugs

Answer 134

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

Question 135

Give examples of reversible AChEI drugs

Answer 135

Pyridostigmine, Neostigmine: can't cross BBB, treat myasthenia gravis Physostigmine: cross BBB, glaucoma

Question 136

Describe irreversible AChEIs

Answer 136

Rapidly react with AChE AS leaving large blocking group which is stable, resists hydrolysis requiring production of new enzymes

Question 137

Give examples of irreversible AChEI drugs

Answer 137

Dyflos, sarin: nerve gas | Ecothiopate: glaucoma

Question 138

What is the effect of AChEIs on the CNS?

Answer 138

Only non-polar organophosphates (physostigmine) cross BBB Low dose: excitation, possible convulsions High: unconsciousness, respiratory depression, death

Question 139

What are the effects of organophosphate poisoning?

Answer 139

``` Salvation Lacrimation Urination Diaphoresis Gastro-intestinal motility Emsis Bronchorrhea Bronchoconstriction Bradycardia ```

Question 140

What systems of the body receive only Symp innervation?

Answer 140

Vascular SM Sweat glands Arrector pili SM of hair follicles

Question 141

Describe the nerves that supply SympNS

Answer 141

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

Question 142

Describe paravertabral ganglia and how they synapse

Answer 142

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

Question 143

Describe prevertebral ganglia

Answer 143

Nerve passes through chain ganglia, synapses in prevertebral ganglia anterior to vertebral column

Question 144

In the Symp chain what do divergence and convergence mean?

Answer 144

Divergence: preganglionic fibre branches, synapse with several post ganglionic cells Convergence: postganglionic cell receives input from numerous preganglia (lots of pathways activate single cell)

Question 145

What is noradrenaline?

Answer 145

Major postganglionic NT in SympNS | Has a and B receptors (GPCR)

Question 146

What is the fate of NAdr?

Answer 146

``` Metabolised in synapse Neuronal reuptake Extraneuronal uptake Postjunctional receptor (a, B) Diffuse into blood Prejunctional receptor (a2) ```

Question 147

Describe how NAdr is synthesised

Answer 147

1. Tyrosine converted to DOPA by tyrosine hydroxylase 2. DOPA to dopamine by dopa decarboxylase 3. Dopamine to NAdr by dopamine B-hydroxylase 4. NAdr to Adr by phentolamine N-methyltransferase

Question 148

Describe the catecholamine synthetic enzymes

Answer 148

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

Question 149

What are the adrenergic receptors?

Answer 149

Gq - a1 - IP3 Ca2+ release Gi - a2 - inhibit cAMP Gs- B1 - stimulate cAMP Gs - B2 - stimulate cAMP

Question 150

What is special about a2 receptor?

Answer 150

Can be post-synaptic receptor and regulatory auto-receptor | NA feeds back on own neuron shut down own system

Question 151

How is BP controlled?

Answer 151

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

Question 152

What drugs can cause vasoconstriction and vasodilation?

Answer 152

a1: phenylephrine B2: salbutamol

Question 153

Describe catecholamine metabolism

Answer 153

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

Question 154

What effect do MAO and COMT inhibitors have on Adr?

Answer 154

Allow greater Adr signalling as block its breakdown

Question 155

Describe reuptake of catecholamines

Answer 155

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

Question 156

How are direct acting Symp agonists classified?

Answer 156

By receptor subtype: a1: selective a2: selective, non-selective B1: selective B2: selective, non-selective

Question 157

What are indirect acting Symp agonists?

Answer 157

Releasers and reuptake inhibitors

Question 158

Describe the modes of action of Symp agonists

Answer 158

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

Question 159

Describe how a1 receptors function

Answer 159

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

Question 160

Describe how a2 receptors function

Answer 160

GiCPR Clonidine activates Gi which inhibits adenylate cyclase reducing production of cAMP causing reduction of release and synthesis of NAdr AND decrease Symp outflow

Question 161

Describe how B1 receptors function

Answer 161

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

Question 162

Describe how B2 receptors function

Answer 162

GsPCR Salbutamol binds, Gs activated enhances adenylate cyclase produces more cAMP causing relaxation of GI, vascular, bronchi, ciliary SM

Question 163

Describe a1 receptor actions

Answer 163

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

Question 164

Describe a2 receptor actions

Answer 164

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

Question 165

Describe B1 receptor actions

Answer 165

Kidney: increased renin secretion Heart SA: increased HR AV: inc conduction velocity Atria, ventricles: inc contractility and conduction velocity

Question 166

Describe B2 receptor actions

Answer 166

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

Question 167

Describe Symp innervation of the vasculature

Answer 167

``` 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

Question 168

Describe cardiac Symp innervation

Answer 168

``` B agonist (isoprenaline): increases rate of cardiac pacemakers, force of contractions, AV node conduction velocity B2 minimal compared to B1 ```

Question 169

Describe GI Symp innervation

Answer 169

``` 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) ```

Question 170

Describe the metabolic and hormonal effects of Symp innervation

Answer 170

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

Question 171

Name some general Symp agonists

Answer 171

Direct: Adr, ephedrine Releases: tyramine, amphetamine Metabolism inhibitors: selegiline, moclobemide Uptake inhibitors: cocaine, tricyclic antidepressants

Question 172

Name some selective Symp agonists NAPCIDSS

Answer 172

``` NAdr a Adr a Phenylephrine a1 Clonidine a2 Isoprenaline Dobutamine Salbutamol Salmeterol ```

Question 173

Describe the effect of tyramine when taking MAO-Is

Answer 173

Tyramine can displace stores monoamines from vesicles especially Adr, NAdr MAO-Is prevent metabolism of CAs leading to tachycardia, vasoconstriction thus hypertension

Question 174

Name some Symp antagonists PPPDYPABL

Answer 174

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)

Question 175

Describe motor division of the NMJ

Answer 175

Controls body movement: appendages, locomotion (whole body) Single neuron: CNS origin, myelinated Terminus: branched (coordinated contraction at same time), NMJ

Question 176

What is NM transmission dependent on?

Answer 176

ACh, AChRs, nicotinic receptors, LGNa+C

Question 177

Describe the structure of skeletal muscle

Answer 177

Fasiciles (bundles of cells) of muscle fibre made up of myofibrils surrounded by sarcolemma and nucleus Whole myofibril in communication

Question 178

What are T-tubules?

Answer 178

Invaginations in the sarcolemma, run perpendicular to length of myofibril

Question 179

Describe transmission of AP along muscle fibre

Answer 179

AP passes along T-tubule activating VGCa2+C in SR, Ca2+ entry causes actin/myosin contraction, shortening of myofibril

Question 180

What do T-tubules allow for?

Answer 180

Rapid transmission of the AP across whole myofibril

Question 181

Explain what miniature end plate potentials are

Answer 181

Small changes in potential caused by spontaneous exocytosis of ACh containing vesicles

Question 182

Describe how an end plate potential is formed

Answer 182

AP activates VGCa2+C in nerve terminals, Ca2+ influx induces release of ~50 synaptic vesicles producing EPP that initiates AP in muscle fibre

Question 183

Name drugs that can inhibit NMJ transmission by limiting ACh release

Answer 183

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

Question 184

Describe some of the functions of botulinum

Answer 184

Treat muscle spasticity, excesssive sweating, neuropathic pain, cosmetic treatment

Question 185

Describe how botulinum functions

Answer 185

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)

Question 186

What are neuromuscular blockers and what are the 2 types?

Answer 186

Drugs which relax skeletal M by acting at NMJ 1. Non-depolarising: prevent ACh reaching nicotinic NMR, preventing depolarisation of the motor end plate (tubocurarine) 2. Depolarising: excessive depolarisation of motor end plate by over stimulating nicotinic NMR (succinylcholine)

Question 187

Describe non-depolarising blockers

Answer 187

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)

Question 188

What are some of the side effects of non-depolarising blockers?

Answer 188

Tubocurarine: histamine released, ganglion blocker, Symp blocker Others more specifically active at NMJ, fewer side effect Main toxicity is inhibitor of ventilator muscle function

Question 189

Describe depolarising blockers

Answer 189

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

Question 190

Describe the mechanism of depolarising blockers

Answer 190

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

Question 191

Describe the side effect of depolarising blockers

Answer 191

Muscarinic stimulation: bradycardia, increased salivation, gastric secretions Excessive K+ release: hyperkalaemia (no longer set RMP) Increased intra-ocular pressure Prolonged paralysis

Question 192

What are some of the clinical uses for NMJ blockers?

Answer 192

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

Question 193

What is myasthenia gravis?

Answer 193

Autoimmune disease characterised by muscle weakness due to decreased NM signal transduction

Question 194

How does myasthenia gravis come about?

Answer 194

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

Question 195

How can myasthenia gravis be treated?

Answer 195

AChEIs relieve system by blocking AChE metabolism thus potentiate ACh Physostigmine, pyridostigmine Act as competitive antagonist to autoantibodies

Question 196

What is a type 1 antibacterial?

Answer 196

Agents that prevent cell wall synthesis

Question 197

How do T1 antibacterials work?

Answer 197

Target peptidoglycan in bacterial cell wall | B-lactams & glycopeptides relevant to dentistry

Question 198

Describe B-lactams

Answer 198

Antibiotics that contain a B-lactam ring e.g. penicillin and cephalosporins

Question 199

How do B-lactams function?

