PCOL2605 Notes

Pharmacodynamics
Selectivity
- Drugs act selectively by binding to certain proteins only
o Drugs are not completely selective, but can act at lower concentrations at some protein
targets than others
- Limits toxic effects, and targets specific proteins that regulate a disease state
- Multi-modal drugs can simultaneously act on multiple targets
- Drug targets Receptors, Ion channels, Carriers, Enzymes

Ion channels
- Protein gates that mediate entry/exit of ions to regulate cell membrane potential
- Voltage-gated, ligand-gated or mechano-sensitive ion channels
- Drugs blockers or modulators (increased or decreased opening probability) of ion channels
- Local anaesthetics, e.g. lidocaine
o Selectively inhibit pain-transmission in nerve fibres and interpretation of pain
o Block Na+ channels in peripheral sensory nerves to block Na+ entry (and thus APs)
- Benzodiazepines (Diazepam) anticonvulsant, anti-anxiety
o GABA produced in presynaptic neuron binds to postsynaptic GABAA receptors
conformational change increased Cl- entry via ion channel
Cl- entry into nerve cell reduces neuronal transmission of APs
o Diazepine allosteric modulator (activator) of GABAA receptor channels
Allosteric binding of diazepine to GABAAR potentiates actions of GABA to further
increase Cl- influx into cell
GABA must be bound to receptor for diazepine to work

Carriers/transporters
- Drugs can block transporters to promote a beneficial therapeutic effect
- Fluoxetine (Prozac) antidepressant
o Selective serotonin reuptake inhibitor (SSRI)
o Inhibits serotonin (5-HT) transporters in brain to increase [5-HT] in neuronal synapse

Enzymes
- Drugs can act as inhibitors, false substrates, or prodrugs of enzymes
- Aspirin inhibits cyclooxygenase to reduce conversion of arachidonic acid to prostaglandins
o Reduces pain and inflammation
- Parkinsons Disease increase dopamine to overcome loss from death of dopaminergic neurons
o L-dopa can cross BBB unlike dopamine bioactivated into dopamine within brain

Receptors
- Membrane or intracellular proteins that receive chemical information to regulate cell function
- Drugs agonists or antagonists
- Cannabinoids THC (main psychoactive constituent) is a partial agonist for CB1 receptors in brain
o 9-THC mimics actions of anandamide (normal endogenous neurotransmitter)
o Anandamide is released from postsynaptic receptors and act on presynaptic CB1R
Inhibit Ca2+ channels to block excess release of glutamate (neurotransmitter)
which can be neurotoxic neuromodulatory/homeostatic mechanism
THC binds presynaptic CB1R to mimic anandamide to offset neurotoxicity
- Rimonabant CB1 antagonist, blocks endogenous neurotransmission of anandamide

Agonists
- Direct or indirect (via transduction mechanisms, G-protein coupling) effects
- Characterised by affinity (KD) and intrinsic activity (efficacy/ability to alter cellular function)
o Affinity depends on association (K1) and dissociation (K-1) rate of drug-receptor complex
Binding forces electrostatic, hydrogen bonding, Van der Waals, covalent
- Affinity does not equal potency, as intrinsic activity must be taken into account (KD EC50)
o KD = [ligand] that gives half occupancy of receptors to form ligand-receptor complex
o EC50 = effective concentration that gives half-maximal response
- Agonists can be endogenous (from body) or exogenous
o ACh endogenous, released from nerves, activates nicotinic and muscarinic receptors
o Adrenaline released from adrenal medulla, activates /-adrenoreceptors
- Log-scale dose-response curves enables comparison of occupancy and potency relationships
o Parallel curves for drugs that act similarly

Antagonists
- Antagonists no effect/intrinsic activity, block endogenous mediators
- Atropine selective muscarinic antagonist
Competitive antagonist
Non-competitive antagonist
Parallel shift of agonist dose-response curve to
Non-parallel shift of agonist curve to right
the right
Reduces maximal effect of agonist
Can be overcome by high [agonist]
Cannot be overcome by high [agonist]









Drug-receptor interactions
Receptors
Location
Effector
Coupling
Examples
Membrane Channel (Vm)
Direct
nAChR, GABAAR
Ligand-gated ion channels
G-protein
mAChR, CB1R
G-protein coupled receptors Membrane Enzyme/channel
Membrane Enzyme
Direct/indirect Insulin, GF
Kinase-linked receptors
Intracellular Gene transcription Via DNA
Steroid/thyroid
Intracellular receptors

Ligand-gated ion channels (ionotropic)
- Contain ~20 transmembrane segments
- Surrounds a central aqueous channel through which ions selectively pass
- Mediate fast synaptic transmission (milliseconds)
- Alter electrical excitability of membranes to make APs more or less likely
- ACh must bind both binding sites to cause conformational change in nAChR, to enable Na+ entry

G-protein coupled receptors (metabotropic)
- Contain 7 transmembrane domains, linked to a G-protein
o Linked to either ion channel or different enzymatic pathways
- Gs stimulatory; GI inhibitory
- Mediate slow synaptic/neuro-transmission (seconds)
- Agonist binds receptor linked G-protein mobilises effector affects ion channel or enzyme
o E.g. Cannabinoids
Block Ca2+ entry into cell decreased release of neurotransmitters
Open K+ channels causing exiting decreased firing/transmission of impulse

Kinase-linked receptors
- Contain only 1 transmembrane helix
- When bound, the receptors activate intracellular kinase cascades
o Growth factor receptors increase cell division, growth and differentiation
o Cytokine receptors increase release of inflammatory mediators
- Response occurs on a minute timescale

Intracellular receptors
- Found intracellularly, regulate gene transcription
- Slow timescale of action hours/days

Autonomic nervous system
- Involuntary/automatic control
- Primarily affects smooth and cardiac muscles
o Regulates contraction and relaxation of vascular and visceral smooth muscle, heart rate,
exocrine and endocrine secretion, energy metabolism
- Afferent (sensory/input) and efferent (motor/output)
Parasympathetic
Sympathetic
Rest and digest response
Fight or flight response
Ganglia close to organ
Ganglia close to vertebral column
- Long preganglionic
- Short preganglionic
- Short postganglionic
- Long postganglionic
Preganglionic neurotransmitter ACh
Preganglionic neurotransmitter ACh
Postganglionic neurotransmitter ACh
Postganglionic neurotransmitter NAd
Most target cells have muscarinic cholinergic
Most target cells have adrenergic receptors
receptors

Neurotransmitter receptors on ANS targets
- Cholinergic receptors bind acetylcholine (ACh)
o Nicotinic preganglionic, ligand-gated ion channel (fast-acting for reflex)
o Muscarinic postganglionic, G-protein coupled receptor
- Noradrenergic receptors bind noradrenaline, adrenaline, isoprenaline (NAd derivative)
o - and -adrenoreceptors 1, 2, 1, 2, 3
o All SNS postganglionic neurons release NAd, except innervation of sweat glands (ACh)
o Noradrenaline main peripheral NS neurotransmitter
- Adrenal medulla modified sympathetic ganglion
o Preganglionic sympathetic neuron from spinal cord leads to adrenal medulla
o Secretes adrenalin (80%) and noradrenalin (20%) directly into bloodstream
Ahlquist suggested the difference in
relative potency of catecholamines were
partly due their affinities for one of two
types of adrenoreceptors
- -adrenoreceptors Ad > NAd >
ISO (excitatory)
- -adrenoreceptors ISO > Ad >
NAd (inhibitory)

Other neurotransmitters
- Non-adrenergic non-cholinergic (NANC) neurotransmitters
- ATP, 5HT, GABA, dopamine, nitric oxide
- Neuropeptides, e.g. VIP (PNS) and NPY (SNS)

Acetylcholine receptors
- Two major subtypes muscarinic (metabotropic) and nicotinic (ionotropic) receptors
- Both activated by ACh, and expressed by neuronal and non-neuronal body tissues

Muscarinic ACh receptors
- Metabotropic second messenger, G protein-coupled seven-transmembrane receptors
- Activated by muscarine (mushroom toxin), and antagonised by atropine (atropa belladonna)
- Five receptor sub-types (M1 M5)
o Drugs that bind to orthosteric site show little selectivity between these subtypes

M1 M5 receptor subtypes
- Group I M1/3/5 couple to Gq proteins stimulatory
o Cause stimulation of PLC, IP3, [Ca2+]I (e.g. smooth muscle contraction, secretion)
- Group II M2/4 couple to Gi proteins inhibitory
o Cause inhibition of adenylyl cyclase, cAMP, Ca2+ conductance (e.g. heart rate)
- M1, 4, 5 mainly found in CNS
- M2 cardiac, found pre-synaptically (on nerve terminals inhibit ACh release)
o Cardiac rate (bradycardia) and force of contraction
o Prejunctional inhibition of parasympathetic postganglionic autoreceptors ( ACh release)
- M3 glandular/smooth muscle, found on salivary glands, smooth muscle, endothelium
o Bronchial smooth muscle contraction increased airway tone
o Peristalsis increased motility
o Exocrine gland secretions salivary, bronchial, sweat
o Vasodilation vascular smooth muscle relaxation
Activate endothelial cell M3 receptors nitric oxide & cGMP vasodilation

Nicotinic ACh receptors
- Ionotropic ligand-gated ion channel receptors
o Heteropentamer with 4 subunits organised around central pore 2, , ,
- Ligand (e.g. nicotine) binds conformational change hydrophilic channel opens
o Channel enables passage of ions, particularly Na+
Subtype
Location
Actions
Muscle nAChR
Found on skeletal Depolarisation, AP propagation and contraction
muscle cell
Skeletal muscle contraction
Neuronal nAChR Found on
Depolarisation, AP propagation and neurotransmitter release:
autonomic ganglia
- Adrenal medulla adrenalin release
- CNS neuronal excitation

Effects of exogenous ACh on blood pressure
- Low dose ACh causes fall in BP due to vasodilation at M3 receptors on endothelial cells
o Atropine (muscarinic receptor antagonist) blocks effect of ACh at low doses
- High dose ACh increases BP even when atropine is present
o ACh activates postsynaptic nicotinic receptors of postganglionic sympathetic fibres and
adrenal medulla NAd release vasoconstriction
o Activation of -adrenoreceptors causing vasoconstriction

ACh in the eye
- Pupil size ACh stimulates M3 receptors, causing circular constrictor muscles to contract
o Miosis (pupillary constriction)
o Atropine causes mydriasis (pupillary dilation)
- Near vision ACh causes ciliary muscle contraction, allowing lens to bulge
o Accommodation increases near vision
o Atropine blocks accommodation cycloplegia

Acetylcholine drugs
Cholinergic neurotransmission
Synthesis (ChAT) storage in vesicles (vAChT) exocytosis and release across synapse receptors
inactivation by acetylcholinesterase (AChE-S) choline reuptake by carrier

Muscarine and mushrooms
- Mimics actions of ACh at mACh receptors
- Mushroom poisoning reflects activation of the PNS lasts 2 hours
o Salivation, perspiration, lacrimation within 15-30min of ingestion
o Large doses abdominal pain, nausea, diarrhoea, blurred vision, laboured breath
o Deaths are rare, but may be due to cardiac/respiratory failure
- Treatment block mAChR
Muscarinic agonists
Muscarinic antagonists
Muscarine
Causes mushroom poisoning
Ipratropium Bronchodilation for asthma
Carbachol
No clinical use, non-selective for
Hyoscine
Used to counter motion sickness
nicotinic and muscarinic receptors
Pilocarpine Treat glaucoma (raised intraocular Atropine
Used in general anaesthesia to dry
pressure) by draining aqueous
secretions and reduce bradycardia;
humour
Treat anticholinesterase poisoning
Bethanechol Treat hypotonia (low muscle tone) Tropicamide Produce mydriasis in opthamology

Nicotine and tobacco
- Nicotine stimulates nAChRs at autonomic ganglia
o Peripheral effects tachycardia, increased BP, decreased GI motility, sweating
o Tachycardia is experienced as SNS dominates over PNS
- Centrally, nicotine acts on nAChRs in hippocampus and cortex excitatory receptors involved in
cognitive function
- First-time smokers nausea and vomiting due to stimulation of stomach sensory receptors
Nicotinic agonists
Nicotinic antagonists
Nicotine
Ganglion stimulant, main
Vecuronium
Binds muscarinic nAChRs, blocks
pharmacological substance in
skeletal neuromuscular junction,
tobacco smoke
muscle relaxant in GA
Suxamethonium Short-acting depolarising
Hexamethonium Ganglion blocker, obsolete
blocker muscle relaxant

Acetylcholinesterase (AChE)
- Enzyme from serine hydrolase group, that hydrolyses ACh to choline and acetate
- Found tethered to postsynaptic membranes
- Contains two main sites anionic site (binding) and esteratic site (cleavage)

Anticholinesterases
- AchE inhibitors, prevent destruction of ACh by acetylcholinesterase
- Myasthenia gravis muscle-weakening autoimmune disease, decrease in APs and muscle tension
o Defect in transmission of nerve impulses to muscles at NMJ due to loss of nAChRs
Anticholinesterase Use
Example
Short-acting
Diagnosis of myasthenia gravis
Edrophonium
ACh competitor
Medium-acting
Treat myasthenia gravis
Neostigmine
Reverses non-depolarising NMJ blockers after surgery
Neostigmine
Treat glaucoma
Physostigmine
Long-acting
Irreversible competitors
Parathion (insecticide)
Act via enzyme phosphorylation
Sarin (nerve gas)

Effects of anticholinesterases
- Cholinergic toxidrome (ACh toxicity) autonomic effects
o SLUDGE salivation, lacrimation, urination, diarrhoea, GI hypermotility, emesis (vomit)
o Bradycardia, hypotension, bronchoconstriction, pupillary constriction
- Neuromuscular junction initial muscle fasciculation, followed by weakness and flaccid paralysis
- CNS initial excitation (seizures), then unconsciousness and respiratory depression
- Antidote pralidoxime

Glaucoma
Anatomy of the eye
- Iris can move closer together (constricted pupil) or apart (dilated pupil)
- Posterior chamber between lens and iris
- Anterior chamber between iris and cornea
- Angle of the eye angle between iris and cornea
- Aqueous humor
o Formed by epithelium cells of ciliary body (2L/min)
o Composition resembles plasma
o Secreted into posterior chamber, circulates through pupil into anterior chamber
o Drained from eye into venous network trabecular meshwork and Canal of Schlemm
(80%) or uveoscleral pathway (20%)
o Transports nutrients and waste products, maintains eye shape and position of retina
- Intraocular pressure (IOP) normally 10-21mmHg
o Determined by balance between AH production (inflow) and drainage (outflow)
o Diurnal variation lowest at night, highest during the day

Glaucoma
- Damage (excavation or atrophy) to optic nerve head
- Loss of retinal ganglion cells
- Very gradual visual field loss initially peripheral vision
o Any visual loss is irreversible if untreated may result in total blindness
- Often associated with raised intraocular pressure; higher cup:disk ratio of optic nerve head
- Ocular hypertension consistently elevated intraocular pressure, but no glaucoma
o No visual field loss and normal optic nerve increased risk of developing POAG

Primary open angle glaucoma (POAG)
- Most common type, and major cause of preventable blindness
- Elevated IOP due to reduced aqueous humor outflow
- Chronic, painless, slow vision loss, generally affects both eyes
- Risk factors increased IOP, family history, age, myopia, large diurnal variation in IOP
o Ethnicity more common in African-American or Hispanic descent
o Some medications, e.g. corticosteroids may increase IOP

Primary closed angle glaucoma
- Shallow anterior chamber depth leading to narrower angle between iris and cornea
o Outer edge of iris may impede drainage of aqueous humor
- Elevated IOP due to reduced aqueous humor outflow
- Gonioscopy measures width of angle and drainage
- Risk factors farsightedness, ethnicity (Asian and Inuit descent)
- Treatment laser iridectomy (surgical removal of part of iris)

Normal tension glaucoma
- Normal intraocular pressure, but visual field loss and optic nerve head changes like POAG
- Occurs in 30% of glaucoma patients
- Treatment same as for POAG slight reduction in IOP

Acute closed angle glaucoma

- Marked rise in IOP due to block of aqueous humor outflow, caused by infection, trauma, etc.
- Blindness can occur within hours medical emergency (laser or surgical treatment)
- Headache, emesis, blurred vision, mid-dilated pupil, redness and cloudiness of cornea
- Anticholinergic drugs may precipitate acute closed angle glaucoma in susceptible people
o Pupillary dilation iris pulled back can block trabecular meshwork ACAG

Primary treatment goals
- Preservation of visual function restoration currently not possible
- Reduction of intraocular pressure (~13-14mmHg) two methods, both effective
o Increasing AH drainage enables AH to maintain its physiological functions
o Decreasing AH production more rapid effect in reducing IOP
- Ongoing monitoring of visual field and optic nerve head

Treatment options
- Medical therapy eye drops, oral therapty (acetazolamide)
- Surgery/laser iridectomy or trabeculoplasty small burns made to increase AH drainage
- Combination products may reduce: number of preparations and drops, exposure to
preservatives, the need to wait between drops
o E.g. bimatoprost and timolol (Ganfort) increases outflow, reduces production
- Adverse effects
o Local burning, stinging, irritation, pain, conjunctival hyperaemia
o Prostaglanding analogues increase brown pigmentation of iris, luscious lashes
o Systemic effects from beta blockers breathlessness, sleep disturbances, bradycardia,
hypotension, depression
- Correct eye drop administration technique requires coordination and dexterity
o Poor technique 80% of drug may be absorbed into systemic circ. (adverse effects)
o Occurs via lacrimal drainage system put pressure on nasolacrimal duct to limit this
o Medication absorbed from eye drops bypasses first-pass metabolism
Medications that AH production (inflow)
Medications that AH drainage (outflow)
Alpha2 receptor agonist
Brimonidine
Alpha2 receptor agonist Brimonidine
Beta receptor antagonist Betaxolol, timolol
Cholinergic agents
Pilocarpine
Carbonic anhydrase
Brinzolamide,
Prostaglandin analogues Bimatoprost, travoprost
inhibitors
acetazolamide

Noradrenaline
Catecholamine synthesis
1. Tyrosine converted to DOPA by tyrosine hydroxylase (TH, rate-limiting enzyme)
2. DOPA dopamine by DOPA decarboxylase
3. Dopamine NAd by DBH enzyme present in vesicles of nerve terminals
4. NAd adrenaline by PNMT found in adrenal medulla

NAd transmission
- Peripheral sympathetic neurons have varicosities along nerve axon release sites for NAd
o NAd released from vesicles by exocytosis triggered by Ca2+ entry
- Autoreceptors negative feedback mechanism to regulate amount of neurotransmitter released
- Recycling/inactivation of NAd uptake systems 1 (more active, presynaptic) and 2 (postsynaptic)
- MAO inhibitors prevent NAd breakdown, [NAd]

Indirect sympathomimetics
- Mimic stimulation of SNS to cause NAd release, e.g. tyramine, ephedrine, cocaine
- Amphetamine (synthetic) NAd, inhibits uptake 1, CNS stimulant
o Displaces NAd in the synaptic vesicles, forcing NAd release into synapse

1-adrenoceptors
Location smooth
muscle
Gq protein
Phospholipase C
activation
IP3
Ca2+
Smooth muscle
contraction

2-adrenoceptors
Nerve terminals
(presynaptic autoreceptor)
Gi
Adenylyl cyclase
inactivation
cAMP
Ca2+ influx
Transmitter release

1-adrenoceptors
Heart

2-adrenoceptors
Smooth muscle

Gs
Adenylyl cyclase
stimulation
cAMP
Ca2+ influx (heart)
Cardiac muscle
contraction/HR

Gs
Adenylyl cyclase
stimulation
cAMP
Inactivates MLCK
Smooth muscle
relaxation

Cardiac myocyte (heart muscle cell)
1. 1 and 2 receptors couple to Gs proteins
2. Activates adenylyl cyclase to form cAMP using ATP
3. Activates PKA phosphorylates L-type Ca2+ channels
o Increases Ca2+ entry and Ca2+ release from SR
o Increases Ca2+ release through ryananodine-sensitive Ca2+ channels
o Causes increase in contractility (force of contraction)

Vascular and bronchial smooth muscle cells
1. 2 receptors couple to Gs proteins
2. Activates adenylyl cyclase to form cAMP
3. Inhibits MLCK (myosin light chain kinase) inhibits myosin phosphorylation
4. Causes smooth muscle relaxation

Inactivation of NAd
- NAd removal from extracellular space (e.g. synapse)
o Uptake 1 presynaptic noradrenalin transporter (removes 75% of released NAd)
o Uptake 2 non-neuronal noradrenalin transporter (removes circulating NAd/Ad)
- NAd removal from cytoplasm
o Vesicular monoamine transporter
o Metabolism by MAO and COMT
- Uptake 1 inhibitors, e.g. desipramine antidepressants
- MAO inhibitors, e.g. tranylcypromine irreversible, non-selective, antidepressant


-agonists
-antagonists
-agonists
-antagonists
Phenoxybenzamine, Adrenaline,
Propanolol,
Non-selective Adrenaline,
noradrenaline
phentolamine
isoproterenol
timolol
1: phenylephrine,
1: prazosin,
1: dobutamine
1: atenolol
Selective
pseudoephedrine
tamsulosin
2: salbutamol,
2: clonidine
salmeterol
Nasal congestion,
Hypertension,
Cardiogenic shock,
Hypertension,
Uses
vasoconstriction,
benign prostatic
asthma, emphysema angina
hypertension, glaucoma hyperplasia

- No PNS innervation in arterioles and skeletal
muscle vessels
- No SNS innervation in bronchial smooth muscle
o Bronchodilation actually occurs via
circulating adrenaline
- All catecholamines increase systolic pressure
- Adrenalin and isoprenaline HR, diastolic
pressure and TPR

Central nervous system

- Consists of brain and spinal cord
- Neuron-neuron synapse (rather than neuromuscular junction in ANS)
- Drugs act directly or indirectly to change activity of relevant brain regions and neural circuits
- Most drugs work by modulating the chemical signals between cells (neuron-neuron, neuron-
glia, or glia-glia) rather than affecting APs (which produce an all-or-none effect)

Synaptic transmission
- Target of most CNS drugs ion channels, receptors, degradation enzymes, transporters
- AP depolarises neuron membrane activates voltage-gated Ca2+ channels Ca2+ enters cell
exocytosis of vesicles at terminal bouton neurotransmitter diffuses through synapse and binds
to postsynaptic receptors to activate intracellular pathways
- Blood brain barrier limits access to brain
o BBB endothelial cells are tightly connected and form tight junctions
o Lipophilic drugs and drugs with transporters can pass
o P-glycoproteins export some substances out of the brain

Amino acid neurotransmitters and mediators
- Glutamate main excitatory AA-N
- GABA main inhibitory AA-N
- Glycine secondary inhibitory AA-N
- Balance of excitation and inhibition is required
- Glutamate and GABA precise synaptic communication, both rapid (ionotrophic receptors) and
slower (metabotropic) responses

Glutamate
- Excitatory, acts as both neurotransmitter (fast effects) and neuromodulator (slower effects)
- Widely and uniformly distributed in CNS
o Potential targets for many diseases, but also means widespread side effects
o Partial agonists/antagonists gives partial (rather than full) effect to reduce side effects
- Metabotropic (G-protein coupled) glutamate receptors
o Regulate cell excitability and synaptic transmission, but not responsible for fast
communication between neurons
o Group 1 postsynaptic Gq-CR that modify ionotropic glutamate responses
o Group 2/3 presynaptic Go-CR that modify neurotransmitter release, such as glutamate
Decrease release possible treatment for excitotoxic conditions
- Ionotropic (ion channel) glutamate receptors AMPA, NMDA, Kainate
AMPA receptors
NMDA receptors
Main glutamate receptor
Similar location to AMPA-R synapses, brain
Ligand-gated cation channel
Voltage-gated cation channel
Responsible for most fast excitatory
Agonists may cause mental disturbances, e.g.
communication between neurons
hallucinations
Very widely expressed, but lack of selective
Blocking NMDA receptors will only work in brain
antagonists leads to extreme side effects
regions of high activity (voltage)
- Full AMPA agonist over-excitation
- May reduce brain damage, epilepsy,
- Full AMPA antagonist CNS and respiratory
Alzheimers, drug dependence, anxiety
depression, cognition and motor impairment - Possible excitotoxicity due to excess Ca2+
Allosteric modulators are promising
- Ketamine non-competitive NMDA antagonist
- Cyclothiazide, piracetam subtly increase
used as anaesthetic/analgesic
AMPA responses to glutamate, rather than
- Mematine low affinity non-competitive
full agonistic response
antagonist for Alzheimers
- Possible uses cognition enhancers, ADHD,
- D-cycloserine partial NMDA agonist for
Parkinsons, depression
substance abuse

GABA
- Inhibitory, occurs at varying concentrations in different brain regions
o 20% of neurons in brain are GABAergic
- Drug targets within the GABA system receptors, enzymes, transporters
- GABAA receptors
o Ionotropic receptor, Cl- channel, mostly postsynaptic
Allows Cl- entry decreases neuron excitability
o Pentamer with numerous possible combinations many sites of action
o Benzodiazepines bind to allosteric site and increase affinity and efficacy of GABAA at
the receptor, allowing GABA to produce a bigger response anti-anxiety, sleeping pills
Barbiturates cause more dramatic increases in GABA response
o Flumazneil inverse agonist at benzodiazepine site to reverse its action
o Anaesthetics many increase GABAA function and therefore inhibition
o Reducing GABAA receptor function increases likelihood of seizures and anxiety
- GABAB receptors
o Metabotropic receptor coupled to Gi/Go
Inhibits Ca2+ channels, activates K+ channels
o Located presynaptic ( neurotransmitter release) and postsynaptic ( excitability)
o GABA has low BBB penetration, but analogue baclofen is antispasmodic
o Gamma hydroxybutyrate (GHB) partial agonist at GABAB receptors
o 2-hydroxysaclofen antagonist, increases excitability, possible cognition enhancer
- Enzyme inhibitors inhibition of GABA transaminase to GABA
o Vigabatrine antiepileptic
- Transporter inhibitors increase [GABA] at receptors to increase activation and thus inhibition
o Tiagabine antiepileptic

CNS: neural substrates of drug action
Widely projecting systems
- Monoamines (dopamine, noradrenaline, serotonin, histamine), ACh, peptides (including opioids)
- Have cell bodies in small number of restricted nuclei
o Axons (and thus their release) are projected widely
o Able to modify activity in many circuits in coordinated manner
- Important modulators of arousal, attention, mood, sleep
- Are important neural substrates for drugs for disorders of mood, cognition, addiction, sleep
- Neuromodulatory circuit transmitters mainly act through metabotropic (slow) receptors
- Act to modulate the rapid communication provided by glutamate and GABA

Dopamine
- Catecholamine
- Dopamine influences reward-related behaviour, cognition control of behaviour, goal-driven
motivation, attention, memory, planning/modulation of movement
- 3 main groups of dopaminergic neurons substantia nigra, VTA, hypothalamus
o Send projections to forebrain and anterior pituitary
- All receptors are metabotropic slow neuromodulatory effect
Gs coupled receptor
Mainly postsynaptic inhibition
D1 type D1, D5
Gi/Go coupled receptors
Pre and post-synaptic inhibition
D2 type D2, D3, D4
- Dopaminergic synapse
o Postynaptic metabotropic receptors affects intracellular responses
o Presynaptic autoreceptors feedback to regulate amount of dopamine released
o Dopamine transporters transport back into presynaptic terminal for recycling
o Enzymatic degradation by MAO and COMT
- Dopaminergic drugs recreation, ADHD, PD, psychosis, nausea, prolactin secretion
o Cocaine (inhibits transporter), selegiline (inhibits MAOB), bromocriptine (D2 agonist)

Cocaine
- Euphoria, energy, talkativeness, raised blood pressure and heart rate, highly addictive
- Faster entry into bloodstream = stronger effect in brain
- Cocaine binding sites correspond to brain reward centres
o Repeated use results in changes in brains reward centres, resulting in addiction
- Inhibits dopamine transporter to increase [dopamine]
o Dopamine remains in synapse to amplify signal over-activates reward centre
- Actions in regions controlling motor function increase stereotypic behaviour (pacing, scratching)

Psychostimulants
- (Includes cocaine) also inhibit dopamine by binding to dopamine transporters
o May also pump dopamine out of cell for stronger response
- Methylphenidate (Concerta, Ritalin)
o Prescribed for ADHD along with behaviour interventions
o Taken orally, start with low dose and build up if needed (lose clinical effect if too high)
o Dopamine will increase cognitive control of behaviour, attention, memory
- Side effects appetite suppression, sleep problems, jittery movements, racing heart
- Also used for sleep disorders, e.g. narcolepsy (to prevent falling asleep)

Parkinsons disease
- Characterised by tremor at rest, bradykinesia, cogwheel rigidity
o Small handwriting, weight loss, alterations in autonomic function, blank facial expression
- Results from death of dopamine neurons in substantia nigra low dopamine levels in striatum
- Treatment approach increase dopamine function in substantia nigra
- Crosses BBB, then converted to dopamine in nerve terminals
L-dopa
- Effective in early disease (works better if many dopaminergic neurons)
- Side effects dyskinesia, hallucination, sleep disturbance, confusion
D2 receptor agonists, e.g. - Directly stimulates receptors
- Less effective than L-dopa, but less side effects
bromocriptine (Parlodel)
- Selective MAOB inhibitor prevent dopamine breakdown by MAO
MAOIs, e.g. selegiline
- May be beneficial in early stages, when dopamine is still being released
(Eldepryl)