Answer 199

Bind to penicillin binding protein enzyme Inhibit X-linking of CW CW precursor subunits accumulate Cell lysis

Question 200

How can resistance to B-lactams arise and how can this be overcome?

Answer 200

B-lactamases which break B-lactam ring | Overcome by B-lactamase inhibitors e.g. clavulanic acid

Question 201

What are the 5 types of penicillins and give an example of each

Answer 201

1. Benzylpenicillin and long-lasting parenteral forms 2. Orally absorbed - phenoxymethylpenicillin 3. Staphylococcal B-lactamase resistance - flucloxacillin 4. Extended spectrum - amoxycillin 5. Pseudomonas aeruginosa active - azlocillin

Question 202

How do glycopeptides function?

Answer 202

Bind terminal acyl-D-alanyl-D-alanine residues | Prevent incorporation of subunits into growing peptidoglycan

Question 203

What are vancomycin and teicoplanin? Describe their function

Answer 203

Glycopeptides active in gram +ve bacteria, must be injected | Widely used to treat MSRA

Question 204

What are T2 antibacterials?

Answer 204

Inhibitors of protein synthesis

Question 205

What are the 5 types of T2 antibacterials?

Answer 205

1. Aminoglycosides - streptomycin 2. Tetracyclines - oxytetracycline (periodontitis) 3. Macrolides - erythromycin 4. Lincosamides - clindamycin 5. Mupirocin, fusidic acid

Question 206

What are T3 antibacterials?

Answer 206

Inhibitors of nucleic acid synthesis

Question 207

How do T3 antibacterials function?

Answer 207

Disrupt DNA-associated enzymic processes

Question 208

What are the 4 types of T3 antibacterials?

Answer 208

1. Inhib of precursor synthesis - trimethoprim 2. Inhib DNA replication - quinolones (nalidixic acid) 3. Inhib RNA polymerase - rifamycins (rifampicin) 4. DNA stand breakage - 5-nitroimidazoles (metronidazole)

Question 209

Why are 5-nitroimidazoles used by dentists?

Answer 209

Good activity against anaerobic bacteria

Question 210

What are antifungal agents?

Answer 210

Antibiotics that act in synthesis/function of fungal CM

Question 211

How do polyenes work?

Answer 211

Bind sterols in fungal CM Interfere with membrane integrity Essential metabolites leak

Question 212

What are polyenes used in?

Answer 212

Topical preparations incl. mouthwashes, lozenges to treat oral candidosis

Question 213

Give examples of polyenes

Answer 213

Nystatin | Amphotercin B

Question 214

How do azoles function?

Answer 214

Disrupts synthesis of ergosterol | Disrupts fungal membrane function

Question 215

Name azoles and what they would be used to treat

Answer 215

Fluconazole, itraconazole, micronazole | Topical candida infections

Question 216

Why is it difficult to develop antivirals with selective toxicity?

Answer 216

Replicate within host cell so have similar metabolisms | Long incubation periods and latent infections

Question 217

What is aciclovir and how does it work?

Answer 217

Antiviral | Viral thymidine kinase phosphorylates aciclovir traps virus within infected cell (inhibits viral DNA synthesis)

Question 218

What are the 2 ways a organism can be resistant to antimicrobial?

Answer 218

Innate resistance - lack susceptible target/impermeable to drug Develop/acquire resistance e.g. MRSA

Question 219

What are the 3 mechanisms of resistance?

Answer 219

1. Altered target: lowered affinity for drug OR new target produced 2. Altered uptake: altered entry OR actively pumped out (efflux system) 3. Drug inactivation: enzymes that inactivate drug (B-lactamases)

Question 220

What are the 2 different killing patterns?

Answer 220

1. Conc. dependent: high conc. = greater rate and extent of killing 2. Time-dependent: dependent on duration of exposure

Question 221

Give an example of both the different killing patterns

Answer 221

Conc. dependent: amphotericin | Time: B-lactams

Question 222

What is hypertension?

Answer 222

Blood pressure consistently over 140/90 mmHg taken in multiple readings

Question 223

What are the 8 consequences of hypertension?

Answer 223

1. Occlusive stroke 2. Haemorrhage stroke 3. Angina 4. Cardiac infarct 5. Kidney disease/failure 6. Sexual dysfunction 7. Hypertensive retinopathy: blindness 8. Heart failure

Question 224

What are the 3 consequences hypertension can have on the heart?

Answer 224

1. L ventricle hypertrophy 2. Cardiac infarction 3. Coronary artery disease and atherosclerosis

Question 225

What are the 3 major target sites for pharmacological treatment of hypertension?

Answer 225

1. Renal system 2. Vascular SM 3. SNS

Question 226

What are the 4 aims of hypertensive medication?

Answer 226

1. Suppress renin/angiotensin production 2. Suppress HR and/or vasoconstriction 3. Inc. vasodilation 4. Inc. diuresis

Question 227

What is angiotensin 2?

Answer 227

Direct vasoconstrictor acting through AT1 receptors on vascular SM

Question 228

How does angiotensin 2 work?

Answer 228

Causes release of ADH (vasopressin) from ant. pituitary which acts on hypothalamus to inc. desire for water and salt Inc. aldosterone release

Question 229

What does aldosterone do?

Answer 229

Promotes Na channel and Na/K transporter expression in distal tubule and collecting duct through mineralocorticoid receptor actions

Question 230

What is the consequence of inc. aldosterone release?

Answer 230

Enhance Na re-uptake, inc. K excretion | Water follows Na, inc. fluid vol. putting more stress on heart

Question 231

What 2 types of drug are currently used to target vascular SM in hypertension?

Answer 231

1. Angiotensin converting enzyme (ACE) inhibitors: captopril, enalapril 2. AT1 antagonists: losartan

Question 232

How do diuretics work in combatting hypertension?

Answer 232

Red. blood vol. and depleting Na

Question 233

What are the 2 types of diuretics commonly used to treat hypertension?

Answer 233

1. Thiazides | 2. K-sparing diuretics:

Question 234

How do thiazide drugs work and give a named example

Answer 234

Inhibit Na, Cl reabsorption in distal tubule Inc. Na in collecting duct causes inc. Na/K antiporter activity Hydrochlorothiazide

Question 235

Give an example of K-sparing diuretics and explain how they work

Answer 235

Spinolactone Inhibits aldosterone effect on Na reabsorption and K excretion in distal tubule

Question 236

For hypertensive drugs that target the heart what is the primary approach?

Answer 236

Block beta 1 adrenoreceptors in heart to cause bradycardia

Question 237

What are some typical hypertensive drugs that target the heart?

Answer 237

ATENOLOL, oxordnolol, pindolol, acebitolol, celliprolol

Question 238

What is the aim of Ca channel blocking hypertensive drugs?

Answer 238

Inhibit influx of extracellular Ca into cardiac and smooth muscle preventing contraction Target L-type channels: coronary and peripheral vasodilation

Question 239

Why is there a limited effect on skeletal muscle by Ca channel blockers?

Answer 239

Large excess of L-type Ca channels in skeletal muscle

Question 240

What are the 2 types of Ca blockers used in hypertension treatment?

Answer 240

1. Dihydropyridines | 2. Non-dihyropyridines

Question 241

Give examples of dihydropyridines and explain how they work

Answer 241

Nifedipine, amlodipine Favour vasculature over heart As potent vasodilator cause reflex tachycardia

Question 242

What are nifedipine and amlodipine not effect at treating and why?

Answer 242

Supraventricular tachyarrhythmias | Has no effect on AV conduction

Question 243

Name non-dihydropyridines, how they work and possible side effects

Answer 243

Verpamil, diltiazem Dec. HR by slowing AV node conduction thus may treat supraventricular tachyarrhythmias Adverse effects: bradycardia, AV block

Question 244

Where do ventrally acting hypertension drugs that work on the SNS target?

Answer 244

Medullary cardiovascular regulatory centres

Question 245

Describe how clonidine and alpha-methyldopa drugs work in combatting hypertension

Answer 245

Selective alpha 2 agonists Alpha 2 receptors in medulla red. SNS outflow Centrally mediated vasodilation and red. HR

Question 246

What is moxonidine and how it works?

Answer 246

Imidazoline subtype 1 receptor (I1R) agonist | I1R in depressor area of medulla, causes dec. SNS outflow thus dec. BP

Question 247

What are the 3 types of hypertensive drugs that are peripheral nerve modulators?

Answer 247

1. Ganglionic transmission 2. False NTs 3. Non-selective alpha adrenoceptors antagonists

Question 248

What is trimethaphan and how does it work?

Answer 248

Short-acting N1 antagonist Prevents SNS stimulation in vasculature causing vasodilation Net tachycardia but dec. BP dictated by dec. vasculature resistance

Question 249

What is guanethidine and how does it work?

Answer 249

False NT drugs | Displaces NA from vesicles thus reducing effect of SNS stimulation

Question 250

Why is guanethidine used?

Answer 250

Acute hypertensive crisis, is rarely long term

Question 251

What are phenoxybenzamine and phentolamine

Answer 251

Non-selective alpha-adrenceptor antagonists used in treatment of hypertensive crisis due to monoamide oxidase inhibitors and pheochromocytoma

Question 252

Why are phenoxybenzamine and phentolamine not used in regular hypertension treatment?