Serotonin (5HT)
- Monoamine
- Serotonin exclusively released from raphe nuclei (axons project widely)
o Neurons send diffuse projections to cortex, limbic system, hypothalamus and spinal cord
o Influences sleep, arousal, attention, sensory processing in cortex, emotion, mood
- All receptors are metabotropic, except 5HT3-ionotropic (limited expression)
o Different metabotropic receptors couple to Gi/Go, Gs, or Gq G-proteins
o Expressed in CNS, PNS and other organs
- Serotonergic drugs migraine, nausea, recreation, anxiety, depression
o Antimigraine triptans (5HT1D agonist), odansetron (5HT3 antagonist), ecstasy (alters
transporter activity)

Anti-nauseants
- Ondanestron used for cancer, chemo, radiation, post-operation, morning sickness
- Antagonist at ligand-gated 5HT3 ionotropic receptor
- 5HT3 receptor has particularly high expression in area postrema (controls nausea/vomiting)
o Decrease activity of this region for anti-nauseant effects
- Well-tolerated due to low expression in rest of brain

Migraine treatment
- Triptans used at onset of migraine
- Agonist at presynaptic 5HT1B/D autoreceptors
- Highly effective for migraine and vomiting/nausea
- Mechanism possibly through reducing vasodilation, dampening dural sensory afferent activity
o Boost 5HT activity in receptors in the dural

Recreation
- MDMA/ecstasy blocks serotonin transporter to increase serotonin in synapse
- Short-term effects:
o Desired warmth, empathy, feelings of intimacy, alter sensory perception
o Side effects/toxicity hyperthermia, cardiovascular issues, renal problems, teeth
clenching, clouded thinking, sensory perception
- During ecstasy elevated mood; after ecstasy depression-like feelings, irritability

Noradrenaline pathways
- Noradrenaline is produced by several medulla and pons nuclei
o Neurons send diffuse projections to cortex, hippocampus, cerebellum, spinal cord
- Noradrenergic receptors all metabotropic, act as neuromodulators (slow)
o 1 (Gq coupled), 2 (Gi/Go), 1 and 2 (Gs)
- Noradrenergic synapse COMT and MAO enzymes, noradrenaline transporter
- CNS noradrenergic system very similar to PNS system
- Noradrenergic drugs are useful for depression, recreation, stimulants, pain

Mood disorder and analgesia
Mood disorders
- Mood predominant emotional state over time
- Depression sad mood, pessimistic, indecisive, loss of interest in and reward from usual
pursuits, changes in sleep/appetite/energy, hopelessness, possible suicide
- Brain regions affected control: psycomotive, cognitive effects, emotion, sleep, appetite, energy
- Depression possibly involves serotonin, noradrenaline and dopamine
o Serotonin mood, emotion, arousal
o Noradrenaline arousal, anxiety, goal driven behaviour
o Dopamine reward, memory, motivation

Antidepressant drug classes
- Different classes have similar efficacy, but side-effects vary
o Monoamine oxidase inhibitors (MAOIs) non-selective or selective for MAOA
o Neurotransmitter uptake inhibitors TCAs, SSRIs, 5HT/NAd uptake inhibitors, NAd
selective uptake inhibitors
- All have slow onset of action take weeks for effects, difficult to modify drug concentrations
- Mild depression use non-drug therapy (no evidence of drug therapy efficacy)
- Moderate/severe depression anti-depressants are moderately effective
o SSRIs often first choice, MAOIs and TCAs are possible more effective
- Non-responsive patients may use electrical stimulation to modify important brain regions

Theories for time lapse for effect
- Simple deficit theory functional deficit in monoamines in brain results in depression
- Drugs can alter monoamine levels within minutes, but anti-depressive effects can take 4-6 weeks
- Suggests that chronic (not acute) adaptive changes to the drug result in the anti-depressive effect
o Adaptive changes include:
Down-regulation of 2 and 1 adrenoreceptors
Possible neurogenesis in hippocampus or changes in gene expression

Monoamine oxidase inhibitors

- Older MAOIs no longer widely used due to side effects and interactions
o Non-selective, irreversibly block both MAO isoenzymes
- MAOA prefers 5HT, MAOB prefers dopamine
- Newer drugs reversible and sub-type MAOA selective
- Side effects postural hypertension, dry mouth, weight gain, insomnia, restlessness, cheese
reaction (tyramine)

Tricyclic antidepressants (TCAs)
- Inhibit NAd and 5HT uptake (but not much dopamine)
- Most have metabolites that affect other receptors, including histamine, muscarinic, 5HT
o TCA anti-muscarinic effect due to muscarinic receptor effect, not changes in uptake
Dry mouth, blurred vision, constipation, urinary retention, sedation, mania
- Overdose may result in dysrhythmias, confusion, mania (used in suicide attempts)

Selective serotonin reuptake inhibitors (SSRIs)
- Most commonly prescribed anti-depressant less side effects and safer than MAOI or TCAs
- Selective for 5HT transporter, no direct actions at receptors
o Less side effects do not cause sedation, lower overdose potential, no cheese reaction
- Side effects nausea, diarrhoea, agitation, insomnia, decreased appetite, increased sweating
- Cannot be taken with MAOI may result in serotonin syndrome (excess serotonin)
o Confusion, rapid heart rate, muscle rigidity, headache, unconsciousness, death

Local anaesthesia
- Act on peripheral sensory nerves block voltage-gated Na+ channels in nerve axons
o LAs cause intracellular mechanism that closes the inactivation gate prevents APs
- Exhibit some selectivity small diameter fibres (pain) are blocked before large ones (motor)
- LAs act on the Na+ channel at a site within the channel i.e. intracellular, must cross membrane

Physicochemical properties
- LAs are weak bases, poorly water-soluble and unstable, pKa 8-9
o Combine with strong acid to form water-soluble stable salts (for injection)
- Non-ionised form crosses membrane, but ionised form binds to Na+ channel
- Crossing the membrane and binding to the channel:
o Hydrophilic pathway B crosses membrane, BH+ binds to channel
Channel must be open (in use) for binding to occur i.e. use-dependent
o Hydrophobic pathway for <10% LAs, no use-dependence
Method of local anaesthesia
Uses
Drugs
Surface (spray)
Nose, mouth, cornea (not skin)
Lignocaine
Infiltration (inject tissue)
Minor surgery
Most
IV regional
Limb surgery
Lignocaine, prilocaine
Nerve block (near nerve trunks)
Surgery, dentistry
Most
Spinal (inject subarachnoid space) Major surgery when GAs cannot be used
Lignocaine
Epidural
Major surgery and for painless childbirth
Lignocaine, bupivacaine

Onset and duration of action
- Speed of onset determined by ionisation (pKa) relatively fast
- Duration of action determined by protein binding to Na+ channel (increases duration)
- Lower vascularity (blood flow) at the site of action prolongs action
o Use vasoconstrictors (adrenalin, felypressin) with LA to increase duration of action,
minimise dosage and decrease toxicity
- Toxicity may occur if absorbed into circulation allergic reactions (rare)
o CNS initial stimulation (convulsions) followed by depression
o Cardiotoxicity e.g. profound bradycardia

General anaesthesia
- Loss of awareness (consciousness) and responsiveness to painful stimuli
- Act on the CNS
- Apply intravenously (induce GA) or via inhalation (maintain GA)
- Non-specific mechanism of GA action (Meyer-Overton)
o Greater lipid solubility of the compound = greater anaesthetic potency
- Four stages of anaesthesia:
o (I) analgesia (II) excitement (III) surgical anaesthesia (IV) medullary depression
o Avoid stage IV starts with respiratory arrest, then cardiac arrest
- Preoperative assessment and premedication induction maintenance reversal recovery
Premedication
Drug
Premedication
Drug
Relieve anxiety
Benzodiazepines
Reduce secretions
Atropine
Sedation and amnesia Benzodiazepines
Reduce nausea/vomiting
Metoclopramide
Relieve pain
Opioids
Neuromuscular blockade
Suxamethonium
(immobility for surgery)

Medically important effects of GAs
- Analgesia blockade of pain pathways
- Anterograde amnesia suppression of hippocampus, prefrontal cortex, amygdala
- Immobility depression of spinal motor neurons
- Loss of consciousness mechanism unknown
- Effects on CNS
o Enhances inhibition e.g. via GABAA receptor potentiation
o Inhibits excitation e.g. block NMDA receptors
o Reduce excitation e.g. opening K+ channels
Intravenous GAs Actions
Thiopental
- Ultra short/fast-acting barbiturate
- Loss of consciousness in 10-20s, regained in 2-3min
- Hangover for up to 24h
- Adverse effects laryngeal spasm, cardiac and respiratory depression,
hypersensitivity/anaphylaxis
Midazolam
- Benzodiazepine, water-soluble
- Slower onset and recovery, but less risk of depression
Propofol
- Can be used alone for short procedures (<1h)
- Acts in 30 seconds
- No hangover, little/no nausea, but cardiac/respiratory depressant
Inhalation GAs
Actions
No longer used
- Nitrous oxide N2O gas lacks potency
- Ether and chloroform more potent, explosive, toxic
Volatile liquids
- Halothane non-explosive, safe
- Isoflurane now widely used, causes hypotension but less cardiodepression
- Desflurane and sevoflurane faster induction and recovery
- All may cause nausea and vomiting

Opioids and analgesia
Opioids
- Any compound with morphine-like effects, whether endogenous or synthetic, that can be
reversed by an antagonist such as naloxone
o Synthetic morphine, codeine
o Endogenous proenkephalin, prodynorphin, dynorphin, -endorphin
- Opiates plant-derived compounds from opium poppy juice
- Opioids are inhibitory and dampen neuronal communication
o E.g. shut down neurons in brainstem that detect pCO2/induce breathing

Opioid actions
- Inhibit excitability via:
o Inhibiting Ca2+ influx and increase K+ efflux to inhibit APs/transmitter release
o Affect intracellular signalling cascades, e.g. cAMP
- High concentration of enkephalins in periaqueductal gray important for analgesia
- Opioids act at all levels of pain pathways to reduce/inhibit pain
o Ascending pain pathway peripheral nociceptors dorsal horn of spinal cord brain
o Descending pathway opioids act to limit excessive pain experience
Cortex sends message periaqueductal gray of midbrain dorsal horn
Opioid causes gating mechanism at dorsal horn to shut gate on ascending
messages to reduce pain (analgesia)
- Despite its inhibitory activity, opioids can activate the descending pathway double-negative
o Opioid receptors are also found in small inhibitory interneurons which usually inhibit
tonic analgesia opioids inhibit their inhibitory influence on the PAG
- Therapeutic actions analgesia, impaired cough reflex (antitussive), constipation
- Side effects nausea, vomiting, respiratory depression, euphoria, tolerance, dependence

Types of opioid receptors
- Metabotropic (G-protein coupled receptors)
- Different opioid compounds have varying selectivity for the different opioid receptors
Strong analgesia, constipation, nausea, respiratory depression, cough
Morphine (MOR)
reflex, tolerance, dependence, euphoria
Spinal analgesia, convulsions, cardiovascular complications
Vas deferens (DOR)
Ketocyclazocine (KOR) Moderate analgesia, diuresis, dysphoria

Opioid antagonists Actions
Naloxone
- Short-acting (t1/2 20min)
- Low oral bioavailability requires subcutaneous injection
- Used for reversal of opioid overdose
Naltrexone
- Long-acting (t1/2 14hr)
- High oral bioavailability can be taken in tablet form
- Opioid-dependency management blocks action but poor outcomes
- Reduces craving in alcohol dependence treat alcoholism

Renin-Aldosterone-Angiotensin System
- Major regulatory system, regulates blood pressure, fluid volume, electrolyte levels (e.g. Na+, K+)
- Medications modifying RAAS can treat hypertension, heart failure, renal disease
Components
Function
Angiotensinogen
- Glycoprotein produced by liver and released into circulation
Renin
- Enzyme secreted by juxtaglomerular apparatus in kidneys
- Hydrolyses angiotensinogen to angiotensin I
- Released in response to:
o Drop in renal blood flow/pressure
o Fall in sodium concentration in renal tubules
o Sympathetic nervous system and prostacyclin
Angiotensin I
- Inactive decapeptide
Angiotensin converting
- Found in many tissues, particularly lungs, identical to kinase II
enzyme (ACE)
- Converts ANGI to ANGII
- Chymase protease, can also convert ANGI to ANGII (minor)
Angiotensin II
- Octapeptide, potent vasoconstrictor
Angiotensin III and IV
- Breakdown products of ANGII
- ANGIII releases aldosterone, involved in thirst
- ANGIV directly stimulates ANGIV receptors role in cognition, CV, renal

Effects of angiotensin II
- Vasoconstriction and increased peripheral vascular resistance
- Release of aldosterone from adrenal cortex
o Acts on distal convoluted tubule of kidneys
o Increases Na+ and water reabsorption, K+ excretion
- Thirst and release of ADH (vasopressin)
- Increase in blood pressure
- Noradrenalin release from sympathetic nerves
- Vascular and cardiac cell growth (hypertrophy)
- Effects are due to stimulation of ANGII type 1 receptors (AT1R)
o ANGII type 2 receptors (AT2R) stimulation effects unknown
Possible importance in embryonic differentiation and development
In cardiovascular system, produces some effects opposite to AT1 (vasodilation)
Only expressed under certain conditions in adult life

Kinase II and bradykinin
- ACE = kinase II breaks down bradykinin to inactive products
- Bradykinin involved in pain and inflammation
o Causes vasodilation, peripheral vascular resistance,
vascular permeability

Drugs affecting RAAS Mechanism of action
ACE inhibitors
- Many are prodrugs
- Inhibit angiotensin converting enzyme (ACE)
- Reduces ANGII levels (inhibit production)
- Increases bradykinin levels (inhibit breakdown)
- Reduces aldosterone (Na+/water retention, BP), vasodilation, TPR
- -pril captopril, enalapril, lisinopril, ramipril
ANGII receptor
- Act as competitive antagonists of ANGII at AT1 receptors
antagonists
- Reduces vasoconstriction and aldosterone release
- No effect on AT2 receptors, ACE/bradykinin or production of ANGII
- -sartan candesartan, eprosartan, irbesartan
Renin inhibitors
- Competitive renin inhibitors which bind to the renin enzyme active site
- Block conversion of angiotensinogen to ANGI
- E.g. Aliskiren (only available overseas)

Treatment of hypertension
Hypertension
- >140/90mmHg (normal is <120/80mmHg)
o BP self-measurement, ambulatory BP monitoring (24h), relax and cuff at heart level
- Risk factor, not a disease
- Increased risk of stroke, heart failure, renal failure, myocardial infarction
- 95% of cases have primary/essential hypertension no single definable cause
o Secondary hypertension identifiable cause, e.g. renal disease, phaeochromocytoma
(tumour of adrenal gland)
o Medication-induced NSAIDs, oral contraceptives, corticosteroids, liquorice

Non-pharmacological treatments (first-line)
- Weight and waist circumference reduction and regular exercise
- Reduced heavy alcohol intake and smoking cessation
- Sodium restriction
- Treatment of sleep apnoea
- Drugs only pharmacologically manipulate BP no cure, do not fix underlying issue

Thiazide diuretics
- E.g. hydrochlorothiazide (Dithiazide)
- Inhibit reabsorption of Na+ and Cl- in early distal tubule of nephron
- Short-term Na+ and water loss, reduction in blood volume
- Long-term produce vasodilation and reduce peripheral resistance
- Side effects dizziness, orthostatic (postural) hypotension, impotence, rash, photosensitivity
o Electrolyte disturbances hypokalaemia (K+), hypomagnesaemia (Mg2+)
o Hyperuricaemia (gout), hyperglycaemia (diabetes)

ACE inhibitors
- Side effects dizziness, orthostatic hypotension, first-dose hypotension, angioedema
o Hyperkalaemia stop potassium supplements (aldosterone K+ excretion)
o Renal artery stenosis (narrowing of renal artery)
- Cough due to bradykinin build-up 20% of cases, persistent dry non-productive
- Pregnancy category D
- ANGII receptor antagonists same side effects, but no cough (no increase in bradykinin levels)

Calcium channel blocking agents
- L-type (voltage) Ca2+ channels involved in contraction of vascular smooth and cardiac muscles
- Bind to alpha1 subunit of L-type channels to block entry of calcium (not intracellular actions)
- Reduced calcium in blood vessels vasodilation, TPR, BP
- Dihydropyridines amlodipine, felodipine, lercanidipine, nifedipine
o Primarily inhibit calcium entry into arterioles treat hypertension and angina
- Non-dihydropyridines diltiazem, verapamil
o Inhibit calcium entry into arterioles and cells in heart and GI tract
o Treat hypertension, angina, some cardiac dysrhythmias
- Side effects hypotension, headache, flushes, gut reflux
o Bradycardia, constipation (diltiazem, verapamil) blocks L-channels/peristalsis in gut
o Peripheral oedema (ankle) arteriole dilation and increased permeability of venules
Does not respond to diuretics reduce dose or change drug

-adrenoceptor antagonists (beta blockers)
- Non-selective blockers (block both B1 and B2 receptors) e.g. propranolol
- Cardio-selective blockers (selective for B1 receptors) e.g. atenolol
- Treat hypertension, angina, cardiac dysrhythmias, heart failure, tremor, migraine
- Possible mechanisms of action:
o Reduced cardiac output blocks B1 receptors on heart
o Reduced renin release blocks B1 receptors on renal juxtaglomerular cells
o Reduced peripheral resistance central effect reducing sympathetic outflow
- Side effects bradycardia, fatigue, reduced exercise tolerance, sleep disturbances, impotence
o Possible wheezing and acute asthma attacks in asthmatics (bronchoconstriction)
- Avoid abrupt withdrawal tachycardia, severe angina, heart attack reduce dose gradually

Triple whammy
- ACE inhibitor/ARAs + NSAIDs + diuretics may produce renal impairment in susceptible patients
- In elderly patients and those with cardiac failure, hypertension, renal impairment or dehydration,
maintenance of renal perfusion is often regulated by:
o A vasodilator effect of prostaglandins on afferent arteriole
Preserves renal blood flow, blocked by NSAIDs and COX-2-selective inhibitors
o A vasoconstrictor effect of angiotensin II on efferent arteriole
Preserves intraglomerular pressure and GFR, blocked by ACEI and ARAs
o Diuretic may produce dehydration
- Use paracetamol, codeine, etc. instead

Drug treatment
- Patients with uncomplicated hypertension begin antihypertensive mono-therapy with any of:
o ACE inhibitors (or ANGII receptor antagonists)
o Dihydropyridine calcium-channel blocking agents
o Thiazide diuretics (for >65yo only)
- Thiazide diuretics can manage isolated systolic hypertension and prevent stroke
o Outweighs risk of diabetes onset (but avoid if glucose intolerant or metabolic syndrome)
- Beta-blockers no longer recommended as first-line therapy in uncomplicated hypertension
o Increased risk of diabetes onset, worse outcomes compared to other antihypertensives
- Recommended combination therapies:
o ACEI/ARA + calcium-channel blocking agent
o ACEI/ARA + low dose thiazide diuretic/indapamide
o Note other conditions e.g. angina (perhaps use beta blockers), diabetes
- Current blood pressure targets ~140/90mmHg
o Elderly 150/90mmHg (postural hypotension may cause falls)

Heart failure
Chronic heart failure
- Occurs in 1.5-2% of Australians (50% of people >85yo)
- Heart failure inability of the heart to pump sufficient blood to meet metabolic needs of the
tissues, in the presence of an adequate filling pressure (poor tissue perfusion)
o Left ventricle (systemic circulation, greater muscle mass), right ventricle (pulmonary)
o Preload venous return, amount heart must pump
o Afterload cardiac output, resistance on arterial side that heart pumps into
- Causes ischaemic HD, hypertension, myocardial infarction, heart valve disease, infections
- Echocardiography painless test using sound waves to create images of the heart (ultrasound)
- NYHA heart failure classification class 1 (no impact on physical activity), class 4 (most severe)
Systolic heart failure
Diastolic heart failure
Heart failure with reduced systolic function
Heart failure with preserved systolic function
Reduced left ventricular ejection fraction
Relatively normal (preserved) left ventricular ejection
(<40%) (normal is >50-55%)
fraction (>40%)
Ventricle unable to pump with enough force
Ventricle becomes thick with stiffened walls and a small
during systole (impaired diastolic function
cavity unable to relax sufficiently to allow normal
often coexists)
ventricular filling during diastole
Reduced cardiac output
Normal ejection fraction, but reduced CO
Most common type of heart failure
Occurs for 30-50% of heart failures
More common in men, frequent for >65yo
More common in women, rare for young/those without
hypertension
Risk factors hypertension, ischaemic heart
Risk factors hypertension, coronary heart disease,
disease
diabetes, vascular disease, left ventricular hypertrophy
Good evidence for effective treatment
Limited evidence for treatment

Homeostatic mechanisms
- Heart failure activates physiological systems to maintain cardiac output
o Beneficial short-term, but deleterious long-term (associated with disease progression)
- Renin-angiotensin-aldosterone system
o Vasoconstriction and Na+/water retention increase preload and afterload
o May cause fluid retention and oedema
- Sympathetic nervous system long-term activation leads to:
o Myocardial stress and increased oxygen use
o Cardiac hypertrophy and fibrosis
o Cardiac muscle cell necrosis and death
o Increased potential for dysrhythmias
- Endothelin, vasopressin, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP)

Treatment of heart failure

- Non-pharmacological patient education/counselling, weight loss if obese, regular exercise, fluid
restriction (1-2L/day), sodium restriction (2-3g/day), low salt foods
o Weigh regularly contact doctor if >2.0kg in 48h (suggests fluid retention)
o Ensure influenza and pneumococcal vaccination severe RTI worsens heart failure
- Diastolic heart failure currently no specific evidence-based drug therapy
- Systolic heart failure ACEI, ARAs, diuretics, beta-blockers, spironolactone, digoxin
o Treat comorbidities hypertension, diabetes, ischaemic heart defects
o Transplantations
o SHF may be exacerbated by NSAIDs, corticosteroids, liquorice, non-dihydropyridine
calcium-channel blockers
- Unless contraindicated, use ACEI as initial therapy
ACE inhibitors
- Reduces preload and afterload (does not stimulate heart)
- Slows progression of heart failure, improves morbidity and mortality
- Start with low dose then increase gradually to target maintenance dose
- Monitor renal function and potassium levels (expect renal function, K+)
ANGII receptor - Effective alternative if ACEI not tolerated, e.g. no coughing with ARAs
- Reduces preload and afterload, no stimulation of heart
antagonists
Combination
- ACEI + ARAs may produce further 15% reduction in major events, however
therapy
increased potential for side effects (best to avoid)
- Both drugs reduce effects of aldosterone Na+ and H2O, K+
Diuretics
- Do not use as mono-therapy for SHF no improvement in prognosis/mortality
- Only helps symptoms (pulmonary & systemic congestion) can be added to ACEI
+
+
Spironolactone - Competitive aldosterone antagonist Na and H2O, K (possible hyperkalaemia)
- Low doses shown to be beneficial to treat severe SHF (improved survival)
- Combination with ACEI may produce severe hyperkalaemia and death
- Side effects anti-androgenic activity (gynaecomastia), aldosterone receptors in
heart may produce fibrosis, hypertrophy and dysrhythmias
- Reduces mortality/sudden death/hospitalisation, improves quality of life
Beta-blockers
- Possible mechanisms of action to treat SHF:
o Reduced sympathetic activity on heart
o Reduced cardiac hypertrophy, ischaemia and dysrhythmias
o Reduced renin release (blocks 1-receptors on renal juxtaglomerular cells)
o Apart from beta-blockade, some also produce vasodilation
- Initiate therapy at very low doses then titrate up slowly
- First 4-8 weeks may cause symptoms to worsen, takes 3-4 months for benefits
- Beta-blocker + ACEI significant added morbidity and mortality benefits

Digoxin
- Naturally occurring cardiac glycoside from plant Digitalis
- Stimulates heart exerts positive inotropic effect (increases force of contraction)
o Inhibits Na+/K+ pump increases intracellular Na+ reduces Ca2+ extrusion from cell via
Na+/Ca2+ pump increases intracellular Ca2+ increased contractibility
- Increases parasympathetic tone on heart slows heart rate (bradycardia)
- Reduces hospitalisations, but does not improve mortality rate limited role in heart failure
o May be useful for patients with heart failure and atrial fibrillation (slows conduction
through AV node and increases refractory period)
- Low therapeutic index (significant toxicity), long t1/2 (36-48h)
- Primarily renally excreted as unchanged drug reduced renal function with age
- Hypokalaemia increases toxicity
- Side effects nausea, vomiting, diarrhoea, green/yellow vision, bradycardia, dysrhythmias

Treatment of angina
Angina
- Myocardial oxygen demand exceeds supply myocardial ischaemia and cardiac pain
- Classification stable, variant, unstable, acute coronary syndrome, STEMI

Stable angina
- Blood supply (oxygen) is reduced by atherosclerotic changes in coronary arteries
- Stable angina pain usually transient and subsides with rest
o Precipitated by increased physical activity or emotion
o Pain typically retrosternal, may radiate to jaw, neck or arm, band-like tightness
- Treatment reduce myocardial oxygen demand, increase oxygen delivery, prevent plaque
progression and thrombotic complications
o Acute attacks rapid-acting organic nitrates (glyceryl trinitrate sublingual tablet/spray)
o Prevention (prophylaxis) organic nitrates, calcium-channel blockers, beta-blockers
o Treat underlying conditions antiplatelet medication (aspirin), antihypertensive (ACEI),
HMGCoA reductase inhibitors (statins)

Organic nitrates
- Used in both acute and prophylactic (preventative) treatment of stable angina
o Acute attack glyceryl trinitrate, isosorbide dinitrate
o Prophylactic treatment glyceryl trinitrate, isosorbide mononitrate and dinitrate
- Available as sublingual tablets, sublingual sprays, tablets, transdermal patches
- Organic nitrates metabolised to nitric oxide (NO) via sulfhydryl (SH) groups
o Nitrates cGMP protein kinase G inhibits Ca2+ vasodilation
- Mechanisms of action:
o Causes venous dilation venous return, preload, cardiac work, oxygen demand
o Causes arterial dilation peripheral resistance, afterload, cardiac work, O2 demand
o Dilates coronary vessels increases myocardial O2 supply particularly to ischaemic areas
- Tolerance with continual use possible reduced conversion of nitrate to NO, depletion of SH
groups, reduced vascular response nitrate-free period restores activity
- Side effects dizziness, postural hypotension, headache
- Drug interactions phosphodiesterase type 5 (PDE5) inhibitors used to treat erectile dysfunction
o PDE5 and organic nitrates both increase cGMP
o Combination therapy results in severe hypotension and cardiovascular collapse avoid
- Glyceryl trinitrate (acute attacks) sublingual tablet/spray avoids high first-pass metabolism
o Glyceryl trinitrate tablets are relatively unstable store in cool place, 3 month expiry

Calcium-channel blocking agents
- For angina (prophylaxis only) amlodipine, nifedipine, diltiazem, verapamil
- Bind to 1 subunit of voltage-gated L-type Calcium channels to block Ca2+ entry
o Causes arterial dilation TPR, afterload, cardiac work, oxygen demand
o Dilates coronary vessels and increase coronary blood flow to increase oxygen supply
o No effect on veins or preload
- Side effects hypotension, headache, flushes, bradycardia, peripheral oedema, constipation

-adrenoceptor antagonists (beta blockers)
- For angina (prophylaxis only) atenolol, metoprolol, propranolol
o Reduce effects of SNS on heart
o Reduce afterload (by reducing BP), cardiac work, oxygen demand
o Reduce heart rate, contractility and cardiac work following exercise or emotion
- Side effects wheezing and acute asthma attacks in those with asthma, bradycardia, fatigue,
reduced exercise tolerance, sleep disturbances, nightmares, impotence
o Diabetes may reduce some signs of and prolong hypoglycaemia
o Abrupt withdrawal is dangerous reduce dose gradually

Drugs which inhibit platelet aggregation

- Atherosclerotic plaque in blood vessel walls possible platelet aggregation/thrombus formation
- Anti-platelet drugs prevent platelet (plug) aggregation to reduce thrombus (clot) formation
- COX1 in platelets convert arachidonic acid to thromboxane A2 (promotes platelet aggregation)
o Low-dose aspirin irreversibly inhibits COX1 to prevent production of TXA2
o Platelets cannot regenerate COX1

Cardiac dysrhythmias
The heart
- Automaticity ability to contract on its own
- Two cell types specialised (form conducting system, initiate and distribute
impulse) and contractile (enable cardiac contraction)
- Mechanical cardiac contraction follows the electrical impulse
- Conducting system of the heart: sinoatrial (SA) node atrial internodal
pathways atrioventricular (AV) node AV bundle (bundle of His)
bundle branches Purkinje fibres
- Electrocardiogram electrical activity only

Wave section Meaning
P wave
Atrial depolarisation (SA node depolarises slightly beforehand)
- Atrial contraction occurs 100msec after start of P wave
QRS complex Ventricular depolarisation (and contraction)
T wave
Ventricular repolarisation (relaxation)
PR interval
Beginning of P wave to first deflection of QRS complex
- Period of conduction time for current to travel from SA node to muscle
- Prolonged conduction (>200ms) suggests conduction block/failure
QT interval
Beginning of QRS complex to end of T wave
- Full time for ventricular contraction and relaxation complete ventricular cycle
- Prolonged QT interval greater risk of arrhythmias
ST segment
Between contraction and relaxation of ventricle (result of plateau in ventricular AP)
TP segment
Ventricular relaxation, heart filling with blood occurs between two cardiac cycles