Answer 252

Can cause postural hypotension and tachycardia

Question 253

What 2 drugs may be used in hypertensive crisis and what type of drug are they?

Answer 253

1. Hydralazine: liberate NO 2. Sodium nitroprusside: stim. guanylate cyclase Direct vasodilators

Question 254

What is anxiety?

Answer 254

Unpleasant state of emotional turmoil often associated by nervous behaviours

Question 255

Differentiate between fear and anxiety

Answer 255

Fear: response to real or perceived immediate threat Anxiety: response to expectation of future threat w/ or w/o justification

Question 256

What are the 4 subtypes of anxiety?

Answer 256

1. Existential: angst, nihilism 2. Social: meeting new people 3. Mathematical: stage, test, stranger 4. Somatic: physical

Question 257

What is an anxiety disorder?

Answer 257

Group of medical conditions characterised by excessive or prolonged anxiety

Question 258

Describe the causes and diagnosis of anxiety disorders

Answer 258

Causes: complex, genetic and environmental bases Diagnosis: symptoms present for 6mns longer than if just anxiety and impaired functioning

Question 259

What are 7 examples of anxiety disorders? Highlight main 2

Answer 259

1. Generalised anxiety disorder - main 2. Specific phobias: main 3. Social 4. Separation 5. Agoraphobia 6. Panic disorder 7. Selective mutism

Question 260

What are the 5 autonomic physical symptoms of anxiety?

Answer 260

Due to excessive SNS 1. Agitation 2. Tachycardia 3. Inc. sweating, tear production 4. GI disorders 5. Restlessness

Question 261

What are the 5 medical conditions that are associated with or can be aggregated by anxiety?

Answer 261

1. CV: angina, hypertension, arrhythmias 2. GI: IBS, peptic ulcers 3. Respiratory: asthma 4. Endocrine: anaemia, hypoglycaemia 5. Neurological: migraine, tremor, seizures

Question 262

What is a specific phobia?

Answer 262

Unreasonable or irrational fear of specific object/concept Person will avoid contact object or even mention of it

Question 263

What are the 5 categories of phobias?

Answer 263

1. Animals: dogs, spiders 2. Natural environment: water, heights 3. Situational: small spaces 4. Blood/injury/injection: needles 5. Other: loud noises, costumed characters

Question 264

What is the treatment for phobias?

Answer 264

Cognitive behavioural therapies Anxiolytics generally unhelpful

Question 265

What is generalised anxiety disorder?

Answer 265

Uncontrollable, irrational, excessive worry about daily activities/events

Question 266

What are 3 causes of generalised anxiety disorder?

Answer 266

1. Genetic 2. Anti-anxiety drugs, caffeine intake, tobacco smoking 3. Dysfunctional amygdala connectivity: encoding for inappropriate threat level to innocuous sensory info

Question 267

What treatments exist for generalised anxiety disorder?

Answer 267

1. Cognitive behavioural therapy | 2. Anxiolytics

Question 268

What is insomnia and its relation to anxiety?

Answer 268

Inability to sleep | Associated with many anxieties, can potentiate each other

Question 269

What are 4 common causes of insomnia?

Answer 269

1. Age: body clock shifts 2. Personal tragedy/grief: bereavement 3. Disease: alcoholism, dementia, anxiety 4. Modern society: jet lag, shift work

Question 270

What is the treatment for insomnia and the associated risks?

Answer 270

Hypnotics 1. Dependency/addiction 2. Dementia 3. Injuries

Question 271

Describe cognitive behavioural therapy

Answer 271

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

Question 272

What are the 5 major classes of anxiolytics?

Answer 272

1. Barbiturates 2. Benzodiazepines 3. Tricyclic antidepressants 4. Beta adrenoceptor antagonists 5. Buspirone

Question 273

How do barbiturates work and what is the consequence of this?

Answer 273

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

Question 274

What do barbiturates induce?

Answer 274

Liver cytochrome P450 enzymes: major source of drug interactions

Question 275

What are the 6 withdrawal symptoms of barbiturates?

Answer 275

1. Vomiting 2. Seizures 3. Agitation 4. Nausea 5. Tremors 6. Anxiety

Question 276

What are the 4 uses for barbiturates now?

Answer 276

1. Hypnotics for intractable insomnia: amobarbital 2. Anaesthesia: thiopental 3. Small animal euthanasia: pentobarbital 4. Human death penalty: thiopental, pentobarbital

Question 277

What are the 5 general effects of benzodiazepines?

Answer 277

1. Anxiolytic 2. Amnesiac 3. Sedative 4. Muscle relaxant 5. Anticonvulsant

Question 278

How do BZDs function?

Answer 278

Bind selectively to GABA-A receptors act as +ve modulators: | inc. Cl- conductance caused by GABA, hyperpolarising cell making AP less likely

Question 279

How are the 5 BZDs effects each mediated?

Answer 279

1. Anxiolytic: promote alpha-2 GABA-A transmission, inhibit limbic system 2. Sedative: greater dose, alpha-1 GABA-A 3. Amnesiac: alpha-1 GABA-A 4. Anticonvulsant: alpha-1 GABA-A 5. Muscle relaxant: spinal cord alpha-2 GABA-A, large dose

Question 280

Describe the BDZs used for anxiety

Answer 280

Diazepam, clonazepam (sustained) Used for GAD Not widely used due to addictive properties and withdrawal syndrome Don't develop tolerance

Question 281

What BDZ is used for muscle disorders with spasm?

Answer 281

Diazepam | Effective in spasticity caused by spinal cord degeneration e.g. motor neuron disease

Question 282

What BDZs are used as sedatives?

Answer 282

Temazepam, diazepam Dec. sleep latency, inc. sleep depth Tolerance rapidly develops and withdrawal symptom of insomnia

Question 283

Describe the use of benzodiazepines as used as amnesiacs

Answer 283

Lorazepam, temazepam Used prior to unpleasant/invasive treatment: endoscopy, some dental, ECT Sedative: makes treatment easier for patient and clinician

Question 284

What 3 benzodiazepines are used as anticonvulsants? Compare and state what they are used to treat

Answer 284

Epilepsy 1. Clonazepam: more potent anticonvulsant 2. Diazepam: fastest onset 3. Lorazepam: greatest duration

Question 285

Why are benzodiazepines not suitable for long term treatment?

Answer 285

Additive and develop tolerance

Question 286

What are the 4 general side effects of benzodiazepines?

Answer 286

1. Over-sedation, mental confusion, ataxia, poor memory 2. Additive effects with other CNS depressants 3. Withdrawal syndrome 4. Addiction and tolerance

Question 287

What is flumazenil?

Answer 287

Benzodiazepine antagonist

Question 288

How does flumazenil work?

Answer 288

Binds to BDZ binding site preventing BDZ binding preventing action

Question 289

What is the clinical use for flumazenil?

Answer 289

Treat BDZ overdose and dependence

Question 290

What is the consequence of taking flumazenil?

Answer 290

May precipitate side effects: confusion, toxic psychosis, convulsions

Question 291

What is buspirone?

Answer 291

Anxiolytic that acts solely on CNS 5-HT pathways | Agonist to 5-HT1-A autoreceptors, red. serotonergic cell firing

Question 292

Compare buspirone to benzodiazepines

Answer 292

Buspirone as potent anxiolytic as BDZs w/o causing sedation

Question 293

What is a side effect of buspirone?

Answer 293

May cause psychological dependence

Question 294

Name a beta adrenoceptor antagonist and how it can function as an anxiolytic

Answer 294

Propranolol | As many symptoms of anxiety caused by excessive SNS tone beta receptor blockers prevent many effects

Question 295

Explain how antidepressants are able to function as anxiolytics

Answer 295

Many have sedative/hypnotic properties

Question 296

What is heart failure?

Answer 296

State in which heart can't provide sufficient CO to satisfy metabolic needs of body

Question 297

What are the 9 symptoms of congestive heart failure?

Answer 297

1. Shortness of breath upon motion 2. Coughing 3. Fluid retention 4. Oedema in lower limbs and abdomen 5. Inc. nocturnal urination 6. Tiredness 7. Muscle weakness 8. Dizziness 9. Irregular HB

Question 298

Define myocardial infarction, coronary heart disease, cardiac arrest

Answer 298

MI: death of piece of heart tissue Coronary heart disease: failure of heart oxygen supply Cardiac arrest: complete cessation of blood supply

Question 299

What diseases does HF have similar symptoms to?

Answer 299

Liver or kidney failure Obesity Anaemia

Question 300

What can trigger HF and what will this ultimately lead to?

Answer 300

MI or coronary heart disease | Will lead to cardiac arrest

Question 301

What are the 6 conditions that affect myocardial efficiency that can cause HF?

Answer 301

1. MI 2. Valve disease 3. Inc. alcohol intake 4. Hypertension 5. Infection 6. Amyloidosis: abnormal deposition of amyloid proteins in tissues

Question 302

What 4 problems can cause HF?

Answer 302

1. Red. stroke vol: failure of systole, diastole or both 2. Red. spare capacity 3. Inc. HR due to inc. SNS activity 4. Hypertrophy: anabolic steroids or EPO

Question 303

What is the Frank-Starling law of the heart?

Answer 303

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

Question 304

What are the 4 physiological responses to HF and red. CO?