Phase AP of cardiac cell
Event
0
Rapid depolarisation Occurs when membrane potential reaches threshold (-60mV) with large
influx of Na+
1
Partial repolarisation Na+ influx ceases
2
Plateau
Results from inward Ca2+ current
3
Repolarisation
Inward flow of Ca2+ ceases and outward flow of K+ commences
4
Pacemaker potential Gradual depolarisation during diastole
Refractory period
Repolarisation

Cardiac rhythm
- Stimulus for cardiac contraction normally originates in SA node and spreads across cardiac
muscle by conducting system (sinus rhythm)
- Other cells of conducting system can also generate AP/contraction, but slower than SA node
- Dysrhythmias occur when:
o Stimulus originates from site other than SA node
o Stimulus spreads across heart via abnormal pathways, or is delayed or blocked
Supraventricular dysrhythmia Atrial ectopic beats, atrial tachycardia, atrial fibrillation
Ventricular ectopic beats, ventricular tachycardia, ventricular fibrillation
Ventricular dysrhythmia
Stimulus impeded or unable to traverse the AV node
Heart block
Can occur when stimulus originates at site other than SA node
Ectopic beats (extrasystoles)
If stimulus occurs in atria, QRS is normal; in ventricle, QRS is abnormal

Anti-dysrhythmic drugs
- Alter hearts electrical properties automaticity, refractory period, conduction velocity
o May also cause pro-arrhythmic effects
- Vaughan Williams classification
- Class IA block Na+ channels, moderate reduction in slope and peak of phase 0 of AP,
and increased AP duration
o E.g. disopyramide
Blocks Na+ channels, reduces automaticity, increases refractory period
Slows conduction, may cause QT prolongation and pro-arrhythmic effects
Exerts anti-cholinergic activity
- Class IB block Na+ channels, small reduction of phase 0 of AP, decreased AP duration
o E.g. lignocaine (IV treatment of life-threatening ventricular arrhythmias)
Blocks Na+ channels, reduces automaticity, decreases refractory period
May induce pro-arrhythmic effects
- Class IC block Na+ channels, large reduction of phase 0 of AP, no effect on AP duration
o E.g. flecainide
Blocks Na+ channels, reduces automaticity
Slows conduction in all parts of heart (greatest on bundle of His and Purkinje)
May induce pro-arrhythmic effects and prolonged QT interval
- Class II beta-blockers (e.g. propranolol)
o Reduce sympathetic activity on heart
o Slows heart rate (bradycardia), reduces automaticity, increased refractory period
o Used following myocardial infarction reduces dysrhythmias and mortality
- Class III primarily acts on K+ channels (e.g. amiodarone)
o Decreases automaticity, prolonged refractory period, increased conduction time
o Increases coronary blood flow and decreases oxygen requirements
o Long t1/2 (100 days)
o Side effects thyroid abnormalities, QT prolongation, pro-arrhythmic effects
- Class IV nondihydropyridine calcium channel blockers (e.g. verapamil)
o Slow heart rate, prolong refractory period and conduction time of AV node









Atrial fibrillation (AF)
- Cardiac dysrhythmia with very fast, disorganised electrical activity in the atria
- No effective atrial contraction atria quiver/squirm >300 times/min (circus movement)
- Ventricular rate ~160bpm and irregular
- Treatment ventricular rate control vs. rhythm control (return to sinus rhythm)
o Amiodarone, beta-blockers, verapamil
o Digoxin is useful for AF increases refractory period of AV node, and slows conduction
through AV node slows ventricular rate (rate control)
- Atria not contracting clots (thrombi) may form in the atria, and if pumped out of the heart
(emboli) to brain they may cause stroke
o Warfarin inhibits synthesis of vitamin K-dependent clotting factors 2, 7, 9, 10

Dyslipidaemia
Cholesterol

Triglycerides

Omega 3
polyunsaturated
fatty acids

-
-

Component of cell membranes

Precursor of bile acids, vitamin D, steroid hormones (aldosterone,
corticosteroids, sex hormones)
- Majority is synthesised in body (liver)
- Glycerol molecule + three fatty acids
- Fatty acids saturated, monounsaturated (one double bond), polyunsaturated
(>1 double bond)
o UFAs normally Hs on double bond are in cis position (bent structure)
o Trans-fatty acids are more rigid (similar to saturated FAs) undesirable
- Fatty acids with first double bond between 3rd and 4th carbon atoms from the
omega end (n-3 PUFAs)
- EPA and DHA cannot be synthesized de novo, found in fish
- ALA found in walnuts is (inefficiently) converted to EPA and DHA in body

Lipoproteins
- Cholesterol and triglycerides are insoluble in water transported bound to lipoproteins
- Very low density lipoproteins (VLDL) transports triglycerides from liver to peripheral tissues
- LDL cholesterol transports cholesterol to tissues
- HDL cholesterol transports cholesterol to some tissues, and back from tissue to liver

Blood lipid profile
- Total cholesterol = LDL-c + HDL-c + triglycerides
- LDL bad cholesterol when in excess
o Elevated LDL-c accumulates in blood vessel walls and may undergo oxidation to cause:
Plaque formation, vessel narrowing, thrombus (clot) formation, CV events
- HDL good cholesterol
o Transports cholesterol mostly to liver, or steroidogenic organs (adrenal, ovaries, testes)
o Cholesterol transported to liver is broken down, e.g. to bile acids
o Protects against atherosclerosis and CVD
- Triglycerides elevated TG levels associated with increased CV events (heart attack, stroke)

Lifestyle control of lipids
- Regular exercise 5% HDL-c, 10% LDL-c, reduced BP and improved glucose control
- Dietary interventions response usually in 4-6 weeks, response varies with individuals
- Consume less saturated FAs (red meat, sausages) and more MUFA, PUFA, omega 3 FA
o Mediterranean diet fish, nuts, vegetables, fruit, olives, olive oil
Limit read meat, processed foods, diary
- Low fat foods often have high sodium and sugars, low MUFA/PUFA/omega 3
Fatty acids
Dietary source
Increases
Decreases
Bad FAs
Saturated fatty acids TC, LDL-c
HDL-c
Trans fatty acids
TC, LDL-c, TG, inflammation, insulin resistance
HDL-c
Good FAs
MUFAs and PUFAs
HDL-c
TC, LDL-c
Omega 3 fatty acids TG and platelet aggregation; anti-dysrhythmic/inflammatory

Omega 3 PUFAs and fish
- All fish (and fish/krill oil supplements) contain the omega 3 fatty acids DHA and EPA
- Regular consumption of fish lowers risks of coronary heart disease and thrombotic stroke
o Studies suggest regular consumption of fish/krill oil do not reduce CV risk
- Triglycerides (requires relatively high doses of 1.2-3.6g of DHA and EPA/day)

Fibrates (fenofibrate, gemfibrozil)
- Stimulate PPAR- nuclear receptors in liver
- Triglycerides, VLDL and LDL-c, and HDL-c and LDL-c uptake by liver

Statins (HMG-CoA reductase inhibitors)

- E.g. Atorvastatin, fluvastatin, pravastatin, simvastatin
- Decrease total and LDL cholesterol levels very slight triglycerides and HDL-c
- HMG-CoA reductase inhibitors inhibits cholesterol synthesis in liver
o Inhibit conversion of 3-hydroxy-3-mehtylglutaryl coA to mevalonate (rate-limiting step)
- Indirect increases no. LDL-receptors on hepatocyte surfaces increases LDL-c uptake from blood
- Take at night cholesterol synthesis is higher at night
- Side effects myopathy, muscle pain/tenderness/weakness, rhabdomyolysis (very rare)
o Measure serum creatine kinase (CK) level normal muscle enzyme
High blood CK level = marker of muscle damage
o Pregnancy Category D (avoid) cholesterol essential for foetal growth
o Adherence often <50% at six months
- Atorvastatin/simvastatin avoid CYP3A4 inhibitors (erythromycin, grapefruit, azole antifungals)
- Use of fibrates with statins may increase risk of myopathy
- Flat dose-response curve to increase response, add second agent to lower statin dose, rather
than increasing statin dose (more side effects, minimal increase in therapeutic effects)

Ezetimibe (ezetrol)
- Total cholesterol, LDL-c and triglycerides, and HDL-c
- Inhibits intestinal absorption of dietary and biliary cholesterol at brush border of small intestine
o Interferes with enterohepatic recycling of cholesterol
o Reduces amount of cholesterol delivered to liver/hepatic stores, increases uptake of
cholesterol from blood
- Side effects myopathy and increased serum CK levels, rhabdomyolysis (very rare)
- Combination with statins dual action (inhibit cholesterol synthesis and intestinal absorption)

Ion exchange resins
- E.g. cholestyramine and colestipol
- Inhibit reabsorption of bile acids from the intestine
o Since cholesterol is a precursor of bile acids, this causes more cholesterol from blood to
be taken up by liver to be broken down to bile acids serum cholesterol
- Drug interactions inhibit GI absorption of digoxin and warfarin, reduce absorption of vitamin K
- Side effects constipation, nausea, flatulence, reflux, must mix with fluids before use

Diuretics
- Increase urine flow and decrease blood pressure treat oedema and hypertension
- Glomerular filtration ultrafiltrate; GFR = 125mL/min
- Diuretics mainly act on the nephron to decrease Na+ reabsorption
o Na+ reabsorption linked to K+, H+, Ca2+ and Mg2+ excretion
+
- Na transport mechanisms vectorial (direction of) transport of solute
o Epithelial cell luminal membrane (cotransporter) and basolateral (ATPase)
o Na+/K+-ATPase on basolateral membrane found in all cells, regulates membrane
potential to prevent depolarisation

Diuretics as anti-hypertensives
- Decrease in ECF volume and hence blood volume diuretic effect
- Direct vasodilatory effect
- Decreased vascular reactivity reduce sensitivity to vasoconstrictors (NAd, ANGII)

Inhibition
Transporter
Site of action
Diuretic class
+
+ +
-
Na reabsorption
Na /K /2Cl
Thick ascending LoH
Loop diuretics
Na+/Cl-
Distal tubules
Thiazides
Na+ channels
Collecting tubule
Potassium-sparing
Water reabsorption
Modify filtrate content
Glomerulus/Bowmans
Osmotic diuretics

Loop diuretics
- E.g. frusemide, bumetanide
- Inhibit Na+/K+/2Cl- transporter of luminal membrane and decrease water reabsorption in the
collecting duct (countercurrent mechanism)
o High-ceiling diuretic (not most potent)
- Marked diuresis (Na+/H2O loss), also increase K+, H+, Ca2+, Mg2+ loss
- Indications heart failure, hypertension, hypercalcaemia
o Oedema congestive HF, hepatic cirrhosis, nephrotic syndrome, renal impairment

Thiazide diuretics
- E.g. hydrochlorothiazide, indapamide
- Inhibit Na+/Cl- cotransporter
- Moderate diuresis (Na+/H2O loss), also increase K+ and H+ excretion, but decrease Ca2+ loss
- Indications hypertension, heart failure, prevention of stone formation in hypercalciuria
- Reduces Ca2+ excretion (compared to loop diuretics)
o Thiazides are sensitive to parathyroid hormone which increases Ca2+ reabsorption

Potassium-sparing diuretics
- Blocks actions of aldosterone (spironolactone) OR blocks Na+ channels (amiloride)
o Aldosterone increases Na+ reabsorption; ADH increases number of Na+ channels
- Mild diuresis (Na+/H2O loss), decrease K+ and H+ excretion, little effect on Ca2+ and Mg2+
- Indications amiloride used with K+-losing diuretics to prevent hypokalaemia
o Spironolactone used in hyperaldosteronism and heart failure

Osmotic diuretics
- E.g. mannitol exerts osmotic action, causing marked water diuresis
- Ideal osmotic diuretic inert, freely filtered at glomerulus, neither absorbed nor metabolised
- Limited use; indications acutely raised intracranial or intraocular pressure, acute renal failure

Potassium-losing diuretics
- Loop and thiazide diuretics cause K+ (hypokalaemia) and H+ loss (alkalosis)
- Upstream decrease in Na+ reabsorption increased delivery of Na+ to LDT/CD increased Na+
reabsorption in LDT/CD increases:
o Activity of Na+/K+-ATPase
o Negative transepithelial (lumen : interstitium) potential difference in LDT/CD
- High Na+ reabsorption in LDT/CD leads to high K+ and H+ secretion
o Blocking p Na+ channels (potassium-sparing diuretics) causes low K+ and H+ secretion

Unwanted effects
Diuretics affected
Hypokalaemia, metabolic alkalosis
Loop and thiazide
Hyperkalaemia, metabolic acidosis
Potassium-sparing
Hypocalcaemia, hypomagnesaemia, ototoxicity
Loop
Hypercalcaemia, impotence
Thiazides
Metabolic alterations hyperuricaemia, hyperlipidaemia, hyperglycaemia
Mainly loop/thiazide
Steroid-related gynecomastia, impotence, menstrual irregularities
Spironolactone

Diuretic
Drug interactions
- Cardiac glycosides hypokalaemia potentiates toxicity of these drugs
Loop and
- Lithium competition for PT secretion (risk of increased toxicity)
thiazides
- ACE inhibitors activate RAA system, causing severe hypotension
- May reduce efficacy of drugs gout, cholesterol, diabetes
- Aminoglycosides increased risk of ototoxicity
Loop
- NSAIDs reduce effect of diuretics

Bronchodilator drugs
Bronchodilators purpose
- Two major features of asthma
o Bronchoconstriction treat with bronchodilators
o Inflammation treat with inhaled corticosteroids
- Relieve bronchoconstriction by relaxing airway smooth muscles
o Asthma mainly -adrenoceptor agonists
o Chronic obstructive pulmonary disease (COPD) all three types used
Anti-cholinergics can block reflex constriction of airways
- 2-adrenoceptor agonists and anti-cholinergics additive bronchodilator effects

Airways
- Inspiration causes distension of alveoli enables distension of airways
o Smoking requires greater inspiration to produce same airway distension
- Cilia on epithelial layer clearance of substances including drugs
- Circular smooth muscle elongation and dilation of airways
- Pathological changes in asthma
o Inflammatory cells eosinophils, mast cells
o Increased epithelial cells and smooth muscle mass (due to hyperplasia + hypertrophy)
o Oedema and mucous plug

2-adrenoceptor agonists
- Usually inhaled bind to 2-receptors of and relax airway smooth muscles (ASM)
- Couples to Gs-alpha protein to activate adenylyl cyclase cAMP sequestration of Ca2+ and
turns off contractile pathways bronchodilation
o Intracellular receptor domain can be phosphorylated to down-regulate the receptor
o Receptor has intrinsic activity down-regulation of receptor causes loss of this activity
- Actions of 2-agonists
o Smooth muscle relaxation
o Reduce Ca2+-dependent release of histamine/leukotriene from eosinophils/mast cells
o Inhibit release of acetylcholine from cholinergic nerves
o Increases muco-ciliary beat frequency to move substances out of lung
1 and 2 (non-selective) 1-receptors on heart ionotropic effects
Isoprenaline
(increased rate/force of cardiac contraction)
Poorer adherence
Salbutamol, terbutaline Short-acting 2
Long-acting 2
t1/2 = 12h, twice daily, long lipophilic tail
Salmeterol, formoterol
Ultralong-acting 2
Once daily, for COPD not asthma
Indacaterol