Answer 304

1. Fall in arterial BP: activates baroreceptors, cause peripheral vasoconstriction restores BP and inc. heart workload 2. Inc. pituitary ADH release: inc. fluid retention, inc. BP 3. Red. kidney perfusion: stimulates RAAS system, Na and H2O retention, vasoconstriction 4. Hormones induce structural remodelling: cardiac hypertrophy

Question 305

What are the 3 aims of HF treatment?

Answer 305

1. Inc. contractility 2. Red. preload/afterload 3. Red. water load (blood vol)

Question 306

What drugs inc. cardiac contractility?

Answer 306

Cardiac glycosides: digoxin, digitoxin

Question 307

How do cardiac glycosides work?

Answer 307

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

Question 308

What is the main problem associated w/ cardiac glycosides?

Answer 308

Improve symptoms but don't prevent mortality

Question 309

What are the 3 side effects of digoxin?

Answer 309

1. Inc. AV conduction time: inc. vagal tone 2. Inc. incidence of ectopic pacemaker activity: inc. automaticity 3. Inc. diuresis

Question 310

What are some of the toxic affects of digoxin?

Answer 310

``` Nausea Vomiting Delirium Vision disturbance Diarrhoea Abdominal pain Headache Dizziness Confusion ```

Question 311

Who is most at risk of digoxin toxicity and how are toxic effects managed?

Answer 311

Patients w/ hypokalaemia | Managed w/ anti-digoxin antibodies

Question 312

What are the 3 types of diuretics?

Answer 312

1. Thiazides 2. Loop 3. K-sparing

Question 313

Describe thiazides

Answer 313

Hydrochlorothiazide | Acts on early DCT: inc. Na and K excretion, prevents Na reabsorption

Question 314

Describe loop diuretics

Answer 314

Frusemide | Act on ascending limb of loop of Henle, inc. Na and K excretion

Question 315

Describe K-sparing diuretics

Answer 315

Spironolacetone act of DCT to inc. Na excretion Important when using cardiac glycosides

Question 316

What are the 2 methods used to red. preload and afterload?

Answer 316

1. Direct vasodilators | 2. Modulate renin/angiotensin/aldosterone system

Question 317

Name ACEIs and angiotensin II receptor antagonists and how they function

Answer 317

ACEIs: enalapril, captopril Angiotensin II R antagonists: losartan, candesartan Both dec. afterload by antagonising vasopressor effect of angiotensin, dec. cardiac work

Question 318

What is the additional benefit of blocking angiotensin?

Answer 318

Angiotensin may directly cause cardiac hypertrophy thus blocking activity slow cardiac deterioration

Question 319

What are the 2 drug types used as direct vasodilators in treatment of HF?

Answer 319

1. Organic nitrates: isosorbide dinitrate | 2. Arterial vasodilators: hydralazine, minoxidil

Question 320

How do organic nitrate drugs work?

Answer 320

Intracellular NO activates guanylate cyclase inc. cGMP Causes inc. Ca2+ sequestration and SM relaxation Venodilator: red. preload

Question 321

What problems are associated w/ organic nitrates?

Answer 321

Headaches Tolerance Flushing Tachycardia

Question 322

How do hydralazine and minoxidil work in treatment of HF?

Answer 322

Are arterial vasodilators, dec. afterload Hydralazine: unclear Minoxidil: K channel opener

Question 323

What treatment is used for HF in African and Caribbean patients?

Answer 323

Isosorbide-hydralazine combination therapy | Patients respond less to ACEIs

Question 324

What is epilepsy and what is it characterised by?

Answer 324

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

Question 325

Describe the genetic cause of epilepsy

Answer 325

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

Question 326

What are the 4 acquired causes of epilepsy?

Answer 326

More common in older people 1. Trauma 2. Stroke 3. Tumours 4. Infection-induced

Question 327

What are the 2 types of seizures?

Answer 327

1. Partial | 2. Generalised

Question 328

What are the 2 types of partial seizures?

Answer 328

Simple: no loss of consciousness Complex: loss of consciousness to some degree, not necessarily full loss

Question 329

Describe partial seizures

Answer 329

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

Question 330

What are the 5 types of generalised seizures?

Answer 330

1. Absence 2. Myoclonic 3. Clonic 4. Tonic-clonic 5. Atonic

Question 331

Describe the 5 generalised seizures

Answer 331

1. Absence: loss of consciousness, vacancy, unresponsive 2. Myoclonic: extremely brief muscle contraction, jerky movements 3. Clonic: repeated myoclonic seizures 4. Tonic-clonic: initial muscle contraction followed by rhythmic muscle contraction 5. Atonic: loss of muscle tone, cause collapse

Question 332

What is status epilepticus?

Answer 332

Rapid chain of seizures | Medical emergency

Question 333

What is grand mal epilepsy?

Answer 333

Another name for tonic-clonic seizure | Classic epileptic fit

Question 334

What is petit mal epilepsy?

Answer 334

Absence and atonic seizures

Question 335

What is the rationale behind epilepsy treatment methods?

Answer 335

Limit neuronal over activity by suppressing excessive synaptic activity OR by enhancing inhibitory NT function

Question 336

What are the 3 types of drug that are used in epilepsy treatment?

Answer 336

1. VGNaC inhibitors 2. GABA enhancers 3. VGCaC modifiers

Question 337

What 2 drugs are used as Na channel modifiers in treatment of epilepsy?

Answer 337

1. Phenytoin | 2. Carbamazepine

Question 338

Describe the action of phenytoin

Answer 338

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

Question 339

Describe the pharmacokinetics of phenytoin

Answer 339

1. Orally well absorbed 2. Eliminated by hepatic metabolism 3. Promotes hepatic enzyme expression

Question 340

What are the 3 adverse effects of phenytoin?

Answer 340

1. Megaloblastic anaemia (large RBCs): treated w/ folic acid 2. Hirsutism: abnormal hair growth due to androgen 3. Gingival hyperplasia

Question 341

Describe carbamazepine

Answer 341

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)

Question 342

What are the 3 acute and 5 chronic adverse effects of carbamazepine?

Answer 342

Acute 1. Respiratory depression 2. Coma 3. Convulsion Chronic 1. Vertigo 2. Vomiting 3. Hyperatraemia 4. Ataxia 5. Hypersensitivity

Question 343

Describe phenobarbitone

Answer 343

Prolongs GABA-A opening inc. Cl- inward current hyperpolarising post-synaptic membrane Net effect red. glutamate excitation Effective against all seizures but absence

Question 344

Describe the pharmacokinetics of phenobarbitone

Answer 344

1. Orally bioavailable | 2. Potent hepatic enzyme inducer

Question 345

What are the 4 adverse effects of phenobarbitone and effect of OD?

Answer 345

1. Megaloblastic anaemia 2. Sedation 3. Osteomalacia: softening of bone, give VitD 4. Hyperactivity in children OD: respiratory and circulatory failure

Question 346

Describe benzodiazepine use in treatment of epilepsy

Answer 346

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

Question 347

Describe tiagabine

Answer 347

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

Question 348

Describe the pharmacokinetics of tiagabine

Answer 348

Good oral absorption Highly protein bound Few drug interactions

Question 349

What are the 4 adverse effects of tiagabine?

Answer 349

1. Ataxia 2. Dizziness 3. Tremor 4. Depression

Question 350

What 3 drugs are used as GABA modifiers in treatment of epilepsy?

Answer 350

1. Phenobarbitone 2. Diazepam/lorazepam 3. Tiagabine

Question 351

What 2 drugs are used to treat grand and petit mal seizures?

Answer 351

1. Valpronic acid | 2. Ethosuximide

Question 352

Describe valpronic acid

Answer 352

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

Question 353

What are the 2 acute and 4 chronic adverse effects of valpronic acid?

Answer 353

Acute 1. Nausea 2. Vomiting Chronic 1. Wight gain 2. Hair loss 3. Tremor 4. Thrombocytopenia: platelet deficiency

Question 354

What is the adverse effect of valpronic acid important for pregnant women?

Answer 354

Significant teratogenicity in 1st trimester | Caused malformation of embryo and possibly induce abortion

Question 355

Describe ethosuximide

Answer 355

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

Question 356

What are the 5 adverse effects of ethosuximide?

Answer 356

1. Ataxia 2. Aggression 3. Drowsiness 4. Euphoria 5. Anxiety

Question 357

What is schizophrenia?

Answer 357

Most complex disorder of thought and emotion resulting in difficulty distinguishing between real and false perceptions

Question 358

Generally describe symptoms of schizophrenia. What are the 3 types of symptoms?

Answer 358

Often heterogenous and liable to change 1. Positive: delusions and hallucinations (auditory), bizarre behaviour 2. Negative: social withdrawal, avoilition, poverty of speech 3. Cognitive: poor conc., disorientation, difficulties in abstract thought and memory

Question 359

What is the single greatest risk factor of schizophrenia?

Answer 359

Having an affected first degree relative

Question 360

What are the 4 other risk factors of schizophrenia?

Answer 360

1. Male: 40% more likely, symptoms earlier; incidence peaks @ 21,40 whereas females 22, 37, 60 2. Living in urban environment when young: 2x risk 3. Birth season: late winter/early spring; low VitD, infection 4. Poor nutrition during 2nd trimester

Question 361

Describe the brain abnormalities seen in schizophrenics

Answer 361

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

Question 362

What are the 4 pieces of evidence that corroborate the dopamine theory of schizophrenia?

Answer 362