Anti-cholinergics
- Atropine, ipratropium, tiotropium
o Tiotropium bromide long-acting, highly potent muscarinic receptor antagonist
- Vagus (PNS) innervation of airway smooth muscle contraction
o Acetylcholine binds M3R, which is coupled to a Gq- protein, causing contraction

Phosphodiesterase inhibitors
- Theophylline bronchodilator
o Inhibits PDE (which degrades cAMP) to increase cAMP causing smooth muscle relaxation
o Narrow therapeutic range nausea and vomiting
- Many isozymes of PDE theophylline is non-selective and weak (max inhibition <50%)
o Recent development of selective inhibitors of PDE isozymes, e.g. PDE4 selective drugs
- PDE4 inhibitors e.g. roflumilast, cilomilast
o Smooth muscle relaxation/bronchodilation and decrease in inflammatory cell number

Preventer drugs (respiratory)

Asthma characteristics
- Airway obstruction is reversible either spontaneously or with treatment
- Airway inflammation airway hyper-responsiveness (AHR) to variety of stimuli
- Pre-disposition hereditary, inducers (virus, antigens, occupational)

Airway hyper-responsiveness (AHR)
- Exquisite sensitivity of the airways to physical, chemical and pharmacological stimuli
o Correlates with severity
o Improves with inhaled corticosteroids
- Measuring AHR: measure baseline FEV1 inhale bronchoconstrictor measure FEV1 again
inhale next increment of bronchoconstrictor repeat until decrease is >20% baseline
o Bronchoconstrictors methacoline, mannitol

Cromoglycate and nedocromil
- Block osmotic challenge and exercise-induced asthma
- Hyperpolarisation of inflammatory mast cells or epithelial cells by increasing Cl- influx prevents
degranulation and enables bronchodilation
- Taken as regular therapy to reduce frequency of symptoms

Inhaled corticosteroids
- E.g. beclomethasone, budesonide, fluticasone, ciclesonide (prodrug)
- Long-term regular therapy only drugs which can reduce AHR
o Shift methacholine dose-response curve to the right
o Combined with LABA, e.g. Seretide, symbicort
- Corticosteroids bind to cystolic receptors, then translocate to glucocorticoid response elements
(GRE) in nucleus of cells to interfere with nuclear transcription factors
o Code for new mediator proteins
Annexin 1 (lipocortin) inhibits phospholipase A2, arachidonic acids, and thus
luekotrienes and prostaglandins (inflammation)
2-receptors

Anti-leukotriene drugs
- Cysteinyl leukotrienes cause:
o LT B4 mediator of neutrophil chemotaxis
o LT C4/D4/E4 mediate bronchoconstriction, vascular leak (oedema), mucous production
o Recruitment of inflammatory cells, e.g. mast cells, eosinophils
- Arachidonic acid is converted to leukotrienes inhibit this
o Direct FLAP inhibitors, e.g. zileuton
o Indirect Cys LT1 receptor antagonists, e.g. montelukast, zafirlukast
- Montelukast used as preventer in children (oral formulation)
o An alternative to inhaled corticosteroids for children with difficulties with puffers

Chronic obstructive pulmonary disease
Asthma
Cigarette smoke
Allergens
Alveolar macrophages + epithelial cells
Epithelial cells + mast cells
CD8 cells + neutrophils
CD4 cell + eosinophils
Small airway fibrosis and alveolar destruction
Bronchoconstriction + airway hyper-responsiveness
Bronchodilators for symptoms
SABA as needed for symptoms or before exercise
LABA tiotropium, salmeterol, formoterol
LABA fixed dose combinations with ICS
Inhaled corticosteroids for advanced disease
ICS for all but mildest of asthma

Non-steroidal anti-inflammatory drugs

Aspirin, ibuprofen, naproxen, piroxicam, indomethacin
Traditional NSAIDs
Celecoxib, meloxicam
COX2 inhibitors
Analgesic, anti-inflammatory, antipyretic, anti-platelet
Effects
Mechanism of action Blocks production of prostaglandins by inhibiting cyclooxygenase
Aches, muscle pain, arthritis, gout, cancer pain, thrombotic events (aspirin)
Indications

Cyclooxygenase (COX)
- COX1 found in most cells (constitutive enzyme)
o Produces prostaglandins involved in homeostasis housekeeping/good prostaglandins
- COX2 induced by inflammatory stimuli
o Synthesises prostaglandins involved in pain and inflammation bad prostaglandins
May be involved in breast and colorectal cancers
o Also constitutive enzyme in kidneys and vascular tissues good prostaglandins

Traditional NSAIDs
- Non-selective (block COX1 and COX2)
o Block production of bad prostaglandins anti-inflammatory, analgesic
o Block production of good prostaglandins adverse effects
- Adverse effects GI bleeding and ulcers, reduced renal function, sodium and water retention
o Early miscarriage and prolongation of labour
o Asthma symptoms/attack in 5-10% of asthmatics
- Use with caution if previous/active peptic ulcer, cardiac failure, hypertension, renal
impairment, aspirin-sensitive asthma, pregnancy, elderly
- Antipyretic effect occurs by inhibiting synthesis of PGE2 in the hypothalamus
- Interactions ACE inhibitors, ARAs, anti-hypertensives, diuretics, warfarin, lithium, methotrexate
Roles of house-keeping prostaglandins
Examples
Help maintain mucosal gastric protection (HCO3- and mucous secretion) and
PGE2 (COX1)
reduce gastric acid secretion
Regulate platelet function require balance of thromboxane and prostacyclin
TXA2 (COX1)
- TXA2 formed in platelets, vasoconstriction, induces platelet aggregation
PGI2 (COX1+2)
- PGI2 formed in vascular tissue, vasodilation, inhibits platelet aggregation
Help maintain renal function
PGI2, PGE2 (COX2)
Help airway function in some patients with asthma
PGE2
Assist implantation of fertilised ovum, contract uterus during labour
PGF2alpha

Selective COX2 inhibitors
- Produce same analgesic and anti-inflammatory effects as traditional NSAIDs
- Less GI bleeding and ulcers
o Do not inhibit platelet aggregation (since synthesis of TXA2 is a COX1 effect)
- Produce same adverse renal effects as traditional NSAIDs triple whammy
- Interactions ACE inhibitors, ARAs, anti-hypertensives, diuretics, warfarin, lithium, fluconazole
- Rofecoxib highly-selective COX2 inhibitor
o Removed from market due to increased risk of heart attack and stroke
o Inhibition of prostacyclin TXA2 promotes platelet aggregation, vasoconstriction
- Increased risk of adverse CV events in long-term use of all NSAIDs (traditional and COX2
inhibitors, except low-dose aspirin which is secondary cardio-protective)
o Only use when necessary, lowest possible dose and duration use paracetamol instead

Paracetamol
- Effects analgesic, antipyretic (not anti-inflammatory)
- Available in many preparations analgesics, antipyretics, cough/cold and sinus medications
- MOA not completely understood, possible central effect or involvement of COX3
o Does not block COX1 or COX2 in peripheral tissues
o No GI bleeding/ulcers, reduced renal function, oedema, etc. as with NSAIDs
o Antipyretic effect due to inhibition of synthesis of PGE2 in the hypothalamus
- Suitable alternative to NSAIDs where contraindicated
- Fewer interactions than NSAIDs, but may interact with warfarin after 3-5 days of paracetamol

Paracetamol hepatotoxicity
- Normally undergoes glucuronidation (45-55%) and sulfation (20-30%)
- Small amount converted to toxic intermediate NAPQI by CYP2E1
o Normally inactivated by glutathione conjugation
- Paracetamol overdose saturation of normal metabolic pathways, formation of NAPQI
o Glutathione store depletion leads to NAPQI cell death, liver failure, renal damage
o Antidote acetylcysteine (restores glutathione), administer within 10-12h of overdose
- Toxicity is more common in alcoholics or malnourished
- Symptoms initial (vomiting, nausea), later (liver toxicity, jaundice, metabolic disturbances)

Pain and inflammation
- Mediators prostaglandins, leukotrienes, substance P, bradykinin
- Prostaglandins involved in pain and inflammation (redness, swelling, oedema)
o Produce vasodilation
o Potentiate increased permeability of blood vessels caused by histamine and bradykinin
o Sensitise nerve terminals and potentiate the pain-producing effects of substances such
as bradykinin and 5-hydroxytrypamine
Do not directly produce pain themselves

Adverse drug reactions
- Information on safety/efficacy of a new drug is only available from pre-marketing clinical trials
o Trials often do not include elderly, children, or enough people to detect rare ADRs
- Post-marketing reports from HCPs and general public
o Blue form (card)
o Database of Adverse Event Notifications (DAEN) information about ADR in Australia

Therapeutic index
- Indicates safety margin of drug
- Ratio of toxic/lethal dose to dose producing therapeutic response (LD50/ED50)
o Low/narrow TI = low margin of safety, e.g. digoxin
o High/wide TI = high margin of safety, e.g. benzodiazepines

Adverse drug reactions
- ADRs determined relative to placebo
- Somnolence/sedation produced by histamine H1-R blockers (antihistamines)
o Placebo 6-7.6% report ADRs
o Ioratadine (Claratyne) 8% relative to placebo: non-sedating
o Cetirizine (Zyrtec) 14.3% relative to placebo: sedating antihistamine
- Pregnancy medications taken by mother may have deleterious effect on foetus
o Pregnancy categories A, B1, B2, B3, C, D and X
o Paracetamol (A), glyceryl trinitrate (B2), amiodarone (C), atorvastatin (D), isotretinoin (X)
- Breast milk some medications taken by mother may diffuse into breast milk
o Breast milk has a lower pH and higher [lipid] than plasma
o Some drugs are fine, e.g. paracetamol (dose to infant is <5% of paediatric dose)

Abrupt withdrawal
- Gradually withdraw do not abruptly cease medication, follow guidelines
- Dependence on drugs are manifested as withdrawal symptoms
- Benzodiazepines temazepam (insomnia, anxiety)
- SSRIs paroxetine (dizziness, agitation, tremor)
- Some ADRs may be very severe and life-threatening anaphylaxis (e.g. amoxicillin)

Extension of therapeutic effect
- Reduce dose, or change to alternative agent (e.g. shorter half-life)
Drug
Extension of therapeutic effect
Insulin
Hypoglycaemia
Antihypertensive therapy Dizziness, light-headedness
Warfarin
Bruising and bleeding (monitor INR)
Beta blockers
Fatigue, breathlessness
Diuretics
Urinary frequency, incontinence, electrolyte disturbances (K+/Na+)
Hypnotics
Drowsiness, hangover the next day

Related to underlying mechanism of action
- ACE inhibitors and ARAs may produce renal impairment and hyperkalaemia ( aldosterone)
o Compensatory auto-regulatory mechanisms are antagonised by these drugs
o Reduce vasoconstrictor effects of ANGII on efferent arterioles
In susceptible people, this reduces intraglomerular pressure and renal function
- SSRIs may produce serotonin syndrome, hyponatraemia
o E.g. fluoxetine, paroxetine, sertraline
o Serotonin secretion of ADH from posterior pituitary, causing dilution of ECF sodium
Syndrome of inappropriate ADH secretion (SIADH)
Risk factors elderly, females, first month of treatment, diuretics
Symptoms occur when <125mM (normally 135-145mM)
Lethargy, confusion, stupor, muscle twitch, arrhythmias, seizures, coma
- Serotonin syndrome overstimulation of 5HT1A/2A receptors in central grey nuclei and medulla
o Sudden onset usually within 24h of: commencing SSRI (unlikely), increasing dose of SSRI,
or introducing second serotonergic agent
o Mental, autonomic and neurological effects
Diarrhoea, tremor, myoclonus, agitation, disorientation, confusion, mania,
tachycardia, sweating, shivering, coma, possible death
o Treatment cease medication, cooling, 5HT-antagonists
Cyproheptadine, chlorpromazine, propranolol, methysergide
o Drugs which increase central serotonin neurotransmission:
Antidepressants SSRIS, MAOIs, tricyclic antidepressants
Some opioid analgesics tramadol, pethidine, dextromethorphan
Cocaine, ecstasy, St Johns wort, lithium, carbamazepine
- Antipsychotic medications e.g. chlorpromazine, haloperidol, olanzapine, risperidone
o MOA block dopamine D2 receptors
o Extrapyramidal side effects (Parkinson-like)
D2-R antagonism in basal ganglia and substantia nigra cause PD-like symptoms
Part of extrapyramidal system which controls muscle movement
Also caused by metoclopramide (antiemetic which blocks D2-R)
o Domperidone (antiemetic) does not cause extrapyramidal ADR (cannot cross BBB)
o Breast enlargement and lactation (gynaecomastia in males)
Dopamine normally acts on D2-R to inhibit prolactin release from anterior pit.
- Metformin T2D drug of choice as it does not cause hypoglycaemia or weight gain
o May produce lactic acidosis if: high dose (>2g/day), reduced renal function, elderly
- Tricyclic antidepressants e.g. amitriptyline
o Anticholinergic side effects dry mouth, blurred vision, constipation, urinary retention

EBL scenarios
Perindopril + hydrochlorothiazide + paroxetine (SSRI)
- Symptoms confusion, poor memory, disorientation, disruptive, waking at night
- Possible causes urinary tract infection, serotonin syndrome, hyponatraemia
- Serotonin syndrome usually occurs within 24h, however patient has been taking SSRI for 2 weeks
- Likely cause HCT, paroxetine and perindopril can all cause hyponatraemia
o HCT inhibit Na+/Cl- transporter to inhibit sodium reabsorption
o ACE inhibitors reduce aldosterone (which acts on Na+/K+ pump) release
o SSRIs [serotonin] increases secretion of ADH from posterior pituitary
- Actions measure serum sodium level, cease paroxetine, restrict fluids
o Reasons for waking at night sleep hygiene, pain, frequent urination, cough due to ACEI

Ramipril + frusemide + potassium chloride + spironolactone
- Symptoms muscle weakness, cardiac dysrhythmia
- Ramipril, potassium chloride and spironolactone all cause hyperkalaemia
o Normal serum potassium levels: 3.5-5.5mM
o Hyperkalaemia ECG changes, dysrhythmias, ventricular fibrillation, cardiac arrest,
skeletal muscle weakness, paralysis
- Spironolactone competitive antagonist of aldosterone at Na+/K+ pump
- Actions never use ACEI with K+ supplements, monitor potassium levels, cease KCl
o Replace spironolactone with increased frusemide dose
o Consider adding beta-blocker
o Ensure ramipril is at target dose (increased from starting dose)