1. All antipsychotics are DA receptor antagonists 2. Almost perfect correlation between therapeutic dose of typical antipsychotic and D2 receptor affinity 3. Cis-flupenthixol is neuroleptic, has DA antagonist properties: trans-flupenthixol not neuroleptic has no DA antagonist properties 4. Amphetamine and cocaine inc. DA release and cause schizophrenic like syndrome

Question 363

What is the relation between glutamate and schizophrenia?

Answer 363

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

Question 364

What evidence discredits glutamate link to schizophrenia?

Answer 364

Glutamate agonists have been unsuccessful thus far

Question 365

Describe the link between inflammation and schizophrenia

Answer 365

Recent studies show microglia active in schizophrenic brains prior to medication Inc. inflammation, inc. risk

Question 366

Describe neuroleptics

Answer 366

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

Question 367

What are the 2 general classes of neuroleptics?

Answer 367

1. First gen/typical antipsychotics: DA antagonists | 2. 2nd gen/atypical antipsychotics: DA and serotonin antagonists

Question 368

What are 2 1st gen antipsychotics?

Answer 368

1. Chlorpromazine | 2. Haloperidol

Question 369

Describe chlorpromazine

Answer 369

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

Question 370

What are the 6 adverse effects of chlorpromazine?

Answer 370

1. Extrapyramidal motor effects 2. Breast swelling or discharge 3. Anti-muscarinic: drowsiness, dizziness, dry mouth, constipation, blurred vision 4. Weight gain 5. Anxiety 6. Impotence

Question 371

Describe haloperidol

Answer 371

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

Question 372

What are the 6 adverse effects of haloperidol?

Answer 372

1. Extrapyramidal motor effects 2. Anxiety 3. Impotence 4. Breast swelling or discharge 5. Hypotension 6. Toxic to developing embryos

Question 373

What neuroleptic is an atypical antipsychotics?

Answer 373

Clozapine

Question 374

Describe clozapine

Answer 374

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

Question 375

What are the 9 adverse effects of clozapine?

Answer 375

1. Extrapyramidal motor effects 2. Anxiety 3. Impotence 4. Breast swelling or discharge 5. Agranulocytosis 6. Weight gain 7. Cardiac inflammation 8. Seizures 9. Hypersalivation

Question 376

What are the 5 extrapyramidal motor effects?

Answer 376

1. Bradykinesia: slowness of movement 2. Tardive dyskinesia: involuntary, repetitive writhing movements of face and limbs 3. Dystonia: continuous spasms and muscle contraction 4. Akathisia: motor restlessness 5. Tremor

Question 377

Describe tardive dyskinesia

Answer 377

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

Question 378

What are the 3 risk factors of tardive dyskinesia?

Answer 378

1. Female 2. African/Afro-Caribbean 3. -ve schizophrenia symptoms

Question 379

What is the treatment for tardive dyskinesia?

Answer 379

No specific treatment | benzodiazepines effective but use limited due to developmental tolerance

Question 380

What are affective disorders?

Answer 380

Mental disorders characterised by changes in mood rather than thought including depression and mania

Question 381

What are the 6 depressive symptoms?

Answer 381

1. Feeling misery, apathy, pessimism 2. Low self-esteem: guilt, ugliness, inadequacy 3. Lack of motivation, indecisiveness 4. Insomnia 5. Slow thoughts and actions 6. Loss of appetite

Question 382

What are the 4 symptoms of mania?

Answer 382

1. Delusions of grandeur 2. Excessive exuberance, over-confidence 3. Irritability, anger, impatience 4. Excessive physical activity

Question 383

What are the 2 types of depression?

Answer 383

1. Dysthymia: mild | 2. Major (MDD): severe

Question 384

What genetic factors are believed to play a role in depression?

Answer 384

Familial component | Genes regulating 5-HT regulation

Question 385

What social factors play a role in depression?

Answer 385

1. Bereavement 2. Financial strain 3. Sexual, physical, emotional abuse 4. Childhood abuse/trauma 5. Social exclusion

Question 386

What medical factors can play a role in depression?

Answer 386

1. Alcohol/illegal drug use 2. Chronic/serious ill health 3. Medicinal drugs: antihypertensives

Question 387

What are the 3 key pieces of evidence that support the monoamine theory of depression?

Answer 387

1. Treatment w/ NA packaging blocker reserpine for hypertension caused depression 2. TB treatment w/ MAOI iproniazid improved symptoms 3. Most antidepressants potentiate monoamine (NA, 5-HT, DA, AD) signalling

Question 388

What are the 3 flaws in the monoamine theory?

Answer 388

1. Treatment w/ monoamine interacting drugs have immediate neurochemical effect but behavioural effect takes 3/4wks to appear - why is there delay? 2. No evidence of monoamine signalling deficient 3. Atypical antidepressants don't target monoamine systems but still effective

Question 389

Explain the hypothalamo-pituitary-adrenal axis

Answer 389

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

Question 390

What are the 5 classes of antidepressants?

Answer 390

1. Tricyclic antidepressants 2. Serotonin Selective Re-uptake Inhibitors (SSRIs) 3. Serotonin and NA RIs, NA Selective RIs 4. Monoamine Oxidase Inhibitors (MAOIs) 5. Atypical antidepressants

Question 391

What 2 other therapies can be used in treatment of depression?

Answer 391

1. Cognitive behavioural therapy: mild | 2. Electroconvulsive therapy: severe

Question 392

How do TCAs work? Name three

Answer 392

Inhibit uptake of 5-HT and NA prolonging synaptic lifetime 1. Imipramine: NA>>5-HT 2. Amitriptyline: NA and 5-HT 3. Desipramine: NA; active metabolite of imipramine

Question 393

What are the 5 adverse effects of TCAs (amitriptyline)?

Answer 393

1. Epileptogenic 2. Antimuscarinic: dry mouth, blurred vision, constipation, urinary retention 3. Alpha-adrenoceptor antagonist: postural hypotension 4. H1 antagonist: sedation 5. Cardiotoxic in OD: induction of atrial and ventricular arrhythmias

Question 394

What are the drug interactions of TCAs?

Answer 394

Strongly potentiate sedative properties of alcohol | Reverses adrenergic antagonists

Question 395

What are the 2 isoforms of monoamine oxidase?

Answer 395

MAO-A: serotonin, NA MAO-B: serotonin, DA, NA Inhibition of MAO-A associated w/ antidepressant effects

Question 396

What are the 2 types of MAOIs? Give examples

Answer 396

1. Nonreversible: phenelzine 2. Reversible: moclobemide Moclobemide has fewer side effects

Question 397

What are the 4 adverse effects of MAOIs?

Answer 397

1. Hypotension: DA accumulation in periphery; vasodilation 2. Central: agitation, tremors, insomnia 3. Antimuscarinic: less than TCAs 4. Foetal abnormalities during pregnancy

Question 398

Explain the 'cheese reaction'

Answer 398

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

Question 399

How do MAOIs interact w/ pseudoephedrine and phenylephrine?

Answer 399

Sympathomimetics in cold cures | Block NA clearance: hypertension

Question 400

Which MAOIs are hepatotoxic? What is the effect of this?

Answer 400

Irreversible MAOIs | Red. metabolism of drugs such as barbiturates, alcohol leading to prolonged, exaggerated effects

Question 401

Describe the interaction between MAOIs and pethidine

Answer 401

Pethidine is opioid analgesic, metabolised by MAOs | Block can result in hyperthermia, hypotension, coma and respiratory depression

Question 402

Name 4 SSRIs

Answer 402

1. Fluoxetine 2. Paroxetine 3. Citalopram 4. Fluvoxamine

Question 403

How do SSRIs function?

Answer 403

Block re-uptake of 5-HT prolonging synaptic lifetime and effects

Question 404

What forms of depression are SSRIs best suited for?

Answer 404

Less effective for short-term mild depression | Effective in chronic/severe depression

Question 405

Describe the side effects of SSRIs

Answer 405

Lack sedative and antimuscarinic affects but more prone to epileptogenic effects

Question 406

What is serotonin syndrome?

Answer 406

Acute toxic reaction caused by use of 2+ types of monoamine modulators

Question 407

What are the 6 symptoms of serotonin syndrome?

Answer 407

1. High body temp: >41 2. Agitation 3. Diarrhoea 4. Dilated pupils 5. Sweating 6. Seizures

Question 408

What is the treatment for serotonin syndrome?

Answer 408

Cessation of monoamine modulators | Administration of serotonin antagonists: cyproheptadine

Question 409

What are 4 new an antidepressants?

Answer 409

1. Venlafaxine: Serotonin and NA RI 2. Nefazodone: Serotonin and NA RI 3. Mirtazapine: NA and Selective Serotonin Antidepressant 4. Reboxetine: Selective NA RI

Question 410

How does venlafaxine work?

Answer 410

Potent block of NA and serotonin re-uptake | SNARI

Question 411

How does nefazodone work?

Answer 411

Potent 5-HT2 receptor antagonists w/ weak SNARI activity | More sedative than venlafaxine, causes nausea

Question 412

How does mirtazapine work?

Answer 412

Alpha-2, 5-HT 2 and 3 receptor antagonists (all autoreceptors) Inc. both NA and serotonin transmission NASSA

Question 413

How does reboxetine work?

Answer 413

NARI | Antimuscarinic and pro-sympathetic side effects: dry mouth, constipation, urinary retention, tachycardia, insomnia

Question 414

What is bipolar affective disorder?

Answer 414

Mental disorder characterised by fluctuating states of depression and mania

Question 415

Describe structural and functional MRI imaging in bipolar affective disorder

Answer 415

Structural: inc. vol. pallidum and lat. ventricles Functional: abnormal modulation of amygdala likely underlie emotional and mood regulation: inappropriate emotional labelling of sensations

Question 416

How is lithium used in antidepressants?

Answer 416

Mood stabiliser Used in treatment of bipolar manic phases Can be used in resistant depression Red. freq. and severity of relapses, red. likelihood suicide