Salbutamol + paracetamol + codeine + naproxen (NSAID)
- Symptoms acute asthma attack after starting naproxen (for dysmenorrhoea) for first time
- Possible causes NSAID-induced asthma, respiratory infection, poor asthma control
- NSAID-induced asthma breathlessness or acute asthma attack in 0.5-3h after taking NSAID
o Inhibition of COX causes increased production of leukotrienes (bronchoconstrictor) from
arachadonic acid and reduction of prostaglandins (bronchodilator)
o Occurs in 20% of asthma patients
- Actions avoid supplying naproxen with asthma (or observe symptoms closely), improve asthma
management and technique, introduce preventer therapy
o Investigate reasons for painful dysmenorrhoea endometriosis, fibroids, inflammation

Ibuprofen + combined contraceptive pill + ginkgo biloba + St Johns wort
- SJW inducer of CYP450 and P-glycoprotein exporter, serotonin syndrome
- St Johns wort and oral contraceptive pill induces CYP3A4 to reduce efficacy of pill
o Breakthrough bleeding, ovulation, unwanted pregnancy
- Ginkgo biloba and ibuprofen reduced platelet aggregation increases risk of bleeding

Paracetamol + NSAIDs + sertraline (SSRI) + tramadol (narcotic)
- Symptoms agitation, confusion, shivering, sweating, elevated temperature
- Possible causes serotonin syndrome (sertraline + tramadol both inhibit 5HT reuptake), infection
- Treatment cease medication, cooling, serotonin receptor blockers, assess chronic pain
o Nociceptive pain stimulation of nociceptors, e.g. head/tooth ache, osteoarthritis
o Neuropathic pain nerve injury/dysfunction, burning, shooting stabbing pain
Often does not respond well to paracetamol, NSAIDs or narcotic analgesics

Atorvastatin + coenzyme Q10 supplement
- Symptoms muscle pain and tenderness in legs
- Possible causes statin-induced, peripheral vascular disease, strenuous exercise
- CQ10 is carried on LDL-c, and synthesis is reduced by statins
- Treatment measure CK levels, reduce statin dose or switch to another statin, trial CQ10

Complementary medicines
Product availability
- All products with therapeutic claims must be listed or registered on the Australian Register of
Therapeutic Goods (ARTG) before supply in Australia

Inclusions
Assessed for
All prescription, most OTC
Quality, safety and efficacy
Registered medicines
Most complementary medicines
Listed medicines
Quality and safety (not efficacy),
no bioequivalence testing

Listed medications
- Considered to be of lower risk than Registered medicines no direct efficacy testing by TGA
- Quality assessment product is manufactured in TGA-approved facilities, according to GMP
- Safety assessment no direct toxicity testing by TGA
o Reliance on lack of reported or documented toxicity
o Historical use with no apparent toxicity (e.g. naturopathy, traditional Chinese medicine)
o Issues collection/assessment of data, acute vs. chronic toxicity, age groups, reliability
- Therapeutic Goods Act requires sponsors of a Listed medicine hold information to substantiate
all of their products claims
o Targeted and random assessments by TGA of efficacy data and claims for Listed
o AUST L number on product label proof of listing

Complementary medicines
- Includes natural, herbal, vitamin, antioxidant and mineral products
- Highest user group younger to middle aged females with higher income/education
- Patients often believe they are not medicines, natural, chemical-free, no side effects
o All complementary medicines are made of chemicals side effects and toxicity
- May produce significant drug interactions with prescribed and OTC medications
- Reasons for taking complementary medicines:
o Treat current condition, e.g. glucosamine
o Protect against future illnesses, e.g. gingko biloba, vitamins, antioxidants
o Control and maintain their own health and wellbeing, e.g. minerals, antioxidants

Vitamins
- TGA does not give dose range/limit marketing terms mega potency and super-strength
o Some vitamin products have recommended doses far in excess of their RDI
- Vitamin C RDI 45mg
o Claims reduce incidence/severity/duration of common cold
o Long-term high dose increases CV mortality in diabetics, lung cancer
- Vitamin D RDI 1000-2000IU (ideally 70-80nM in blood)
o Long-term high dose increased total and cancer mortality
- Vitamin E RDI 22.4IU/day
o Claims antioxidant, assists in maintaining healthy heart and circulation
o Long-term high dose (>400IU/day) increases incidence of heart failure, stroke, lung
cancer, prostate cancer, all-cause mortality
- Beta carotene average intake is 2-4mg/day
o No reduced risk of cancer, instead increases incidence of lung cancer (avoid in smokers)
- High dose vitamin supplements:
o Do not contain co-factors and regulatory factors found in food (regulate vitamin activity)
o Do not act as antioxidants, instead exert pro-oxidant activity which can cause cellular
dysfunction and pro-carcinogenic effects
Need for some reactive oxygen species for normal cellular function
o Vitamin levels often far in excess of those found in food
- Vitamin supplements are appropriate in patients with documented deficiency
o Recommend product with doses close to the RDIs

St Johns wort (Hypericum perforatum)

- Plant extract growth conditions affects chemical constituents and ratios
o Many active ingredients hypericin, pseudohypericin, hyperforin, flavonoids, etc.
- Pharmacological activity
o Inhibits neuronal re-uptake of serotonin, noradrenalin and dopamine
o Binds to GABA receptors, causing GABA release and inhibiting GABA re-uptake
o Increases sensitivity of 5HT receptors
o Affinity for opioid sigma receptors
o Can inhibit many enzymes, e.g. catechol-o-methyl transferase
- Indications effective in treatment of major depression, fewer side effects, may take 2-4 weeks
o Anxiety, nervous tension, low mood, stress, sadness
o Side effects allergy, dizziness, headache, anxiety, dry mouth, sleep disturbances
- Drug interactions
o Inducer of CYP450 (increases activity), e.g. CYP3A4, CYP1A2, CYP2C9
Oestrogen (oral contraceptive pill), olanzapine, phenytoin, warfarin
o Inducer of p-glycoprotein
Reduces absorption/serum levels and increases excretion reduced efficacy
o Serotonin syndrome

Co-enzyme Q10
- Ubiquinone, ubiquinol, ubidecarenone fat-soluble antioxidant
- Present in every human cell, produced from tyrosine
o Vital in supporting ATP production in mitochondria
- Statin therapy reduces serum co-enzyme Q10 levels
o Side chain of CQ10 is synthesised from acetoacetyl CoA involving HMG-CoA reductase
o Majority of serum co-enzyme Q10 is carried on LDL-c
o Low CQ10 may cause muscle symptoms and heart failure
- Routine CQ10 therapy not necessary with statins; may use for benign statin-induced myalgia
- CQ10 may reduce clinical signs of heart failure, used prior to cardiac surgery to assist recovery
o Heart has high levels of CQ10 energy production, antioxidant, etc.
- Caution with warfarin monitor INR (CQ10 has similar structure to vitamin K)
- May potentiate effects of diabetic medications hypoglycaemia (monitor blood glucose)
- Doses 100-300mg/day, better absorbed when taken with fatty meal
o Side effects generally well-tolerated, mild GI symptoms, rash, photophobia

Glucosamine
- Naturally occurring amino-monosaccharide glutamic acid + glucose
- Involved in production of constituents of cartilage (proteoglycans, hyaluronic acid, etc.)
- Indications relieving pain and stiffness of osteoarthritis in knee, preserves joint function
- Dose 1500mg/day glucosamine sulfate (knee), slow onset of action (~3 months)
o Commercial preparations may be derived from crustaceans caution in seafood allergy
o May increase blood glucose levels, can still be used in diabetics, monitor BGL
o Possible interaction with warfarin, can still be used, monitor INR
o Side effects nausea, diarrhoea, skin rash, headache
- 1500mg glucosamine sulfate = 2000mg glucosamine sulfate/potassium chloride complex =
1890mg glucosamine sulfate/sodium chloride complex

Gingko biloba
- Extract from dry leaves, contains flavone glycosides and terpenes
- Claims inhibition of platelet aggregation, vasodilation, anti-oxidant, anti-inflammatory,
enhance memory, aid mental alertness and learning
- Avoid with aspirin and warfarin (serious haemorrhage), one week prior to surgery, antiplatelet
agents, anticoagulants, NSAIDs

Histamine
Autacoids
- Autopharmacological agents endogenous agents which modify body functions (local action)
o Local hormones paracrine or autocrine
o Mediators autacoids often mediate inflammation
- E.g. histamine, serotonin, prostaglandins, angiotensin, leukotrienes, kinins, nitric oxide
- 5 cardinal signs of inflammation heat, redness, swelling, pain, loss of function
o Histamine causes contraction of tissues/airways

Histamine chemical structure
- Basic amine, synthesised from histidine (via L-histidine decarboxylase (HDC))
- Histidine and histamine can be obtained from diet (champagne, wine, foods)

Metabolism
- Degradation within 1-2 min (no reuptake)
- Two enzymes activity depends on tissue type, [substrate]-dependent
o Histamine N-methyltransferase (HMT, intracellular) to N-methylhistamine
o Diamine oxidase (DAO/histaminase, extracellular) to imidazole + acetic acid

Storage and release
- Mast cells large cells (5-15m) in connective tissue (particularly nose, airways, skin and GIT)
o Possible role in homeostatic regulation affects nerves, blood vessels and host defence
o Histamine is stored in mast cell granules along with heparin-acidic protein complex,
chemotactic factors and enzymes
- Release can be immune or non-immune:
o Complement components C3a and C5a perforate mast cells (non-immune)
o IgE activated by allergen
o Exposure to certain basic drugs, e.g. morphine and tubocurarine
o Physical stimuli, e.g. cold or heat
o 2-adrenoceptor agonists release
o Variable degree of degranulation
- Basophils (circulating WBC), enterochromaffin cells of GIT (for peristalsis), platelets, neurons
- Histaminocytes in stomach, histamine causes secretion of gastric juices (pepsin, H+)

Histamine release
- Preformed histamine release is calcium-dependent
1. Antigen induces cross-linking of IgE bound to its high-affinity receptor FceRI
2. IP3-mediated calcium release from SER enables capacitative calcium entry
o Must crosslink at two IgE/FceRI to Ca2+ to induce histamine release





- Newly formed mediator release is calcium-independent
o Activated phospholipase-A2 generates arachidonic acid release of mediators
- Release of histamine, prostaglandins, leukotrienes (LTC4 and LTD4)
o Bronchoconstriction, vasodilation via endothelial cells (increased vascular permeability)
o Uticaria (rash), mucosal edema (nasal discharge)
o Increased calcium in endothelial cells releases NO which relaxes smooth muscle
Inducers of histamine release
Inhibitors
Allergens (e.g. penicillin) Ca2+-dependent release 2-adrenoceptor agonists salbutamol, adrenaline
activate adenylyl cyclase and cAMP, Ca2+
Morphine, tubocurarine, substance P alkalinity
2+
causes Ca -independent release of granules
Sodium cromoglycate

Histamine receptors
H1 (Gq-protein linked)

Actions and location

- Linked to PLC, IP3 and DAG
- Found on smooth muscle and endothelial cells, and CNS neurons
H2 (Gq-protein linked)
- Linked to adenylate cyclase, [cAMP]i
- Found on parietal cells (stomach) and myocytes (heart)
- H2 stimulation increases heart rate and contractility, stimulates gastric
acid secretion from parietal cells
H3 (Gi/o-protein linked) - Inhibits adenylate cyclase, [cAMP]I, stimulates MAPK
- Found in brain, presynaptic of M2-cholinergic neurons
- Inhibits release of many neurotransmitters in CNS (feedback)
H4 (Gi-protein linked)
- Mast cell chemotaxis

Main physiological effects of histamine
- Mediates type 1 hypersensitivity reactions (anaphylaxis) which involves mast cell IgE receptors
o Local reaction use H1 antagonists
o Systemic i.e. anaphylactic shock use adrenaline/steroids (H1 antagonists only adjunct)
o Skin (uticaria, eczema), eyes (conjunctivitis), nasopharynx (rhinorrhoea, rhinitis), airways
(asthma), GI tract (gastroenteritis)
- Gastric acid secretion clinical use of H2 antagonists
- cAMP increases heart force of contraction and smooth muscle relaxation
- H1 mediated actions
o Direct contraction of most smooth muscles (except blood vessels)
o Indirect relaxation of vascular smooth muscles (vasodilation, redness, hypotension)
o Increased microvascular permeability
Extravasation leakage of proteins (VE-cadherin) and fluids, swelling of tissues
o Itching and sneezing via stimulation of sensory neurons
o Control of many brain functions via neurons in posterior hypothalamus
Sleep/wakefulness, hormone secretion, thermoregulation, memory, CV control

Urticaria (hives)
Due to nitric oxide release from endothelial cells
Flush/local redness Vasodilation
Permeability of
Due to endothelial contraction in response to substance
Wheal
venules
P and neurokinin-A
Vasodilation
a
nd
H
1-
Stimulation of sensory nerve fibres and release of CGRP
Flare
mediated axon reflex (a vasodilator peptide)

Menieres disease
- Increased pressure in inner ear
- Treatment betahistine, an H3-R antagonist (strong) but H1-R agonist (weak)
o Increases blood flow and permeability to reverse effects within the vestibular system
o Half-life 3-4h, excreted in urine in 24h
o Side effects nausea, decreased appetite, hypersensitivity, headache

Anaphylaxis
Symptoms
Treatment
Respiratory
- Wheezing, shortness of breath
- 2-agonists
distress
- Swelling of lining membrane (mucosa)
- Beta-receptors on heart and
- Constriction of airway smooth muscle
airway smooth muscle
Vascular collapse - Vasodilation
- -agonists
- Increased microvascular permeability
- Alpha-receptors on blood vessels
- Low blood pressure and slow heart rate
Skin
- Swelling around lips
- Epipen injected since adrenalin
manifestations
- Itchy skin (pruritis) and urticaria
broken down by enzymes in gut

Hayfever (allergic rhinitis)

- Disorder characterised by sneezing, itchy nose, runny nose (rhinorrhoea), nasal blockage
(swelling of mucosa and dilated vessels)
o Nose nasal mucosa (epithelial layer), humidifies air, adjusts temperature, ~10m filter
- Hayfever allergy develops from exposure, re-exposure induces allergic reaction
o Dendritic cells present antigens to T-cells in lymph nodes
o Release of inflammatory mediators histamine, PG, LT, bradykinin
o Vasodilation (redness), microvascular permeability (swelling of tissues)
- Intermittent allergic rhinitis (IAR) seasonal pollen
- Persistent allergic rhinitis (PAR) perennial dust mites, fungi

Treatment of hayfever
- Corticosteroids inflammation
- 1-adrenoceptor agonists constrict nasal blood vessels
o Pseudoephedrine (oral) and oxymetazoline (topical)
- 2-agonists dilate airways
- Antihistamines H1-receptor inverse agonists (basal activity of histamine)
o Effective for irritative symptoms in hayfever and conjunctivitis
Itch, sneezing, redness, rhinorrhoea
Little effect on nasal congestion
Reduce number, size and duration of uticarial lesions