Question 417

What are the 5 acute and 4 severe toxic affects of lithium?

Answer 417

1. Drowsiness 2. Ataxia 3. Nausea 4. Blurred vision 5. Coarse tremor 1. Delirium 2. Convulsion 3. Coma 4. Death

Question 418

Explain the 2 mechanisms of lithium action

Answer 418

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

Question 419

Describe ECT

Answer 419

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

Question 420

What are the 3 brain areas involved coordination of movement?

Answer 420

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

Question 421

What are the functions of cerebellum?

Answer 421

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

Question 422

What are the 4 nuclei of the basal ganglia?

Answer 422

Striatum: caudate nucleus, putamen Globus pallidus: int. (med.), ext. (lat.) Subthalamic nucleus Substantia nigra: pars reticulata, pars compacta

Question 423

What are the 4 functions of the basal ganglia?

Answer 423

1. Integrate desire and fine movement: stop and start movement 2. Fine smooth motor behaviour 3. Suppress unwanted movements 4. Exerts inhibitory influence on motor functions, relief allows motor behaviours to occur

Question 424

How is the basal ganglia modelled?

Answer 424

3 interacting pathways that regulate cortical activity through thalamus 1. Direct 2. Indirect 3. Hyper-direct

Question 425

How is the basal ganglia organised?

Answer 425

Topographically: specific sub parts of each nucleus regulate specific motor functions

Question 426

Describe the direct pathway

Answer 426

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

Question 427

Describe the indirect pathway

Answer 427

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

Question 428

Describe the hyper-direct pathway

Answer 428

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

Question 429

Describe DA regulation of the basal ganglia

Answer 429

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

Question 430

How do basal ganglia disorders manifest?

Answer 430

Involuntary movements: dyskinesias

Question 431

What are hyperkinetic disorders? What are the 4 types?

Answer 431

Excessive involuntary movements 1. Chorea: involuntary, rapid, freq., purposeless jerks of extremities, head, trunk w/ facial grimaces 2. Athetosis: slow, writhing, worm-like motions of distal extremities 3. Ballism: violet, flinging continuous movements of limbs 4. Dystonia: twisting, slow, contorting movements

Question 432

What are kypokinetic disorders? What are the 2 types?

Answer 432

Impairment in initiation of movement 1. Akinesia: impairment of initiation, rigidity 2. Bradykinesia: red. amplitude and velocity movements

Question 433

What is Parkinson's caused by and what are the 7 symptoms?

Answer 433

Degeneration of nigrostriatal DA neurons and consequent dysregulation of BG 1. Resting tremor 2. Dementia 3. Micrographia 4. Difficulties speech and swallowing 5. Postural instability 6. Bradykinesia 7. Rigidity

Question 434

What is the rationale and targets of Parkinson's treatment?

Answer 434

Replace lost DA Target: DA synthetic pathways, DA catabolism, DA receptors

Question 435

What is levodopa?

Answer 435

Immediate precursor of DA | Converted to DA by endogenous L-DOPA decarboxylase

Question 436

What 2 symptoms does L-DOPA red. in Parkinson's?

Answer 436

1. Bradykinesia | 2. Rigidity

Question 437

What are the 6 adverse effects of L-DOPA? Highlight the 2 main ones

Answer 437

1. Involuntary writhing: dyskinesia 2. On-off effects: effectiveness fluctuates 3. Nausea and vomiting 4. Hypotension 5. Clouds thoughts 6. Schizophrenia like syndrome

Question 438

What is carbidopa? How does it help adverse effects when taken in combination w/ L-DOPA?

Answer 438

Peripheral DOPA decarboxylase inhibitor | Prevents nausea

Question 439

What are the 2 methods of DA modulation in Parkinson treatment?

Answer 439

1. MAO-B inhibitors: selegiline | 2. DA agonists: bromocriptine

Question 440

Describe the use of MAO-B inhibitors in PD treatment

Answer 440

MAO-B predominate in CNS Improve motor function in early and advanced Lack cheese reaction of MAO-A inhibitors

Question 441

What are bromocriptine and apomorphine?

Answer 441

D 1 and 2 receptor agonists used in treatment of PD | Apomorphine stabilises patients during L-DOPA treatment

Question 442

What is benzatropine?

Answer 442

Centrally acting M1 receptor antagonist | Anticholinergic

Question 443

How can anticholinergic drugs be used in PD treatment?

Answer 443

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

Question 444

What is amantadine?

Answer 444

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

Question 445

What is an analgesic?

Answer 445

Drug that acts in the CNS to relieve pain w/o affecting other sensory perception or consciousness

Question 446

What are the 3 classes of analgesics? Give examples

Answer 446

1. Opioids: morphine, codeine, diamorphine (heroin) 2. Non-steroidal anti-inflammatory: aspirin, ibuprofen, diclofenac 3. Local anaesthetics: lidocaine, novocaine, benzocaine

Question 447

Define opium

Answer 447

Dried poppy latex | Mix of analgesic, non-analgesic, inert agents

Question 448

Define opiate

Answer 448

Drugs derived from opium: morphine, codeine, heroin | Semi-synthetic drugs derived from them and thebaine: naloxone, nalorphine, buprenorphine

Question 449

Define opioid

Answer 449

All agonists and antagonists w/ morphine-like pharmacology

Question 450

Name 4 synthetic opioids

Answer 450

1. Pethidine 2. Fentanyl 3. Methadone 4. Pentazocine

Question 451

Name the 4 classes of endogenous opioids

Answer 451

1. Enkephalins: leu and met-enkephalin 2. Dynorphins: A and B 3. Endorphins: beta-endorphin, beta-neoendorphin, alpha-neoendorphin 4. Endomorphins: 1 and 2

Question 452

What are the 5 classes of opioid receptor? Which are involved in analgesic? How do they all function?

Answer 452

1. Mu: analgesic 2. Kappa: analgesic 3. Delta: analgesic 4. NOP (nociceptin) 5. Zeta All 7TM GPCRs acting through Gi/o

Question 453

What are the 4 classes of opioids?

Answer 453

1. Agonists 2. Antagonists 3. Agonists/antagonists 4. Partial agonists

Question 454

What are the 3 groups of opioid agonists? Give examples

Answer 454

1. Opiate: morphine, codeine, heroin 2. Synthetic opioid: pethidine, fentanyl, methadone 3. Endogenous: endorphins

Question 455

Name a opioid antagonist

Answer 455

Naloxone

Question 456

Name 2 opioid agonists/antagonists

Answer 456

Nalorphine and pentazocine Different effects on different receptors Competitive mu antagonists and kappa agonists Dose dependent effects, agonists at high conc.

Question 457

Name a partial opioid agonist

Answer 457

Buprenorphine: partial mu agonist 10x more potent than morphine but lower maximal effects Most cases block morphine actions

Question 458

Describe the effectiveness of opioid analgesics and where they act

Answer 458

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

Question 459

Explain descending pain control and how opioid analgesics interact w/ this

Answer 459

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

Question 460

Explain the spinal actions of opioid analgesics

Answer 460

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

Question 461

Why is euphoria important in analgesia? Explain the mechanism

Answer 461

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

Question 462

How do opioids suppress respiration? Why is this a major problem?

Answer 462

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

Question 463

How do opioids cause miosis?

Answer 463

Morphine and mu/kappa agonists cause contraction by excitatory action at oculomotor nucleus Activate parasympathetic innervation of pupil

Question 464

What is the clinical relevance of miosis in opioids?

Answer 464

Diagnostic feature of opioid OD | Distinguish between opioid induced coma/respiratory depression from other causes (usually cause dilation)

Question 465

Explain the anti-tussive effect of opioids

Answer 465

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

Question 466

Why is anti-tussive dangerous?

Answer 466

Coughing reflex is protective mechanism: allows clearing of airways

Question 467

Describe the effects of opioids on the GIT

Answer 467

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.

Question 468

What are the 3 general effects of opioids on GIT?

Answer 468

1. Constipation 2. Delayed digestion of food in small intestine 3. Retarded absorption of other drugs

Question 469

Explain how nausea/emesis is triggered in opioid use. Describe changes in recumbent and ambulatory patients

Answer 469

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

Question 470

How are opioids usually administered?

Answer 470

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

Question 471

Describe the metabolism of morphine

Answer 471

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

Question 472

Describe the onset of tolerance to opioids

Answer 472

Occurs rapidly Affects most effects: analgesic, euphoria, respiratory depression Mechanism not understood: suggested that gene expression changes are responsible

Question 473

What are the 2 types of tolerance to opioids? Describe them

Answer 473

1. Physical: withdrawal syndrome; pupillary dilation, sweating, fever, piloecrection, nausea, diarrhoea, insomnia 2. Psychological: craving irrespective whether to ward off withdrawal or for euphoric actions

Question 474

What are the 5 major LAs?

Answer 474

1. Lidocaine 2. Articaine 3. Procaine 4. Prilocaine 5. Mepivacaine

Question 475

What are the 6 uses of LAs?

Answer 475

1. Infiltration 2. Nerve block 3. Spinal 4. Epidural 5. Ventricular dysrhythmias 6. Surface

Question 476

Describe a infiltration LA

Answer 476

Injection into tissues to reach nerve branches and terminals for minor surgery

Question 477

Describe the use of nerve block LA

Answer 477

Close to nerve trunk | Causes loss of peripheral sensation, used in surgery and dentistry (lidocaine, prilocaine)

Question 478

Describe the use of spray LA

Answer 478

Applied as spray (lidocaine) or powder to mucus membrane of mouth, nose, cornea

Question 479

Describe use of spinal LA

Answer 479

Injected into subarachnoid space to act on spinal roots and cord (lidocaine)

Question 480

Describe epidural LA use

Answer 480

Injected into epidural space to block spinal roots (lidocaine, bupivacaine)

Question 481

What LA is used for ventricular dysrhythmias?

Answer 481

Lidocaine

Question 482

Compare procaine, lidocaine, prilocaine

Answer 482

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

Question 483

Briefly describe the action of VGNa+Cs and their 3 stages

Answer 483

Driver of AP propagation Voltage opening responsible for rapid depolarisation phase of AP Following opening, channels blocked by slow-acting inactivation gate 1. Resting 2. Open 3. Inactivated

Question 484

What is the relationship between VGNa+Cs and LA?

Answer 484

LA block channels, prevent neuronal depolarisation | LA binds on intracellular side

Question 485

What 3 factors determines LAs effectiveness?

Answer 485

1. MUST enter neuron 2. Lipophilicty: inc. lipophilicity, inc. potency 3. Ionisation: inc. protonated, inc. potency

Question 486

What conformation of VGNa+C do LAs bind most strongly? What is the effect of this?

Answer 486

Inactivated form, hold in conformation | Inc. proportion of inactivated channels impairing AP propagation; neuronal membrane can't depolarise

Question 487

What is the relationship between nerve stimulation and LA onset?

Answer 487

More nerve stim., more rapid anaesthetic onset | Use dependent block

Question 488

Describe the relationship between ionisation and diffusion across PM. What is ionisation dependent on?

Answer 488

Only non-ionised drugs cross lipid PM | Ionisation depends on relationship between drugs pKa and environmental pH

Question 489

Describe the relationship between pH, pKa and ionisation

Answer 489

pH < pKa: drug accepts H+; non-ionised/protonated | pH > pKa: drugs disassociates; ionised/non-protonated

Question 490

What are most LAs? What is the relevance of this to their action?

Answer 490

Weak bases pKa ~8.9 thus mostly ionised (not completely) @ physiological pH (7.4) Less cross PM

Question 491

What are the 2 pathways by which LA can block VGNaCs?

Answer 491

1. Use dependent (hydrophobic) | 2. Use independent (hydrophilic)

Question 492

How do LAs prevent pain?

Answer 492

Preventing conduction along nerve fibres

Question 493

What is the relationship between fibre diameter and ease of blocking?

Answer 493

Smaller, myelinated fibres (A delta) blocked more easily than larger, unmyelinated fibres Myelinated blocked before unmyelinated

Question 494

What is the rate of LA blockade dependent on?

Answer 494

How quickly sufficient Na channels can be inhibited to prevent neuronal depolarisation

Question 495

Explain why autonomic fibres and blocked before pain fibres by LA

Answer 495

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

Question 496

What is the relevance of vasodilation to LA?

Answer 496

LA block sympathetic vasoconstrictive alpha-1 stimulation causing vasodilation Inc. blood flow causes more rapid clearance of drug

Question 497

What is administered w/ LA to combat vasodilation?

Answer 497

AD to induce vasoconstriction red. loss of LA

Question 498

Why must care be taken when using AD w/ LA?

Answer 498

Must not inject intravenously as risk systemic effects

Question 499

Why LAs come w/ AD preparations?

Answer 499

Lidocaine Articaine Mepivacaine

Question 500

What affects the potency of LA?

Answer 500

pKa and lipophilicity

Question 501

What are the 2 classes of LAs? How do they differ?

Answer 501

1. Esters 2. Amides Toxic potential, metabolism, duration

Question 502

Describe ester LA

Answer 502

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)

Question 503

Describe amide LAs

Answer 503

More stable to hydrolysis Primarily hepatic metabolism Can accumulate on repeated dosage Dose-related toxicity, can be delayed by mins-hrs

Question 504

What are the 7 amide LAs?

Answer 504

1. Lidocaine 2. Bupivacaine 3. Levobupivacaine 4. Etidocaine 5. Ropivacaine 6. Mepivacaine 7. Prilocaine

Question 505

What are the 5 ester LA?

Answer 505

1. Procaine 2. Cocaine 3. Chloroprocaine 4. Tetracaine 5. Benzocaine

Question 506

What are the 2 principal target systems of toxicity to LAs?

Answer 506

1. CNS | 2. CVS

Question 507

What are the 3 early signs of CNS LA toxicity?

Answer 507

1. Tinnitus 2. Dizziness 3. Light-headedness

Question 508

What are the progressively worsening toxic affects of LA on CNS?

Answer 508

Anxiety -> disorientation -> unconsciousness -> seizures -> respiratory arrest

Question 509

What are the effects on the CVS of LA?

Answer 509

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

Question 510

What order do toxic effects of LA follow? Why is this useful? How can they be treated?

Answer 510

Usually CNS before CVS; show warning signs: tinnitus, motor twitching, grand mal seizures, coma Maintain O2 and normal CO2

Question 511

What 4 factors inc. risk of seizure and CVS collapse of LAs?

Answer 511

1. Cold temp (slow metabolism) 2. Metabolic/respiratory acidosis 3. Hypoxia 4. Pregnancy

Question 512

Describe platelets

Answer 512

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

Question 513

Describe the structure of platelets

Answer 513

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

Question 514

Explain the feedback control of platelet production

Answer 514

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

Question 515

What are the 2 special organelles present in platelets?

Answer 515

1. alpha granules: store von Willebrand factor, platelet fibrinogen (originate from liver), clotting factor V 2. Dense-cross granules: store ADP, ATP, serotonin, Ca2+

Question 516

What is the main role of platelets?

Answer 516

Essential for haemostasis (stopping blood flow) by formation of clot

Question 517

Describe clots and thrombi

Answer 517

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

Question 518

Describe the formation of a clot

Answer 518

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

Question 519

Why must clotting be regulated?

Answer 519

Inadequate clotting would lead to leakage of blood from vascular Overactive would cause thrombosis and cessation of blood flow

Question 520

Discuss antithrombotic

Answer 520

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

Question 521

Discuss prothrombotics

Answer 521

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

Question 522

What are the 2 stages of the coagulation cascade?

Answer 522

1. Coagulation: formation of clot, arrest bleeding | 2. Fibrinolysis: dissolve clot after served purpose

Question 523

In what state are clotting factors present in the blood? Why is this important?

Answer 523

Present as zymogens (inactive) | Prevent unwanted clotting but allow for rapid clotting when required

Question 524

What are the 3 pathways of the coagulation cascade?

Answer 524

1. Intrinsic: triggered by contact w/ -ve phospholipid surfaces, mimic w/ glass 2. Extrinsic: contact w/ material from damaged cell membranes, cell debris 3. Common: both converge, leads to thrombin clot and stable fibrin

Question 525

Compare where the intrinsic and extrinsic coagulation pathways occur

Answer 525

Intrinsic: at membrane of activated platelets Extrinsic: at membrane bound tissue factor

Question 526

What is thrombin? What are its 3 main actions?

Answer 526

Central protease of coagulation cascade 1. Activation of downstream components - catalyse proteolysis of fibrinogen to fibrin 2. +ve feedback on upstream components - catalyse formation of thrombin from prothrombin, platelet factors Va, VIIIa 3. Paracrine actions that influence haemostasis - endothelial cells release NO, PGI2, ADP, vWF

Question 527

What are the 2 paracrine anticoagulant factors?

Answer 527

1. Prostacyclin: vasodilation, inhibit platelet activation and clotting 2. cGMP: NO inhibits platelet adhesion and aggregation

Question 528

What are the 5 anticoagulant factors?

Answer 528

1. Tissue factor pathway inhibitor: blocks VIIa protease activity 2. Antithrombin III: inhibits Xa, thrombin 3. Thrombomodulin: forms complex w/ thrombin, removing from circulation 4. Protein C: protease; inhibits Va, VIIIa 5. Protein S: protein C cofactor

Question 529

Describe fibrinolysis

Answer 529

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

Question 530

What is thrombocytopenia?

Answer 530

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)

Question 531

Describe Von Willebrand disease

Answer 531

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)

Question 532

What liver factors are dependent on VitK?

Answer 532

Prothrombin | F VII IX X

Question 533

Define general anaesthetic

Answer 533

Compounds that induce reversible loss of consciousness in humans or loss of righting reflex in animals

Question 534

Define sedative, hypnotic, analgesic

Answer 534

Sedative: red. irritability/excitation Hypnotic: induce sleep Analgesic: red. pain sensation w/o loss of consciousness

Question 535

What are the typical GAs?

Answer 535