1st generation sedating antihistamines
- Dexchlorpheniramine and promethazine (Phenergan)
- Indications allergy, motion sickness, sedation, itch, urticarial
- MOA non-selective competitive antagonist of H1-receptors
o Some antagonism at muscarinic receptors, 5-HT and 1-AR
o Highly lipophilic cross BBB to cause sedation
- Side effects sedation, antimuscarinic (dry mouth, urinary retention, GI upset)
o Caution with prostatic hypertrophy, glaucoma, epilepsy, other sedatives (alcohol)
- Orally active, OTC, peak plasma concentration 1-2h, duration of effect 3-6h
o Metabolised in liver and excreted in urine

2nd/3rd generation non-sedating antihistamines
- Cetirizine (Zyrtec), loratidine (Claratyne), fexofenadine (Telfast), levocabastine (Livostin)
- Indications allergy, hayfever, urticarial
- MOA selective competitive H1-R antagonist
o Does not cross BBB
- Side effects 2nd generation may have cardiac side effects
o Fexofenadine ventricular arrhythmia in those with pre-existing prolonged QT interval
o Cetirizine may cause fatigue or sedation
- Orally active, OTC, peak plasma concentration 1-2h, duration of action 12h
o All metabolised to some extent by liver and excreted in urine, except fexofenadine
which is excreted largely unchanged in urine
o No evidence of teratogenicity

Plasma kinins (autacoids)

- Bradykinin and kallidin
o Bradykinin 9AA polypeptide
o Kallidin 10AA polypeptide, Lys-bradykinin
- Polypeptides formed and immediately active in plasma, ECF, kidney, exocrine glands
- Formed via cascade activation initiated by physicochemical surface reactions
o E.g. contact with collagen, damaged cells, heparin released from mast cells, bacterial
LPS, particulate matter, pH/temperature change
o Low molecular weight kinins (LK) tissue kallikrein (which forms kallidin and bradykinin)
o High molecular weight kinins (HK) plasma kallikrein
- ACE inhibitors vasodilation (due to bradykinin PGE2)
Kininase I (carboxypeptidase N)
Kininase II (angiotensin converting enzyme)
Cleaves C-terminal Arg from plasma kinins
Cleaves 7-8 (Phe-Ser) then 5-6 (Pro-Phe)
Non-specific carboxypeptidase in plasma
Dipeptidase on luminal surface of vascular
endothelial cells (mainly lung)
Metabolites only act on the inducible B1-receptor
Inactivates kininase I metabolites (t1/2 ~15sec)

Physiological effects of plasma kinins
- BP regulation vasodilator actions
o Kidney autoregulation, microcirculation control, fluid secretion and blood flow
- Inhibition of thrombin activation of cells, anti-adhesion, cellular fibrinolysis
- Inflammatory mediator vasodilation, increased vascular permeability, pain sensation
- Carcinoid syndrome plasma kinin (also other mediators) formation and release
o ? CVD hypertension, efficacy of ACE inhibitors seems to be due to plasma kinin levels
o ? Septic shock lipopolysaccharide-induced plasma kinin formation
o ? Asthma, pancreatitis, other GI disorders, chronic pain
- Bradykinin effects are mediated through 2 receptors B1 and B2 (GPCRq)
Bradykinin B1 receptors
Bradykinin B2 receptors
GPCRq
GPCRq
PLC IP3 & DAG
PLC IP3 & DAG, and PLA2 eicosanoids
Inflammation causes induction of B1R possibly
Normally present in most tissues (constitutive)
constitutively expressed for nociception
B1 agonist (selective) des-Arg9-bradykinin, des-
B2 agonist bradykinin (B2 affinity > B1)
Arg10-kallidin i.e. metabolites only
B1 antagonist des-Arg10-icatibant
B1 antagonist icatibant (5AA-substituted kallidin)

B2-receptor mediated actions
- Vascular smooth muscle relaxation (endothelium-dependent)
o PLA2 PGI2
o PLC NO cGMP smooth muscle relaxation
- Smooth muscle contraction (GI, bronchial and uterine smooth muscles)
o Smooth muscle PLC contraction
o Activity on endothelium (relaxation) is the opposite for smooth muscle (contraction)
- Increased post-capillary venule permeability oedema
- Neuro-excitation in sensory/pain afferents
o Partly direct pain, also neurogenic inflammation caused by axonal reflexes
Via antidromic firing in convergent sensory afferent axons localised
vasodilation and inflammation, e.g. axon flare response in skin
o Partly indirect, e.g. PLA2 activation PGE2, PGF2 sensitivity to nociceptive and
pain-causing (algesic) agents including plasma kinins
- Ion transport/fluid secretion, e.g. GI, respiratory epithelia

Serotonin 5-HT
Location of 5-HT
- Mammalian tissue locations GI tract (enterochromaffin cells) 90%, blood platelets 9%, CNS 1%
- Enterochromaffin cells specialised storage cells in GIT
o 5-HT found in granules on basal side and released into capillaries due to peristalsis and
vagal efferents
- 5-HT taken up by platelets via Na+ transporter
o Increased concentration of 5-HT in patients with carcinoid syndrome
- In peripheral tissues, 5-HT acts as an autacoid mediator does not usually cross BBB
- Other sources wasps, scorpion venom, stinging nettle, bananas, tomatoes, cheese

Receptor Category
Actions
1A, 1B, 1D Gi coupled to adenylyl cyclase cAMP (inhibits adenylyl cyclase)
2A, 2B, 2C Gs coupled to adenylyl cyclase cAMP
3
Ionotropic
5HT3R mainly found on nerves (fast transmission)
4-7
G/q-coupled activates PLC
IP3 and DAG (SM: contraction, endothelium: relaxation)

Actions of 5-HT1 in peripheral tissue
- Neuroinhibition of non-5-HT neurons subtypes 1B/1D
o Neurogenic inflammatory peptide release
o Important in migraine triptans activate the receptor to inhibit release of non-5-HT
mediators that normally cause vasodilation/migraine in the brain
- Vascular smooth muscle contraction in some vessels subtypes 1B/1D
o Contraction of cranial arteries, coronary artery, pulmonary and umbilical arteries
o 5-HT1 receptor agonists may cause heart attack in susceptible individuals
- Vascular smooth muscle relaxation
o Indirect effect due to 5-HT1 on endothelial cells (which release nitric oxide)
- 5-HT1B/D muscle = contraction
- 5-HT1B/D endothelium = relaxation

Actions of 5-HT2 in peripheral tissue
- Smooth muscle contraction
o IP3/DAG, intestinal, bronchial, bladder, uterine smooth muscle contraction
- Vascular smooth muscle relaxation
o Indirect effect due to: 5-HT2 on endothelial cells NO release cGMP Ca2+ uptake
into cells relaxation
- Increased capillary permeability oedema
- Platelet aggregation

Receptor Actions
5-HT3R
- Neuroexcitation in efferent ANS
o Release of ACh from GI parasympathetic postganglion
- Neuroexcitation in afferent nerves
o GI vagal afferents CND activation nausea/emesis
o Sensory/pain afferents axon flare response in skin
5-HT4R
- Neuroexcitation in GI parasympathetic pre- and post-ganglions ACh release
- Increased: peristalsis, intestinal fluid to lumen, cardiac rate, atrial contractility
5-HT7R
- Vascular smooth muscle relaxation and GI smooth muscle relaxation

Clinical applications of 5-HT
- Anti-migraine 5-HT1D agonist (e.g. triptans) or 5-HT2 antagonist (IP3 & Ca2+ contraction)
- Anti-nauseant 5-HT3 antagonist (e.g. ondansetron)
- Carcinoid syndrome 5-HT2 antagonist (e.g. cyproheptadine, methysergide)
- Irritable bowel syndrome 5-HT4 agonist (want to increase peristalsis to treat IBS)

Eicosanoids (autacoids)
- All products generated from arachidonic acid, including prostaglandins and leukotrienes
- Membrane disturbance activates PLA2 in plasma membrane generates arachidonic acid
o Arachidonic acid substrate for enzymes such as COX and 5LO that generate PG and LT
o 5-Lipoxygenase generates leukotrienes
- Lipocortin/annexin A inhibits phospholipase A2

Prostaglandins
- Inactivated by PG dehydrogenase to dihydro and keto metabolites
- Roles inflammation, vasodilation, blood clotting, uterine SM
contraction, cytoprotective in gastric mucosa
o Vasodilators PGE2 and PGI2
o Permeability agents histamine, bradykinin
- Inhibition of COX may shunt arachidonic acid to lipoxygenase/LT pathway causing asthma attacks
and bronchoconstriction in 20% asthmatics

NSAIDs and platelets
- Aspirin (prodrug) acetyl cleaved from acetylsalicyclic acid
o Irreversible non-selective COX1/2 inhibitors
o Platelets lack nuclei and cannot regenerate COX enzyme (unlike endothelium)
o TXA2 synthesis is inhibited by low dose (<100mg) aspirin
Low dose aspirin is selective for platelets
High dose inhibits COX in both platelets and endothelium
- Platelet aggregation is initiated by ADP, collagen and arachidonic acid
- Dipyridamole inhibits phosphodiesterase to increase cAMP and decrease platelet aggregation
Thromboxane A2
Prostaglandin I2
Platelets contain thromboxane synthetase
Endothelial cells contain prostacyclin synthase
Promotes platelet aggregation, vasoconstriction
Inhibits platelet aggregation, vasodilation
Acts on TP receptor to activate IP3/DAG/Ca2+
Acts on IP receptor to increase cAMP
Rapidly hydrolysed to TXB2 (inactive)
Rapidly hydrolysed to 6 ketoPGF1a (inactive)

Leukotrienes
- Conjugated trienes 3 double bonds
- LTB4 dihydroxy derivative of LTA4
o Potent chemotactic for neutrophils
o Increases microvascular permeability
- LTC4 and LTD4 cysteinyl leukotriene derivatives
o Roles recruit inflammatory cells, bronchoconstriction, oedema, mucus secretion
o Exert effects at Cys LT1 receptors
Antagonists montelukast, zafirlukast for asthma
o Metabolised to LTE4 (low activity)

Heavy metal poisoning
Toxic metals
- Metal dyshomeostasis and toxicity (including endogenous metals e.g. iron)
o Originate from environmental runoff and waste from industrial processes
o Mercury, arsenic, lead, cadmium
- Anaerobic bacteria methylate mercury as part of their respiratory process
o Methylmercury is fat soluble consumed by fish, enter food chain
- Dimethylmercury potent neurotoxin, readily crosses BBB
o Symptoms ataxia, sensory disturbances (tingling, prickling), coma and death
- Form and oxidation state of metal relates to its toxicity
o Different half-life, excretion, absorption %, interaction with biomolecules
o E.g. chromium 3+ is non-toxic, but Cr6+ is carcinogenic

Chelation therapy
- Metals bind potentially-critical biomolecules, thus interfering with physiological processes
- Chelator competes with target (biomolecule) binding sites for metal
o E.g. arsenic has high affinity for sulfur atoms, and denatures S-containing enzymes
Dimercaprol has higher affinity for arsenic to liberate the enzyme from arsenic
- Ideal chelating agent
o Ligand groups highly specific toward the metal, e.g. OH, SH, COOH
o Polydentate many teeth/ligand groups to coordinate with the metal
o Forms metal-complex more stable than metal-biomolecule complex
o Non-toxic and easily excreted

Coordination (metal-ligand) chemistry
- Ligand groups that donate electron pair to +ve metal ions to form coordinate bond
o E.g. H2O, OH-, Cl-, NH3 are monodentate
- Chelates ring system in which single ligand forms 2 bonds with metal ion
o E.g. [Cu(glycine)2] where glycine is a bidentate
- Want agent that is highly selective for a particular metal
o Otherwise can interfere with other good metals in the body

Hard-soft acid-base design concept
- Hard bases like hard acids (soft bases like soft acids)
- Polarity separation of charge
o Small atom dense electrons, stronger magnet for charge separation (less polarised)
- E.g. Fe3+ metal poisoning design oxygen-rich chelating agent to increase iron-selectivity
3+
Acid = metal Hard acid Atom with small diameter and large charge, e.g. Fe
Atoms with large diameter and small charge, e.g. Cu+, mercury, arsenic
Soft acid
Base = ligand Hard base Ligand with small diameter, less polarised, e.g. oxygen-donors
Soft base Ligand with large diameter and polarisable, e.g. sulfur-donors

Chelating agent Binds
Description
Dimercaprol
As, Hg, Pb
- Contraindicated for cadmium (chelate unstable in kidney)
(2SH, OH)
- Poor oral biovailability IM administration at high doses
DMPS and DMSA Hg, Pb
- Orally-available dimercaprol analogues
- Contain sulfate group sodium salt form increases
hydrophilicity
Penicillamine
Cu, Hg, Pb, Zn - R-penicillamine is toxic
- S-penicillamine is active, unsuitable for penicillin allergy
o Stable in regards to enzyme hydrolysis
EDTA (4O-, 2N)
Pb
- Calcium salt form due to poor membrane permeability
o Calcium then exchanged for lead in the body
o IM or IV administration
DTPA
Plutonium
- EDTA-derivative, administered as calcium salt
- Expanded molecule with 8 teeth for metals with large radii

Beta-thalassemia
- Dysfunctional haemoglobin (anaemic) need blood transfusions
- Frequent blood transfusions causes release of excess iron fatal organ damage
- Daily iron chelation therapy with desferrioxamine B (6 oxygens to bind iron)
o Short half-life (10-12min) and poor oral-bioavailability requires overnight infusions

Cannabinoids
- Potential indications cancer, epilepsy, neuropathic pain, anti-emesis
- Components vary in concentration between individual plants up to 15% THC
o Cannabis has long carbon side chain lipophilic
o Cannabidiol (CBD) may offset adverse effects of THC and potentiate therapeutic effects
Possible applications in anti-psychosis and anti-anxiety
- Mainly inhibitory effects
Euphoria, appetite stimulation, analgesia
Good effects
Anxiety, memory impairment, sedation
Adverse effects
Schizophrenia, addiction, irreversible cognitive damage
Long-term effects

Cannabinoid receptors
- G-protein coupled receptors
o CB1 CNS and periphery, mainly presynaptic; implicated in opioid addiction
o CB2 periphery, largely immune cells
o Gi/o-coupled receptors that inhibit Ca2+ channels and adenylate cyclase
- High numbers of receptors in cortex, prefrontal cortex (planning, addiction, cognition,
schizophrenia), hippocampus (memory), substantia nigra (motor function), amygdala (anxiety)
- Few receptors in brainstem
o Opioids have many receptors in brainstem, causing respiratory depression
- Cannabis may induce paralysis by shutting down motor areas of brain
- Neuregulin 1 gene susceptible to schizophrenia

Endocannabinoids
- Anandamide and 2-AG naturally occurring endogenous ligands, also found in breast milk
o Undergo enzymatic degradation and reuptake
- Released from postsynaptic neuron where it travels back to interact with presynaptic receptors
o Offsets excessive excitation by inhibiting calcium channels to inhibit neurotransmission
o E.g. prevents excess glutamate release (neurotoxic)
- CB1 receptors on inhibitory interneurons increase neuronal communication
o Cannabinoids inhibit the inhibitory interneurons to cause neuronal excitation
o CB1-R also found on pyramidal neurons