``` Desflorane, isofluorane, sevoflurane, halothane Nitrous oxide Fentanyl Thiopentone Propofol Ketamine ```

Question 536

What 4 actions should a GA induce?

Answer 536

1. Hypnosis/sedative 2. Immobility 3. Analgesia 4. Amnesia

Question 537

What are the 7 characteristics of an ideal GA?

Answer 537

1. Cause loss of sensation, especially pain 2. Cause loss of noxious reflex 3. Induce muscular relaxation 4. Induce amnesia 5. Have smooth onset and recovery 6. Have no systemic toxicity 7. Cause no hazard to others

Question 538

What are the 4 stages of anaesthesia?

Answer 538

1. Analgesia: induction to loss of consciousness 2. Excitement: loss of consciousness to automatic breathing 3. Surgical Anaesthesia: automatic respiration to respiratory paralysis 4. Medullary Depression: stoppage of respiration to death

Question 539

Describe the 3 planes of stage 1 anaesthesia

Answer 539

1. No analgesia or amnesia 2. Amnesia, partial analgesia 3. Complete analgesia and amnesia, disorientation, vertigo/ataxia; inc. respiration, BP, HR

Question 540

Describe the excitement stage of anaesthesia

Answer 540

Coughing, vomiting, struggling, irregular respiration w/ breath holding

Question 541

Describe the 4 planes of surgical anaesthesia

Answer 541

1. Cessation of eyeball movement, loss of swallowing reflex 2. Laryngeal reflex lost, inc. lacrimation, regular deep breathing, response to skin stim. lost 3. Progressive intercostal paralysis, diaphragmatic respiration persists, pupils dilation, loss of light reflex 4. Paralysis of intercostal and diaphragmatic (apnea)

Question 542

Describe stage 4 anaesthesia

Answer 542

Medullary paralysis: respiratory depression, vasomotor collapse, death

Question 543

How are the changes between the stages of anaesthesia prevented?

Answer 543

Use of neuromuscular blockers

Question 544

Explain the lipid theory of anaesthetic mechanism

Answer 544

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

Question 545

Explain the protein theory of anaesthetic mechanism

Answer 545

Specific targeting of CNS receptors GABA, glycine, ionotropic glutamate receptors VGIC

Question 546

What are the 2 classes of GAs? Give examples

Answer 546

1. Intravenous: propofol, thiopentone 2. Inhalation: - gaseous: nitrous oxide - volatile liquids: desfluorane, sevofluorane, isofluorane, halothane

Question 547

Describe minimum alveolar conc.

Answer 547

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

Question 548

What is the relationship between MAC value and anaesthetic potency?

Answer 548

Indirect | Lower MAC value, more potent anaesthetic

Question 549

Describe sevofluorane and its mechanism of action

Answer 549

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

Question 550

What are the adverse effects of sevofluorane?

Answer 550

Trigger malignant hyperthermia | Inc. intracranial pressure

Question 551

Describe isofluorane and its effects

Answer 551

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)

Question 552

Describe nitrous oxide

Answer 552

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

Question 553

What is malignant hyperthermia and how is it treated?

Answer 553

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)

Question 554

Why are IV GAs preferable?

Answer 554

Faster, more stable and more reliable

Question 555

Describe propofol

Answer 555

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

Question 556

What are the 4 adverse effects of propofol?

Answer 556

1. Respiratory depression 2. Hypotension: peripheral vasodilation 3. Induction cardiac dysrhythmias 4. Induce priapism: persistent, painful erection

Question 557

Describe thiopentone

Answer 557

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

Question 558

What are the 6 effects of pre-medications?

Answer 558

1. Anxiety relief w/o excessive sedation and stress red. 2. Amnesia during preoperative period, retain cooperation 3. Relief preoperative pain 4. Red. requirement for inhalational agents 5. Red. side effects: salivation, bradycardia, postoperative vomiting 6. Red. acidity and vol gastric contents

Question 559

What are the 3 types of premedication?

Answer 559

1. Anti-emetics 2. Opioid analgesic 3. Benzodiazepines

Question 560

Describe anti-emetics

Answer 560

Droperidol, domperidone Act in chemoreceptor trigger zone in brainstem Highly effective

Question 561

Describe opioid analgesic use as premedication

Answer 561

Alfentanil, fentanyl, remifentanil Pain relief, sedation, red. GA dose Adverse: respiratory and CV depression, emesis

Question 562

Describe benzodiazepine use as premedication

Answer 562

Diazepam, lorazepam Anxiolytic/sedative Little respiratory and cardiac depression Amnesia

Question 563

What are diuretics?

Answer 563

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

Question 564

What are the 2 main mechanisms by which diuretics work?

Answer 564

1. Direct actions on epithelial cells of nephron | 2. Indirectly modifying filtrate content

Question 565

What are the 5 classes of diuretics?

Answer 565

1. Osmotic 2. Carbonic anhydrase inhibitors 3. Loop: Na/K/2Cl transporter 4. Thiazide: Na, Cl transporters 5. K-sparing: Na channel blockers, mineralocorticoid receptor antagonists

Question 566

Describe loop diuretics

Answer 566

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

Question 567

What are the 5 uses for loop diuretics (furosemide)?

Answer 567

1. Pulmonary oedema: due to L ventricle failure 2. Congestive heart failure 3. Diuretic-resistant oedema 4. Control resistant hypertension 5. Hypercalcaemia

Question 568

What are the 6 adverse effects of loop diuretics (furosemide)?

Answer 568

1. Hypokalaemia 2. Hyperuricaemia 3. Metabolic alkalosis 4. Hyponatremia 5. Ototoxicity 6. Mg depletion

Question 569

What are the 6 contra-indications of loop diuretics?

Answer 569

1. Severe hypokalaemia 2. Severe hyponatremia 3. Anuria 4. Liver cirrhosis 5. Drug-induced renal failure 6. Pregnancy

Question 570

Describe thiazide diuretics

Answer 570

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

Question 571

What are the 3 uses of thiazide diuretics?

Answer 571

1. Hypertension (diuretic treatment): effective at low dose 2. Renal stones: inc. DT Ca reabsorption slows stone growth 3. Heart failure: not first line

Question 572

What are the 4 adverse effects of thiazide diuretics?

Answer 572

1. Hypokalaemia: aggravates cardiac arrhythmias 2. Metabolic alkalosis 3. Hyperuricaemia: aggravate gout 4. Hyperglycaemia: impaired pancreatic insulin release (K dependent)

Question 573

What are the 4 contra-indications of thiazide diuretics?

Answer 573

1. Hypokalaemia 2. Hyponatraemia 3. Symptomatic hyperuricaemia 4. Hypercalcaemia

Question 574

Describe osmotic diuretics

Answer 574

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

Question 575

What are the 3 uses of osmotic diuretics?

Answer 575

1. Acute renal failure 2. Cerebral oedema 3. Glaucoma

Question 576

What are the 3 adverse effects of osmotic diuretics?

Answer 576

1. Headache 2. Nausea 3. Vomiting

Question 577

What are the 2 types of K-sparing diuretics?

Answer 577

Mineralocorticoid receptor antagonists | Epithelial Na channel blockers

Question 578

Describe spironolactone

Answer 578

``` K sparing diuretic Mineralocorticoid receptor antagonist Weak diuretic Limits aldosterone Na retention Down-regulates ENaC expression ```

Question 579

Describe amiloride and triamterene

Answer 579

K sparing diuretics ENaC blockers Limit Na re-uptake

Question 580

How do K sparing diuretics work?

Answer 580

Limit intraepithelial Na accumulation thus prevent resulting excess K excretion

Question 581

What are the uses of K sparing diuretics?

Answer 581

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

Question 582

What are the side effects of K sparing diuretics?

Answer 582

Hyperkalaemia GIT disturbances, nausea, vomiting Triamterene, spironolactone: sexual dysfunction Spironolactone: precipitate gynecomastia

Question 583

Describe carbonic anhydrase inhibitors

Answer 583

Acetazolamide Blocks HCO3- production leads to less bicarbonate reabsorption consequently less Na reabsorption Greater HCO3- loss causes metabolic acidosis Weak diuretics

Question 584

What are the 3 uses of CAIs?

Answer 584

1. Glaucoma treatment Acetazolamide: oral administration; weak diuresis, metabolic acidosis Dorzolamide, brinzolamide: topical administration; red. intraocular pressure, no diuretic or systemic metabolic effect 2. Acute mountain sickness: due to respiratory alkalosis - breathing rate inc. to maintain O2 delivery - ppCO2 falls, alkalising plasma 3. Metabolic alkalosis

Question 585

Explain the relationship between filtrate pH and drug clearance

Answer 585

Entry of non-carrier transported molecules into filtrate depends on them crossing epithelial membrane Highly dependent on drug pKa and local pH

Question 586

Describe the uses of drugs that modify urinary pH

Answer 586

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

Question 587

Explain the cause of gout

Answer 587

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)

Question 588

Outline the treatment of gout

Answer 588

1. Allopurinol: xanthine oxidase inhibitor 2. Probenecid: block uric acid reabsorption by inhibiting specific uric acid transporter in tubule epithelium Agents that inc. filtrate pH (NaHCO3), inc. uric acid clearance